Giles Kisby
GE Y1 Pharmacology II
Pharmacology II:
Spring / Summer Term:
LECTURES:
09/01/14: Tutorial 1
Notes:
-
BMI = H(m) / W^2(Kg)
-
Hypertension:
o Results in increased risk of
 myocardial infarction
 stroke
 heart failure
 renal disease
-
How changing the following can affect blood pressure:
[the mechanisms are largely unclear but known to be strong risk factors]
[note that with blood pressure are thinking MAP = CO * TPR]
o Weight:
 Adipose tissue thought to contain components of the RAS system thereby
giving increased BP
 Will likely have high cholesterol  therefore atheroschlerosis which will
increase TPR  inc BP
o Exercise
 Widens blood vessels; therefore dec TPR and dec BP
 More efficient use of the CO means that lowered CO sufficient for a given
amount of work therefore direct decrease in TPR and lower systolic blood
pressure will give less endothelial damage and so avoid this source of inc
TPR too
o Salt
 High blood Na will give high entry of water to blood at gut
 High blood Na will give high water reabsorbtion at the kidney to reduce
excretion; will also be high Na in tubules but this will be reabsorbed to blood
leaving high grad for water to move
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Giles Kisby
GE Y1 Pharmacology II
o
Smoking
 Gives proinflam background for atheroschlerosis to develop  high TPR and
high BP
 Nicotine acts at the sympathetic nervous system to stimulate blood vessel
contraction and is also an ADH stimulant
 Nicotine also acts (via sympa mech) to give release of cholesterol to the
blood  atheroschlerosis  high TPR and high BP
-
Bendrofluazide:
o Can be used to lower blood pressure / vs hypertension
o Is a Thiazide diauretic:
 Blocks Na/Cl cotransporter on the tubule lumen side
 Therefore reduced Na reuptake so reduced water following it out so
increased water loss from body
 However increased Na in tubules means that some Na is instead
exchanged further along; is exchanged for K instead giving K exit
from body and hypokalemia
o Give K supplements but in the long term will likely have to
use a K sparing drug which will be less potent but will avoid
the hypokalemia
 Importantly the decreased Na reuptake will signal via the JGA (via
the ECF vol depletion) to give RAS activation; this is bad and is the
reason that is often used in conjunction with ACEi [the Thiazide
diuretic makes the ACEi give a bigger effect]
 Also gives dilation at blood vessels
-
ATII:
o
As well as its range of other effects:
 Angiotensin II enhances noradrenaline release from sympathetic nerves
 Gives increased reabsorbtion at the proximal tubule [acts at the Na/H
exchanger]
-
Bradykinin
o Gives vasodilation [ie ACEi will also give benefits via this mechanism through buildup
of bradykinin]
o Dry cough via sensitisation of the lungs [ie ACEi will give dry cough]
-
Mechanism of BP negative effects:
o Arterial damage
o Organ damage
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Giles Kisby
GE Y1 Pharmacology II
o
o
o
Decreased coronary artery perfusion
Increased afterload (due to high artery pressure) and preload (due to high venous
pressure) giving high heart workload
Risk factor for a range of cardiovasc diseases (MI, etc)
-
Warfarin inhibits the reduction of VitK to its active form
o Active VitK is used in the production of a range of clotting factors: (especially 2, 7, 9,
10)
-
Prinzmetal's = Prinzmetal = variant angina [the other types are stable / unstable]
o angina (cardiac chest pain) at rest that occurs in cycles.
o It is caused by vasospasm, a narrowing of the coronary arteries caused by
contraction of the smooth muscle tissue in the vessel walls rather than directly by
atherosclerosis
-
Some specific drugs for angina:
o Simvastatin:
 Statin; as would be able to tell from _statin suffix; lowers LDL levels
o Bisoprolol:
 BB; as would be able to tell from _olol suffix; decreases heart workload and
increases diastolic filling
o Aspirin:
 To avoid MI
o GTN
 Acts mainly at veins but will have some effect on the arteries; decreases
preload, some decrease in afterload
-
MI: MONA acronym: morphine, oxygen, nitrates, aspirin
-
Some specific drugs for heart failure:
o Frusemide:
 Is a very potent loop diauretic: potency order for decreasing potency is:
loop diauretics  thiazide diuretics  K sparing diuretics
 Blocks the Na/2Cl/K carrier of the ascending part of the loop of Henle
 Would help with HF edema and heart workload
o Perindopril
 An ACEi as can tell from _pril suffix
o Beta blocker:
 For heart failure can decrease the heart’s oxygen demand by reducing its
work but must be introduced gradually to avoid dangerous drops to CO; the
heart is already struggling and may be reliant on sympa activity
3
Giles Kisby
GE Y1 Pharmacology II
09/01/14: Drugs and the Heart: Dr Chris John
Los (from Slides&booklet for first two lecs):
-
-
-
Explain the mechanisms regulating heart rate and contractility that are therapeutic targets in
the heart
Identify the determinants of myocardial oxygen supply and demand and explain how these
are favourably influenced by: Beta blockers, Organic nitrates and potassium channel
openers, calcium antagonists.
Recognise the major adverse effects of: Beta blockers, Organic nitrates and potassium
channel openers, calcium antagonists.
Demonstrate awareness of the Vaughan Williams classification and explain its limitations
Identify the mechanisms of action of: Adenosine, Verapamil, Amiodarone, Digoxin and
cardiac glycosides
Recognise the mechanisms of action of cardiac inotropes and their clinical
Identify the mechanisms regulating vascular tone and peripheral vascular resistance.
Explain how the various inhibitors of the renin angiotensin aldosterone system act (i.e.
angiotensin converting enzyme inhibitors, angiotensin (AT1) receptor antagonists,
aldosterone antagonists) and identify the major indications for their use and their major
adverse effects
Explain how calcium channel antagonists cause vasodilation and list the major indications for
their use and their major adverse effects
Explain how inhibitors of the sympathetic nervous system act and list the major indications
for their use and their major adverse effects
Identify the mechanism of action of sumitriptan and explain why it is used in migraine.
List the major adverse effects of sumitriptan.
Explain the principles underlying the treatment of hypertension and heart failure.
Notes:
-
Overview:
o Renin-angiotensin system,
o calcium antagonists,
o beta blockers,
o nitrates
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Giles Kisby
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GE Y1 Pharmacology II
AT II:
o
Classical effects: [Increased BP etc]
 Vasoconstriction (AT1 receptors)
 Increased Na+/fluid retention (AT1 receptors)
 Cardiovascular remodelling
 SNS activation [inc NA release]
 thirst
 Aldosterone secretion (AT1 receptors)
 ADH secretion
o Non classical effects:
 Increased insulin resistance
 Activation cellular immunity
 Pro-fibrotic
 Pro-thrombotic
o The effects then lead to a range of diseases:
[some of the links detailed on the above diagram but don’t worry too much about
the detail]
 Diabetes
 Kidney disease
 Hypertension
 Heart failure
 Athero-thrombotic disease
Aldosterone:
o Acting on the nuclear mineralocorticoid receptors (MR) within the principal cells of
the distal tubule and the collecting duct of the kidney nephron:
 Increases the number of Na channels on lumen side
 Increases number of, and activates, NA/K pumps on the blood side [a
consequence of this is that increased K will be secreted (will then exit on
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Giles Kisby
GE Y1 Pharmacology II
o
-
lumen side: Aldosterone stimulates the secretion of K+ into the tubular
lumen) potentially giving a risk of hypokalemia [nb also; hyperkalemia if ACEi
etc used]]
 [together the above effects give increased Na transport across to the blood;
the water will follow  inc blood volume]
Other effects:
 Aldosterone stimulates Na+ and water reabsorption from the gut, salivary
and sweat glands in exchange for K+.
 Aldosterone stimulates secretion of H+ in exchange for Na+ in the
intercalated cells of the cortical collecting tubules, regulating plasma
bicarbonate (HCO3−) levels and its acid/base balance
ADH = vasopressin:
o Increasing the water permeability of distal tubule and collecting duct cells in the
kidney, thus allowing increased water reabsorption and excretion of more
concentrated urine
 Via insertion of water channels (Aquaporin-2) on tubule side
o Increasing permeability of the inner medullary portion of the collecting duct to urea
by regulating the cell surface expression of urea transporters, which facilitates its
reabsorption into the medullary interstitium
o At high concentrations, it also raises blood pressure by inducing moderate
vasoconstriction.
From renal; notes:
- ANTIDIURETIC HORMONE:
- As described in the preceding section, ADH has three actions on the renal tubule [but note
that the hormone does have other effects; see endocrinology for full detail]:
o (1) It increases the water permeability of the principal cells of the late distal tubule
and collecting ducts.
o (2) It increases the activity of the Na-K-2Cl cotransporter of the thick ascending limb,
thereby enhancing countercurrent multiplication and the size of the osmotic
gradients to aid water retention.
o (3) It increases urea permeability in the inner medullary collecting ducts, enhancing
urea recycling and therefore giving greater urea concentration in urine and eventual
excretion in a smaller volume of water
-
ACEI
o
Uses:
•
•
•
hypertension
heart failure and post-myocardial infarction
- reduced afterload and reduced preload to reduce the load on the
heart/how hard it must work
diabetic nephropathy
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Giles Kisby
GE Y1 Pharmacology II
- When the level of blood glucose rises beyond the kidney's capacity to
reabsorb glucose from the renal ultrafiltrate, glucose remains diluted in the
filtered fluid
- This raises its osmotic pressure and causes more water to be carried out
from blood thereby increasing the excreted urine volume. [ie in fact would
likely not want to lose so much fluid]
- The increased volume dilutes the sodium chloride in the urine, signalling the
macula densa to release more renin, causing vasoconstriction
- Because the kidney is nurtured exclusively by the blood it filtrates, the
vasoconstriction also reduces the nutrients supplied to it, causing infarct of
kidney tissues and reduction of renal function
- can solve these problems using ACEi which will increase kidney perfusion
(to counter the ischaemia) and reduce the GFR (to counter the high fluid
excretion); sufficient filtering should still occur
•
•
progressive renal insufficiency
patients at high risk of cardiovascular disease
-
Angiotensin receptor blockers: (ARB = ATIIA)
o Example: Losartan
o Antagonists of type 1 (AT1) receptors for ATII
 prevent the renal and vascular actions of ATII
o Uses: hypertension, heart failure
-
Direct Renin Antagonists
o Example: aliskiren (if binds renin will inactivate it)
o Inhibit enzyme activity of renin preventing conversion of angiotensinogen into
angiotensin I and hence generation of ATII
o A new class of agents, probably similar to other RAS inhibitors but limited clinical
experience as yet.
o Allows avoidance of some of the side effects associated with ACEi eg dry cough
-
Unwanted effects of ACEI and ARB
[Generally well tolerated – particularly ARBs]
o Angioedema (ACEi)
o Urticaria [a kind of skin frequently caused by allergic reactions] / Angioedema
[swelling of the deeper layers of the skin] (ACEI - v. rarely)
o Cough (ACEI; due to bradykinin)
o
o
Hypotension (both)
Hyperkalaemia (because of a decrease in aldosterone; therefore should be careful
with K supplements or K sparing diuretics)
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Giles Kisby
GE Y1 Pharmacology II
o
o
-
Fetal injury (both; the fetus will also be targetted)
Renal failure in patients with renal artery stenosis (both) [have low kidney perfusion
therefore the ATII is playing an essential role in maintaining GFR; ACEi results in
reduced filtration of the already small amount of blood passing through]
*** L-type calcium channel is a type of voltage-dependent calcium channel. L-type calcium
channels are responsible for excitation-contraction coupling of skeletal, smooth, and cardiac
muscle
o ***Dihydropyridine receptors = L-type Ca2+ channels: this is explained by the fact
that dyhydropyridine is a drug that acts via binding to the L-type Ca2+ channel (on
its extracellular side)
o Smooth muscle:
 It is important to note that contraction of smooth muscle need not require
neural input—that is, it can function without an action potential:
humoral/paracrine, metabolic or physical stimuli.
 Unlike skeletal muscle, which requires depolarization of the cell membrane
and t-tubules, smooth muscle uses second messenger systems to open the
calcium channels on the S.R.
 Receptors on the smooth muscle membrane for such ligands as
endothelin, Adrenaline/noradrenaline (including the NA sympa
vascular SM innervation), and Ach (released as a neurotransmitter:
actually extremely little para innervation of vascular smooth muscle
but SM elsewhere will be activated in this way)) connect to the Gq
protein and lead to the production of inosital triphosphate (IP3).


-
The IP3 is then directly responsible for opening the
calcium channels on the S.R. membrane (IP3 sensitive
Ca2+ channel on SER gives Ca release that will via Ca induced Ca
release activate the ryanodine receptors), allowing the calcium to
enter the cytoplasm of the cell.
Increased intracellular calcium binds calmodulin, which activates
myosin light chain kinase (MLCK). MLCK phosphorylates the
regulatory light chains of the myosin heads. Phosphorylated myosin
heads are able to cross bridge  CONTRACTION.
Calcium antagonists:
o Arteries have muscle, very little on veins so CCBs have their effects an arteries; very
little effect at veins; therefore help afterload but not so much preload
o May also give effects at heart if are “rate slowing”
o TWO CLASSES:
 Rate slowing:
 Cardiac (striated) and smooth muscle actions
 Are the best option for angina as decrease heart workload / O2
demand (dec contractility and rate (both depend on Ca entry), Dilate
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Giles Kisby
GE Y1 Pharmacology II
o
o
o
coronary vessels to increase myocardial oxygen supply, and
decrease afterload) - ie despite some reflex tachy
 Benzothiazepines (e.g. Diltiazem)
 Phenylalkylamines (e.g. Verapamil)
o [Verapamil especially likely to give constipation side effect
due to disruption of Ca channels in the gut]
o Gives greater reduction in rate / ionotropy compared to
Diltiazem
o Is a supraventricular antiarrhythmic
 Non-rate slowing
 smooth muscle actions only; are more potent here than “rate
slowing” drugs
o therefore are the best option for hypertension
o would not be useful for angina as would give severe reflex
tachy  inc heart work / palpatations
 Dihydropyridines (e.g. amlodipine)
Verapamil and Diltiazem act on intracellular side
 Therefore show use dependant actions
Dihydropyridines act on extracellular side
 Therefore do not show use dependant actions
Unwanted effects of calcium antagonists
 Verapamil
 Bradycardia and AV block (Ca2+ channel block)
 Constipation (Gut Ca2+ channels)
 Dihydropyridines
 Ankle Oedema
 Headache / Flushing
 Palpitations (prob is reflex tachy)
 Vasodilation/reflex adrenergic activation
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Giles Kisby
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GE Y1 Pharmacology II
Beta blockers (β-adrenoceptor antagonists):
o Beta blockers no longer 1st line for hypertension in UK.
o Mechanism of hypotensive action not fully understood but beta1 antagonists
preferred.
o Beta blockers do not reduce peripheral resistance (PVR) (except partial agonists /
vasodilatory beta blockers).
o Beta blockers
 Reduce cardiac output
 reduce renin release by the kidney (ie a1 at JGA)
 may diminish noradrenaline release by sympathetic nerves
 via block of β1 presynaptic receptors
 eg there will be some inhibition of the signalling at α1 synapses (for
constriction) because β1 presynaptic receptors exist which ordinarily
encourage NA synth and release (but this effect to lower BP is
relatively small)
[nb this β1 presynaptic receptor mech will also be a further way that
adrenaline will be able to yield inc a1 effects]
 lipophilic agents (e.g. propranolol) exert central sympatho-inhibitory
actions.
o Uses:
 Angina
 Post myocardial infarction & Chronic heart failure [ie trying to decrease
heart exertion]
 Cardiac dysrhythmias
 Hypertension
 Also thyrotoxicosis [Thyrotoxicosis means an excess of thyroid hormone in
the body; Many of the common symptoms of hyperthyroidism such as
palpitations, trembling, and anxiety are mediated by increases in beta
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Giles Kisby
GE Y1 Pharmacology II
o
-
adrenergic receptors on cell surfaces. Beta blockers offset this effect]
glaucoma, anxiety states, migraine, benign essential tremor
Unwanted effects can be due to actions on beta1 (and sometimes beta2 receptors
due to only partial selectivity)
 Worsening of cardiac failure
 Bradycardia (heart block)
 Bronchoconstriction
 Hypoglycaemia (in diabetics on insulin)
 Fatigue
 Cold extremities and worsening of peripheral arterial disease
 impotence
 CNS effects (lipophilic agents) e.g. nightmares
Organic nitrates:
o Example: Glyceryl trinitrate (GTN), nicorandil
o Uses
 Angina
 Acute and chronic heart failure
 BP control during anaesthesia
o Mechanism of action:
 Reduce preload (venous return) Venodilation
 Reduce afterload (peripheral resistance) Vasodilation [ie some reduction
here but smaller than at veins]
o Minor effects:
 Are antiplatelet agents
o
o
 Are coronary artery vasodilators
pharmacokinetics & unwanted effects
 Nitrates undergo extensive ‘first pass’ metabolism by the liver; therefore do
not give orally:
 Glyceryl trinitrate is often given sublingually for rapid relief of
angina - has a short half life (~5 mins).
 Longer acting forms of nitrate (e.g. isosorbide mononitrate) (eg
glyceryl trinitrate via a transdermal patch) are available for
sustained actions
 Nitrates can cause hypotension, headaches and flushing as a result of
vasodilation
 Excessive/prolonged use of nitrates is associated with tolerance
 Use for flareups/symptomatic relief, not regularly
molecular mechanisms:
 Sodium nitroprusside (SNP) can directly ie non enzymatically donate NO
 Other nitrates used typically undergo enzymatic processes to generate NO
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Giles Kisby
GE Y1 Pharmacology II


NO activates guanylyl cyclase to give inc cGMP  Cyclic-GMP activates
protein kinase G  K channel opening for hyperpolarisation and blocks PLC
(so reduced Ca channel opening)
Nicorandil directly stimulates guanylyl cyclase (ie not via NO)
[cGMP  PKG activation  Ca entry inhibited (via PLC inhib) and K+ efflux
for hyperpolarisation]
12
Giles Kisby
GE Y1 Pharmacology II
09/01/14: anti arrhythmic drugs: Ruth Tarzi
Los (from booklet):
-
-
-
Explain the mechanisms regulating heart rate and contractility that are therapeutic targets in
the heart
Identify the determinants of myocardial oxygen supply and demand and explain how these
are favourably influenced by: Beta blockers, Organic nitrates and potassium channel
openers, calcium antagonists.
Recognise the major adverse effects of: Beta blockers, Organic nitrates and potassium
channel openers, calcium antagonists.
Demonstrate awareness of the Vaughan Williams classification and explain its limitations
Identify the mechanisms of action of: Adenosine, Verapamil, Amiodarone, Digoxin and
cardiac glycosides
Recognise the mechanisms of action of cardiac inotropes and their clinical
Identify the mechanisms regulating vascular tone and peripheral vascular resistance.
Explain how the various inhibitors of the renin angiotensin aldosterone system act (i.e.
angiotensin converting enzyme inhibitors, angiotensin (AT1) receptor antagonists,
aldosterone antagonists) and identify the major indications for their use and their major
adverse effects
Explain how calcium channel antagonists cause vasodilation and list the major indications for
their use and their major adverse effects
Explain how inhibitors of the sympathetic nervous system act and list the major indications
for their use and their major adverse effects
Identify the mechanism of action of sumitriptan and explain why it is used in migraine.
List the major adverse effects of sumitriptan.
Explain the principles underlying the treatment of hypertension and heart failure.
Notes:
-
Overview:
o Anti-dysrrhythmics
o Alpha blockers and sympatholytics
o Vasoconstrictors
o Therapeutic applications
-
Anti-dysrrhythmics:
Arrhythmias / disarrhymias:
o Aims of treatment are
 Reduce sudden death
 Prevent stroke
 Alleviate symptoms
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Giles Kisby
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GE Y1 Pharmacology II
May be associated with decreased heart rate (bradyarrhythmias) or increased heart rate
(tachyarrhythmias).
A simple classification of arrhythmias is based on site of origin:
o Supraventricular arrhythmias (e.g. adenosine, amiodarone [/dronedarone],
verapamil)
o Ventricular arrhythmias (e.g. amiodarone [/dronedarone], flecainide, lidocaine).
o Complex (supraventricular + ventricular arrhythmias) (e.g. disopyramide).
The Vaughan-Williams classification of anti arrhythmic drugs:
o is of limited clinical significance and not all drugs fit the system
o Class
o I Sodium channel blockade
II Beta adrenergic blockade :
o
III Prolongation of repolarisation ('Membrane stabilisation',mainly due to
potassium channel blockade)
IV Calcium channel blockade
o
o
ie Beta Blockers!!
o
Not all drugs fit the classification system:
 Adenosine (energy metabolite and therefore will be relaxing cells / counter
contractions)
 Uses
o Used intravenously to terminate supraventricular
tachyarrhythmias (SVT).
o Its actions are short-lived (20-30s) and it is consequently
safer than verapamil.
 Mechanism of action:
o An endogenous mediator produced by the metabolism of
adenosine triphosphate (ATP).
o Acts on adenosine (A1) receptors to hyperpolarize cardiac
tissue and therefore slow conduction through the AV node.
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Giles Kisby
GE Y1 Pharmacology II

Adenosine  via the A1 receptor, inhibiting adenylyl
cyclase, reducing cAMP and so causing cell
hyperpolarization by increasing outward K+ flux (ie
cAMP would otherwise prob act to give some K
influx [ie is the mech for b1 signalling at heart to
shorten refractory period etc])


Adverse effects
o Chest pain,
o shortness of breath,
o dizziness and nausea
Amiodarone & dronedarone
 Uses:
o superventricular and ventricular tachyarrhythmias
 Mechanism of action:
o Complex action probably involving multiple ion channel
block
 Adverse Effects
o Amiodarone accumulates in the body (t½ 10 - 100days) and
has a number of important adverse effects including:
 photosensitive skin rashes
 corneal deposits


o
-
hypo- or hyper-thyroidism
pulmonary fibrosis
 neurological disturbances
 and gastrointestinal disturbances
Dronedarone is non iodinated (ie hence avoids the thyroid
side effects) and is less toxic than amiodarone but is also
less effective
Digoxin and cardiac glycosides
o Action:
Digoxin has some positive ionotropic activity and slows ventricular rate
 Ionotropy:
 Inhibition of Na-K-ATPase (Na/K pump). [ie Na leaves by Ca
exchanger rather than NaK pump]
 Results in higher sodium level in the cell as illustrated by the arrow
next to the letters on the below diagram
 Therefore increased Na / Ca cotransport occurs to bring more Ca
into the cell and increase the ionotropy
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GE Y1 Pharmacology II

HR and AV conduction:

Central vagal stimulation (ie at brain) by Dijoxin causes
increased refractory period and reduced rate of conduction through
the AV node
o
o
o
o
o
o
It can be used in atrial fibrillation and relieves symptoms in chronic heart
failure
Long t½ (~40 hours)
Narrow therapeutic window
Is metabolised at KIDNEY so should consider / check kidney function, esp if want to
give high dose because if impaired metabolism the effects will be even more potent!
An immune Fab (Digibind) is available for digoxin toxicity.
Adverse Effects (common and severe)
 Triggers dysrhythmias (e.g. AV conduction block, ectopic pacemaker
activity)
 Note: Hypokalaemia (usually a consequence of diuretic use) lowers the
threshold for digoxin toxicity: this is because Dijoxin acts by competing with
K for acess to the Na/K pump (ie binds the same area as K then if binds will
inhib the pump); therefore less K means greater Dijoxin action
Note: Hyperkalaemia gives bracycardia because K gradient will become less so phase 3 of action
potential is prolonged (takes longer to repolarise to be ready for a new action potential) (impaired
excitability if persistent partial depolarisation!)
-
Ivabradine
o Mechanism of action:
 blocks If channel (f is for "funny“); a Na/K channel important in the sinoatrial
node.
 Therefore slows heart rate
o Uses
 Angina in patients in normal sinus rhythm
o Contraindications
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GE Y1 Pharmacology II
o
 severe bradycardia / sick sinus syndrome / 2-3rd degree heart block
 cardiogenic shock
 recent myocardial infarction
Adverse Effects
 bradycardia
 first-degree heart block
 triggers ventricular and supraventricular dysrhythmias
-
Cardiac Inotropes
o Agents that increase the force of cardiac contraction are used to treat acute heart
failure in some situations
 (e.g. after cardiac surgery or in cardiogenic or septic shock).
o Dobutamine is a beta1 adrenoceptor agonist that stimulates cardiac contraction
without a major effect on heart rate due to reflex tachy (is B1 selective)
o Inhibitors of phosphodiesterase, such as milrinone, have inotropic effects
 by inhibiting breakdown of cyclic AMP in cardiac myocytes. [ie B1 receptors
signal via cAMP so this same pathway for contractility will be mimicked]
 But despite increasing cardiac contractile function so far all inotropes have
reduced survival in chronic heart failure.
-
Alpha blockers & sympatholytics
[sympatholytic (or sympathoplegic) drug is a medication which inhibits the postganglionic
functioning of the sympathetic nervous system: eg. alpha2-adrenoceptor agonists]
o Alpha blockers: 1-adrenoceptor antagonists: direct antihypertensive effect
 They can be competitive (e.g. doxazosin)
 or irreversible (phenoxybenzamine)
o Sympatholytics:
 Centrally acting antihypertensive agents e.g. clonidine (alpha2-adrenoceptor
agonists),
 moxonidine (imidazoline agonist; Imidazoline receptors are receptors for
clonidine and other imidazolines)
 antihypertensive:
 a2 agonists in the brain act to decrease sympathetic outflow
 will also be effect of increased NA uptake at synapses so dec sympa
activity
o Use of alpha blockers has declined since they were shown to be associated with
increased rates of chronic heart failure in the ALLHAT study.
 However Phenoxybenzamine (combined with a beta blocker) is still used:
used to provide long-lasting alpha-blockade in catecholamine secreting
tumours (phaeochromocytoma = tumours that secrete mostly
norepinephrine, plus epinephrine to a lesser extent; the drug helps counter
the hypertensive effects)
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Giles Kisby
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GE Y1 Pharmacology II
Vasoconstrictors
o Sumatriptan [“triptan” because is stimulating the 5-hydroxytryptophan receptors]
 Agonist at 5-HT1D receptors (ie serotonin receptors)
 Constriction of some large arteries including vessels in brain
 inhibits trigeminal nerve transmission [which, it is presumed, accounts for
sumatriptan's efficacy in treating cluster headaches/migraine]
 Therefore used to treat migraine attacks, but
contraindicated in patients with coronary disease.
o
-
Sympathomimetic agents
 Adrenaline
 the endogenous catecholamine produced by the adrenal gland
 is used in cardiac arrest and anaphylactic shock
Selected therapeutic applications
o Angina = myocardial ischaemia
 how drugs act:
 [summary of the info given prev on below diagram:]
[nb nitrate vs preload; CCB vs afterload]
 Clinical usage:
 Beta blocker [or CCB in beta-blocker intolerant patient] to provide
background anti-anginal cover
 Glyceryl trinitrate (for symptomatic relief)
 Therapy to prevent cardiovascular disease:
o statin (to lower LDL cholesterol)
o and aspirin (to inhibit platelet activation)
o
Hypertension
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


o
Typically patients require at least 2 drugs of different classes to control BP
 Angiotensin converting enzyme inhibitor (ACEI) or Angiotensin
Receptor Blocker (ARB)
 Calcium antagonist (long acting dihydropyridine)
 Thiazide diuretic
 Other CVD prevention measures (e.g. statin to lower LDL
cholesterol)
If the above drugs fail there are the many other antihypertensives that have
been mentioned that can be considered
Beta blockers are no longer first line agents for hypertension in UK but may
have a role in younger patients
 Ie due to weak hearts in older patients not coping with block: may
be reliant on sympa stimulation
 Also BBs give some inc in load from skeletal muscle block of B2 if not
cardio selective
Chronic heart failure (CHF)
 Impaired cardiac function due to ischaemic heart disease (ie MI),
hypertension or cardiomyopathy that results in:
 fluid retention
 oedema
 fatigue
 Decreased blood flow due to HF can trigger ATII production (due to the
mechanisms at kidney)  in turn gives range of potentially negative
consequences eg heart remodelling
 Typically patients will receive
 Diuretic
 ACEI (/ARB)
 Beta blocker
 +/- spironolactone [an aldosterone receptor antagonist]
 +/- digoxin
 Note – while beta-blockers can occasionally precipitate acute heart failure in
at risk patients due to their negative inotropic effects they have been shown
to benefit survival in chronic heart failure and are standard therapy.
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23/01/14: Haemostasis & thrombosis: Dr Sohag Saleh
Los (from Slides&booklet for first two lecs):
•
•
•
•
•
Define the terms haemostasis and thrombosis and differentiate between them
Explain the process of coagulation and the actions of drugs that affect production or
activation of clotting factors
Explain the process of platelet activation and the action of specific antiplatelet drugs
Explain the actions of fibrin and the role of thrombolytic drugs
Understand the major clinical conditions for which each class of drug (i.e: anti-platelet,
anticoagulants, thrombolytics) is indicated.
With his notes:
- Define the terms haemostasis and thrombosis and differentiate between them
o Haemostasis is a physiological process preventing blood loss whereas thrombosis
is a pathophysiological process
- Outline the process of coagulation and the actions of drugs that affect production or
activation of clotting factors
o The cell based theory of coagulation consists of three stages. Anticoagulants
inhibit stage 1 and affect the activity/ production of clotting factors
- Outline the process of platelet activation and the action of specific antiplatelet drugs
o Platelets are activated by thrombin, which causes Ca2+ rise, ADP release and
GPIIb/IIIa receptor expression
o Antiplatelet drugs fall into 4 categories
- Summarise the actions of fibrin and the role of thrombolytic drugs
o Fibrin is produced from fibrinogen and stabilises blood clots
o Plasmin can degrade fibrin strands and thrombolytic drugs activate plasmin
- To understand which of these classes of drugs can be used in specific clinical situations
o Anticoagulants: More effective in the treatment of venous red thrombi e.g. Deep
vein thrombosis
o Antiplatelets: More effective at treating arterial white thrombi e.g. Acute coronary
syndromes, ischaemia
o Thrombolytics: used in the treatment of MI, stroke & pulmonary embolism
Notes:
Overview:
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-
Blood constituents
o BLOOD CELLS
 Platelets
o PLASMA CLOTTING FACTORS
 Procoagulants
 Prothrombin
 Factors V, VII-XIII
 Fibrinogen
 Anticoagulants
 Plasminogen
 TFPI [tissue factor pathway inhibitor]
o Tissue factor pathway inhibitor (or TFPI) is a single-chain
polypeptide which can reversibly inhibit Factor Xa (Xa)
 Proteins C & S
 Antithrombin
-
HAEMOSTASIS vs THROMBOSIS
o Haemostasis - an essential physiological process where blood coagulation prevents
excessive blood loss
o Thrombosis - pathophysiological process where blood coagulation occurs within an
intact blood vessel  obstructs blood flow
 Emboli
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

Clot becomes life-threatening if it dislodges from the vessel
(embolises)  becomes trapped in another vessel
red thrombi
 form on the surface of the vessel
 Venous thromboses (= red thrombi)
 high fibrin components; also contain RBCs which give the red
colour

white thrombi
 A thrombus can form within an atherosclerotic plaque within the
wall of the vessel
 If the plaque ruptures the thrombus is released into the lumen
 If the thrombus embolises  myocardial infarction (coronary artery)
 Arterial thromboses (= white thrombi)
 high platelet components

VIRCHOW’S TRIAD
 Rate of blood flow
o Blood flow is slow/stagnating  no replenishment of
anticoagulant factors & balance adjusted in favour of
coagulation
 Consistency of blood
o Natural imbalance between procoagulation &
anticoagulation factors e.g. Factor V leiden
 Blood vessel wall integrity
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o
o
Damaged endothelia means blood exposed to
procoagulation factors
Alternatively direct endothelial dysfunction can be the cause
of the clotting
-
Coagulation: cell based theory
o Initiation
 Small scale production of thrombin
 ANTICOAGULANTS act here
o Amplification
 Large scale thrombin production on the surface of platelets
 ANTIPLATELETS act here
o Propagation
 Thrombin mediated generation of fibrin strands
 THROMBOLYTICS act here
-
Coagulation: cell based theory
o Initiation
 Small scale production of thrombin
 Tissue factor (TF)
o TF bearing cells [on leukocytes and on the endothelium]
activate factors V & X forming prothrombinase complex [ie
TF, Va and Xa where a=activated]
 Prothrombinase complex [ie TF, Va and Xa]
o This activates factor II (prothrombin) creating factor IIa (=
thrombin)
 ANTICOAGULANTS act here
 Antithrombin (AT-III)
o AT-III inactivates thrombin
 Direct thrombin inhibitors (DTI)
o Inhibit thrombin (e.g. Dabigatran [the only orally available
drug of this type], Bivalirudin)
o Mainly used against VENOUS clots
o Prophylaxis of:
 venous thromboembolism (VTE) during surgery
 stroke in patients with atrial fibrillation
 Heparin and derivatives
o Heparin potentiates antithrombin activity; short half life
[sometimes good to be able to stop effects fast eg renal
failure]
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o


o
Low-molecular weight heparins, (LMWHs, e.g. Dalteparin)
have same effect as Heparin except also inhibit factor Xa
and have a longer half life
 Largely replaced Heparin
 Mainly used against VENOUS clots
 prophylaxis & treatment of deep vein thrombosis
Factor Xa inhibitors
o Inhibit factor X (e.g. Rivaroxaban [the only orally available
drug of this type], Fondaparinux)
o Mainly used against VENOUS clots
o prophylaxis & treatment of DVT
Vitamin K antagonists
o Vitamin K - essential for production of factors II, VII, IX & X
o Eg Warfarin
 Can be used orally (but not the only oral one of this
type)
 Long delay of onset (~ 5 days)
 Narrow therapeutic window
 Unpredictable pharmacokinetics
 Numerous drug interactions
Amplification
 Large scale thrombin production on the surface of platelets
 Amplification of thrombin:
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GE Y1 Pharmacology II
o

Thrombin activates platelets, which produce a number of
other clotting factors (eg vWF as below)
o von Willebrand factor (vWF) liberation: This indirectly will
inc activation of factor II (prothrombin) creating factor IIa
(thrombin) [ie amplification of effect]
 Platelet activation
o Thrombin - acts on protease-activated receptors (PAR)
located on the surface of platelets.
o PAR activation  rise in intracellular Ca2+
o Ca2+ rise  change in platelet shape & exocytosis of
adenosine diphosphate (ADP) from dense granules
ANTIPLATELETS act here
 At ADP receptors:
o ADP has both autocrine and paracrine effects activating
P2Y12 receptors  results in platelet aggregation
o P2Y12 receptors antagonists - Clopidogrel & Prasugrel
o Mainly used for atherothrombotic disorders
[ie on the arterial side not veins]


Cyclo-oxygenase
o PAR activation also liberates arachidonic acid (AA) [ie 2x
mechs for PAR signalling  clotting]
o Cyclo-oxygenase (COX) generates thromboxane A2 (TXA2)
from AA [will then lead to clotting as detailed immediately
below] [nb inhib of PG also occurs but this effect of proplatelet is outweighted by TX effect]
o COX-1 irreversible inhibitor – Aspirin
 [irrev means has antiplatelet effect; eg ibuprophen
reversible so lacks antiplatelet effect]
 Secondary prevention of cardiovascular disease
 NB: High doses no more effective BUT more sideeffects
Glycoprotein IIb/IIIa receptor (GPIIb/IIIa)
o TXA2 activation  expression of GPIIb/IIIa integrin
receptor [ie GPIIb/IIIa integrins of other platelets will bind to
them] on platelet surface
o GPIIb/IIIa - involved in platelet aggregation ie clotting
o GPIIb/IIIa receptor antagonists e.g. Abciximab
o Limited use AND only by specialists
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o
Propagation
 Thrombin mediated generation of fibrin strands
 Generation of fibrin strands: Large-scale thrombin production
converts fibrinogen to fibrin strands [ie clotting]
 THROMBOLYTICS act here
 Anticoagulants & antiplatelets - DO NOT remove preformed clots [they can only prevent an increase in the
size of the clot]; thrombolytics DO!:
o Thrombolytics convert plasminogen to
plasmin

o Plasmin - natural protease that degrades fibrin strands
Pharmacology
o Alteplase: a tissue-type plasminogen activator. (tPA) [ie is a
serine protease activator]
o Streptokinase - bacterial product that is cheap and effective
o Thrombolytics used for myocardial infarction and
other thromboembolic disorders e.g. DVT (Deep vein
thrombosis) [arterial or venous]
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GE Y1 Pharmacology II
23/01/14: ATHEROSCLEROSIS, LIPOPROTEINS AND LIPIDLOWERING DRUGS: Mike Schachter
Los (from Slides&booklet for first two lecs):
vascular disease.
Notes:
-
Pathogenesis of atherosclerosis
o Chylomicrons get their fats from the gut and release their fats to skeletal muscle and
adipose tissue to become “chylomicron remnants” which are then taken up by the
liver or contribute to atherosclerosis:
 The remnants, if in the vessel walls, will encourage macrophage recruitment
to play a role in inc atheroschlerosis
o By contrast to chylomicrons the fats in HDLs (implies ApoA1), LDLs (implies ApoB),
IDLs, VLDLs are derived from the liver where lipogenesis and cholesterol synthesis
occur
 Endothelial dysfunction gives leaky or broken vessel walls and Upregulation
of endothelial adhesion molecules to allow lipids to pass from LDLs to the
vessel walls
[whole LDLs enter; HDLs leave]
[HDLs can perform ‘reverse transport’ but thought to be only certain HDL
subsets so not all HDL incs give benefits]
 Migration of smooth muscle cells occurs and Inflam response attracts
macrophages to help remove the fats: However macrophages and smooth
muscle cells become laden with fat to become foam cells [ie prob now
useless and just contributing to plaques structure]
 The remnants, if in the vessel walls, will encourage macrophage recruitment
to play a role in inc atheroschlerosis
 Fibrous cap and necrotic core form
 Plaque rupture  thrombus
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[pre liver]
[post liver]
-
Angina proportional to lumen size
MI risk proportional to thickness of boundary between atheromatous plaque and the blood
lumen
-
LDL Cholesterol
o Strongly associated with atherosclerosis and CHD events
 10% increase results in a 20% increase
in CHD risk
o Level Modified by risk factors
 low HDL cholesterol
 smoking
 hypertension
 diabetes
-
HDL Cholesterol
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o
o
o
HDL cholesterol has a protective effect for risk of atherosclerosis and CHD
The lower the HDL cholesterol level, the higher the risk for atherosclerosis and CHD
HDL cholesterol tends to be low when triglycerides are high
o HDL cholesterol is lowered by:
 smoking,
 obesity
 physical inactivity
-
Therapy
- Bile acid sequestrants
- Nicotinic acid
- Fibrates - Gemfibrozil
- Statins
- Ezetimibe
-
Therapy vs cholesterol level
- Bile acid sequestrants
o These prevent bile acid reabsorbtion therefore liver must make more
cholesterol; however liver is able to compensate effectively so these drugs are
not very effective vs blood cholesterol level and the dec in BAs gives big
digestive side effects
- Nicotinic acid = niacin
o Dec LDL inc HDL (it stimulates higher reverse cholesterol transport) BUT:
 Extensive side effects
 and actually also there is little benefit to patient in reality too
- Fibrates eg Gemfibrozil
o Main mechanism of action is activation of PPAR alpha receptors
 PPAR = peroxisome proliferator activated receptors
 Actions at liver and adipose tissue lead to reduced plasma FAs and TGs
but it is the inc in HDLs that they cause which is the main help vs
atheroschlerosis
 ALSO:
 reduce inflam,
 inc plaque stability
o PPAR gamma activators are used in diabetes
 Ie ligands for this receptor have emerged as potent insulin sensitizers
used in the treatment of type 2 diabetes
- Statins
o HMG-CoA reductase is blocked but not just cholesterol further down the
pathway; certain other components have key role in post transl mods so can
give disfunction of a range of prots: (rho, ras, etc)
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o
o
o
o
-
-
Response to HMG-CoA reductase block (at liver) is to Increase number of LDL
receptors (LDLRs) on hepatocytes to gain cholesterol in this way instead
Will lead to inc HDLs and dec LDLs
Note “rule of 6” for alkl statins: double the dose but only 6% further reduction in
LDL [but bad for side effects if v high doses have to be used]
Note that statins also have an anti-inflammatory
effect which is a
second means by which plaques are combatted
o As preventative medicines: vast majority of people will gain no help; must treat
v many to save someone
o Example: Rosuvastatin [nb all end _statin so can easily tell what they are]
Ezetimibe
o Absorbed then activated by glucuronidation phase I reaction
o Inhibits cholesterol absorption from dietary intake
 Liver will inc its synth but OVR the drug does translate to a very
significant dec in plasma LDL
o However: the LDL dec doesn’t translate well to patient benefits [‘how the LDL
(or HDL) change is achieved matters’]; despite this is still used
PCSK9 inhibitors
o [Proprotein convertase subtilisin/kexin type 9]
o PCSK9 is a LDLR inhibitor; ie bad effect: blocks the removal of LDLs from the
blood when statins stimulate this removal (as above)
o Therefore use PCSK9 inhibitors eg mAbs (with statins)
31
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GE Y1 Pharmacology II
23/01/14: NSAIDS: Prof Sue Smith
Los (from Slides&booklet for first two lecs):
NSAIDS;
Cycloxygenase inhibitor e.g. aspirin & ibuprofen (non-selective), celecoxib (COX-2 selective)
Identify the underlying mechanism of action by which all NSAIDs have their therapeutic effects.
2. Explain how the underlying mechanism of action produces the analgesic, anti-inflammatory and
antipyretic effects of NSAIDs.
3. List the most important side effects of NSAIDS, explain why these occur and what attempts have
been made to minimise them.
4. Explain why selective COX-2 inhibitors have proved less successful than hoped.
5. Explain why paracetamol is not a NSAID.
6. Identify the key difference between the mechanism of action of aspirin and other NSAIDs and
explain how this difference can be harnessed clinically
Notes:
-
From cardio:


Prostacyclin [=PGI2] (is a prostaglandin): signals via inc IP & inc cAMP
 Smooth Muscle
o Relaxation
o Inhibition of Growth
 Myocytes
o Increase Blood Flow
 Platelets
o Inhibit Aggregation
Thromboxane [=TXA2]: signals via inc TP and inc IP3
 Smooth Muscle
o Contraction
 Myocytes
o Reduce Blood flow
 Platelets
o Stimulates Aggregation
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[+ = vasoconstriction; - = vasodilation]
-
Non-Steroidal Anti-Inflammatory Drugs: inhibit COX
o Major Clinical Uses
 Relief of mild-to-moderate pain (Analgesic)
 Toothache, headache, backache
 Postoperative pain (opiate sparing)
 Dysmenorrhea (menstrual pain)
 Reduction of fever (antipyretic) e.g.
 Influenza
 Reduction of inflammation in many diseases e.g.:
 Rheumatoid arthritis
 Osteoarthritis
 Other forms of musculo-skeletal inflammation
 Soft tissue injuries (strains and sprains)
 Gout
o NSAIDS inhibit production of prostanoids
 Prostanoids: = Prostaglandins and thromboxanes
 They are derived from arachidonic acid (lipids)
 Inflammatory mediators; Actions receptor mediated
 Widely distributed
 Not stored pre-formed; they are synthesised in response to stimuli
(makes sense – is lipid derived, not from prot)
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
 Prostaglandins: many types: if PGI2 = prostacyclin
Mechanism: NSAIDs inhibit Cyclo-oxygenase [ie COX 1/2]
 COX 1/2 catalyses Arachidonic Acid  Prostaglandin H2 [is the
parent molecule for all PGs and TXs]
o Cox-1 [nb is the one at platelets]
 Constitutive (made all the time)
 Ubiquitous (found in nearly all cell types)
 Physiological
o Cox-2 [nb is the one at endothelium]
 Mainly inducible (made in response to specific
stimuli)
 Very widespread
 Physiological and pro-inflammatory roles [ie
important physiological effects but it is the form
involved in the inflam effects that want to counter]

Prostanoid receptors
 10 known receptors:
o These known receptors are all G protein coupled, but
the Prostanoids also definitely also have effects
independent of G proteins
o PGE2 has 4 Receptors
 Prostanoid effects are extremely complex: Physiological and proinflammatory

Ibuprofen and Indomethacin



Typical non-selective NSAIDs: Inhibit both COX-1 and COX-2
Have anti-inflammatory, analgesic (ie anti-pain) and anti-pyretic
actions
Inhibit cyclo-oxygenase REVERSIBLY
34
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-
GE Y1 Pharmacology II
Inhibition of PGE2 synth by NSAIDs:
o analgesic

1. Stimulation of PG receptors on nerve endings sensitizes
nociceptors to chemical and thermal stimuli which cause pain; Therefore
o
o
o
if we block production of PGE2, we will raise the pain threshold and thus,
reduce the perception of pain
 2. COX inhibitors may increase levels of endocannabinoids; these dull pain
perception via central and peripheral mechanisms
 [Analgesic NSAID use Usually occasional so Relatively low risk of side effects]
anti-pyretic
 PGE2 stimulates hypothalamic neurones initiating a rise in body
temperature
 Therefore NSAIDS reduce raised temperature
anti-inflammatory
 PGE2 has complex effects on immune and inflammatory pathways: May
contribute to converting acute to chronic inflammation; therefore the
NSAID mech is complex and poorly understood
 [Anti-inflammatory use Often sustained and Higher doses so Relatively high
risk of side effects]
Unwanted Effects of NSAIDS
 NSAIDS inhibit cytoprotective mechanisms in the stomach
 PGE2 downregulates HCl secretion  NSAID gives Increased HCl
secretion
 PGE2 stimulates mucus and bicarbonate secretion  NSAID gives
Reduction or loss of protective mucus and bicarbonate
 This can lead to gastric ulceration
 Renal toxicity
 Due to reduction in renal artery flow (PGE2/I2 give vasodilation)
 Cardiovascular effects
 (hypertension, myocardial infarction, stroke)
 Mechanisms unclear
 In part due to a small raising of blood pressure
 Disruption of Arachidonic acid pathways in the airways
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
-
NSAIDs block the Cyclooxygenase branch [to PG and TX] so inc
production of leutotrienes via Lipoxygenase will occur 
bronchospasm
Aspirin (is an NSAID)
o
Binds more avidly to COX-1 than COX-2 [COX1 selective]
o
Unique among the NSAIDS
 Binds IRREVERSIBLY to COX enzymes
 Irreversible so reduces platelet aggregation [unlike other NSAIDs]:
o Platelets mainly give TXA2 [ie in response to FIIa; TXA2 is
pro clotting as in notes from CV] and can’t regenerate their
COX as have no nucleus  ASPIRIN anti clotting effect
o Endothelial cells mainly give PGI2 [anti-clotting; see notes
pasted from CV] and can regenerate their COX as have a
nucleus  ASPIRIN no effect; PGI2 anti-clotting retained
o Also: Inhibition of PGI2 is proportional to inhibition of COX-2
 ASPIRIN little effect at COX2 so anti-clotting retained
 Irreversible so serious side-effects at therapeutic doses
o Gastric irritation and ulceration [as prev is standard NSAID
side effect due to some dec in PGE2; “COX 1 is the most
important for physiological roles so this side effect
enhanced in aspirin”]
o Bronchospasm in sensitive asthmatics
o Prolonged bleeding times
o Nephrotoxicity [inhibits the kidneys' ability to excrete uric
acid]
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-
NSAID: Celecoxib
o Reversibly, selectively inhibits COX-2
o therefore reduced side effects associated with interrupting COX1: Fewer ulcers with
Celecoxib
o HOWEVER COX2 is important in some physiological roles: inhib gives enhanced CVD
risk; mech unclear but as prev it is a classic NSAID side effect:
 Suggested that they selectively inhibit PGI2 production and spare TxA2
production leading to more aggregation
-
Strategies for limiting side effects
o Topical application: ie lower doses needed
o
Administration with omeprazole or other proton pump inhibitor [ie esp good
with aspirin use]
-
Paracetamol
o Is a good analgesic for mild-to-moderate pain
o Has anti-pyretic action
o Does NOT have any anti-inflammatory effect: Therefore it is not a NSAID
o Nb its Mechanism of action Not understood
o Side-effects
 In overdose it may cause irreversible liver failure
 Antidote = cysteine donor for glutathione synth = intravenous Nacetylcysteine or Occasionally oral methionine
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23/01/14: Anti-emetics: Professor Glenda Gillies
Los (from Slides&booklet for first two lecs):
1. Explain the physiological control of vomiting (see Fig.)
2. Identify the receptor specificity, the main sites of action and the specific antiemetic uses of
promethazine, metoclopramide, hyoscine and ondansetron.
3. List the main pharmacokinetic features and unwanted actions of promethazine,
metoclopramide, hyoscine and ondansetron
Notes:
-
Overview:
o Key pathways and events involved in nausea and vomiting (emesis)
o Major classes of antiemetic drugs, clinical uses, proposed mechanisms of action: Mixed receptor antagonists
 Dopamine type 2 receptor antagonists
 Muscarininc receptor antagonists
 Serotonin (5HT3) receptor antagonists
N.B. ANTIEMETIC/ANTINAUSEANT DRUGS are used ONLY when the cause of the nausea/vomiting is
known, otherwise they could mask the diagnosis of potentially serious conditions, e.g. digoxin
excess, diabetic ketoacidosis.
-
Vomiting:
o Effect of Severe Vomiting:
 Dehydration
 Loss of gastric hydrogen and chloride ions may lead to
 hypochloraemic metabolic alkylosis (raise blood pH)
 hypokalaemia (renal K+ excretion in response to proton loss)
o Physiological control of vomiting: [receptors are as on diagram below]
 Stimuli from peripheral organs [eg if punched there]
 [pharynx, stomach, duodenum, heart, bladder, uterus, viscera,
testicles] 
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



5-HT (=serotonin) released on stimulation of
mechanoreceptors/chemoreceptors or from gut enterochromaffin
cells 
o A) Activation of glossopharyngeal nerve IX and vagus nerve
X [visceral afferents]  Nucleus of the solitary tract 
Stimulation of vomiting centre (medulla)
o B) CTZ [CHEMORECEPTOR TRIGGER ZONE] of brain at area
postrema (improper BBB allows sampling)  Stimulation of
vomiting centre (medulla)
Endogenous toxins, drugs
  Release of emetogenic agents eg. 5HT, prostanoids, free radicals

 A) Activation of glossopharyngeal nerve IX and vagus nerve X
[visceral afferents]  Nucleus of the solitary tract  Stimulation of
vomiting centre (medulla)
 B) CTZ [CHEMORECEPTOR TRIGGER ZONE] of brain at area postrema
(improper BBB allows sampling)  Stimulation of vomiting centre
(medulla)
 C) Direct CTZ activation by the drug/toxin  vomiting center
Motion sickness
 Labyrinth of ear  Vestibular nuclei [ie of vestibular nerve] 
CHEMORECEPTOR TRIGGER ZONE  VOMITING CENTRE
Pain, repulsive sights & smells, emotional factors.
  SENSORY AFFERENTS & CNS PATHWAYS  HIGHER CENTRES 
VOMITING CENTRE
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NB the locations of these receptors as above: [AChM = muscarinic receptors; H1R = Histamine 1
receptors; D2 = dopamine 2 receptors; 5HT3 = 5HT receptors = serotonin receptors]
-
Hyoscine
o Muscarininc receptor antagonist
o MODE OF ACTION
 Order of antagonistic potency: Muscarinic (>>>D2 = H1 receptors)
 Therefore acts centrally, especially in the vestibular nuclei, NTS, vomiting
centre to block activation of vomiting centre.
o USE AS AN ANTI-EMETIC
 Prevention of motion sickness
 Has little effects once nausea/emesis is established
 In operative pre-medication
 NOTE: Atropine is less effective than hyosine as an anti-emetic
o UNWANTED EFFECTS
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





Typical anti-muscarinic side-effects:
Drowsiness / CNS effects
dry mouth, no sweating
cycloplegia [paralysis of the ciliary muscle of the eye, resulting in a loss of
accommodation]
mydriasis
constipation (not usually at anti-emetic doses)
-
Promethazine (a phenothiazine derivative) [the only one classed as an actual Mixed
receptor antagonist!!]
o MODE OF ACTION
 competitive antagonist at histaminergic (type H1), cholinergic (muscarinic,
M) and dopaminergic (type D2) receptors.
 Order of potency of antagonistic activity: H1> M > D2 receptors
 Therefore acts centrally (vestibular nucleus, NTS, vomiting centre)
to block activation of vomiting centre.
o c.f.
 other phenothiazines, which are used as neuroleptic drugs, have a different
order of potency with greater antagonistic effects at D2 receptors.
o USE AS AN ANTI-EMETIC
 Motion sickness – normally used prophylactically, but some benefit may be
gained if it is taken after the onset of nausea and vomiting
 Disorders of the labyrinth eg, Meniere’s disease
 Hyperemesis gravidarium [a complication of pregnancy characterized by
intractable nausea, vomiting, and dehydration]
 Pre- and post-operatively (sedative and anti-muscarinic action are also
useful).
o For other uses see relevant parts of course for further details
 Relief of allergic symptoms
 Anaphylactic emergency
 Night sedation; insomnia
o UNWANTED EFFECTS
 Dizziness
 Tinnitus
 Fatigue
 Sedation (‘do not drive or operate machinery')
 Excitation in excess
 Convulsions (children more susceptible)
 Antimuscarinc side-effects
-
Metoclopramide; Domperidone
o Dopamine (D2) receptor antagonists
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o
o
o
o
-
MODE OF ACTION
 Order of antagonistic potency: D2 (>> H1 >>> Muscarinic receptors)
 Therefore acts centrally, especially at CTZ
 Prokinetic effects in the gastrointestinal tract [encourages craniocaudal
movement (think of as countering vomiting effect)]
 increases smooth muscle motility (from oesophagus to small
intestine)
 accelerated gastric emptying
 accelerates transit of intestinal contents (from duodenum to ileocoecal valve)
 Therefore possible dangers:
o absorption and hence effectiveness of digoxin may be
reduced
o nutrient supply may be compromised; especially important
in conditions such as diabetes mellitus
USE: To treat nausea and vomiting associated with:
 uraemia (the illness accompanying severe renal failure)
 radiation sickness
 gastrointestinal disorders
 cancer chemotherapy (high doses) eg. cisplatin (intractable vomiting)
 Parkinson’s disease treatments which stimulate dopaminergic transmission
 [NB is Not effective against motion sickness]
UNWANTED EFFECTS
 In CNS (metoclopramide only; domperidone does not cross BBB so NOTE:
No anti-psychotic actions)
 dizziness
 drowsiness
 anxiety
 extrapyramidal reactions; children more susceptible than adults
(convulsions: Parkinsonian-like syndrome: rigidity, tremor, motor
restlessness)
 In the endocrine system
 hyperprolactinaemia
 galactorrhoea [ie inc milk production due to the inc prolactin]
 disorders of menstruation [prob due to the inc prolactin]
PHARMACOKINETIC CONSIDERATIONS
 may be administered orally; rapidly absorbed; extensive first pass
metabolism
 may also be given i.v.
Ondansetron
o Serotonin (5-hydroxytryptophan) receptor antagonist (ie acts at 5-HT3R)
o MODE OF ACTION
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o
o
o
 Acts to block transmission in visceral afferents and CTZ.
USE AS AN ANTI-EMETIC
 main use in preventing anticancer drug-induced vomiting, especially
cisplatin
 radiotherapy-induced sickness
 post-operative nausea and vomiting
UNWANTED EFFECTS
 headache
 sensation of flushing and warmth
 increased large bowel transit time (constipation)
USE IN COMBINATION WITH CORTICOSTEROIDS
 Eg in chemotherapy for inc anti-emetic effects: [nb chemotherapy gives
extensive vomiting]:
 5-HT3 receptor antagonists may be used for low emetogenic
chemotherapy
 Corticosteroids, such as dexamethasone, may be used in
combination with 5-HT3 receptor antagonists for high or moderately
high emetogenic chemotherapy
 Improved efficacy of combined therapy may be due to anti-inflammatory
properties of corticosteroids [imm system suppression]
Tutorial notes:
-
-
Adrenal neurones are not really presynaptic neurones
Airway resistance is measured in cmH2OL-1s
Liver endothelium is fenestrated / discontinuous to allow for drug removal from circulation
Lung has M4 receptors
Drugs that are only wanted to have a local effect are often made hydrophilic: large
hydrophilic group added
o Firstly helps hold them at the tissue by slowing transfer through to blood
o Secondly may help metabolism as may already be activated for phase ii metabolism
o Note that may also have inc direct excretion ability at kidney compared to a lipid
soluble drug but the main driver of excretion is the adding of large groups to the
drug as these can then be recognised by active transport mechanisms at the kidney
for excretion
Local application may improve speed / magnitude of benefits but the main reason for local
use is to allow for a reduced dose to be used and thereby avoid side effects
Ipratropium bromide is used for COPD and asthma
Asthma patients have to thoroughly warm up to adapt to the exercise
Arachidonic acid product effects in lungs [ie are in addition to their blood vessel effects
which are detailed elsewhere]
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o PGs: mainly positive effects in lung vs bronchoconstriction
o TX: prob little effect either way
o Bradykinin: negative effects in lung vs bronchoconstriction [ie hence ACEi dry cough]
o Leukotrienes: negative effects in lung vs bronchoconstriction
Asthma: dilator [Ipratropium bromide, Salbutamol, LABA], anti-disease med; ie vs the
production of material, mucus etc in lungs [leukotriene receptor antagonists], anti-disease
AND dilator [lipogenase inhibitor; give shift in Arachidonic acid pathway to PG/TX AND dec
leukotriene level; but rarely used as not necessary], Not used: [not histamine antagonists:
because there are many other mast cell products that will just give bronchoconstriction
anyway]
Vs glaucoma:
o A1 agonist
o BB
o Musc agonist [major mech for this is via circular muscle contraction; cilary muscle
contraction plays only minor role]
o CA inhibitor: but extensive side effects due to CA elsewhere: gut, pancreas, liver, etc
Adrenaline has a net positive effect vs glaucoma because a1 agonism as a mechanism is so
excellent vs glaucoma
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03/02/14: Diuretics: Chris John
Los (from booklet):
Learning objectives
1. Recall the physiology of the kidney, focusing on the mechanisms which regulate the ionic
composition (particularly Na+, Cl- and K+), volume and osmolarity of the urine.
2. Explain how the following groups of diuretic drugs alter the ionic composition, volume and
osmolarity of the urine: osmotic diuretics, e.g. mannitol; carbonic anhydrase inhibitors, e.g.
acetazolamide; loop diuretics, e.g. furosemide (frusemide); thiazides, e.g. bendroflumethiaze
(bendrofluazide); potassium sparing diuretics. e.g. amiloride, spironolactone.
3. Recognise that loop diuretics, thiazides and K+ sparing diuretics are clinically the most important
groups of diuretics.
4. Identify the principal conditions for which frusemide, bendrofluazide, amiloride and
Spironolactone are used clinically, and identify their principal adverse effects.
Notes:
-
Basic physiology at different parts of the kidney:
o
o
65-70% of the filtered Na+ is reabsorbed here
Note that therefore the events at the proximal tubule will contribute to urine acidity
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o
o
o
Note that both the H+ and the HCO3- from CA act to move Na across (then water
follows; hence CA inhibitors used as diuretics – cf)
Note that both the H+ and the HCO3- from CA act to counter an acidaemia;
therefore high levels of this process in acidosis and low levels in alkylosis [prob
means there is dec Na reabsorbtion in alkylosis]
o
[nb COUNTERCURRENT EFFECT as described in renal lecs]: is the reason for the
hyperosmolarity of the interstitium as is labelled; lumen is isotonic as both Na and
H2O exited at proximal tubule: THEREFORE OSMOTIC GRADIENT FOR WATER EXIT
Descending limb – permeable to water
More concentrated medullary interstitium draws water from the permeable
descending limb
Fluid in descending limb increases in osmolarity
o
o
o
o
o
[nb COUNTERCURRENT EFFECT as described in renal lecs]
Ascending limb – impermeable to water
Na+ leaves the ascending limb and enters medullary Interstitium
Fluid in ascending limb decreases in osmolarity
15-30% of filtered Na is reabsorbed here
o
o
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o
o
o
o
o
o
Note that Na/Cl transport is cotransport into the cell
Note that the events of the ascending tubule also contribute to the osmotic gradient
that exists here for water to move down
Note the actions of Aldosterone and ADH are both needed for water reabsorbtion to
occur: aldosterone to help establish the osmotic gradient and ADH to allow water to
move down that gradient.
5-10% of filtered Na is reabsorbed here
Note that the events of the ascending tubule also contribute to the osmotic gradient
that exists here for water to move down
Note that the pathway of Na movement across cell is coupled to inc intracellular K+
[eg Aldosterone directly increases the Na/K pump activity] which then exits on apical
side as shown [this prob is not possible at the distal tubule]
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o
Note aldosterone: increases the basolateral/basal Na/K pump activity; increases
apical Na channel activity
-
Five main classes of DIURETIC DRUGS:
o 1. Osmotic diuretics
 e.g. mannitol
o 2. Carbonic anhydrase inhibitors
 e.g. acetazolamide
o 3. Loop diuretics
 e.g. frusemide (furosemide)
o 4. Thiazides
 e.g. bendrofluazide (= bendroflumethiazide)
o 5. Potassium sparing diuretics
 e.g. amiloride, spironolactone.
-
Five main classes of DIURETIC DRUGS:
o 1. Osmotic diuretics

e.g. mannitol



Pharmacologically inert
Filtered by the glomerulus but NOT reabsorbed
Increase the osmolarity of tubular fluid   H2O reabsorption where the
nephron is freely permeable to water, i.e. proximal tubule, descending
loop of Henle, collecting duct (presumably distal tubule too)
NB will also increase the osmolarity of the blood plasma giving unwanted
effects:
  ECF volume  (pseudo)Hyponatraemia; (nausea, vomiting,
pulmonary oedema due to expanded blood volume)
Clinical Uses:


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
o
o
Prevent acute renal failure:  H2O excretion helps maintain urine
production which helps with renal failure
 intra-cranial pressure / intra-ocular pressure (ie glaucoma): 
plasma osmolarity due to the water loss means fluid will move out
of brain / eyes
 NB Small  in Na+/Cl- loss occurs [prob don’t worry about mech; “water
pulling the NaCl with it”]
2. Carbonic anhydrase inhibitors
 e.g. acetazolamide
 Act mainly on the proximal tubule  Prevent the reabsorption of Na+ and
HCO3-  subsequent H2O reabsorption is therefore reduced
 (if CA not present: HCO3- transiently becomes CO2 in lumen 
transported to cells with water  CA action  HCO3- transport
with Na to interstitum / blood while the H+ from CA aids Na
transport through the apical side)
 Also indirect effects at the collecting duct: proximal tubule effects  
tubular fluid osmolarity   H2O reabsorption in the collecting duct.
 OVR effect is in Na+/ K+/ HCO3- loss (alkaline urine) coupled to water loss
 However:
 Metabolic acidosis will result from low HCO3- reuptake (BAD)
 Are only weak diuretics / their effects quickly lost with time: prob
because because the low HCO3- reuptake to serum will soon give
low lumen HCO3- and therefore will lose the diuretic component
of inc tubular fluid osmolarity due to the drug (tubular osmolarity
could even fall)
  delivery of HCO3- to distal tubule   K+ loss
 Clinical Uses:
 Renal stones:  uric acid loss: Uric Acid in urine coming out of
solution gives renal stones; the acid will stay in solution if HCO3- is
present as is the case with CA inhibitors
 Metabolic Alkalosis: due to inc HCO3- loss
 intra-ocular pressure (ie glaucoma): as in prev notes CA inhib gives
drop in eye HCO3- level which is a key component of the intraocular
fluid so helps vs glaucoma
3. Loop diuretics
 e.g. frusemide (furosemide)
 Inhibit Na+ and Cl- reabsorption in ascending limb [blocks the Na2ClK
pump]   tubular fluid osmolarity AND  osmolarity of medullary
interstitium =  H2O reabsorption in the collecting duct.
 Large  in urine volume and Na+, Cl- & K+ loss
 Clinical Uses:
 Oedema: Heart failure, pulmonary, renal, hepatic, cerebral
 Moderate Hypertension: Piretanide [actually rare to use in
hypertension as v potent]
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
o
 Vs Hypercalcaemia
 Vs Hyperkalaemia
Unwanted effects:
 Hypovolaemia & Hypotension: are very potent diuretics!
 Ca2+ & Mg2+ loss caused: The Na2ClK pump net effect is to make
the lumen more positive because the K+ is recycled back to lumen
while the Cl- is not (see diagram). Therefore there is a charge
gradient in diuretic absence for Ca2+ & Mg2+ absorbtion to body
 K+ loss (not reabsorbed at ascending tubule and  delivery of Na+
to distal tubule so  K+ loss by Na+/K+ exchange
 Metabolic Alkalosis
o Hypokalemia causes metabolic alkalosis by several
mechanisms. transcellular shift occurs in body tissues in
which K leaves and H+ enters the cells, thereby raising the
extracellular pH. Also, in the presence of hypokalemia,
hydrogen excretion and HCO3- reabsorbtion in proximal
tubules increases.
4. Thiazides
 e.g. bendrofluazide (bendroflumethiazide)
 Inhibit Na+ and Cl- reabsorption in distal tubule so dec water re-uptake
there
 Also:  tubular fluid osmolarity =  H2O reabsorption in the collecting duct.
 OVR:
 Moderate  in urine volume and Na+, Cl- & K+ loss
 Also:  Mg2+ loss and  Ca2+ reabsorption (unknown mechanisms!;
nb ca explanation in renal notes)
 Clinical Uses:
 Heart failure
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


o
Severe resistant oedema
Hypertension:
o initially  blood volume is the benefit; this prob will be
compensated for long term but the thiazides also have a
vasodilation effect which is maintained
 Idiopathic hypercalciuria [ie risk of stone formation]
 Nephrogenic diabetes insipidus (paradoxical; see note from renal
module)
Unwanted effects:
 K+ loss [ delivery of Na+ to distal tubule  K+ loss ( Na+/K+
exchange)]
 Metabolic Alkalosis
o Hypokalemia causes metabolic alkalosis by several
mechanisms. transcellular shift occurs in body tissues in
which K leaves and H+ enters the cells, thereby raising the
extracellular pH. Also, in the presence of hypokalemia,
hydrogen excretion and HCO3- reabsorbtion in proximal
tubules increases.
 Diabetes Mellitus: Inhibits insulin secretion [ie help treat DI but
give you DM!]
 Mg2+ loss (see above)
5. Potassium sparing diuretics
 e.g. amiloride, spironolactone. Triamterene
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





Inhibit Na+ reabsorption (and concomitant K+ secretion) in late distal
tubule / collecting duct so reduced water re-uptake here.
 Ie even for amiloride: just slowing Na entry will be enough to slow
the action of the Na/K pump thereby reducing K+ exit to lumen:
Hyperkalemia does occur!
Also:  tubular fluid osmolarity =  H2O reabsorption in the collecting duct.
OVR:
  reabsorption of Na+ and water [ie Small  in urine volume and
Na+ loss]
 Renal stones:  uric acid loss [prob don’t worry about mech]
Clinical Uses:
 With K+ losing diuretics: Amiloride
 Primary/Secondary hyperaldosteronism: Spironolactone
Unwanted effects:
 Hyperkalaemia
 Metabolic Acidosis
o Hyperkalemia causes metabolic acidosis by several
mechanisms. transcellular shift occurs in body tissues in
which K enters and H+ leaves the cells, thereby lowering the
extracellular pH. Also, in the presence of hyperkalemia,
hydrogen excretion and HCO3- reabsorbtion in proximal
tubules decreases.
 Spironolactone: Gynaecomastia [boys' and men's breasts to
become larger than normal], Menstrual Disorders, Testicular
Atrophy
Types:
 Aldosterone receptor antagonists
o e.g. spironolactone
 Inhibitors of aldosterone-sensitive Na+ channels
o e.g. amiloride
o ie just slowing Na entry will be enough to slow the action
of the Na/K pump thereby reducing K+ exit to lumen:
Hyperkalemia does occur!
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15/02/14: Tutorial: Variability in the human response to
drugs
Learning objectives (from booklet):
Identify causes of variations in response to any specific drug between individuals or within an
individual at different times in terms of: Differences in the concentrations of drug reaching the
tissues (ie factors affecting absorption, distribution, metabolism and excretion of the drug)
Identify causes of variations in response to any specific drug between individuals or within an
individual at different times in terms of: Differences in response of the target tissues to the same
degree of stimulation (ie factors such as variation in receptor sensitivity, number and distribution).
Notes:
-
Both the desired and unwanted responses to any given drug may vary between individuals.
The reasons for this can be subdivided into:
- 1. Absolute differences in dose administered
 This may be deliberate or accidental
 eg due to:
 a) error in prescription or dispensing
 b) patient non-compliance
 c) drug formulation
- 2. Relative overdose or underdose
 Because the patient varies from the text book standard.
 Some of the factors which may cause this variation include:
- a) Environmental exposure to chemicals, including other drugs
o i) enzyme induction
o ii) enzyme inhibition
- b) Food intake – drugs may interact chemically with components of
food; this may reduce their absorption
-
-
o - foods delay gastric emptying and alter gastric pH.
c) Fluid intake
o – most drugs are better absorbed if taken with water eg
may dissolve better
o - fluids may stimulate gastric emptying.
d) Age
Newborn infants have
o i) relatively more body water than adults
o ii) poorer renal function, with immature tubular secretion
o iii) an immature blood brain barrier
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-
o iv) lower capacity for drug metabolism.
The elderly have an overall deterioration in many physiological
functions that may affect
o i) drug absorption: decreased absorptive surface of small
intestine
 altered gastric and gut motility
 increased rate of gastric emptying
o ii) drug distribution: reduced lean body mass and reduced
body water, relative increase in fat (ie all diffs are after
having considered their OVR size)
 lipid soluble drugs have increased Vd (volume of
distribution) and decreased blood levels
 water soluble drugs have decreased Vd and
increased blood levels
 reduced plasma albumin, so fewer plasma protein
binding sites
o iii) drug metabolism
 - splanchnic and hepatic blood flow decrease by 0.3
– 1.5%/year
 - liver size and hepatocyte number decrease
 - hepatic enzyme activity and induction capacity
decrease
o iv) drug excretion – changes in renal function are probably
the most important factors affecting drug handling in the
elderly. With age there is a steady decline in the following
factors:
 - reduced renal mass
 - reduced renal perfusion
 - reduced glomerular filtration rate
 - reduced tubular excretion
 These changes are normal – the situation may be
compounded if the patient has renal disease.
o v) organ sensitivity – the elderly tend to be more sensitive to
CNS active drugs
e) Disease
o i) General nutritional status
 - unbalanced diets may lead to deficiency states and
enzyme abnormalities
 - starvation – decreased plasma protein binding and
metabolism
 - obesity – increased lipid fraction
o ii) Gastrointestinal disorders e.g. achlorhydria, coeliac
disease, Crohn’s disease
 altered drug absorption
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o
o
o
o
-
iii) Congestive heart failure (especially in the elderly) may
lead to
 - reduced splanchnic blood flow
 - intestinal mucosal oedema
 - reduced hepatic clearance
iv) Kidney failure (especially in the elderly) may lead to
 - decreased drug excretion leading to toxicity
 - water overload leading to changes in drug
concentrations in different body fluid
compartments
v) Liver failure may lead to
 - reduced metabolism
 - reduced first pass metabolism (hence increased
bioavailability)
 - decreased biliary secretion and hence decreased
removal
 - decreased albumin synthesis and hence reduced
plasma protein binding
vi) Other acute or chronic disease states
CYP3A4: a CytP450 enzyme in the liver responsible for the metabolism of a range of drugs
including warfarin
Digoxin: Is metabolised at KIDNEY so should consider / check kidney function, esp if want to
give high dose because if impaired metabolism the effects will be even more potent!
INR:
o Normal: 0.9-1.2
o International normalised ration
o A measure of the prothrombin time
o Plasma isolated and TF (tissue factor added); time taken to clot measured
-
Effect of what food is in the stomach:
o Tetracycline: Food or dairy products reduce the absorption of tetracycline; works
best when taken on an empty stomach [tetracycline binds to calcium in stomach;
When it is bound the body can't absorb it]
o Bisphosphonates: food may decrease and delay the absorption of the drug
-
Effect of old age:
o Benzodiazapines:
 More sensitive CNS, reduced liver metabolism and kidney excretion means
should consider using lower doses
 Note that some Benzodiazapines actually need to be activated in the body
by liver enzymes in which case a higher dose would be required!
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-
Effect of weight:
o Weight loss, other than being an important symptom also means that may need to
change the dosage of drug that a patient is on; as patient loses weight the drugs
become more potent
o Mech:
 low protein uptake giving reduced plasma proteins so increased free drug
 relatively lower body water so reduced volume of distribution of the drug so
acts more potent
-
Drugs increasing warfarin potency:
o Clarithromycin:
 Is an antibiotic but through mechanisms separate to its bac killing it can also
irreversibly inhibit CYP3A4 that would otherwise metabolise warfarin
o Other drugs with the same effect on CYP3A4:
 Other antibiotics
 Fluconazole (anti-fungal)
 Omeprazole (PPI)
 Grapefruit juice
 Disulfiram (alcohol aversion therapy: inhibits aldehyde dehydrogenase)
 Cimetidine (histamine H2-receptor antagonist; inhibits stomach acid
production)
-
Drugs decreasing warfarin potency:
o St John’s Wort:
 Used as antidepressant as it blocks 5HT reuptake transporter in brain
 Induces CYP3A4 which metabolises Warfarin
o Drugs which increase metabolism by liver by more general or alternative means:
 Alcohol (inc CYP2E1 and aldehyde dehydrogenase activity)
 Brussel sprouts (induces diff CYPs)
 Smoking (induces diff CYPs)
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17/02/14: ADVERSE DRUG REACTIONS AND INTERACTIONS:
Mike Schachter
Los (from booklet): [these seem irrelevant to the lecture
given]
1. Explain the physiological control of vomiting
2. Identify the receptor specificity, the main sites of action and the specific antiemetic uses of
promethazine, metoclopramide, hyoscine and ondansetreon.
3. List the main pharmacokinetic features and unwanted actions of promethazine, metoclopramide,
hyoscine and ondansetron
Los (from slides):
-
to appreciate clinical importance of adverse drug reactions (ADRs)
to outline how they might be classified
to introduce ways in which they can be detected
to outline how drugs interact, both intentionally and harmfully
Notes:
-
Adverse Drug Events
o ME: Medication Errors (preventable)
o ADR: preventable or unpredicted medication event
-
Classification of ADRs
o Onset
 Acute
 Within 1 hour
 Sub-acute
 1 to 24 hours
 Latent
 > 2 days
o Severity
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


o
Type


Mild
 requires no change in therapy
Moderate
 requires change in therapy, additional treatment, hospitalisation
Severe
 disabling or life-threatening
Overview of types/summary:
 A
Augmented pharmacological effect
 B
Bizarre
 C
Chronic
 D
Delayed
 E
End-of-treatment
Type A: “Augmented pharmacological effect”
 extension of pharmacologic effect of the drug
 therefore usually predictable and dose dependent
 commonest: responsible for at least two-thirds of ADRs
 May (paracetamol; non linear toxicity) or may not (dijoxin; linear
toxicity) demonstrate dramatic therapeutic window effect


Examples:
o eg atenolol and heart block,
o eg anticholinergics and dry mouth,
o eg NSAIDS and peptic ulcer
Type B: “Bizarre”
 idiosyncratic or immunologic reactions; ie both mean that the effect
is individual to that person; some suffer ADR and some don’t
 includes allergy and “pseudoallergy”
 rare and unpredictable
 Examples:
o Eg chloramphenicol (an antibiotic) and aplastic anemia [=
BM failure; is a blood disorder in which the body's bone
marrow doesn't make enough new blood cells]
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o



Eg ACE inhibitors and angioedema (is a pseudo anaphylaxis;
similar traits to a proper anaphylaxis but is less severe) (not
same as urticaria)
Type C: “Chronic”
 associated with long-term use
 involves dose accumulation [total drug taken in life is what counts]
 Examples:
o Eg methotrexate and liver fibrosis,
o Eg antimalarials and ocular toxicity [includes Chloroquine
treatment of rheumatoid arthritis]
Type D: “Delayed”
 delayed effects; ie occur a long time after having taken the drug
(sometimes dose independent)
 Examples:
o (e.g. immunosuppressants) Eg carcinogenicity
o (e.g. thalidomide [producing fetal malformation]) Eg
teratogenicity
Type E: “End-of-treatment”
 Withdrawal reactions
o Eg Opiates
o Eg benzodiazepines
o Eg corticosteroids
 Rebound reactions [relationship to withdrawal: is often an aspect of
withdrawal; ie refers to the swinging back of the physiologic event
being targeted that occurs when the drug is removed]
o Eg Clonidine,
o Eg beta-blockers,
o Eg corticosteroids

“Adaptive” reactions
o Eg Neuroleptics (= Antipsychotics = “major tranquillisers”)
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 Withdrawal-related psychosis from antipsychotics is
attributed to increased number and sensitivity of
brain dopamine receptors, due to blockade of
dopaminergic receptors by the antipsychotics, which
often leads to exacerbated symptoms in the absence
of neuroleptic medication
-
Allergies [these would all prob be classified as Type B]:
o Types of allergic reactions
 Type I - immediate, anaphylactic (IgE)
 e.g., penicillins giving anaphylaxis
 Type II - cytotoxic antibody (IgG, IgM)
 e.g., methyldopa and hemolytic anemia
 Type III - serum sickness (IgG, IgM)
 antigen-antibody complex
 e.g., procainamide-induced lupus [used for the medical treatment of
cardiac arrhythmias]
 Type IV - delayed hypersensitivity (T cell)
 e.g., env substance giving contact dermatitis
o “ allergies” [nb these reactions only occur in a fraction of the group of people on
these drugs]
 Aspirin/NSAIDs
 Give bronchospasm [due to redirection of arachidonic acid from the
neutral/dilator prostanoids to the constrictor leukotrienes]
 ACE inhibitors
 Give cough (~20% of patients; due to bradykinin build-up)
 Give angioedema (~anaphylaxis response)
-
ADR detection:
o [note that rare ADRs are not picked up on until are in general use]
o Genetic testing for known susceptibility genes (only used in a small number of
specific scenarios)
o Yellow cards (esp for black triangle drugs; less than 2yrs old)
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Drug Interactions
o Pharmacodynamic
 Ie acting via the drug’s effects in the body
 Ie Additive, synergistic, or antagonistic effects from co-administration of two
or more drugs
 Eg acting via receptor site occupancy
 Examples:
 Synergistic actions: of antibiotics
 Overlapping toxicities: ethanol & benzodiazepines
o [alcohol increases the binding affinity of benzodiazepines to
the benzodiazepine binding site, which results in a very
significant potentiation of the CNS and respiratory
depressant effects]
 Antagonistic effects of two drugs: anticholinergic medications (eg
amitriptyline) and acetylcholinesterase inhibitors
o Pharmacokinetic
 Ie acting via the body’s effects on the drug
 Eg
 Alteration in absorption
o Chelation
 Irreversible binding of drugs in the GI tract
 [ferrous sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2),
dairy products (Ca+2)]
 Tetracyclines
 quinolone antibiotics
 Protein binding effects
o Competition between drugs for protein or tissue binding
sites
o Increase in free (unbound) concentration may lead to
enhanced pharmacological effect
o Many interactions previously thought to be PB interactions
were found to be primarily metabolism interactions
o Protein binding interactions are not usually clinically
significant but a few are (mostly with warfarin; warfarin is
almost 100% bound to plasma proteins so any loss in plasma
prot level will at least give temporary effects to inc warfarin
level)
 Changes in drug metabolism
o Drug metabolism inhibited or enhanced by coadministration
of other drugs
o Phase 1 = CYP 450 system [more studied than phase 2]
 Members: CYP3A4, CYP2D6, CYP1A2, CYP2B6,
CYP2C9, CYP2C19 and others
 A) Metabolism by multiple isozymes:
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
Most drugs metabolized by more than one
isozyme
 Eg Imipramine: CYP2D6, CYP1A2, CYP3A4,
CYP2C19
 Redundancy: If co-administered with
CYP450 inhibitor, some isozymes may “pick
up slack” for inhibited isozyme
 B) Metabolism by a single isozyme predominantly:
 Examples are drugs used primarily in
research on drug interactions
 There are few examples of clinically used
drugs though warfarin is mainly CYP2C9 or
3A4 and paracetamol/caffeine is mainly
CYP1A2
 CYP 450 Inhibitors [Nb Inhibition is very rapid]
 Cimetidine: histamine H2-receptor
antagonist that inhibits stomach acid
production
 Erythromycin and related antibiotics
 Ketoconazole etc [antifungal medication]
 Ciprofloxacin and related antibiotics
 Ritonavir and other HIV drugs
 Fluoxetine and other SSRIs
 Grapefruit juice
 CYP 450 Inducers [Nb Induction takes hours/days]
 Rifampicin [antibiotic]
 Carbamazepine [anticonvulsant and moodstabilizing drug]
 St John’s wort (hypericin)
 (Phenobarbitone) [barbiturate]
 (Phenytoin) [antiepileptic drug]
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o

Phase 2 metabolic interactions (glucuronidation, etc.) also
can occur, is less studied but research in this area is
increasing
Alteration in elimination
o Almost always in renal tubule
 - probenecid and penicillin (good)
 probenecid [increases uric acid excretion in
treatment of gout] reduces
paracetamol excretion
 - lithium and thiazides (bad)
 Thiazides volume deplete you, so the prox
tubule wants to reabsorb greater quantities
of Na+ there, and Lithium is
reabsorbed with the Na but lithium
has narrow therapeutic window so inc level
bad (eg can cause NEPHROGENIC DI)
Nb [lithium = mood-stabilizing drug,
primarily in the treatment of bipolar
disorder]
o
-
Pharmaceutical
 drugs interacting outside the body (mostly due to chemical/physical
interactions in IV infusions)
Deliberate interactions:
o levodopa + carbidopa
o ACE inhibitors + thiazides
o penicillins + gentamicin
o salbutamol + ipratropium
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17/02/14: Tutorial: population studies and family studies
Los (from booklet):
-
Explain how genetic differences influence individual response to drugs.
Identify differences between population studies and family studies in terms of assessing
genetic differences.
Notes:
-
Pharmacogenetics:
o Is regarding effects of genetic differences on reaction to drugs
Pharmacogenomics:
o Genome based techniques in drug development
-
Polygenic control
o Several genes act together to give rise to a CONTINUOUS or UNIMODAL (GAUSSIAN)
distribution of the measured variable.
o It is not possible to recognise or discern the influences of single genes.
o there may be large quantitative differences between the extremes of this
distribution
o Example: Salicylate rate of phase 2 metabolism: conjugation with glycine (as in prev
notes) or glucuronic acid
-
Monogenic control
o Owing to the action of a single gene that has a large overriding effect. This gives rise
to a DISCONTINUOUS or MULTIMODAL distribution of the measured variable.
o Example in Drug Metabolism:
 (a) Rare trait
 succinylcholine hydrolysis by plasma cholinesterase
 (b) Polymorphism
 debrisoquine (+ other drugs) hydroxylation by cytochrome P450 2D6
 sulphadimidine (+other drugs) N-acetylation by N-acetyltransferase
o Simplest if just two alleles are governing the phenotype:
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



Possibilities:
 If recessive or dominant inheritance this would give two peaks
(two phenotypes)
 If codominance there would be three peaks (three phenotypes)
Analysis:
 Ideally the two peaks would be separated ie with no overlap of the
peaks relating to the diff phenotypes
 If overlap occurs will have to assign a cutoff point to separate the
peaks into discrete groups
Hardy-Weinberg
 Hardy-Weinberg law: allele and genotype frequencies remain
constant through time in the absence of a selection pressure
 Hardy-Weinberg Equation: (p + q)2 = p2 + 2pq + q2 = 1
 Nb p = dominant
Example: Sulphadimidine metabolism by acetylation
 Population study:
o Shows two peaks; both peaks almost same frequency:
 This does not give info on type of inheritance other
than is not codominant; ie the frequency is
dependent on both the type of inheritance AND the
frequencies of the alleles in the population
 To establish the type of inheritance must do a family
study: in this case parents are FAST metabolisers but
one daughter is SLOW metabolizer so SLOW must
be recessive [split between SLOW and FAST is at
0.51-0.60 so dividing the family members based on
this categorises them]
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 Then use equation:
 Use p2 + 2pq + q2 = 1: assign q2=SLOW (eg =
0.51) phenotype and p2 + 2pq (= 0.49) as
FAST phenotype; know SLOW frequency so
can learn q value
 Then use (p + q)2 = 1 to find p value
 Then use p2 + 2pq + q2 to determine the
frequencies of each genotype (ie can
distinguish the p2 and 2pq genotypes
despite their same phenotype
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02/05/14: Drugs of Abuse1: General/ Cannabis: Chris John
Los (from booklet):
-
Drugs of Abuse 1&2 (Dr C. John)
General introduction/Cannabis & Nicotine and Cocaine
1. Identify the ‘reward’ pathways in the brain activated by drugs of abuse, list the main
abused substances and explain how they specifically activate reward pathways.
2. Explain the pharmacokinetics for the major drugs of abuse (e.g. routes of administration,
metabolism).
3. Summarise the basic pharmacology for the main abused substances (cannabis, nicotine,
cocaine).
Notes:
-
All drugs that give euphoria act by influencing the Mesolimbic dopamine system = the
central reward pathway.
o Dopaminergic transmission
o As shown below this passes from the Ventral Tegmental Area [midbrain; see below
pic] to the Nucleus Accumbens in the Ventral Striatum [in front of hypothalamus]
where dopamine is released to give the euphoria:
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[VTN]
[nucleus accumbens]
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-
Routes
o ‘Snort’ – Intra-nasal
 ‘Snort’ – Mucous membranes of nasal sinuses.
 Slow absorption
o ‘Eat’ - Oral
 ‘Eat’ – Gastrointestinal tract
 Very slow absorption
o ‘Smoke’ - Inhalational
 ‘Smoke’ – Small airways and alveoli
 Rapid absorption (slightly faster than IV)
o ‘Inject’ – Intra-venous
 ‘Inject’ – Veins
 Rapid absorption
-
Smoking is the fastest route of action: alveoli v thin walled so straight to blood then straight
to heart and up to the brain (IV has to go through full venous system then lungs and heart
and finally brain)
o (ascending order for onset of euphoria): Oral < Intranasal < Intravenous <
Inhalational
Classification [only certain ones will be covered in depth]
-
Narcotics/Painkillers: opiate like drugs
o e.g. heroin
Depressants – ‘downers’
o e.g. alcohol, benzodiazepines (valium), barbiturates
Stimulants – ‘uppers’
o e.g. cocaine, amphetamine (‘speed’), caffeine, metamphetamine (‘crystal meth’)
Miscellaneous
o e.g. Cannabis, Ecstasy (MDMA)
Cannabis
- Cannabis is from any part of the Cannabis Sativa plant esp yellow trichomes (glandular hairs)
- 9-THC: Delta 9 THC is the most prevalent and active cannabinoid in the cannabis plant
- Hashish oil can be used in combination to increase the cannabis dose further
- Greater dose = greater effect; eg can be used to treat glaucoma better at higher dose
- Smoked or eaten:
o Smoked
 50% bioavailability (is typical for smoking route of most drugs)
o Eaten
 10/15% bioavailability
 delayed onset/slow absorption
 first pass metabolism occurs
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Slow excretion of drug from the body:
- 1. High fat solubility:
o fat soluble but fast has poor bloodflow so initially drug is mainly at brain and other
highly perfused tissues
o However eventually will peak in fat and remain there for a long time due to the fat
solubility
-
-
2. First metabolite is more potent than the parent compound!
o so initially metabolism is not helping
3. main excretion is via liver to gut but then extensive enterohepatic cycling occurs due to
its high lipid solubility
o 65% exits via liver to GIT but very little successfully excreted by this route so reliant
on the 25% exiting in urine [10% must exit via another mech]
o Excreted as 11-hydroxy THC
Hence persists in body for 30 days after smoking a cannabis cigarette
Target
- two types of cannabinoid receptor: are Gi linked hence inhibitory to adenylate cyclase (are
not GPCRs though): endogenously Anandamide is the NT acting at CB receptors
o CB1 receptors
 Central: Hippocampus/cerebellum/cerebral cortex/basal ganglia
o CB2 receptors
 Peripheral: Immune cells
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-
Euphoria: due to inhibition of GABA interneurone which otherwise gives inhibition of VTA
o Ie disinhibition / ‘releasing the brake’ of dopamine release
-
Schizophrenia and psychosis
o Due to cannabinoid signalling at ACC [Anterior Cingulate
Cortex]: important in error detection and is an
amplifier/filter to improve emotional processing
(Insight/ response to emotional cues)
Food intake: increases apetite
o Disinhibition of orexin  increased appetite
o Ie Positive effect on orexigenic neurones in lateral hypothalamus
Memory loss: (Amnestic effects)
o ↓ BDNF in limbic regions: BDNF important in the laying down of memory but levels
are reduced in cannabis use [low BDNF will prob contribute to increased hunger too]
Psychomotor decline
o Due to disruption at Cerebral cortex
Antiemetic
Pain inhibition:
o Is known to reduce pain levels (cf)
Infertility
Stroke
Peripheral effects;
o Immunosuppressant
 [expected due to effects at CB2 receptor]
o Tachycardia/vasodilation [“is what the T and V stand for in TRPV1”]
 Ie Conjunctivae: red eyes
 Effect mediated by TRPV1 rather than cannabinoid receptor
o Respiratory
 Only due to the side effects due to smoking anything (CO etc); possibly
hotter to lungs too
-
-
-
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Upregulation of CB receptors occurs: Important info:
o 1. Multiple sclerosis to help cope with the pain: this is a regulatory response = good
 Agonists therefore used to enhance such effects:
 Dronabinol
 Nabilone
 Sativex

o
CB agonists can be used in MS vs the pain and in other conditions to help
with pain
 CB agonists can be used in AIDS patients for weight gain
 CB agonists can be used in chemotherapy patients as antiemetic
2. Infertility/obesity/stroke: all can increase with cannabis use: this is a pathological
response = bad
 Antagonists therefore used to counter these effects:
 Rimonabant


-
CB antagonists can be used vs obesity for weight loss:
“would also help avoid any CB mediated stroke or infertility problems”
Cannabis – Summary
o Cannabis Sativa  9-THC ( potency)
o Pharmacokinetics;
o Onset = Seconds  Minutes
o Tissue t1/2 = 7 days
o Elimination  11-hydroxy THC: Gut (65%), Urine (25%)
o Pharmacodynamics;
o CB1 (brain), CB2 (periphery) – anadamide
o Euphoria/Food intake/Memory Loss
o ‘Autoprotection’ – Dronabinol, Sativex
o ‘Autoimpairment’ - Rimonabant
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02/05/14: Psychoactive drugs 4: Cocaine & Nicotine: Chris
John
Los (from booklet):
-
Drugs of Abuse 1&2 (Dr C. John)
General introduction/Cannabis & Nicotine and Cocaine
1. Identify the ‘reward’ pathways in the brain activated by drugs of abuse, list the main
abused substances and explain how they specifically activate reward pathways.
2. Explain the pharmacokinetics for the major drugs of abuse (e.g. routes of administration,
metabolism).
3. Summarise the basic pharmacology for the main abused substances (cannabis, nicotine,
cocaine).
Notes:
Cocaine
- From leaves of the coca part
- Types:
o ‘Paste’ ~ 80% cocaine - dissolve in organic solvent
o ‘Cocaine HCl’ - dissolve in acidic solution
 i.v., oral, intranasal
 cannot smoke it: heat labile
 Medicinal form
o ‘Crack’ - precipitate with alkaline solution (e.g. baking soda)
 Inhalation / smoking
 Most used form as a drug of abuse
o ‘Freebase’ - dissolve in non-polar solvent
 (e.g. ammonia + ether)
 Inhalation
- Quickly enters the blood system but also is quickly removed
o Unless taken orally: pKa = 8.7: oral cocaine ionized in GIT hence slower absorption
and prolonged action
o Otherwise: T1/2 is short: 20-90min
o Metabolism: Some breakdown in the blood, mainly in the liver: Plasma/liver
cholinesterases and non-specific esterases
o Excretion: Extensively metabolised by the liver and then excreted in the urine as
ecgonine methyl ester or benzoylecgonine; little is excreted without having been
metabolised
o Quick response allows strong association with euphoria hence high addictability;
exacerbated by the rapid speed of loss of the effect: possibly the most addictive
drug
 Ritalin similar but taken orally so avoid the addictability
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Blocks uptake 1: inhibits monoamine transporters
o Will increase levels of the following at that synapse:
 NA/Ad
 5-HT
 Dopamine
Targets:
-
-
Local Anaesthetic
o Is an Na channel blocker hence pain blocker
o [“via hydrophilic pathway”]
Euphoria:
o Via uptake 1 block:
o
o
cocaine has no effect on dopamine affinity (effect of one molecule to bind at the
receptor)/efficacy (ability of one molecule to act at the receptor) for the dopamine
receptor
Relatively harmless if not used in very high levels / chronically:
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o
o
-
Dangers peripherally: May be harmful peripherally due to its stimulant activity and
binds receptors on platelets but need to have genetic predisposition:
  sympathetic stimulation
 Vasoconstriction
 Increased heart rate
 platelet activation
Some CNS effects but only harmful if underlying pathology that is exacerbated:
 CNS vasocontriction and Hyper-pyrexia [fever-mimic] can lead to Epilepsy in
some people
Cocaine – Summary
o Erythroxylum coca  Cocaine
o Cocaine HCl – ‘Intranasal’
o Crack/Freebase – ‘Inhalation’
o Pharmacokinetics;
o Onset = Seconds
o Tissue t1/2 = <90min
o Elimination  ecgonine methyl ester, benzoylecgonine :
o Urine (75-90%)
o Pharmacodynamics;
o Blockade of Na+ channels – Local Anaesthesia
o Transport Inhibitor – Euphoria (CNS effects), CVS problems
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Cigarettes
- Components:
o Volatile: (95%)
Particulate: (5%)
o Nitrogen
Alkaloids [nicotine]
o Carbon Monoxide/Dioxide
Tar [alkaloids dissolve in the hot tar]
o Benzene
o Hydrogen Cyanide
- Nicotine tends to be ionised in lung so poor transfer in upper airways though can still cross
at alveoli [Absorption in alveoli independent of pH / charge]
o 20% bioavailability via inhalation/smoking compared to 50% for most smoked drugs
o pKa 7.9 but cigarette smoke is acidic hence ionised and no buccal absorption.
o All nicotine replacement therapies have a better bioavailability than smoking
- Not as addictive as cocaine but blood level change through time of nicotine is nearly as
drastic [see pic below]
- Nicotine replacements do not achieve the same peaks of nicotine so may not be sufficient to
quit; e-cigarettes may be able to get closer to level of cigarette
-
-
Metabolism:
o Hepatic CYP2A6
 70-80% forms Cotinine [nicotine  Cotinine]  urine excretion
o T1/2 = 1-4hrs
Target:
o nAChR
 5 subunits
 Diff subunit compositions throughout the body: nicotine targets all nAChR
types but drugs may in future be able to antagonist effects at certain
nicotine receptor subtypes [DHTK]
o Not just peripheral effects as have looked at in prev parts of the course on nAChRs;
also extensive CNS effects due to nAChRs in CNS
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o
-
-
-
Euphoria via nACHRs in CNS:
Cardiovascular effects:
o Extensive CV effects of nicotine lead to Cardiovascular Disease
o Already parasympathetic tone so the effects seen are:  sympathetic stimulation
(CNS & Adrenals)
  H.R. & S.V.
 Vasoconstriction
 Coronary arterioles
o Constriction (ie more NA like effects than Adrenaline like
effects)
 Skin arterioles
o Constriction: skin temperature drops by up to 5 degree
 Vasodilation
 Skeletal muscle arterioles
 Negative lipid profile of change in serum:
  lipolysis, FFA, VLDL,
  HDL
 Clotting increased:
 TXA2,  NO
Weight
o Increased metabolic rate
o Sympathetic stimulation decreases appetite
o Hence if stop smoking will put on weight
Potential for helping Parkinson’s or Alzheimer’s:
o protective vs these diseases as removes toxins associated with these diseases;
however only delays the onset of these diseases and only protective prior to onset
of these diseases:
 Parkinson’s Disease;  brain CYPs →  neurotoxins
 Alzheimer’s Disease:  -amyloid toxicity;  amyloid precursor protein
(APP)
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-
Nicotine – Summary
o Nicotana tabacum  Nicotine
o Cigarettes – Nicotine  5% Particulate
o Pharmacokinetics;
o Onset = Seconds
o Tissue t1/2 = 2-3h
o Elimination  cotinine; liver (75-80%)
o Pharmacodynamics;
o Activation of nicotinic acetylcholine receptors
o Euphoria, CVS disease, ↑ metabolic rate & ↓ appetite
o ++ - Alzheimer’s/Parkinson’s
-
Dhtk:
o
o
Caffeine:
 Adenosine positively signals presynaptically for an anti-dopaminergic effect;
this brake is removed by caffeine’s opposition to adenosine signalling
Chocolate: No effect of chocolate on reward pathway
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02/05/14: Psychoactive drugs 3:Alcohol: Chris John
Los (from booklet):
-
Alcohol - (Dr C. John)
Identify the dose-dependent effects of acute ethanol ingestion on: CNS function and put
forward theories to explain the underlying mechanism of action; Other body systems
Identify the consequences of long-term excessive ethanol consumption
Summarise the main pharmacokinetic features of ethanol.
Explain how tolerance to the effects of ethanol is produced and identify which symptoms are
associated with alcohol withdrawal in dependent subjects.
Notes:
-
-
-
Absolute amount:
o % ABV x 0.78 = g alcohol/100ml (ABV = alcohol by volume)
o 80mg/ml = (Legal driving limit) but x 4 risk of driving accident at this dose
Units:
o [%ABV x volume (ml)] / 1000 1 unit = 10ml or 8g of absolute alcohol
Safe level:
o brackets = high risk level / percent of people in high risk bracket
o non bracketed = is for low risk figures
 Men <4 (8) units at least 1/7
42% (19%)
 Low dose consistently is potentially protective against cardiovasc
risk (and any kind of binge is harmful)
 Women < 3 (6) units at least 1/7
36% (8%)
Absorption:
o 20% = from stomach
o 80% = from intestine
 Hence a high rate of absorption is achieved when the stomach is empty and
drinking on a full stomach keeps alcohol in stomach where absorption is
less favourable: ie lower peak of blood alcohol
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Metabolism [liver and stomach]
o 10% not metabolised: some of this is via the lungs hence breath test works
o 90% of the alcohol is metabolised: 85% by liver; 15% by stomach
 Two major enzyme systems:
 Alcohol dehydrogenase (75%)
o This system is the method utilised by the stomach [the liver
uses both enzyme systems]
 Mixed function oxidase (25%)
o This can be increased if person regularly drinks
 Metabolised to acetaldehyde: toxic
o
Alcohol passes via the liver first hence liver enzymes can quickly become
saturated: means that repeated small doses far far lower blood alcohol than if take
all at once.
o
Why women more sensitive to alcohol:
 1. More body water in an equivalent male vs women of same weight as
women made up more of fat; more body water in men to dilute out the
alcohol
 Body water: 50% in female
 Body water: 59% in male
 2. Women have greatly reduced Alcohol dehydrogenase level compared to
men
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o
IMPORTANT DRUG INFO: Aldehyde dehydrogenase converts the acetaldehyde to
acetic acid; this occurs in both the liver and the stomach:


-
Disulfiram = inhibitor of Aldehyde dehydrogenase hence used in alcohol
eversion therapy by causing build-up of the toxic acetaldehyde in the blood
giving unpleasant effects
Genetic polymorphism: Mutation prevalent in Asians to Aldehyde
dehydrogenase hence less able to tolerate alcohol: natural alcohol eversion!
Asian races possess genetic variations in the enzyme alcohol dehydrogenase associated with
alcoholism
Asian races possess genetic variations in the enzyme aldehyde dehydrogenase associated
with alcohol intolerance
- IMPORTANT: LOW pharmacological potency, selectivity, affinity and
efficacy; effects due to high doses and effects at many many targets:
o
o
-
-
affinity and efficacy for its targets is low
comparison:
 Nicotine 20ng/ml
 Cocaine 200ng/ml
 Alcohol 200 microg/ml [ie high!]
Acute CNS effects:
o Both depression and excitation: Primarily a depressant in absence of social
stimulation or at high dose but CNS excitation at low dose in a social setting
o Enhance: Promotes increase in GABAergic activity:
 mech is via inc stim of Allopregnenolone release which then has the
positive effect at GABA neurones
o Block: decreased signalling at Glutamate NMDA receptors [mech is Allosteric
modulation]
o Block: decreased signalling at Ca2+ channels [mech is involving Neurotransmitters]
Euphoria: arguably no euphoria as inc GABA inhibition and dec NMDA stimulation of
dopamine release:
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ACUTE EFFECTS: Little known about what targets correspond to which effects
- Cutaneous vasodilation:
o Mech: Ca2+ entry or ACETALDEHYDE  prostaglandins  vasodilation
- Cardiovascular: increase to heart rate  : [but BP will not inc due to the above
vasodilation]
o Mech: Baroreceptors signal tonically for parasympathetic and inhib of sympa but
alcohol counters para baroreseptor signalling so dec para and inc sympa and
increase in HR
- Diuresis (polyuria):
o Mech: K+ entry or mediated by ACETALDEHYDE
o Alcohol inhibits the pituitary secretion of anti-diuretic hormone ( ADH)
- Certain brain regions appear to be more sensitive;
o CORTICAL region; here alcohol impairs both:
 (a)  Sensory function
 (b)  Motor function
o Corpus Collosum
 Function: Passes info from the left brain (rules, logic) to the right brain
(impulse, feelings) and vice versa.
o Hypothalamus
 Function: Controls appetite, emotions, temperature, and pain sensation.
o Reticular Activating System
 Function: Consciousness
o Hippocampus
 Function: Memory
o Cerebellum
 Function: Movement and coordination
o Basal Ganglia
 Function: Perception of time
CHRONIC EFFECTS: [long term high alcohol usage]
- Dementia
o Cortical atrophy and dec volume cerebral white matter
- Ataxia
o Cerebellar cortex degeneration
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Wernicke-Korsakoff syndrome
o Due to thiamine = vit B1 deficiency: alcoholic is getting calories from alcohol so not
getting certain nutrients
o Wernicke’s encephalopathy
 Reversible
o Korsakoff’s psychosis
 Irreversible
Liver:
o Alcohol dehydrogenase uses up NAD+; leads to impaired metabolism of glycerol
and fatty acids hence lipid droplets build up
 (reversible but constantly present if chronic drinking)
o
o
-
Acetaldehyde etc leads to inflammatory changes: increased ROS and Hepatic
cytokine changes (e.g.  IL-6 and TNF-) giving hepatitis
 (reversible but constantly present if chronic drinking)
Cirrhosis: fibroblast infiltration and reduced hepatocyte regeneration leads to
impaired regeneration of the liver  cirrhosis
 (relatively irreversible and may lead to liver failure)
Cardiovascular System: BENEFICIAL EFFECTS
o Mortality from coronary artery disease reduced in Men drinking 0-4 units/day due
to:
 Inc HDLs
 Inc t-PA levels /  platelet aggregation
 Polyphenols of red wine may be particularly effective
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Other effects:
- Gastrointestinal tract
o Alcohol dehydrogenase in stomach gives high acetaldehyde build-up in gut leading
to:
 Damage to gastric mucosa  increased permeability
 Carcinogenic effect
- Endocrine System
o Increased ACTH secretion [“stress response”]
 Ethanol can induce a pseudo-Cushing’s syndrome
o Decreased Testosterone secretion
o Alcohol inhibits the pituitary secretion of anti-diuretic hormone ( ADH)
- HANGOVER
o Symptoms peak as blood alcohol concentration reaches zero
o Nausea
 Irritant  Vagus  Vomiting center
o Headache
 Due to Vasodilation
o Fatigue
 1. Sleep deprivation,
 2. ‘Rebound sympa’
 Restlessness and muscle tremors ‘Rebound’ excitation of the CNS
(muscle cramps etc) hence poor quality of sleep
o Polyuria and polydipsia
 ↓ ADH secretion
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08/05/14: Dopaminergic pathways of the brain and drugs
used to treat Parkinson’s Disease and schizophrenia:
Professor David Dexter
Los (from booklet):
the main symptoms displayed by patients with Parkinson’s disease (PD) and
explain their underlying pathology
for PD and the side-effects
associated with levodopa in particular
neural pathways
-generation antipsychotic drugs in clinical use and identify their sideeffects
-generation antipsychotic drugs in clinical use and identify their sideeffects
Notes: [can use last years lec by sohag or booklet info if
want clarification / detail]:
-
Describe the main symptoms displayed by patients with Parkinson’s disease (PD) and their
underlying pathology
o Motor deficits: bradykinesia, resting tremor, rigidity, postural instability
o Due to degeneration of nigrostriatal dopaminergic neurones
-
Name the 3 main drug classes used to treat PD and describe their mechanisms of action
o DA replacement: Levodopa acts as DA precursor
o DA receptor stimulation: D2 agonists: bromocriptine, ropinirole
o Prevention of breakdown: MAOB inhibitors (selegiline), COMT inhibitors
(entacapone)
-
Summarise the problems with the current drug treatment for PD and the side-effects
associated with levodopa in particular
o Drug therapies not disease modifying
o Levodopa induces dyskinesias and eventually ‘off’ periods
o D2 agonists associated with psychosis
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Describe the major symptoms displayed by schizophrenic patients and the associated neural
pathways
o Positive symptoms: mesolimbic pathway; hallucinations, delusions, thought disorder
o Negative symptoms: mesocortical pathway; affective flattening, reduced selfawareness, lack of motivation
-
Name the main typical antipsychotic drugs in clinical use and provide details of their sideeffects
o Chlorpromazine: phenothiazine causing antimuscarinic side-effects
o Haloperidol: potent D2 antagonist causing extrapyramidal side-effects
-
Name the main atypical antipsychotic drugs in clinical use and provide details of their sideeffects
o Clozapine: very effective but causes agranulocytosis
o Risperidone: effective but associated with weight gain & EPS
o Quetiapine: low incidence of EPS
o Aripiprazole: partial agonist, low incidence of hyperprolactinaemia
-
Dopaminergic pathways:
o Nigrostriatal
 substantia nigra zona compacta  striatum
 Control of Movement: involved in motor actions
 Associated with parkinsons
o Mesolimbic
 ventral tegmental area  nucleus accumbens, frontal cortex, limbic cortex
and olfactory tubercule
 Involved in emotion (and consciousness)
 Associated with schitophrenia
o Tuberoinfundibular system
 Short neurones running
 arcuate nucleus of the hypothalamus  median eminence &
pituitary gland
 Regulate hormone secretion: specifically prolactin inhibition
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Dopamine synapse:
o Tyrosine hydroxylase: Tyrosine  DOPA
 Is the RDS and hence slow therefore do not give Tyrosine as a dopamine
replacement: is better to give DOPA
o DOPA decarboxylase: DOPA  dopamine
o
VMAT: uptake of dopamine to vesicles for storage until release

o
In addition to the neuronal death, the storage capacity of neurons for
dopamine is lost as disease progresses hence “on/off” response to DOPA
treatment develops ; cf
Dopamine transporters: Presynaptic dopamine transporters recycle dopamine
once it has served its synaptic function
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PARKINSON’S
-
How common is Parkinson’s disease
o 1 in 1000 of the general population.
o 1 in 100 of those aged over 60 years of age.
o Mean age of onset 65 years but younger people can develop the disease.
o Women are less likely to develop the disease than men (4:1 males:females)
o Familial Parkinson’s Disease
 accounts for ~8% of all cases
 6 main gene mutations are observed in these cases
o Idiopathic Parkinson’s Disease
 92% of cases
 possibly due to a combination of environmental and oxidative stress giving
altered protein metabolism
-
Relative prevalence to other conditions:
o Increasing prevalence:
 Parkinson’s  Alzheimer’s  schizophrenia = epilepsy  stroke
[note that schizophrenia is common: 1% of general population]
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[Symptoms: see neuro notes for better / comprehensive coverage]
-
-
-
Cardinal signs of Parkinson’s Disease [diagnosis is purely clinical and requires at least 2/4]:
o Rest tremor
 Shaking of the limb when relaxed
o Rigidity
 Stiffness, limbs feel heavy/weak
o Bradykinesia
 slowness of movement: problems in initiating movement
o Postural abnormality
 flexion of the neck and trunk
Presenting symptoms of PD
o Difficulty with fine movements
o Lack of blinking.
o Impassive face.
o Speech problems:
 Monotony of speech & loss of volume of voice.
 Because is a motor task and the excess secretion will not help
o Lack of arm swing
o Loss of balance
 lack of righting reflex
o Short steps, shuffling gait
Presenting symptoms of PD
o Symptoms appear on one side of the body first (unilateral onset).
o Symptoms then spread to both sides of the body.
o Generally symptoms worsen with some patients becoming severely disabled.
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-
Non-Motor symptoms of PD
o Depression
o Pain
 Due to the disruption of motor movements eg the constant tremor
o Taste/smell-disturbances
o Cognitive decline / Dementia / Memory impairment
o Autonomic dysfunction
 Constipation: loss of dopaminergic neurons in the ENS; is treated separately
 Postural hypotension
 Urinary frequency/urgency
 Impotence
 Increased sweating
-
Neuropathology of Parkinson’s disease
o Principal area: Substantia nigra
 a-syneuclein deposits
 Lewy bodies:
 Develop as part of a defence mechanism: attempt to clear the asyneuclein
 However when become full of a-synuclein toxic products begin to
escape hence become pathological
o Other brain areas are affected [these involve other neurotransmitters; is not just
dopaminergic neuron loss]
 e.g. Locus coruleus (NA), Dorsal motor nucleus of Meynert (ACh), Raphe
nuclei (5HT)
o Aetiology of PD is not known!
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Parkinson’s Disease Staging
o Corresponds to progression upward in the brain (see below): disease starts in
brainstem then midbrain then cortex
o Only beyond stage 3 does it become symptomatic in terms of motor dysfunction:
Corresponds to death of SNc dopaminergic neurons giving motor dysfunction
[note the grouping of stages]
-
BIOCHEMICAL CHANGES
o Marked reduction in caudate nucleus/putamen dopamine content
o Necessary to lose 80% of the dopaminergic neurons and deplete 70% of the striatal
dopamine before symptoms appear!
o Compensatory mechanisms prevent the appearance of clinical symptoms
 Upregulation of dopamine receptors
 Increased exocytosis from neurons that have been spared
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Dopamine Replacement Therapy
-
-
-
Dopamine
o NOT SUITABLE: can’t cross blood-brain barrier; just crosses where BBB is incomplete
such as at CTZ where it will give vomiting!
L-DOPA
D2R agonists: but side effects
Inhibitors to the dopamine breakdown pathways
L-DOPA [is the gold standard treatment for early parkinsons]:
o DOPA is the precursor to dopamine, converted to dopamine in the brain by enzyme
DOPA decarboxylase (DD).
o L-DOPA = short half life
o However, DD also present in peripheral tissues.
 If administered alone 95% of L-DOPA is metabolised to dopamine in the
periphery  CTZ  major side effects of nausea & vomiting.
 SOLUTION: Use peripheral DOPA decarboxylase inhibitor + L-DOPA.
 DOPA decarboxylase inhibitor:
o Carbidopa
o Benserazide
 Eg Sinemet (Carbidopa + L-DOPA)
 Eg Madopar (Benserazide + L-DOPA)
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o
o
TREATS
 Hypokinesia, rigidity & tremor
 Start with low dose of the drug and increase dose until maximum benefit
without side effects
 Effectiveness of L-DOPA declines with time!: have to keep increasing the
dose until eventually side effects too severe: see below
Side effects: [nb Impulse control disorders that include gambling, eating and hypersexuality
seem to occur more commonly with dopamine receptor agonists than L-DOPA]
o
ACUTE

o
o
Nausea/vomiting - prevented by Domperidone (peripheral acting D2
antagonist acting at CTZ)
 Some of the DOPA is being converted to dopamine in the periphery
then passing to CTZ giving the nausea; solution is to use peripheral
inhibitors
 Hypotension
 The most likely hypothesis is that L-DOPA forms dopamine which
acts as a false transmitter in the peripheral sympathetic nervous
system.
 Psychological effects
 Schizophrenia like syndrome with:
o Delusions, hallucinations, confusion, disorientation &
nightmares
 Ie due to also increasing dopamine in the mesolimbic system
CHRONIC
After 6 years of therapy:
 Dyskinesias (54%):
 uncontrollable muscle movements of limbs and face
 are due to the drug not the parkinsons,
 if taken off drug parkinsons symptoms reappear, patient will just
freeze; need to try the other drugs that are not acting via the
neurons
 On-off oscilations (64%)
 Eg periods of being locked-in due to period of extreme motor
dysfunction
 Rapid fluctuations in clinical state. Off periods may last from
minutes to hours. Occurs more with L-DOPA use than without
 In addition to the neuronal death, the storage capacity of neurons
for dopamine is lost as disease progresses hence “on/off” response
to DOPA treatment develops ; need to try the other drugs that are
not acting via the neurons
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DOPAMINE AGONISTS
o ACTIONS
 Act on D2 receptors
 Ergot derivatives:
 Bromocriptine/Cabergoline & Pergolide


problems with heart valves: dangerous cardiopulmonary fibrotic
reactions.
 Any drug with ergot ring can target the heart valves to cause
damage
Non-ergot derivatives:
 Ropinirole & Rotigotine
o
o
o
o
Ropinirole also available as extended-release formulation
Rotigotine also available as a patch
Vs L-DOPA:
 longer half-lives
 Longer duration of action than L-DOPA:
 Smoother & more sustained response: Incidence of dyskinesias is
less
 Actions independent of dopaminergic neurons
 Can be used in conjunction with L-DOPA
ADVERSE EFFECTS
 Common
 nausea/vomiting
 Schizophrenia like syndrome with:
o Delusions, hallucinations, confusion, disorientation &
nightmares
 Rare
 Hypersexuality [high libido]
 Addictive behaviours eg gambling
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Preserving dopamine that is present:
-
MAO B INHIBITORS
o Selegiline = Deprenyl




Selective for MAO-B which predominates in dopaminergic areas of CNS
hence avoid peripheral side effects of non-selective MAO-I’s
 Eg avoid non-selective giving the ‘cheese reaction’ etc
Can be given alone in the early stages of the disease.
Or in combination with L-DOPA, allows you to reduce the dose of L-DOPA
by 30-50%; hence less side effects of the L-DOPA
Side effects are rare: [relatively safe drug]
 hypotension, nausea/vomiting, confusion and agitation.
o Resagiline


-
Inhibits MAO-B AND inhibits apoptosis
Shown to have neuroprotective properties by inhibiting apoptosis; promotes
anti-apoptosis genes. Early clinical trials suggest that this drug may slow the
disease down but subsequent studies not so positive: no disease modifying
qualities
Catechol-O-methyl transferase (COMT) inhibitors
1. Tolcapone (= CNS & peripheral)
2. Entacapone (= peripheral only)
o
o
-
Mechanism:
 CNS
 Prevents breakdown of dopamine in the brain
 Peripheral
 COMT in the periphery not only degrades catecholamines but also
converts L-DOPA to 3-O-methylDOPA (3-0MD).
 3-OMD and L-DOPA compete for same transport system across the
blood brain barrier (BBB).
 COMT inhibitors stop 3-OMD formation thus increasing the
penetration of L-DOPA across the BBB thus increasing brain
concentrations, where it is converted to dopamine.
 In this way allows reduction of L-DOPA dosage!
Side Effects
 Cardiovascular (esp entacapone) and liver (esp Tolcapone) complications
Anticholinergic drugs: helps to relieve tremor in mild to moderate disease [vs M4R’s]
Deep brain stimulation:
o Like a brain pacemaker; elec stimulation to specific areas
 the lead may be placed in either the globus pallidus or the subthalamic nuc
o Purpose is to stimulate nerve signals to prevent tremor and other parkinsons
symptoms
o Linked to causing depression though
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SCHIZOPHRENIA
-
Symptoms:
o Positive symptoms:
 Delusions, hallucinations, confusion, disorientation & nightmares
o Negative symptoms:
  emotion, speech, ability to experience pleasure, desire to form
relationships, motivation
-
Genetics:
o Genetic component exists as shown but details are poorly characterised
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Once Schizophrenia has been diagnosed there are four main outcomes:
o The illness resolves completely, with or without treatment and never returns (1020% subjects).
o The illness recurs repeatedly with full recovery after each episode (30-35% subjects)
o The illness recurs repeatedly, but recovery is incomplete and a persistent defective
state develops, becoming more pronounced with each successive relapse (30-35%
subjects)
o The illness pursues a downhill course from the beginning (10-20% subjects)
NEUROCHEMICAL INVOLVEMENT
- Dopamine theory
o Positive: Excessive dopamine transmission in the mesolimbic and striatal (see below)
region leading to positive symptoms
 mediated through D2 receptors.
o Negative: Whilst dopamine deficit in pre-frontal region, leads to negative symptoms.
 mediated by D1 receptors
 No drugs to help vs negative symptoms
 Ie dopamine can be excitatory but is inhibitory in other scenarios
o Evidence
 Dopamine agonists e.g bromocriptine, and amphetamine can induce various
psychotic reactions.
 Typical anti-schizophrenic drugs are dopamine receptor antagonists and
there is a strong correlation between antipsychotic potency and activity in
blocking D2 receptors.
- Glutamate theory: = Effects due to lack of glutamate
o Evidence
 NMDA receptor antagonists e.g. phencyclodine, ketamine etc. produce
psychotic symptoms.
 Reduced glutamate concentrations and glutamate receptor densities in
post-mortem schizophrenic brains.
 In mice where NMDA receptor expression is reduced, show stereotypical
behaviours suggestive of schizophrenia which respond to antipsychotic
therapy.
 Glutamate (excitatory) and dopamine (inhibitory) exert effects on GABAergic striatal neurons:
 These GABA striatal neurons inhibit sensory neurons en route to
the cortex
 Too little glutamate (or too much dopamine), disables the GABA
gate, allowing uninhibited sensory input to reach the cortex.
-
Aetiology & Pathogenesis of Schizophrenia
o Disease shows a strong but incomplete hereditary tendency.
o Genetic linkage studies have identified a number of risk genes, but no single gene is
responsible.
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o
o
o
o
-
There are significant polymorphisms in individual genes which may trigger
schizophrenia but many are weak associations.
Genetics: The first and most robust is the gene for neuregulin-1
 synaptic development and plasticity
 has effects on NMDA receptor expression.
8 other susceptibility genes have also been discovered all associated with glutamate
or dopamine mediated neurotransmission.
No specific neurotransmitter abnormality so far identified
Mechanism of action of Antipsychotics
o ALL NEUROLEPTIC DRUGS ARE ANTAGONISTS AT DOPAMINE “D2 LIKE” RECEPTORS.
o Most neuroleptics block other receptors too e.g. 5-HT, thus accounting for some of
their effects.
o Drugs treat positive symptoms but not the negative ones!
o Delayed effects, takes weeks to work.
o Initially neuroleptics induce an increase in Dopamine synthesis and neuronal
activity. This declines with time.
 Ie body trying to compensate for the drug action, then after failing to do so
will stop attempting this, treatment then starts being more effective
o Antipsychotics lack dopamine receptor selectivity as shown hence a range of side
effects occur:
[just to illustrate the diverse targets]
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OTHER ACTIONS/SIDE EFFECTS OF NEUROLEPTICS
o Anti-emetic effect
 Most antiemetics were developed from antipsychotics
 Blocking dopamine receptors in the chemoreceptor trigger zone.
Neuroleptic Phenothiazine, effective at controlling vomiting and nausea
induced by drugs (e.g. chemotherapy) , renal failure.
 Many neuroleptics also have blocking action at histamine receptors.
Effective at controlling motion sickness.
o Extrapyramidal side effects
 Blockade of dopamine receptors in the nigrostriatal system can induce
“Parkinson” like side effects.
 Atypical antipsychotics avoid or have reduced incidence of the
extrapyramidal effects:
 Acute dystonia
 involuntary movements: muscle spasm, protruding tongue, fixed
upward gaze, neck spasm etc.
 often accompanied by Parkinson’s features.
 Occur in the first few weeks , often declining with ongoing therapy.
 Reversible on drug withdrawal or anti-cholinergics.
 More associated with typical antipsychotics.
 Tardive dyskinesias
 Involuntary movements, often involving the face & tongue, but also
limb and trunk. Occur in about 20% of patients after several months
or years of therapy (hence ‘tardive’ [Tardive means "delayed"]).
 More associated with typical antipsychotics.
 Irreversible: Made worse by drug withdrawal or anti-cholinergics:
are permanent effects!.
o May be related to proliferation in pre-synaptic DA D2
receptors or glutamate excitotoxic striatal
neurodegeneration .
o Endocrine Effects
 Dopamine is involved in the Tuberoinfundibular system and acts to inhibit
prolactin secretion via the D2 receptors.
 Antipsychotics increase serum prolactin concentrations which can lead to
breast swelling (men & women) and sometimes lactation in women.
o Blocking a-adrenoceptors
 causes orthostatic hypotension
o Blocking 5-HT receptors
 weight gain “serotonin signals from gut when are full”
o Blockade of cholinergic muscarinic receptors
 Typical peripheral anti-muscarinic side effects e.g blurring of vision,
increased intra-ocular pressure, dry mouth, constipation, urinary retention.
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Drug detail: [is from sohags lec from last year but we prob have to know about them; is in Los]:
-
Typical:
o
o
-
Chlorpromazine: phenothiazine causing antimuscarinic side-effects
Haloperidol: potent D2 antagonist causing extrapyramidal side-effects
Atypical:
o
o
o
o
Clozapine: very effective but causes agranulocytosis
Risperidone: effective but associated with weight gain & EPS
Quetiapine: low incidence of EPS
Aripiprazole: partial agonist, low incidence of hyperprolactinaemia
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Typical:
- Chlorpromazine
o
o
o
o
Discovered whilst trying to develop new antihistamines
Primary mechanism of action is thought to be due to antagonism of dopamine D2
receptors
High incidence of anti-cholinergic side-effects especially sedation
Low incidence of extrapyramidal side-effects (despite being a typical antipsychotic!)
- Haloperidol
o
o
o
o
-
Very potent D2 antagonist (~ 50 times more potent than chlorpromazine)
High incidence of extrapyramidal side-effects (EPS)
Therapeutic effects develop over 6-8 weeks
Has little impact on the negative symptoms of schizophrenia
Atypical:
- Clozapine
o
o
o
o
The most effective antipsychotic but dangerous side-effects mean it is only used as a
last resort
Very potent antagonist of 5-HT2A receptors
 potentially fatal neutropenia and agranulocytosis
 myocarditis and tachycardia
 weight gain
Only drug to show efficacy in treatment resistant & PD psychosis
Has shown efficacy in treating the negative symptoms of schizophrenia
- Risperidone
o
o
o
Indicated for the treatment of acute & chronic psychoses, mania and aggressive
behaviour
antagonist of 5-HT2A (as well as antag to D2 receptors)
 Some weight gain
Causes more extrapyramidal side-effects & hyperprolactinaemia than other atypical
antipsychotics (ie despite being an atypical antipsychotic!)
- Quetiapine
o
o
o
Indicated for the treatment of schizophrenia, mania and PD psychosis
Very potent antagonist of H1 receptors
Lower incidence of extrapyramidal side-effects than other antipsychotics
- Aripiprazole
o
o
o
o
Indicated for schizophrenia, mania & control of agitation
Partial agonist of D2 & 5-HT1A receptors!!
No more efficacious than typical antipsychotics
Significantly reduced incidences of hyperprolactinaemia and weight gain than other
antipsychotics
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TUTORIAL:
-
-
-
Loss of SNc function leads to pathological rise in Ach signaling
o Anti ACh medications can therefore be used in parkinsons
o High ACh explains the autonomic dysfunction effects
Tyramine is a breakdown product of tyrosine
Cocaine has local anaesthetic properties
Ethanol can induce a pseudo-Cushing’s syndrome
Asian races possess genetic variations in the enzyme alcohol dehydrogenase associated with
alcoholism
Asian races possess genetic variations in the enzyme aldehyde dehydrogenase associated
with alcohol intolerance
[easter egg]
I bet you think you are so big and clever using CTRL + F “easter egg” to find this. Well $*%& you! Or
was it the squiggly red lines that gave away my hiding place?
[/easter egg]
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09/05/14: Opioids: Dr Chris John
Los (from booklet):
Learning objectives
1. Define the terms opiate and opioid; identify the importance of opiates and opioids in the clinical
control of severe pain.
2. List the principal subtypes of opioid receptor and identify their endogenous ligands
3. Identify the signalling mechanisms used by opioid receptors.
4. Identify the main central nervous pathways concerned with pain transmission/perception. Identify
sites within these pathways where opiates/opioids modify transmission.
5. Explain how opiates influence physiological function (e.g. respiration) and identify which of these
actions may be advantageous clinically and which may cause unwanted effects.
6. Explain how opiates/opioids may produce tolerance and dependence.
7. Identify the main pharmacokinetic characteristics of morphine.
8. Explain how the following drugs differ from morphine in their pharmacokinetic properties: Heroin
(diamorphine), Codeine, Methadone, Fentanyl
9. Identify the clinical use of opioid receptor antagonists.
Notes:
-
-
opiate
o narcotic analgesic derived from a opium poppy (natural)
o Common opiates include morphine and codeine, both made directly from poppy
plants.
opioid
o narcotic analgesic that is at least part synthetic, not found in nature
-
OPIATES / OPIOIDS: Tertiary nitrogen [with <3xC’s] = confers analgesia effects
o Permits receptor anchoring
o Extend side chain to 3+ carbons and you generate antagonist to agonists at all the
targets that an agonist would give an analgesic effect at
 Ie side chain off the nitrogen must be short for the analgesic effects
-
OPIATES
o Morphine



Tertiary nitrogen present and short side chain therefore analgesic agonist
POOR lipid solubility
 Short 30min half life (quick liver metabolism)
Oral 40-50% bioavailability
 High plasma protein binding
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


Quickly metabolised at the liver
 However morphine-6 glucuronide is an active metabolite that will
continue to give an analgesic effect
Urine excretion
 (as with most opioids!)
 Due to ionisation at physiological pH: pKa of morphine is 8.2
Hydroxyl modifications give:

Heroin = “diacetyl-morphine” at carbon 3 and 6
o
o
o

More lipophilic as a result
 hence access the brain faster  high brain effects
 Hydroxyl group at position 6: Oxidise the OH group
and lipophilicity Increases 10-fold
Must be converted back to morphine before can have its
effect
 This is fast
 Hydroxyl group at position 3: Required for Binding
i.e. heroin is a prodrug
Is short acting: plasma esterases quickly metabolise the
drug
Codeine = “methyl-morphine” at carbon 3
o
o
NB 5-10% codeine → morphine:
 CYP2D6 O-dealkylation to morphine (slow)
 CYP3A4 deactivation (fast: most codine is process in
this way instead and hence lost)
Must be converted back to morphine before can have its
effect:
 This is a slow conversion therefore codine is not as
powerful as morphine
 Hydroxyl group at position 3: Required for binding
i.e. codeine is a prodrug
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Pharmacokinetics of Other Opiates
o Fentanyl:





Benzene ring gives its potency
highly lipid soluble
Oral
 50-100% bioavailability
 Alternatively buccal/Intra-nasal or -dermal
Metabolism: Very short acting! [much faster metabolism than morphine]
 Liver oxidation of Fentanyl
Urine excretion
 (as with most opioids!)
 Due to ionisation at physiological pH
o Methadone


EXTREMELY Lipophilic
 Long half life due to distribution to fat where it remains
Urine excretion
 (as with most opioids!)
 Due to ionisation at physiological pH
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Opioids
o They act via specific ‘opioid’ receptors
o Endogenous opioid peptides exist; [it is the receptors to these that are targeted]:
 Endorphins
 Enkephalins
 Dynorphins/neoendorphins
o OPIATE RECEPTORS
 Mu ()
 Endorphins bind here
 Pain/Stress
 Delta ()
 Enkephalins bind here
 Kappa ()
 Dynorphins/neoendorphins bind here
 Appetite/Temp. regulation
o OPIATE RECEPTORS
 Cellular Mechanism of Action:
 Have depressant inhibitory action at
targets!!
o
o Hyperpolarisation ( K+)
o  Ca2+ inward current
o  Adenylate cyclase activity
Pharmacodynamics [detail given below]:
 Analgesia
 Euphoria
 Depression of cough centre (anti-tussive)
 Depression of respiration (medulla)
 Stimulation of chemoreceptor trigger zone (nausea/vomiting)
 Pupillary Constriction
 G.I. Effects
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ANALGESIA MECHANISMS: opioids can do both the mechs!
o Decrease pain perception
o Increase pain tolerance
o
Signalling for pain from periphery is as illustrated on the below diagrams:
o
Periphery  thalamus  Thalamus outputs:
 1. Via cortex for processing: info from past experience is integrated before
signalling of pain info to PAG region
 2. Direct signalling of pain info to PAG region
PAG = Periaqueductal gray
 is beginning of the inhibitory signalling; this is where the extent of the
descending inhibition is determined
 Signals to NRM: nucleus raphe magnus, which passes on the descending
inhibitory signals sensations of pain
NRPG: Nucleus reticularis paragigantocellularis
 Is an automatic feedback system bypassing brain to NRM to give initial
weak diminishment of pain
 Fast acting but weak inhibition
Hypothalamus
 sends info to PAG to give integration to PAG of general info regarding state
of health of the body
LC: locus coeruleus
 Stress response information is integrated at the level of the dorsal horn
 can directly inhibit the pain signalling
 Eg during exercise do not feel pain at time, only after / the next day
Specifically, all the inhibitory signals act at dorsal horn Substantia gelatinosa [where
first order neurons of the spinothalamic tract synapse]
o
o
o
o
o
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o
Opiod receptors are in:
 dorsal horn: to dec pain sensation
 peripherally: to dec pain sensation
 NRPG: to inc inhib signalling
 PAG: to inc inhib signalling
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-
Euphoria:
o Via a standard disinhibition mech as below:
-
Antitussive:
o Sensory neurons activate vagal afferents; these project to the cough center from
which cough is stimulated
o 1. Opioids give decreased Ach and NK [neurokinin] release from sensory neurons so
reduced activation of vagal afferents
o 2. Centrally act in (dorsal) Raphe nucleus to inhibit 5HT1A R receptors
 Ie act at dorsal part of the raphe nucleus [“blocking disinhibition”: in opioid
absence the receptor supresses serotonin which would otherwise supress
cough]
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-
Respiratory depression:
o 1. Opioids decrease firing of the central chemoreceptors by acting at Mu receptors
o 2. Disrupt resp rhythm at central higher centers [not shown on diagram]
-
Nausea/Vomiting:
o 1. Opioids OVR increase signalling to CTZ by acting at Mu receptors
o 2. Disrupt signalling from the vestibular system: increase firing to give nausea [not
shown on diagram]
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-
Miosis:
o Opioids OVR stimulate parasympathetic nerves to eye: Opioid inhibition of GABA
inhibition at Edinger-Westphal nucleus = the oculomotor nucleus
-
GI tract:
o Opioids dec gut activity via inhibitory actions on the ENS  Constipation by acting at
Mu and kappa receptors:
 Dec gastric emptying
 Dec GI motility
 Inc water absorption
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-
Opioid side effects:
o Histamine mediated; take antihistamines to treat
 Itching (pruritis)
 hives (urticaria)
 Hypotension
-
Tolerance:
o 1. Opioid receptor internalisation
 Occurs at a physiological level for recycling but opioids increase arrestin
level which leads to increased capacity for internalisation
o 2. Cells also will upregulate adenylate cyclase levels (cf)
o Hence cells become less responsive to opioids
-
Withdrawl:
o Withdrawal associated with:
 1. Psychological craving
 2. Physical withdrawal (resembling flu)
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o
-
-
Body will increase adenylate cyclase in response to opioids to try to reinstate normal
positive signalling; hence if opioid removed there will be increased positive cellular
signalling from the cell
 “compensation unmasking”
Prolonged Treatment
o Coma
o Respiratory depression
o Pin-point pupils
o Hypotension
Treatment of overdose:
o
Naloxone (opioid antagonist) i.v.


Works due to long sidechain on the tertiary nitrogen
Will precipitate a withdrawl reaction in addicts
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09/05/14: Anxiolytics, sedatives and hypnotics:
Dr Martin Croucher
Los (from booklet):
1. List the principal clinical uses (with routes of administration) of the benzodiazepines and
the barbiturates.
2. Identify the main undesirable effects of the benzodiazepines. Explain how these compare
with the unwanted effects of the barbiturates.
3. Compare the mechanisms, profiles and durations of action of individual benzodiazepines.
4. Explain, providing examples, how differences in durations of action influence the
therapeutic usefulness of these compounds.
5. Define the term ‘anxiolytic drug’. Identify three classes of drug which have useful
anxiolytic properties.
6. Identify three drugs widely used for their hypnotic effects. Explain why diazepam is not
used in this capacity.
Notes:
-
Outline:
o Gaba A receptor complex
o Benzodiazepines (bzs) & barbiturates (barbs)
o Basic and clinical pharmacology
o Other drugs
GABA receptors:
-
1. GABA B = presynaptic = GPCRs = regulate GABA release
-
2. GABA A receptors = postsynaptic = inhibitory action in brain when GABA binds
o Focus of lec
o Is a Cl- channel; Cl ions will enter the cell
 Hyperpolarises the postsynaptic cell
 Ie inhibitory action
o 4 main proteins:
 1. GABA receptor protein
 2. Benzodiazapine receptor protein
o Increases the affinity of binding for GABA
 effect is reciprocated back to give increased
benzodiazepine affinity at the BZ R
o Increased Cl- influx results
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

3. Barbiturate receptor protein
o 1. Increases the affinity of binding for GABA
 effect is NOT reciprocated back to the
benzodiazepine
o 2. At higher concentrations can directly act on Cl channel to
open it [NOT done by benzodiazapines]
 This is due to the low selectivity demonstrated by
barbiturates
o Increased Cl- influx results
4. [one other protein]: GABA modulin polypeptide
Gaba A receptor complex (fig. 1)
-
Bzs & barbs :
o I) no activity alone
 Ie just enhance action of gaba; no effect by self
 Is allosteric action
o II) different binding sites and different mechanisms
 
bzs  frequency of openings
 
barbs  duration of openings
o III) barbiturates are less selective than bzs
  other membrane effects
 eg can act directly at the chloride channels at high doses
 May explain
 
induction of surgical general anaesthesia
 
low margin of safety
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Clinical pharmacology of bzs & barbs:
-
Clinical uses:
o General Anaesthetics

o
Anticonvulsants
 used in the treatment of epileptic seizures


o
barbs only : Thiopentone
Diazepam; Clonazepam
Barb: Phenobarbital
BZ:
 But give sedation; hence alternatives are used in reality
Anti-spastics
 Diazepam
o
Anxiolytics
 Diazepam
 Oxazepam
 Other:
 Propranolol
 Buspirone
o
Sedatives / Hypnotics: ie Often are same drugs just at different doses




-
Oxazepam
Temazepam
Amobarbital
Other:
 Zopiclone
 Chloral hydrate
Definitions: [spectrum of activity:]
o Anxiolytics:
 Remove anxiety without impairing mental or physical activity
 May be called “minor tranquillisers”
o Sedatives:
 Reduce mental and physical activity without producing loss of consciousness
o Hypnotics:
 Induce sleep
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 Often are same drugs as the sedative just at higher doses
Ideally: they should:
o I)
have wide margin of safety
o Ii)
not depress respiration
o Iii)
produce natural sleep (hypnotics)
o Iv)
not interact with other drugs
o V)
not produce ‘hangovers’
o Vi)
not produce dependence
(i) barbiturates
o Structures : have a 6 membered barbiturate ring which is modified to give the
different barbiturates
o highly lipid soluble  wide distribution
o Metabolism
 
usually extensive metabolism by the liver  glucuronide conjugates
o Excretion
 
urine as glucuronide conjugates
o Range of clinical uses (above) including:
 Sedative / hypnotic

o

Amobarbital
 
use vs severe intractable insomnia
 
t½ 20-25h
Unwanted effects (not drugs of 1st choice: “dirty drugs”)
 Low safety margins
 
depress respiration
 
overdosing lethal
 Alter natural sleep
 ( rem)  hangovers/ irritability
 Enzyme inducers
 Eg decreased warfarin potency
 Potentiate effect of other cns depressants
 e.g. potentiates Alcohol
 Tolerance
 Tissue tolerance: receptor donwnregulation
 Pharmatokinetic tolerance: liver enz upregulation
 Withdrawal syndrome: gives dependance
 Insomnia
 Anxiety
 Tremor
 Convulsions
 Death
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(ii) benzodiazepines
o Key examples:
 Diazepam
 Temazepam
 Oxazepam
o
Antagonists:
 Flumazenil

o
o
o
o
o
o
o
o
competitively inhibits ie antagonizes benzodiazepines at the
benzodiazepine receptor protein on GABA A
All act at GABAA receptors
Pharmacodynamics: All similar potencies & profiles
Pharmacokinetics largely determine use:
Admin.
 
well absorbed p.o. (per os) = orally
 
peak [plasma]  1h
 
i.v. Vs Status Epilepticus:
 = prolonged / repeated seizures without patient regaining
conciousness
Distribution:
 
bind plasma proteins strongly
 Hence risk of problems with aspirin / heparin giving displacement
 
highly lipid soluble  wide distribution
Metabolism
 
usually extensive metabolism by the liver  glucuronide conjugates
Excretion
 
urine as glucuronide conjugates
Duration of action
 
Duration of action vary greatly
o I) short-acting
o Temazepam
o Oxazepam
o
Ii) long-acting
o Diazepam


1. Slow metabolism
And / or
2. Generate active metabolites which will be able to
continue to act [see diagram below for illustration of this for
diazepam]
 Diazepam  Temazepam & Oxazepam!!
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Anxiolytics:
o
Diazepam

(= valium)
‘long-acting’
o Oxazepam
-
 Gives hepatic impairment
Sedative / hypnotics:
o
o
o
-
-
Temazepam (‘short-acting’)
Oxazepam (‘short-acting’)
Nb. Zopiclone: not a benzodiazepine
Bz advantages:
o Wide margin of safety:
 Milder effect on REM sleep
 Do not induce liver enzymes
 Overdose  prolonged sleep (but rousable) but not death
 Flumazenil: antidote: antagonises bz at the gaba a receptor
Unwanted effects
o Sedation
o Confusion
o Ataxia (impaired manual skills)
o Potentiate other CNS depressants
 Eg alcohol
 Eg barbs
o Tolerance occurs
 But less marked than barbs: only causes tissue tolerance (receptor
downreg), unlike Barbituates, which cause both pharmacokinetic and
tissue tolerance.
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o
o
-
Withdrawl (dependence):
 withdrawal syndrome similar to barbs (but less intense) therefore must
withdraw slowly
Free [plasma]  can be triggered by other drugs
 e.g. Aspirin, heparin
Other anxiolytics
o Propranolol

Improves physical symptoms:
 Tachycardia (1)
 Tremor (2)
o Buspirone
-
 5HT-1A agonist
 Few side-effects
 BUT: Slow onset of action (days / weeks)
Other sedative/hypnotics
o Zopiclone
o Chloral hydrate




ccl3ch(oh)2

ccl3ch2oh
chloral hydrate
trichlorethanol
Is a prodrug
Method of action unknown
Wide margin of safety (children ) (elderly )
- Bicuculline
o
o
o
competitive antagonist of GABAA receptors at GABA binding site
hence reduces action of all of GABA/Bzs/Barbs
Since it blocks the inhibitory action of GABA receptors, the action of bicuculline
mimics epilepsy
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15/05/14: Principles of General Anaesthesia: Dr Chris John
Los (from booklet):
1 Explain the clinical objectives of general anaesthesia
2 Explain using examples the pharmacology of inhalational anaesthetics.
3 Explain using examples the pharmacology of intravenous anaesthetic drugs.
4 Identify the potential neuroanatomical sites of general anaesthetic action.
5 Recognise that other drugs are used clinically to facilitate anaesthesia and explain
why they are used.
Notes:
-
Clinically desirable effects of GA: [ALL GA’s only share the first two traits!! Though some
have some of the others too]
o Loss of consciousness
 at low concns
o Suppression of reflex responses
 at high concns
o Amnesia
o Relief of pain (analgesia)
o Muscle relaxation
-
Types of General Anaesthetics [very structurally dissimilar!]
o Gaseous/Inhalation




o
Nitrous Oxide
Diethyl Ether
Halothane
Enflurane [the most utilised inhaled form]
Intravenous
 Propofol
 Etomidate
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Meyer/Overton Correlation:
o GA’s more effective the more lipid soluble they are
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Mechanism of Action:
o [NOT due to disruption of the lipid membrane]
o Either: Reduced neuronal excitability
 TREK K+ channels (background leak): Increase in background leak K+ activity
thus giving hyperpolarisation and decrease in activity of the nerve
 Main result is suppression of reflex responses
 All the GAs prob do this
o OR Altered synaptic function
 Intravenous agents:
 GABAA receptors: Bind to GABA-A receptor to modulate it and
make it more responsive to GABA
o GABAA receptors with high numbers of 3 subunits are
associated with suppression of reflex responses
 Act at Synapses
o GABAA receptors with high numbers of 5 subunits are
associated with causing amnesia
 Extra-synaptic
 Inhalation agents:
 Target GABAA receptors to make them more sensitive but not as
powerful in this action as the IV agents
 Target Glycine receptors receptors to make them more sensitive to
Glycine but not very powerful
 Nitrous oxide: Blocks NMDA-type glutamate receptors
 BOTH target Neuronal nicotinic ACh receptors to give:
 Amnesia
 Relief of pain
 [effect on consciousness / reflex responses is via a diff mech!!]
o Inhalated agents tend to hit many more targets:
[Dark green or pink spot indicates significant potentiation or inhibition, respectively.
A light green or light pink spot indicates little potentiation or inhibition,
respectively.]
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How specific effects are mediated:
- Loss of consciousness
o Thalamocortical area:
 Depress excitability of thalamocortical neurons
o Reticular activating system:
 Influences reticular activating neurons
- Suppression of reflex responses
o Depression of reflex pathways in the spinal cord
 Eg beta-3 containing GABAR enhancement by IV agents at synapses
- Amnesia
o ↓ synaptic transmission in hippocampus/amygdala
 Eg alpha-5 containing GABAR enhancement by IV agents near synapses
 Eg via ACh block by both IV and inhalational agents
- Pain relief:
o ACh block by both IV and inhalational agents
- Muscle relaxation:
o None discussed
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IV to induce, inhalation to maintain anaesthesia:
-
Eg Induction: Propofol; Maintenance: Enflurane
-
Iv
-
o Good for fast action
o Bad for careful modulation
o Less coughing/excitatory phenomena
Inhaled
o Bad for fast action
 Excitatory phenomena: patient thrashes around (hence use IV to induce)
o Good for careful modulation
o Choose one of low solubility: Low blood:gas partition coefficient:
 Is no barrier to alveoli transfer but will quickly exit at brain
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
o
o
o
-
-
Loss of consciousness and suppression of reflex responses
o
Induction: Propofol
o
Maintenance:Enflurane
Relief of pain (analgesia) = Opioid
o (e.g. i.v. fentanyl)
Muscle relaxation = Neuromuscular blocking drugs
o
-
(e.g. suxamethonium)
Amnesia = Benzodiazepines
o
-
Also quick recovery as if stop applying at lungs the drug leaving brain will
quickly be lost at the alveoli
 This allows careful control
High solubility gives slower blood  brain steps and recovery pathway of brain 
blood is also slowed
 Only use if has a better side effect profile for that patient and the type of
surgery being performed
Rapidly eliminated
Rapid control of the depth of anaesthesia
(e.g. i.v. midazolam)
Chloroform gives hepatotoxicity
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15/01/14: LOCAL ANAESTHETICS: Dr M.J. Croucher
Los (from booklet):
1 Recall the properties of electrically excitable cells that underlie the generation of
neuronal action potentials.
2 Identify the general chemical structures of local anaesthetics (LAs) and the two main
classes into which they can be divided.
3 Explain the principal cellular mechanism of action of LAs and explain how this gives
rise to the property of ‘use-dependency’ of these agents.
4 Identify the effects of LAs on i) AP generation and propagation and ii) resting
membrane potential. Explain how and why these effects differ in infected tissue
compared to healthy tissue?
5 Identify the six main routes of administration of LAs, including their clinical
usefulness. Explain why vasoconstrictor substances are often co-administered with
Las.
6 Identify the pharmacokinetic properties of i) lidocaine and ii) cocaine, indicating how
their respective routes of metabolism influence their plasma half lives.
7 List and compare the major unwanted effects of lidocaine and cocaine on i) the CNS
and ii) the CVS.
Notes:
LAs = Drugs which reversibly block neuronal conduction when applied locally
-
Generation of neuronal AP
o Nb no calcium involvement
o Refractory: AP possible but requires a greater stimulus
o 1x cycle = ~12msec
o APs are all or nothing: all that occur are the same size [by contrast endplate
potentials are graded potentials]
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Structure of LAs
o 1. Aromatic region
o 2. Ester / amide bond
o 3. Basic tertiary amide side chain
 Are tertiary amines
 All LAs are weak bases
o [ie greater consistency than is observed with GAs]
o RE structures: Only HTK:



Lidocaine = amide linkage
Cocaine = ester linkage
Benzocaine = no tertiary amine
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Mech:
o Hydrophillic pathway:
 Is the primary mechanism of action of most LAs
 Only unionised unprotonated form can pass through connective tissue
sheath and the neuronal wall
 Once inside the ionised protonated structure must form: this binds the
voltage gated sodium channel
 Sterically hinders access of Na into the cell
 Show use dependency: greater block with greater ion channel usage ie high
neuronal firing [LA can only bind when the channel is open]
 Allows selectivity of pain conducting fibres because of their high
firing rate
o Hydrophobic pathway:
 Some highly lipid soluble LAs can access channels from within the bilayer in
the unionised unprotonated form (as opposed to fully traversing the memb
as above)
 This is a non use dependant mechanism
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Effects
o EFFECTS OF LAs: They:
 Prevent generation and conduction of APs
 Do NOT influence resting membrane potential
 May also influence
 Slowed resetting of channel gating [some LAs can hold channels in
their inactivated state during the cycle for a longer duration than
would occur naturally]
 Decreased surface tension [can lodge in bilayer and give drop in
surface tension for a non-specific disruption of proteins in the
membrane (including the Na channels) this is different to the
hydrophobic pathway specific targeting of the channels
 Selectively block
 Small diameter fibres are more greatly affected
 Non-myelinated fibres are more greatly affected
 Ie vs the c fibres: small diameter non mylinated fibres!! carry pain
 LAs are weak bases (pKa 8-9)
 Only a small proportion are unionised
 Infected tissue is more acidic so is harder to anaesthetise
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ROA [route of action]
o Surface anaesthesia
 Mucosal surface (mouth, bronchial tree)
 Spray (or powder)
 But via this mech will require high concentrations of LA → systemic toxicity
o Infiltration anaesthesia
 Directly into tissues → acts on sensory nerve terminals rather than the
axons
 Minor surgery
 Adrenaline co-injection (but adrenaline NEVER given at extremities because
would give risk of ischemia):
 vasoconstriction gives reduction of diffusion of the LA away from
the area
o lowered systemic effects
o lower dose necessary
o reduced bleeding
o Nerve block anaesthesia
 Close to nerve trunks to give block at axon e.g. dental nerves
 Widely used – low doses required – slow onset
 Adenaline co-injection
o Intravenous regional anaesthesia
 i.v. distal to pressure cuff [to keep the LA in that area]
 used vs Limb surgery
 Systemic toxicity of premature cuff release
 Risk of bolus release to systemic circulation
o Spinal anaesthesia
 Injected to sub-arachnoid space at L3 level: will act on the spinal roots
 Ie inject more to give effects at higher level
 Use vs Abdominal, pelvic, lower limb surgery
 Side effects:
 ↓ b.p. [presynaptic sympathetic neurons are also blocked]
 prolonged headache [if the anaesthetic diffuses up to the brain]
o Epidural anaesthesia
 Fatty tissue of epidural space: is acting on the spinal roots but prior to their
entry to the meninges
 Between the spinal dura and the walls of the canal is the epidural
space
 Uses as for Spinal anaesthesia: vs Abdominal, pelvic, lower limb surgery and
painless childbirth too
 Slower onset and need to use higher doses
 More localised action: less effect on b.p. and brain
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Pharmacokinetics
o Both well absorbed so both suitable as surface anaesthetics [cocaine use is
restricted to surface LA use]
o Lidocaine



Liver by Hepatic N-dealkylation
Longer half life
Plasma protein binding = 70%
o Cocaine



-
Liver and plasma by Non-specific esterases and cholinesterases
Shorter half life
Plasma protein binding = 90%
Unwanted effects
o Lidocaine is representative of most LAs
o Lidocaine


CNS [GABA most sensitive so initially is stimulation; at higher doses will be
depression]:
 stimulation
 restlessness, confusion
 tremor
CVS [Na+ channel blockade]
 ↓ HR: myocardial depression
 ↓ b.p.
 vasodilatation
o Cocaine [Sympathetic actions due to block of uptake 1; not due to its block of Na
channels which it does do as well (for the LA effects)]
 CNS
 Euphoria
 excitation
 CVS [are opposite to lidocaine]
 ↑ HR
 ↑ b.p.
 vasoconstriction
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15/01/14: Antiepilepsy Drugs (AEDs): Dr Michael Johnson
Los (from booklet):
• Explain what an epilepsy seizure is
• Explain what epilepsy is and identify its causes
• Recognise that anticonvulsant treatment decisions are based on a balance of risk and benefit.
• Identify the pharmacokinetic principles of prescribing, with reference to at least one important,
commonly used anti-epileptic drug.
• Identify the genetic associations with anti-epileptic drug-related hypersensitivity, and explain
how and why these are used in clinical practice.
Notes: [he isn’t setting the questions; see the Los above;
despite Los some drug names are on the essential drug list
but seems likely that this lec will not be heavily examined as
he avoids exam role etc]
Epilepsy:
-
-
-
Definitions [is an LO]
o Epilepsy is a physical condition defined as a tendency to recurrent, unprovoked
seizures
o An epileptic seizure is the manifestation of an abnormal and excessive synchronised
discharge of a set of cerebral neurones
Causes:
o Seizures and epilepsy may occur as a result of:
 A primary epileptic process
 (idiopathic epilepsy = genetic basis)
 Secondary to underlying disease processes
 (symptomatic epilepsy = pathological cause)
 brain injury, stroke, brain cancer, drug and alcohol misuse
Epilepsy seizure types:
o Generalised seizures
 impairs consciousness and distorts the electrical activity of the whole or a
larger portion of the brain
o Focal = partial seizures
 seizures which affect initially only one hemisphere of the brain
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Diagnosis of Epilepsy
o Can be difficult
o Up to 20% receiving AEDs misdiagnosed
o Diagnosis of epilepsy should be made by an epilepsy-competent specialist service
-
When to institute long-term treatment of epilepsy:
o Personal decision - involves careful consideration of potential harm from further
Seizures versus benefits and harms of antiepileptic drugs (AEDs)
o In general, do not treat after single unprovoked seizure unless:
 Seizure associated with appropriate structural lesion of the brain
 Seizure associated with clearly epileptiform EEG (focal or generalized spike
and sharp waves)
 Seizure is in the context of a progressive neurological disorder (e.g.,
Alzheimer)
o In general, do treat after 2 unprovoked seizures unless:
 diagnostic uncertainty (possible psycogenic basis or recurrent syncope)
 widely separated seizures (>1 year)
 the presence of clearly identifiable and avoidable provoking factors (e.g.,
alcohol intoxication/withdrawal)
 certain benign childhood epilepsy syndromes
-
Principals of AED therapy
o Be clear about indication for AED therapy [see above]
 Discuss risks and benefits with patient
o Always consider potential for drug interactions
 Effect of AED on other drugs (including other co-prescribed AEDs and OCP)
 Effect of other drugs on AED
o Never withdraw drugs suddenly
 Suddenly stopping these drugs can provoke a seizure or seizures
 Make one change at a time.
 If replacing, add-in before withdrawing other
-
OCP / Pregnancy:
o contraception is an issue with antiepileptics as can reduce OCP efficacy
o antiepileptics negatively impact on IQ of foetus and increase foetal malformation
risk
o however can’t stop medication without risk of death to mother!!
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Genetics: [is an LO]: HLA B – 1502 genotype:
o gives 15x greater risk of skin problem in response to Carbamazepine and phenytoin
 [gives Stevens–Johnson syndrome and toxic epidermal necrolysis]
o [is common in Han Chinese population]
-
Mech: Most existing antiepileptic drugs act by one or more of these mechanisms:
o Enhancing GABA mediated inhibition
o Reduce glutamate-mediated Excitation
o Inhibiting neuronal action potentials by blocking voltage-gated sodium channels.
o Blocking Neuronal Ca channels; ie by binding and blocking presynaptic Ca channels
-
Newer drugs are not more effective but are safer with fewer drug interactions
-
Some drug examples: [not in Los but are in essential drugs list so surely HTK!!]]
o Voltage-gated sodium channel inhibitors
 Phenytoin
 Carbamazepine
 Lamotrigine
o
GABA transaminase inhibitor [would otherwise inactivate GABA]
 Vigabatrin
o
Voltage-gated sodium channel inhibitor/GABA transaminase inhibitor
 Sodium valproate
o
GABA analogue
 Gabapentin
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Prob DHTK great detail on the below, just need to cover “know the
pharmacokinetic principles of prescribing”; however is useful info!
-
PHENYTOIN
o Complex pharmacokinetics
 Hepatic metabolism: oxidation, followed by hydroxylation then conjugation
 Potent P450 enzyme inducer - hence large number of important
drug interactions
 Saturatable kinetics:
o I.e., non-linear kinetics (rising quickly after point of enzyme
saturation)
o Blood drug levels increase suddenly once the enzymes are
saturated (also occurs in alcohol)
o Start low dose and incrementally increase
 Renal excretion metabolites
 If urgent, can load IV
 Highly (70-90%) protein bound (displacement by some drugs, low albumin
states)
o Indications:
 Partial seizures
 Secondary generalized seizures
 Status epilepticus
o Mechanism of action:
 Blockade of v-gated Na channels
o ADRs:
 Acute side effects:
 hypersensitive rash, fever, hepatitis, vasculitis
 Toxic side effects:[on target effects]:
 ataxia, dizziness, sedation, diplopia,
 Chronic side effects: [from chronic enzyme induction]: gingival hypertrophy,
folate deficiency, megaloblastic anaemia, vit K deficiency, depression,
hirsutism, peripheral neuropathy, osteomalacia (vit D) hypocalcaemia,,
myopathy, coagulation defects, bone marrow hypoplasia
o Effect of other drugs on PHENYTOIN: all increase PHT level!!
 Amiodarone, Isoniazid [TB medication]
 Potent inhibitors of PHT metabolism, lead to increased PHT levels
 Aspirin
 displaces PHT from protein binding - only a prob near satn
 Sodium Valproate
 displaces PHT from protein binding AND inhibits PHT metabolism.
Can result in PHT toxicity with normal total PHT levels (measure free
PHT levels with this drug combination). Avoid combination where
possible.
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o
-
Effect of PHT on other drugs
 Increases metabolism of Carbamazepine, Lamotrigine, (Sodium) Valproate
 WARFARIN
 Complex pharmacokinetics, increases clearance of warfarin with
chronic use. Monitor INRs closely after any change in PHT dose.
 Estrogen containing OCP [oral contraceptive pill]
 efficacy reduced (min 50ug eostradiol req)
Carbamazepine
o Indications:
 Partial seizures
 Secondary generalized seizures
o Mechanism of action:
 Blockade of v-gated Na channels
o Metabolism:
 Hepatic oxidation then conjugation.
 CBZ is a potent hepatic enzyme inducer
o Active metabolites:
 carbamazepine epoxide
o ADRs:
 Acute:
 Hypersensitive rash, hepatitis, nephritis, bone marrow suppression
 Toxic:
 ataxia, dizziness, sedation, diplopia
 Chronic: vit K & D deficiency, depression, impotence,
osteomalacia, hyponatraemia, bone marrow dyscrasias,
o Drug interactions
 Susceptible to its own induction (auto-induction)
 Steady state reached at about 1 month
 Effect of other drugs on CBZ
 PHENYTOIN, Phenobarbital
o induce CBZ metabolism  reduced CBZ
2+
 Ca channel blockers (diltiazem/verapamil)
o Massively elevate CBZ levels
 Valproate:
o 4-fold increase in CBZ-epoxide levels - inhibition of epoxide
hydrolase.
 Macrolide antibiotics (e.g., erythromycin)
o inhibit CBZ metabolism: can increase CBZ levels
 Effect of CBZ on other drugs
 Reduces levels of Lamotrigine, (Sodium) Valproate [not Phenytoin]
 OCP reduced efficacy
 Inc clearance / Reduced levels of Warfarin
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Lamotrigine
o Indications:
 Partial seizures
 Secondary generalized seizures
o Mechanism of action:
 Blockade of v-gated Na channels
o Metabolism:
 Hepatic glucuronidation
 No phase 1 metabolism
 No hepatic enzyme induction.
 so does not alter metabolism of warfarin
o ADRs:
 usually well tolerated, but high incidence of rash
o Drug interactions
 Effect of other drugs on LTG
 Enzyme inducing drugs (e.g., CBZ, PB, PHT)
o reduce half-life and lower LTG levels
 Valproate
o increases LTG levels
 OCP
o can lower LTG levels
 Effect of LTG on other drugs
 OCP
o reduced efficacy
-
(Sodium) Valproate
o Indications:
 Partial seizures
 Secondary generalized seizures
o Mechanism of action:
 Unclear, enhance GABA by a variety of mechanisms
o Metabolism:
 Hepatic oxidation and then conjugation.
 Potent inhibitor of hepatic enzymes
o ADRs:
 hepatic toxicity
 pancreatitis
o
Effect of VPA on other drugs
 VPA is a potent inhibitor of both oxidation and glucuronidation
 PHT, PB, LTG levels all increased
 CBZ-epoxide levels increased
 Effect of other drugs on VPA
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


Levels reduced by hepatic enzyme inducers (e.g., PHT, PB, CBZ)
Antacids
o may impair absorption
Aspirin
o displaces VPA from its albumin binding sites and may result
in toxicity
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15/01/14: Cytotoxic drugs: Dr Sohag Saleh
Los (from booklet):
• Summarise the epidemiological findings and main hallmarks of cancer
• Explain the actions of drugs used for adjuvant chemotherapy of colorectal cancer
• Explain the actions of drugs used for adjuvant chemotherapy of early non-small cell lung
cancer
• Explain the actions of drugs used for treatment of advanced non-small cell lung cancer
• Explain the actions of the cytotoxic drugs used for adjuvant chemotherapy of breast cancer
• Summarise the different categories of cytotoxic drugs
1. Summarise the epidemiological findings and main hallmarks of cancer
 Four most common cancers affect - Bowels, lungs, breasts & genitals
 Cancer cells - Grow independently & without limit. Generate their own blood supply
& can evade detection
2. Describe the actions of drugs used for adjuvant chemotherapy of colorectal cancer
 FUFA (5-fluorouracil & folinic acid) - Given as adjuvant treatment. 5-FU inhibits
thymidylate synthase
 Bevacizumab - Antibody directed against the VEGF
3. Describe the actions of drugs used for adjuvant chemotherapy of early non-small cell
lung cancer
 Platinum compounds (cisplatin) - Form DNA adducts
 Etoposide - Inhibits type II isomerase enzyme
 Gemcitabine - Inhibits the DNA polymerase enzyme
4. Describe the actions of drugs used for treatment of advanced non-small cell lung
cancer
 The taxanes (e.g. docetaxel) - Inhibit microtubule disassembly
 The vinca alkaloids (e.g. vinorelbine) - Inhibit microtubule assembly
 Erlotinib- Small molecule inhibitor of the epithelial growth factor receptor
Notes: 11 DRUGS!!; learn these NOT those on the essential drugs
list; he will make sure that it is these that are tested
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Cancer background
o Biology
 Cause - Uncontrolled proliferation & growth of abnormal cells
 Due to - Multiple genetic mutations
 Cancer cell characteristics:
 Self sufficient growth
 Angiogenesis
 Evasion of apoptosis
 Avoiding immune detection
 Limitless replication potential
o Epidemiology
 4 most common cancers affect:
 Digestive system (colorectal)
 Respiratory system (lung cancer)
 Genitalia (prostate)
 Breast
 Pancreatic cancer - Worst prognosis
-
Comparison of cancer staging prognoses b(r)est to worst(!):
o Breast  colorectal  lung
-
Colorectal cancer (CRC)
o Background
 Presentation
  60% due to colon cancer
 Mostly adenocarcinomas - from polyps
 Common symptoms - Rectal bleeding, change in bowel habits
 Biology
 25% due to genetic defects, e.g. familial adenomatous polyposis
(FAP)
 Risk factors - Inflammation, meat consumption & smoking
 Protective - High fibre diets, folic acid intake & NSAID use
 Non-pharmacological treatment
 Surgical resection
 Cornerstone of treatment
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o
o
Adjuvant chemotherapy [ie drug given before or after chemotherapy]
 Offered to all stage C patients who are able to tolerate drugs following
surgery
 Standard treatment
 5-fluorouracil & folinic acid (FUFA)
 Bevacizumab - Licensed as secondary treatment for metastatic CRC
In detail:
 5-fluorouracil

An antimetabolite pyrimidine analogue,
o  Interferes with thymidylate synthase enzyme involved in
dUMP  dTMP

The folinic
acid helps potentiate its effects: 5-fluorouracil +
folinic acid = FUFA
 Bevacizumab


Monoclonal antibody
inhibits vascular endothelial growth factor (VEGF) [ie binds the
actual ligand of the receptor]
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Non-small cell lung cancer
o Background
 Presentation
  80% of lung cancers cases = non-small cell lung cancer (NSCLC)
 Common symptoms - Haemoptysis, cough, shortness of breath
 Biology
 3 major NSCLC categories
 90% of cases are due to cigarette smoking
 Epidermal growth factor receptor (EGFR) mutations in ~15% of lung
cancer patients
 Non-pharmacological treatment
 Surgery - lobectomy or pneumonectomy
 Often combined with adjuvant chemotherapy and/or radiotherapy
 Adjuvant chemotherapy
 Given post-surgery  stage 2

Cisplatin (I-V)
o
o

Etoposide (oral)
o
o

Is a platinum-compound based therapy
Alkylating (-like) agent - covalently bonds with and
crosslinks DNA guanine residues forming adducts to prevent
replication of the DNA
Topoisomerase type II inhibitor
In this way DNA replication is prevented
Gemcitabine (I-V)
o

Anti-metabolite:
 Inhibits ribonucleotide reductase
 Inhibits DNA polymerase
 Incorporates into DNA causing chain termination
Advanced chemotherapy
 Add 3rd-generation drug :
o Docetaxel, paclitaxel, vinorelbine
 In EGFR mutants
o Erlotinib & gefitinib

Docetaxel
o

All the Taxanes [also include paclitaxel] work by preventing
microtubule disassembly
Vinorelbine (I-V)
o
o

(I-V)
Vinca alkaloid
inhibits microtubule assembly
Erlotinib (I-V)
o
o
Selective small molecule inhibitor of EGFR tyrosine kinase
Binds on intracellular side
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
o Is NOT an antibody
o Only effective in individuals with an EGFR mutation
5 year survival is the worst out of the cancers looked at in depth here (see
table below)
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Which is the mechanism of action of the antimetabolite, 5-fluorouracil?
o It is a folate antagonist
o It is a dioxyuridine monophosphate antagonist
o It is methyl tetrahydrofolate antagonist
o It inhibits the thymidylate synthase enzyme
o It inhibits the dihydrofolate reductase enzyme
Which receptor does the antibody bevacizumab bind to?
o Platelet derived growth factor receptor
o Epidermal growth factor receptor
o Vascular endothelial growth factor receptor
o CD220 receptor
o None of the above [binds to the ligand not the receptor]
Breast Cancer
o Background
 Presentation
 Common symptoms - lumps, shape change, skin dimpling, discharge
 Biology
 Gene expression patterns distinguish between four main types of
breast cancer
 Risk factors - Age, breast tissue density, alcohol & exposure to
oestrogen


Numerous gene mutations implicated - BRCA1, BRCA2 & TP53
Non-pharmacological treatment
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
o
Lumpectomy & radiotherapy or mastectomy & surgical
reconstruction
 Survival rates are good through the stages compared to the other cancers
that are looked at in this lecture (see table below)
Adjuvant chemotherapy
 Eostrogen receptor positive


o Antagonism at ER
Early node-positive


“Nitrogen mustard”
forms covalent bonds with DNA & RNA
Doxorubicin (I-V)


TAC regimen (Docetaxel, Doxorubicin & Cyclophosphamide)
Cyclophosphamide (I-V)



Hormone therapy (e.g. Tamoxifen)
‘Poison’ topoisomerase II by intercalating DNA [can still cut the DNA
but then remains attached due to the drug]
Trastuzumab (I-V) = Herceptin


Use vs Her2 + cancers
Monoclonal antibody acting at the HER-2/neu receptor [ie binds
the receptor!] [= Herceptin]
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Or to put another way:…
-
Cytotoxic drugs- nucleic acids
o Nucleic acid inhibitors
 Antimetabolites
o

A) 5-fluorouracil inhibits nucleic acid synthesis

B) Gemcitabine inhibits DNA polymerase
DNA replication inhibitors
 Topoisomerase inhibitors


DNA intercalators


C) Etoposide inhibits type II topoisomerases
D) Doxorubicin intercalates DNA & poisons type II
topoisomerase
Alkylating agents

E) Nitrogen mustards (Cyclophosphamide) form covalent
bonds with DNA

F) Platinum compounds (Cisplatin) form DNA adducts
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Cytoskeleton & Receptors
o Microtubule inhibitors
 Vinca alkaloids


Taxanes

o
G) Vinorelbine inhibits microtubule assembly
H) Docetaxel inhibits microtubule disassembly
TyR kinase receptor inhibitors
 Antibodies


I) Bevacizumab binds to VEGF

J) Trastuzumab binds to HER-2 receptor
Small molecules

K) Erlotinib inhibits epithelial growth factor receptor (EGFR)
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Which three drugs constitute the TAC regimen used in the treatment of early node positive
breast cancer ?
o 5-fluorouracil & folinic acid
o Docetaxel, doxorubicin & cyclophosphamide
o Cisplatin & etoposide
o Carboplatin & gemcitabine
o Trastuzumab, doxorubicin & cyclophosphamide
What is meant by topoisomerase II ‘poisoning’?
o The topoisomerase II can no longer bind to DNA
o The topoisomerase II can no longer cleave DNA
o The topoisomerase II is unable to unbind from DNA
o The topoisomerase II loses its enzymatic activity
o The topoisomerase II is only able to cleave one strand of DNA
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BONUS INFO:
 Cycloplegia is paralysis of the ciliary muscle of the eye
 Nitrous oxide inhibits muscular nicotinic acetylcholine receptors
 Misoprostol (prostaglandin analogue) is commonly co-prescribed with
chronic use of NSAIDS
 Absence seizures: a type of generalised seizure, characterized by a brief
loss and return of consciousness, generally not followed by a period of
lethargy
 The action of the 5-HT3 receptor is to efflux K+
 C Fibers carry dull burning pain in the lateral "neospinothalamic" tract
 A delta fibers carry sharp “fast” pain in the anterior,
"paleospinothalamic" tract.
 primary somatosensory cortex found at Postcentral gyrus
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