YEAR 2 PHARMACOLOGY
& THERAPEUTICS
ESSENTIAL DRUG LIST
Alexandra Burke-Smith
1. Drugs and the Autonomic
Nervous System
Overview of the ANS
Sympathetic NS = “fight or flight”, Parasympathetic NS = “rest + digest”
• NT = Ach + NA
• Ach Receptors: nicotinic + muscarinic cholinoceptors
•
•
•
Nicotinic = ionotrophic (ligand-gated ion channel)
Muscarinic – metabotrophic (G-protein)
Muscarinic subtypes:
•
•
•
•
M1 – neural (excitatory)
M2 – cardiac (inhibitory)
M3 – exocrine (excitatory)
NA receptors: adrenoceptors
•
•
•
•
A1 > PLC > IP3 + DAG > PKC + Ca2+
A2 >  cAMP >  PKA
B1 >  cAMP >  PKA
B2 >  cAMP >  PKA
Cholinomimetics
• “drugs which mimic the action of Acetylcholine
(Ach agonists)”
– Principally mimic parasympathetic NS
– Directly acting: choline esters + alkaloids that have
agonistic action at Ach receptors
– Indirectly acting: anticholinesterases that potentiate
the action of Ach; preventing its breakdown by
inhibiting acetylcholinesterase and/or
butyrylcholinesterase (plasma ezyme)
• Reversible = alkaloid carbamyl esters
• Irreversible = organophosphate compounds
Drug
Acetylcholine (choline ester; neurotransmitter)
Class
Directly acting cholinomimetic
Pharmacodynamics (MOA)
Agonist at nicotinic + muscarinic Ach receptors
(parasympathetic + sympathetic action)
Pharmacokinetics
Metabolism: cholinesterases
Duration of action: seconds
Notes:
No therapeutic use as non-selective and quickly degraded
Drug
Pilocarpine
Class
Directly acting cholinomimetic (alkaloid)
Pharmacodynamics (MOA)
Partial agonist at muscarinic Ach receptors
(parasympathetic activation)
Clinical Use
Treat glaucoma (contraction of ciliary muscle + sphincter
pupillae > miosis + improved drainage of aqueous humour)
Pharmacokinetics
Administration: locally as eyedrops
Half-life: 3-4 hours
Side Effects
Predicted by PNS actions:
Blurred vision, sweating, GI disturbance, hypotension,
respiratory distress
Drug
Bethanechol (choline ester)
Class
Directly acting cholinomimetic
Pharmacodynamics (MOA)
M3 (exocrine + smooth muscle) Ach receptor agonist
(parasympathetic action)
Clinical Use
Assist bladder emptying + enhance gastric motility
Pharmacokinetics
Orally active
Half-life 3-4 hours
Side Effects
Sweating, impaired vision, nausea, bradycardia,
hypotension + respiratory difficulty
Other Relevant Information:
Similar in structure to Ach; added methyl group means
resistant to degradation
Drug
Phyostigmine (alkaloid carbamyl ester)
Class
Indirectly acting cholinomimetic (reversible
anticholinesterase)
Pharmacodynamics (MOA)
Competitive inhibitor of cholinesterase enzyme (donates
carbamyl group which blocks active site) >
parasympethetic + sympathetic action (primarily acts on
PNS) by prolonging Ach activity
Clinical Use
Treatment of glaucoma
Treat atropine poisoning (Ach antagonist)
Pharmacokinetics
Half-life 30 minutes (carbamyl group removed by slow
hydrolysis)
Drug
Ecothipate (organophosphate compound)
Class
Indirect cholinomimetic (irreversible anticholinesterase)
Pharmacodynamics (MOA)
inhibitor of cholinesterase enzyme (reacts with enzyme
active site; blocking it with stable group ) >
parasympethetic + sympathetic action (primarily acts on
PNS) by prolonging Ach activity
Clinical Use
Treatment of glaucoma
Pharmacokinetics
Administered as eye drops
Duration of action weeks (new cholinesterase enzyme
must be synthesised)
Side Effects
Sweating, blurred vision, GI pain, bradycardia,
hypotension, respiratory difficulty
Cholinoceptor Antagonists
• “drugs which show affinity but no efficacy at
Ach receptors, thus preventing agonists from
transducing a response and activating
intracellular signalling pathways”
Drug
Hexamethonium
Class
Nicotinic receptor antagonist
Pharmacodynamics (MOA)
Competitive antagonistic action at all autonomic ganglia
Clinical Use
First anti-hypertensive (inhibition of sympathetically driven
kidneys + blood vessels)
No longer used clinically
Side Effects
Parasympethetically driven side-effects (ie what happens
when you block the PNS)
Loss of bladder control, pupil dilation, loss of GI motility +
secretions
Drug
Trimetaphan
Class
Nicotinic cholinoceptor antagonist
Pharmacodynamics (MOA)
Ganglion blocking drug; not technically a nicotinic receptor
antagonist, but blocks ion channels (use-dependent block;
more agonist > more block)
Clinical Use
Controlled hypotension during surgery
Pharmacokinetics
IV administration
Duration of action 2-3 minutes
Drug
Atropine
Class
Competitive muscarinic cholinoceptor antagonist
Pharmacodynamics (MOA)
Competitively inhibits parasympethetic (+ sympathetic)
action at mAChR
Clinical Use
Anaesthetic premedication (dilate bronchi, dry throat +
reduce lung secretion > easier to administer gas mask +
reduced aspiration risk)
Treatment of sinus bradycardia (normal, slow rhythm)
Pharmacokinetics
Oral administration
Hepatic metabolism
Duration of action 2-3 hours
Side Effects
Dry mouth, blurred vision, urinary retention, pupil
dilation, irritability, hyperactivity
Other relevant information:
NB: atropine poisoning may occur in children who eat the
deadly nightshade. This is treated with phyostigmine (see
earlier)
Drug
Hyoscine
Class
Competitive muscarinic cholinoceptor antagonist
Pharmacodynamics (MOA)
Competitively inhibits parasympethetic (+ sympathetic)
action at mAChR
Clinical Use
Anaesthetic premedication (dilate bronchi, dry throat +
reduce lung secretion > easier to administer gas mask +
reduced aspiration risk)
Treatment of sinus bradycardia
Motion sickness (reduces flow of information from
Labyrinth to vomiting centre)
Parkinsons (reduces inhibitory effect of M4 receptors on
dopamine signalling)
Pharmacokinetics
Administered orally or transdermally
Duration of action 2-3 hours
Side Effects
Decreased sweating, reduced secretions, blurred vision,
agitation, restlessness, confusion
Drug
Tropicamide
Class
Competitive muscarinic cholinoceptor antagonist
Pharmacodynamics (MOA)
Acts on M3 receptors within the iris of the eye to cause
pupil dilation (reduces ciliary + sphincter pupillae
constriction)
Clinical Use
Dilation of pupil for retina examination
Pharmacokinetics
Administered as eye drops
Side Effects
Dry mouth, blurred vision, urinary retention
Drug
Ipratropium Bromide
Class
Competitive muscarinic cholinoceptor antagonist
Pharmacodynamics (MOA)
Antagonism removes PNS bronchostrictor effect in lungs
Clinical Use
Used to treat asthma and COPD
Pharmacokinetics
Administered as aerosol
Other Relevant Information:
Quaternary amine structure localises response as positive
charge prevents crossing of lipid membrane in lungs
Sympathomimetics
• SNS agonists
• Act on adrenoreceptors of post-ganglionic SNS
neurons
• Directly acting: mimic actions of NA/A by binding and
stimulating adrenoceptors – used principally for
actions in CVS, eyes + lungs
• Indirectly acting: act at the adrenergic nerve terminal
as opposed to adrenoceptor
Class
Directly acting sympathomimetic
Pharmacodynamics (MOA)
Non-selective (alpha + beta) agonists acting at
adrenoceptors of SNS
Clinical Use
Anaphylaxis:
• B2 action = dilation of skeletal blood vessels > decreased
TPR, bronchodilation + reduced inflammatory mediator
production
• A1 action = profound subcutaneous vasoconstriction >
increased BP
• B1 action = positive chronotropic + inotropic
COPD
Acute heart block
Anaesthesia (vasoconstriction used to localise effect)
Glaucoma (a1 mediated vasoconstriction + B mediated
decreased aqueous humour production)
Pharmacokinetics
Administered IV, IM or locally (eye drops)
Poorly absorbed
Duration of action minutes
Metabolised by MAO-A (uptake 1) and COMT (uptake 2)
Side Effects
Dry mouth, tachycardia, arrythmias, cold extremities,
hypertension, tremor, palpitations
Drug
Phenylephrine
Class
Directly acting Alpha-1 selective sympathomimetic
Pharmacodynamics (MOA)
Selective action on alpha-1 adrenoceptors
Clinical Use
Stop superficial bleeding (vasoconstrictor)
Mydriasis (a1 adrenoceptors > radial muscle constriction
> pupil dilation)
Nasal decongestant (reduced secretions)
Pharmacokinetics
Administered as eye drops, IV, intranasal
Duration of action minutes
Broken down by MAO
Other Relevant Information:
Chemically related to adrenaline, but more resistant to
COMT
Drug
Clonidine
Class
Directly acting Alpha-2 selective sympathomimetic
Pharmacodynamics (MOA)
Agonistic action at alpha-2 adrenoceptors. A2 receptors
present pre-synaptically; act to autoinhibit release of
noradrenaline/adrenaline (reduce SNS action)
Clinical Uses
Treatment of hypertension + migraine. Reduces sympathetic
tone via central action in brainstem within the baroreceptor
pathway (reduced pre-synaptic release of NA)
Pharmacokinetics
Orally active
Duration of action hours
Broken down by COMT + MAO-A
Drug
Isoprenaline
Class
Directly acting non-selective B adrenoceptor agonist
Pharmacodynamics (MOA)
Acts to potentiate action of NA/A on beta adrenoceptors
Clinical Uses
Treat heart block
Pharmacokinetics
IV administration
Broken down by COMT
Duration of action hours
Side Effects
Fatal reflex tachycardia/dysrhythmias
Other relevant information
Difference in structure to adrenaline means less susceptible
to metabolism by MAO-A
Drug
Dobutamine
Class
Directly acting beta-1 selective adrenoceptor agonist
Pharmacodynamics (MOA)
Potentiates NA/A action at beta-1 receptors
Clinical Uses
Acute heart block
Pharmacokinetics
Administered IV
Half-life 2 minutes
Rapidly metabolised by COMT
Other relevant information
Lacks isoprenaline’s reflex tachycardia due to lack of B2
action
Drug
Salbutamol
Class
Directly acting beta-2 selective sympathomimetic
Pharmacodynamics (MOA)
Agonistic action at beta-2 adrenoceptors
Clinical Uses
Asthma (relaxation of bronchial smooth muscle + inhibition
of pro-inflammatory mediator release from mast cells)
Treatment of threatened uncomplicated premature labour
(relaxes uterus)
Pharmacokinetics
Administration via inhalation (ventolin) or IV (for premature
pregnancy)
Duration of action hours
Side Effects
Some reflex tachycardia, tremor
Contraindications
Patients with diabetes (B2 receptors mobilise glycogen)
Other relevant information
Relative resistance to metabolism by MAO and COMT
Drug
Cocaine
Class
Indirectly acting sympathomimetic
Pharmacodynamics (MOA)
Acts to prevent uptake 1 (no MAO metabolism) so there is
greater concentration of catecholamines in synaptic cleft
Pharmacokinetics
Well absorbed from all sites + crosses BBB
Metabolised by plasma esterases + hepatic enzymes
Half-life 30 mins
Excreted in urine
Side Effects
CNS: excitement + increased motor activity
Activation of vomiting centres, tremors, convulsions
CVS: tachycardia, vasoconstriction and hypertension
Drug
Tyramine (dietary amino acid found in cheese, red wine +
soy sauce)
Class
Indirectly-acting sympathomimetic
Pharmacodynamics (MOA)
Some weak agonistic activity at post-synaptic adrenoceptors +
competitive inhibition of uptake 1
Also displaces NA from intracellular vesicles, therefore
increased cytosolic [NA] > leakage into synaptic cleft
Pharmacokinetics
Extensive first pass metabolism
Side Effects
Under normal conditions, no effect as undergoes extensive
first pass metabolism
However when MAOs are inhibited (eg use of
antidepressants), ingestion of foods containing tyramine may
cause hypertensive crisis known as CHEESE REACTION
SNS Antagonists
• Act with antagonistic action at adrenoceptors
• These may be:
– Non-selective
– Non-selective alpha
– Alpha 1 selective
– Non selective beta
– Beta 1 selective
Drug
Labetalol
Class
Directly acting Non-selective b1 and a1 SNS antagonist
Pharmacodynamics (MOA)
Antagonism > block of SNS activity
Clinical Uses
Hypertension (decreased renin secretion + peripheral
subcutaneous vasoconstriction > decreased peripheral
resistance)
Pharmacokinetics
Broken down by COMT + MAO-A
Other relevant information
No long-term change in heart rate or cardiac output
Drug
Propanolol
Class
Directly acting Non-selective B-adrenoceptor antagonists
Pharmacodynamics (MOA)
B-blocker > reduced SNS effects
Clinical Uses
Hypertension (reduced effect of exercise or stress)
Anti-arrythmic (class II)
Pharmacokinetics
Orally active
Broken down by COMT + MAO-A
Duration of action hours
Side Effects
Bronchoconstriction, hypoglycaemia (loss of warning signs
for diabetics eg palpitations), fatigue, cold extremities, bad
dreams
Contraindications
Asthma
Other relevant information
Little cardiac effects at rest
Drug
Atenolol
Class
B1 selective (cardioselective)
Directly actingBb1-selective
blocker
SNS antagonist
Pharmacodynamics (MOA)
Competitive antagonist
“cardioseelctive”
at B1 adrenoceptors
– antagonises
in heart,
the effect
thusof
preventing action
noradrenaline
of NA (negative
on the
ionotropic
heart + chronotropic
effect)
Angina, post MI,Hypertension
cardiac dysrythmias, chronic heart failure,
Angina
hypertension
Clinical
Clinical Uses
Uses
Pharmacokinetics
Side Effects
Contraindications
Other relevant information
Atenolol
down
by COMT and MAO-A
Clinical doses > Broken
action on
B2 receptors:
Worsening of cardiac failure
Bradycardia, bronchoconstriction, hypoglycaemia, fatigue,
Asthma (despite less b2 effect)
cold extremities, CNS effects eg nightmares
Also use in glaucoma, migraine, benign essential tremor
Not first line treatment for hypertension as does not reduce
TPR
Drug
Phentolamine
Class
Directly acting Non-selective alpha-adrenoceptor antagonist
Pharmacodynamics (MOA)
Blockade of a1 receptors > vasodilation > fall in TPR + BP
Blockade of a2 receptors > loss of inhibition of pre-synaptic
NA release
Clinical Uses
No longer used clinically
Side Effects
Postural hypotension, diarrhoea, reflex tachycardia
Drug
Prazosin
Class
Directly acting a1 selective adrenoceptor antagonist
Pharmacodynamics (MOA)
Blockade of a1 > vasodilation > fall in TPR + BP (less reflex
tachycardia)
Clinical Uses
Antihypertensive (minor use in associated dislipidaemia)
Pharmacokinetics
Broken down by COMT + MAO-A
Side Effects
Hypotension
Modest decrease in LDL, increase in HDL
Other relevant information
Lack of a2 blockade > no change in synthesis and release of
NA
Drug
Methyldopa
Class
SNS false transmitter
Pharmacodynamics (MOA)
Indirectly acting adrenoceptor antagonist; in the same way
that DOPA is taken up and packaged into vesicles,
methyldopa is packaged and hydroxylated to form false NT
alpha-methyl-noradrenaline
A-m-NA is released into the synaptic cleft, but has greatest
activity on alpha 2 receptors to reduce NT release.
Clinical Uses
Antihypertensives (in patients with renal insufficiency) as
maintains renal blood flow. Also in pregnancy-related
hypertension, as no effect on foetus.
Side Effects
Dry mouth, sedation, orthostatic hypotension
Other relevant information
Not deaminated by MAO-A, therefore accumulates in
synaptic cleft
Neuromuscular Blocking Drugs
• Drugs which act at the NMJ To prevent
depolarisation of the motor end-plate
– Non-depolarising: competitive antagonsts
– Depolarising: agonists
Drug
Tubocurarine
Class
Non-depolarising NM blocking drug
Pharmacodynamics (MOA) Competitive nicotinic Ach receptor antagonist which produces a graded block
of somatic NMJs
Clinical Uses
Surgery (reduces amount of anaesthetic required + allows for artificial
ventilation)
Pharmacokinetics
Administered IV
Doesn’t cross BBB or placenta
Onset of action within 2-3 mins
Duration of action 40-60 mins
Not metabolised, excreted in bile + urine
Side Effects
Flaccid paralysis (onset in order…)
1. Extrinsic eye muscles > double vision
2. Small muscle paralysis of face, limbs + pharynx
3. Respiratory muscle paralysis
Unwanted effects:
Ganglion block + histamine release from mast cells > decreased TPR +
bronchospasm
Contraindications
Renal/hepatic impairment
Other relevant
information
Naturally occurring quaternary ammonium alkaloid
Reversed by anticholinesterases; recovery of movement is in reverse order to
effects
Drug
Atracurium
Class
Non-depolarising NM blocker
Pharmacodynamics (MOA)
Competitive nAChR antagonist (somatic NMJ blocked)
Pharmacokinetics
Shorter duration of action than Tubocurarine
Drug
Suxamethonium
Class
Depolarising NM blocker
Pharmacodynamics (MOA)
Post-synaptic nAChR agonist, therefore causes prolonged
excitation. This prevents new action potential generation,
thus inactivating ion channels (somatic NMJ blocked)
Pharmacokinetics
Degraded by butyrylcholinesterases (plasma enzyme)
Duration of action mins (use in short term endotracheal
intubation)
Other relevant information
Structure related to acetylcholine
Different to HEXAmethonium = nAChR antagonist
2. Drugs and the
Cardiovascular System
RAAS
• RAAS = renin angiotensin aldosterone system
– Primarily responsible for fluid + BP regulation
• Drugs interfering with RAAS:
– ACE inhibitors
– Angiotensin II receptor antagonists (ARB)
– Renin inhibitors, eg Aliskiren (no significant clinical
experience)
Drug
Enalapril
Class
ACE inhibitor
Pharmacodynamics (MOA)
Inhibits the somatic form of ACE, thus preventing the
conversion of Ang I > Ang II
Clinical Uses
Used in conditions which confer increased CV risk:
Hypertension, heart failure, post MI, diabetic nephropathy,
progressive renal insufficiency
Side Effects
Hypotension, dry cough, urticaria + angioedema,
hyperkalemia, fetal injury, renal failure (in patients with renal
artery stenosis)
Other relevant information
Germline form of ACE is significantly different, therefore not
affected
Drug
Captopril
Class
ACE inhibitor
Pharmacodynamics (MOA)
Inhibits the somatic form of ACE, thus preventing the
conversion of Ang I > Ang II
Clinical Uses
Used in conditions which confer increased CV risk:
Hypertension, heart failure, post MI, diabetic nephropathy,
progressive renal insufficiency
Side Effects
Hypotension, dry cough, urticaria + angioedema,
hyperkalemia, fetal injury, renal failure (in patients with renal
artery stenosis)
Other relevant information
Germline form of ACE is significantly different, therefore not
affected
Drug
Losartan
Class
Angiotensin Receptor Blocker
Pharmacodynamics (MOA)
Non-competitive Antagonist of type 1 receptors for Ang II,
thus preventing renal and vascular actions of Ang II
Clinical Uses
Hypertension, chronic heart failure
Side Effects
Hypotension, hyperkalemia, fetal injury, renal failure (in
patients with renal artery stenosis)
Other relevant information
Fewer side effects than ACE inhibitors
Calcium Antagonists
• Rise in intracellular calcium key step in excitationcontraction coupling in both cardiac and vascular
myocytes
• Involves L-type voltage-dependent calcium
channel
• 2 classes of calcium channel blockers (CCBs)
– Rate limiting (bind to IC domain of receptor; exert
both cardiac and smooth muscle effects)
– Non-rate slowing (bind to EC domain of receptor;
exerts only smooth muscle action), eg amlodipine
Drug
Verapamil
Class
Rate-limiting calcium channel blocker
Pharmacodynamics (MOA)
Binds to the intracellular domain of L-type calcium channel
receptor, blocking influx of calcium
• Negative chronotropic + ionotropic effects on heart and
smooth muscle
Clinical Uses
Angina (arising from IHD)
Antidysrhythmias
Pharmacokinetics
Oral administration
Duration of action 6-8 hours
Hepatic metabolism
Side Effects
Bradycardia, AV block, negative ionotropic effect (worsening of
HF), constipation (effect on GI smooth muscle)
Drug
Diltiazem
Class
Rate-limiting calcium channel blocker
Pharmacodynamics (MOA)
Binds to the intracellular domain of L-type calcium channel
receptor, blocking influx of calcium
• Negative chronotropic + ionotropic effects on heart and
smooth muscle
Clinical Uses
Angina (arising from IHD)
Antidysrhythmias
Pharmacokinetics
Oral administration
Duration of action 6-8 hours
Hepatic metabolism
Side Effects
Bradycardia, AV block, negative ionotropic effect (worsening
of HF), constipation (effect on GI smooth muscle)
Beta Blockers
• Sympathetic neurons innervating cardiac
muscle release NA on depolarisation
• NA acts on B1 receptors on cardiac myocytes,
to increase heart rate, contractility and
excitability
• Competitive antagonists, ie beta blockers, thus
tend to have a negative chronotropic and
ionotropic effect
Drug
Atenolol
Class
B1 selective (cardioselective) B blocker
Pharmacodynamics (MOA)
Competitive antagonist at B1 adrenoceptors in heart, thus
preventing action of NA (negative ionotropic + chronotropic
effect)
Clinical Uses
Angina, post MI, cardiac dysrythmias, chronic heart failure,
hypertension (not first line for hypertension as no TPR
effect)
Side Effects
Clinical doses > action on B2 receptors:
Worsening of cardiac failure
Bradycardia, bronchoconstriction, hypoglycaemia, fatigue,
cold extremities, CNS effects eg nightmares
Other relevant information
Also use in glaucoma, migraine, benign essential tremor
Not first line treatment for hypertension as does not reduce
TPR
Organic Nitrates + Related Agents
• Organic nitrite is absorbed (particularly in
SMC), where it undergoes degradation into
nitrite free radical, then converted to nitric
oxide
• Nitric oxide is an endogenous vasodilator; it
acts on guanylate cyclase to increase cGMP
production
• cGMP then acts to vasodilate the smooth
muscle
Drug
Glyceryl Trinitrate
Class
Nitrate
Pharmacodynamics (MOA)
Directly causes release of NO in smooth muscle cells, as well as
minor release in platelets. Vasodilation reduces venous return
and total peripheral resistance, thus reduces preload and
afterload, and therefore the heart does not need to work as
hard
Clinical Uses
Angina
Heart failure
BP control during anaesthesia (easy to titrate)
Pharmacokinetics
Undergoes extensive first pass metabolism by the liver,
therefore administered sublingually for rapid relief, or via
transdermal patch for long term use
Half life approx 5 mins
Side Effects
Vasodilation > hypotension, headaches, flushing
Other relevant information Long term use associated with tolerance; one of the reasons
GTN is used for immediate relief
Often used in conjunction with beta blockers for treatment of
angina
Drug
Nicorandil
Class
Nitrate; stimulates guanylate cyclase to cause vasodilation
Pharmacodynamics (MOA)
Guanylate cyclase acts to increase cGMP production, which
causes myocyte vasodilation
Clinical Uses
Used to increased oxygen supply to coronary vessels, and
increase venous capacitance (often post MI)
Pharmacokinetics
Hepatic metabolism
Side Effects
Vasodilation > hypotension, headaches, flushing
Reflex tachycardia
Anti-dysrhythmics
• Arrythmias/dysrhythmias = abnormalities of
cardiac rhythm
• Classified according to association with heart
rate (tachy = increase, brady = decrease), and
site of origin:
– Supraventricular: arise from atria and conduction
tissue
– Ventricular: arise from ventricles
– Complex: multiple sites of origin
Drug
Amiodarone
Class
Antidysrhythmic
Pharmacodynamics (MOA)
Wide spectrum anti-dysrhythmic with complex MOA involving
multiple ion channel blocks
Clinical Uses
Supraventricular + ventricular arrythmias
Pharmacokinetics
Half life 10-100 days
Side Effects
Accumulates in the body, therefore number of adverse
effects: photosensitive skin rash, hypo/hyperthyroidism,
pulmonary fibrosis
Drug
Diltiazem
Class
Rate-limiting calcium channel blocker (class IV antiarrhythmic)
Pharmacodynamics (MOA)
Binds to the intracellular domain of L-type calcium channel
receptor, blocking influx of calcium
• Negative chronotropic + ionotropic effects on heart and
smooth muscle
Clinical Uses
Angina (arising from IHD)
Tachyarrythmias
Pharmacokinetics
Oral administration
Duration of action 6-8 hours
Hepatic metabolism
Side Effects
Bradycardia, AV block, negative ionotropic effect (worsening of
HF), constipation (effect on GI smooth muscle)
Drug
Verapamil
Class
Rate-limiting calcium channel blocker
Pharmacodynamics (MOA)
Binds to the intracellular domain of L-type calcium channel
receptor, blocking influx of calcium
• Negative chronotropic + ionotropic effects on heart and
smooth muscle
Clinical Uses
Tachyarrythmias
Pharmacokinetics
Oral administration
Duration of action 6-8 hours
Hepatic metabolism
Side Effects
Bradycardia, AV block, negative ionotropic effect (worsening
of HF), constipation (effect on GI smooth muscle)
Drug
Digoxin
Class
Cardiac glycoside
Pharmacodynamics (MOA)
CVS: Inhibition of Na-K ATPase > accumulation of intracellular
Ca2+ via Na/Ca exchanger = positive ionotropic
CNS: increased vagal outflow > increased refractory period +
reduced rate of conduction through AVN = negative
chronotropic
Clinical Uses
Atrial fibrillation
Pharmacokinetics
T ½ 40 hours
Narrow therapeutic index
Side Effects
New dysrhythmia, eg AV conduction block
Other relevant information
AF may cause thrombus formation in the atrium; embolus to
the brain may cause a stroke
High risk of digoxin toxicity; treated with immune Fab
digibind, which “mops up” excess
Other Cardiac Drugs
Drug
Doxazosin
Class
Competitive alpha-1 adrenoceptor antagonist
Pharmacodynamics (MOA)
Competes with NA for active site of alpha-1 adrenoceptors,
thereby preventing vasoconstrictor action > coronary
vasodilation
Clinical Uses
Used in conjunction with antihypertensives in resistant
hypertension
Side Effects
Increased rate of chronic heart failure
Drug
Sumitriptan
Class
5HT1D receptor agonist
Pharmacodynamics (MOA)
Acts on seratonin receptor to inhibit trigeminal nerve
transmission and constrict cerebral and coronary arteries
Clinical Uses
Treatment of migraine
Contraindications
Coronary disease – causes coronary vasoconstriction
Anti-Thrombotics + Anti-Coagulants
• Drugs that interfere with normal haemostasis and thrombosis
pathways
• Haemostasis: the essential physiological process where blood
coagulation prevents excess blood loss
• Thrombosis: the pathophysiological process where blood
coagulation occurs within an INTACT blood vessel and obstructs
blood flow
– venous thrombosis = red thrombi (high fibrin)
– Arterial thrombosis = white thrombi (high platelet)
• Virchow’s triad (addresses why thrombi may form):
– Rate of blood flow – slow/stagnating
– Consistency of blood – viscous [more procoagulation factors]
– Blood vessel wall integrity – atherosclerotic
• Drugs that target = anti-coagulants, anti-platelets, thrombolytics
Anti-Coagulants
• Target the initial phase of the clotting cascade,
which occurs following tissue factor exposure
• 4 types of drugs:
– Direct thrombin inhibitors, eg Hirudin
– Heparin + derivatives
– Factor Xa inhibitors
– Vitamin K antagonists
Drug
Heparin
Class
Anti-coagulant
Pharmacodynamics (MOA)
Natural anti-coagulant found on mast cells in the body;
exerts a conformational change which activates
antithrombin III, potently inactivating thrombin
Clinical Uses
Immediate anticoagulation in venous thrombosis +
pulmonary embolism
Pharmacokinetics
Heparin = continuous infusion, short half life
LMW derivatives = longer half life, not orally available but
only require regular administration
Side Effects
Haemorrhage, hypersensitivity reactions,
thrombocytopenia, osteoporosis, hypoaldosteronism
Other relevant information
Derivatives also inhibit Factor X, therefore preventing
formation of prothrombinase complex
To reverse effects. Promatine can be given IV (forms
inactive complex)
Drug
Warfarin
Class
Vitamin K antagonist (anti-coagulant)
Pharmacodynamics (MOA)
Vitamin K is essential for clotting factor synthesis, therefore
prevents normal clotting cascade
Clinical Uses
Long term anticoagulation following thrombosis or MI
Pharmacokinetics
Oral administration
Delayed onset of action (5 days)
Narrow therapeutic window, strongly plasma protein bound
Side Effects
Haemorrhage, teratogenic
Other relevant information
Numerous drug interactions which make pharmacokinetics
more complex – requires INR monitoring. This is because
highly plasma protein bound therefore changes in pp binding
affect bioavailability
Anti-Platelets
• Used in CV disease as thrombosis prevention
• If AT-III does not inactivate thrombin, thrombin activates
platelets > production of clotting factors and ADP
– Thrombin also releases endothelial bound vWF, which activates
factor II > IIa (thrombin)
• ADP acts on active platelets via P2Y receptors, leading to
platelet aggregation and formation of a clot
• Anti-platelets include:
–
–
–
–
PAR antagonists (protease activated receptor)
ADP receptor antagonists
COX inhibitors
Glycoprotein Iib/IIIa receptor antagonists
Drug
Clopidogrel
Class
ADP receptor antagonist
Pharmacodynamics (MOA)
Prevents platelet plug formation. ADP binding leads to the
expression of GpIIb/IIIa, which act as a molecular glue for
the formation of the unstable plug
Clinical Uses
Anti-platelet
Pharmacokinetics
Oral administration
Other relevant information
Drug of choice in aspirin-sensitive patients
Drug
Apirin
Class
COX inhibitor
Pharmacodynamics (MOA)
PAR activation liberates arachidonic acid. The action of COX
on arachidonic acid in platelets generates thromboxane-A2
(pro-coagulant), therefore prevents this
Clinical Uses
Anti-platelet
Pharmacokinetics
Administered orally at low dose (75mg)
Side Effects
Reyes syndrome, bronchospasm, GI bleeding and stomach
ulcers
Contraindications
Children under 16, haemophiliacs, asthmatics
Drug
Abciximab
Class
Glycoprotein IIb/IIIa antagonist
Pharmacodynamics (MOA)
ADP receptor binding + thromboxane A2 lead to expression
of GpIIb/IIIa. These act as a molecular glue in the formation
of unstable platelet plug
Clinical Uses
Anti-platelet
Treatment of thrombotic disorders
Pharmacokinetics
IV administration
Other relevant information
Only single use, therefore used in high risk patients
Thrombolytics
• Large scale thrombin converts fibrinogen to
fibrin.
• Fibrin strands wrap around the clot, with the
eventual formation of a thrombus within the
intact blood vessel
• Fibrinolytics are effective at removing preformed clots. They convert plasminogen to
plasmin, a natural protease that digests fibrin
strands
Drug
Alteplase
Class
Thrombolytic/fibrinolytic/clot buster
Pharmacodynamics (MOA)
Recombinant tissue type plasminogen activator (tPA) >
degradation of fibrin clot and release of fibrin degradation
products
Clinical Uses
Acute MI and ischaemic stroke
Pharmacokinetics
IV short infusion
Duration of action hours
Other relevant information
Needs to be given within 12 hours of symptom onset
Drug
Streptokinase
Class
Thrombolytic/fibrinolytic/clot buster
Pharmacodynamics (MOA)
Bacterial product that binds to plasminogen, causing a
conformational change that exposes the active site
Clinical Uses
Reduce mortality from acute MI
Pharmacokinetics
IV short infusion
Half life 3-4 hours
Side Effects
Bleeding, GI haemorrhage, stroke
Other relevant information
Tolerance develops after first administration; develop
immunity to bacterial antigens
Cholesterol Drugs
• Hypercholesteramia is a key risk factor in the
development of atherosclerosis
• LDL cholesterol is the primary target to prevent
atherosclerotic plaques + CHD
• Different classes of drugs include:
–
–
–
–
Statins
Bile acid sequestrants
Nicotinic acid
Fibrates
• Triglycerides are also associated with an increased risk
of CHD, therefore are an important target. However
this mechanism is not fully understood
Statins
• First-line drugs in treatment of dyslipidaemias
• MOA: inhibition of HMG-CoA reductase (ratelimiting enzyme in cholesterol synthesis)
• In response to this…
– Hepatocytes up-regulate/increase number of LDL
receptors, increasing binding and removal of LDL
cholesterol from the plasma
– Increase in HDL cholesterol (mechanism not fully
understood)
Drug
Simvastatin
Class
Statin
Pharmacodynamics (MOA)
HMG-CoA reductase inhibitor – inhibits cholesterol
synthesis. Effects include:
• Raised HDL
• Lowered LDL
• Formation of plaque stabilisers
Clinical Uses
Hypercholesteramia, dyslipidaemia
Pharmacokinetics
Oral administration
Hepatic metabolism
Half life 1-2 hours
Side Effects
Caused by non-selective effects on body (target organ is
liver)
Other relevant information
COCHRANE review has shown reservation in use of statins in
primary prevention
3. Diuretics
Diuretics
• Drugs that act on the renal tubule to promote an increased loss of
water in the urine = diuresis
• Gross structure of renal tubule can be divided into 4 sections:
– Proximal convoluted tubule
– Loop of Henle (descending and ascending limb)
– Distal convoluted tubule
– Collecting duct
• There are 5 main classes of diuretics, each with a different MOA:
– Osmotic diuretics – act on entire kidney tubule
– Carbonic anhydrase inhibitors – act principally on PCT
– Loop diuretics – act on ascending limb of LOH
– Thiazides – act on early DCT
– Potassium sparing diuretics – act on late DCT and collecting duct
Drug
Mannitol
Class
Osmotic diuretic
Pharmacodynamics (MOA)
Pharmacologically inert substance which is freely filtered into
kidney lumen, but poorly reabsorbed. Therefore increases
osmolarity of kidney filtrate, and decreases water absorption
where the nephron is freely permeable to water (PCT,
descending LOH, CT)
Clinical Uses
Prevention of acute renal failure
Decreasing intra-cranial pressure, intraocular pressure
Pharmacokinetics
IV administration
Side Effects
Increased ECF volume > hyponatremia. This may cause
nausea, vomiting, headache + pulmonary oedema
Carbonic Anhydrase Inhibitors
Drug
Acetazolamide
Class
Carbonic anhydrase inhibitor
Pharmacodynamics (MOA)
Inhibits action of CA, therefore increasing bicarbonate and
sodium loss in the PCT. This reduces water reabsorption in the
PCT as well as the CT
Clinical Uses
Renal stones
Metabolic alkalosis
Decreasing intra-ocular pressure (glaucoma)
Altitude sickness
Side Effects
Hypokalemia, reduced H+ excretion > alkaline urine +
metabolic acidosis
Other relevant information
Relatively weak; only act on PCT and further reabsorption of
sodium occurs in later nephron
Loop Diuretics
Drug
Frusemide
Class
Loop diuretic
Pharmacodynamics (MOA)
Acts to block the Na+-2Cl--K+ co-transporter on the apical
membrane of the ascending limb, thus reducing the
osmolarity of the medullary interstitium > less water
reabsorption in descending limb + 15-30% more filtrate loss
Clinical Uses
Oedema (HF, pulmonary, renal, hepatic or cerebral)
Moderate hypertension
Hypercalcaemia, hyperkalemia
Pharmacokinetics
Oral or IV administration
Half life 3-6 hours
Excreted unmetabolised by kidney
Side Effects
Hypokalaemia, metabolic alkalosis, hypocalcaemia, and
possibly hypotension, nausea and vomiting, and may induce
an allergic reaction.
Thiazides
Drug
Bendrofluazide
Class
Thiazides
Pharmacodynamics (MOA)
Blocks Na/Cl co-transporter in early DCT, thus increasing
osmolarity of tubule lumen and Na+ delivery to late DCT and
CT. This results in decreased water reabsorption, increased
K+ loss, increased Mg2+ and Ca2+ reabsorption
Clinical Uses
Hypertension
Cardiac failure, resistant oedema, nephrogenic diabetes
insipidus (pradoxical effect here = anti-diuretic effect)
Pharmacokinetics
Oral administration
Half life 24 hours
Side Effects
Hypokalemia
metabolic alkalosis
Diabetes mellitus
Other relevant information
Mild diuretic – first line treatment of hypertension in the
elderly
Potassium Sparing Diuretics
Drug
Spironolactone
Class
Potassium sparing diuretic
Pharmacodynamics (MOA)
Aldosterone receptor antagonist, therefore acts to inhibit Na+
reabsorption in late DCT, as well as concommitant K+ excretion
(basal Na/K exchanger)
Results in increased tubular osmolarity + water loss, with
increased H+ retention (uric acid loss)
Clinical Uses
Used in primary and secondary hyperaldosteronism
Pharmacokinetics
Oral administration
Duration of action days
Side Effects
Hyperkalemia, metabolic acidosis
Gynaecomastia, menstrual disorders/testicular atrophy
Drug
Amiloride
Class
Potassium sparing diuretic
Pharmacodynamics (MOA)
Inhibitor of aldosterone-sensitive Na+ channel, , therefore
acts to inhibit Na+ reabsorption in late DCT, as well as
concommitant K+ excretion (basal Na/K exchanger)
Results in increased tubular osmolarity + water loss, with
increased H+ retention (uric acid loss)
Clinical Uses
Used in conjunction with other diuretics
Side Effects
Hyperkalemia and metabolic acidosis
4. NSAIDs
NSAIDs
• Inhibit COX enzyme; involved in rate limiting step of prostanoid synthesis,
thus prevents production of prostaglandin H2 from arachidonic acid
• Two isoforms of COX enzyme:
– COX 1 – found in nearly all cells, actions tend to be homeostatic
– COX 2 – found predominantly in pro-inflammatory cells
• Actions of NSAIDs can be predicted by actions of prostanoids, eg
prostaglandin E2:
– PGE2 sensitizes nociceptors, thus lowering pain threshold and causing pain.
NSAIDs raise the threshold therefore reduce perception of pain = ANALGESIC
– PGE2 stimulates hypothalamic neurones to increase body temperature.
Therefore blocking its production prevents this temp rise = ANTI-PYRETIC
– PGE2 enhances Th1 differentiation (>IFN-gamma) + Th17 expansion (>IL-17) –
both of these have pro-inflammatory effects therefore blocking = ANTIINFLAMMATORY
– PGE2 downregulates gastric acid secretion + stimulates mucus/bicarbonate
secretion. NSAIDs block this so remove cytoprotection + increase risk of
GASTRIC ULCERATION
Drug
Ibuprofen
Class
Non-selective NSAID
Pharmacodynamics (MOA)
Reversibly inhibits COX 1 and COX 2 with equal affinity, thus
preventing prostaglandin H2 synthesis
Clinical Uses
Anti-inflammatory
Anti-pyretic
Analgesic
Pharmacokinetics
Orally active
Side Effects
Gastric ulcers, decreased glomerular filtration rate, renal
ischaemia, salt and water retention
Drug
Aspirin
Class
NSAID
Pharmacodynamics (MOA)
Irreversible COX 1 and COX 2 inhibitor, although selective for
COX 1. High affinity for COX 1 reduces thromboxane A2
synthesis in platelets, thus preventing platelet aggregation.
COX 2 action prevents PGI2 synthesis, which has inhibitory
actions against platelet aggregation, but this effect is much
less.
Also same actions as other NSAIDs
Clinical Uses
Anti-platelet
Anti-inflammatory, anti-pyretic, analgesic
Pharmacokinetics
Orally active
Irreversible inhibitor therefore prolonged action; requires de
novo COX synthesis
Side Effects
Gastric irritation + ulceration, bronchospasm (in sensitive
asthmatics), prolonged bleeding and nephrotoxicity
Drug
Celecoxib
Class
COX-2 selective NSAID
Pharmacodynamics (MOA)
Selectively inhibits COX-2
Clinical Uses
In patients with high risk of GI side effects
Pharmacokinetics
Orally active
Side Effects
Increase in CVS related side-effects
Other relevant information
less effect on COX-1 mediate processes > fewer risks of
gastric ulceration
Drug
Paracetamol
Class
NOT an NSAID
Pharmacodynamics (MOA)
Not completely understood
Clinical Uses
Analgesic + anti-pyretic
Pharmacokinetics
Paracetamol is a phase I metabolite of a pro-drug (thus has
free OH). Phase I metabolism of paracetamol > production of
NAPQI (toxic), which then undergoes glutathione conjugation
(involves glutathione transferase
Other phase II metabolism pathways that can occur include
methylation, sulphation or glucuronidation
Side Effects
NAPQI toxicity treated with cysteine – forces NAPQI to
undergo Phase II metabolism
Contraindications
Hepatic impairment
5.Drugs and the GI Tract
Anti-Emetics
• These should only be administered when the
cause of the nausea/vomiting is know,
otherwise could mask the diagnosis of a
potentially serious condition
Vomiting Pathways
Drug
Promethazine
Class
Anti-emetic (H1 antagonist)
Pharmacodynamics (MOA)
Histaminergic antagonist: Competitive antagonist at H1,
AchM and D2 receptors, therefore acting centrally (NST,
vestibular nuclei, higher centres, CTZ) to block the activation
of the vomiting centre
Clinical Uses
Motion sickness, Meniere’s (disorder of Labyrinth),
hyperemesis gravidarium, pre-/post-operatively
Also relief of allergic symptoms, anaphylaxis, insomnia
Pharmacokinetics
Oral administration
Onset of action 1-2 hours, peaks at 4 hours
Duration of action 24 hours
Side Effects
Dizziness, tinnitus, fatigue, sedation, convulsions, antimuscarinic side effects (dry mouth etc)
Other relevant information
Potency of antagonistic action H1 > AchM > D2
Drug
Metoclopramide
Class
Anti-emetic (D2 antagonist)
Pharmacodynamics (MOA)
Dopaminergic antagonist: competitive antagonist of D2, H1
and AchM receptors acting in the chemoreceptor trigger
zone, as well as in the GIT to increase smooth muscle motility
+ accelerate intestinal transit
Clinical Uses
Renal failure, radiation sickness, GI disorders, cancer
chemotherapy
Pharmacokinetics
Oral or IV administration
Extensive first pass metabolism
Crosses BBB and placenta
Side Effects
Drowsiness, dizziness, anxiety, extrapyramidal reactions
(Parkisonian-like syndrome), hyperprolactinaemia,
galactorrhea, disorders of menstration
Other relevant information
Causes faster transit time through GIT, therefore may affect
boavailability of co-administered drugs, and comprimise
nutrient supply
Drug
Hyoscine
Class
Anti-emetic (AchM antagonist)
Pharmacodynamics (MOA)
Muscarinic cholinoceptor antagonist; acts centrally to block
the activation of the vomiting centre (AChM > D2 = H1)
Clinical Uses
PREVENTION of motion sickness
Pre-operative
Pharmacokinetics
Oral, IV or transdermal administration
Peak of action 1-2 hours
Side Effects
Drowsiness, dry mouth, mydriasis, cyclopegia (loss of vision
accomodation), constipation
Other relevant information
Little effect once nausea/vomiting has been established
Drug
Ondasetron
Class
Anti-emetic (5HT3 antagonist)
Pharmacodynamics (MOA)
5HT3 receptor antagonist; acts to block transmission via the
visceral afferents to the chemoreceptor trigger zone and thus
prevents activation of the vomiting centre
Clinical Uses
Preventing anti-cancer drug-induced vomiting
Radiotherapy-induced sickness
Post-operative nausea and vomiting
Pharmacokinetics
Oral administration
Excreted in urine
Side Effects
Headache, flushing, constipation
Anti-Ulcer Drugs
• Peptic ulcer disease results from the imbalance of
the protective and potentially damaging factors of
the mucosal barrier.
• Almost 100% of patients with peptic ulcer disease
are infected with H. Pylori
• Triple Therapy is currently the best practice in
treating peptic ulcer disease:
– Antibiotic – eg Metronidazole, Amoxicillin or
Clarithromycin
– Inhibitor of Gastric Secretion – PPI (eg omeprazole), or H2
receptor antagonist (eg cimetidine, ranitidine)
– Cytoprotective drug – eg Sucralfate, bismuth chelate,
misoprostal
Drug
Metronidazole
Class
Antibiotic
Pharmacodynamics (MOA)
Active against anaerobic bacteria and
protozoa
Drug
Amoxicillin
Class
Antibiotic
Pharmacodynamics (MOA)
Broad spectrum antibiotic
Drug
Clarithromycin
Class
Antibiotic
Pharmacodynamics (MOA)
Macrolide structured antibiotic which
inhibits the translocation of bacterial tRNA
Drug
Omeprazole
Class
Proton Pump Inhibitor
Pharmacodynamics (MOA)
Inhibitors of gastric secretion. Irreversibly inhibit the H/K
ATPase responsible for H+ secretion into the canaliculi.
Clinical Uses
Component of triply therapy
Peptic ulcers resistant to H2 antagonists
Reflux oesophagitis
Pharmacokinetics
Orally active
Administered as enteric-coated slow-release formulation
Duration 2-3 days
Side Effects
Uncommon; headaches, mental confusion, impotence,
gynaecomastia, pain in muscles and joints
Other relevant information
Inactive at neutral pH. In acid environment of the
stomach, are protonated and rearranged into their active
form.
Inhibit secretion by >90%
Drug
Cimetidine
Class
Histamine Type 2 Receptor Antagonist
Pharmacodynamics (MOA)
Competitive antagonists at H2 receptors on parietal cells;
prevent histamine binding > less acid secretion, but also
reduce effect of Ach/Gastrin binding
Clinical Uses
Duodenal ulcer treatment
Pharmacokinetics
Orally active
Duration of action 2-3 days
Side Effects
Uncommon; diarrhoea, dizziness, muscle pains, transient
rashes, hypergastrinaemia
Contraindications
Withdrawal often results in relapses
Other relevant information
Reduces secretion by 60%
Drug
Ranitidine
Class
Histamine Type 2 Receptor Antagonist
Pharmacodynamics (MOA)
Competitive antagonists at H2 receptors on parietal cells;
prevent histamine binding > less acid secretion, but also
reduce effect of Ach/Gastrin binding
Clinical Uses
Duodenal ulcer treatment
Pharmacokinetics
Orally active
Duration of action 2-3 days
Side Effects
Uncommon; diarrhoea, dizziness, muscle pains, transient
rashes, hypergastrinaemia
Contraindications
Withdrawal often results in relapses
Other relevant information
Reduces secretion by 60%
Drug
Sucralfate
Class
Cytoprotective Drug
Pharmacodynamics (MOA)
Polymer containing aluminium hydroxide and sucrose
octasulphate; acquires strong negative charge in acidic
environment, binds to positively charge compounds (eg
glycoproteins) to form gel-like complexes which coat the
ulcer, limiting H= diffusion and pepsin degradation
Clinical Uses
Peptic ulcers
Component of triple therapy
Pharmacokinetics
Orally active
Duration of action 3 hours
Side Effects
Constipation, dry mouth, nausea, vomiting, headaches
Other relevant information
Reduces absorption of other drugs, eg digoxin. Important to
consider therapeutic window + bioavailability
Drug
Bismuth chelate
Class
Cytoprotective drug
Pharmacodynamics (MOA)
Toxic effects on H. pylori, prevents its adherence to mucosa
+ inhibits its proteolytic enzymes. Enhances local
prostaglandin synthesis to stimulate bicarbonate secretion
Clinical Uses
Resistant cases of triple therapy
Pharmacokinetics
Orally active
Side Effects
Nausea and vomiting, blackening of tongue and faeces
Drug
Misoprotol
Class
Cytoprotective drug
Pharmacodynamics (MOA)
Stable prostaglandin analogue; mimics action of locally
produced prostaglandins to maintain the gastroduodenal
mucosal barrier:
Inhibits acid secretion via G-protein coupled receptor
mediated inhibition of adenylate cyclase
Stimulates increased secretion of protective mucus
Increased mucosal blood flow
Clinical Uses
Prevention of NSAID induced gastric ulcers
Side Effects
Diarrhoea, abdominal cramps, uterine contractions
Contraindications
Pregnancy – induces premature labour (use in abortion)
Drugs and Inflammatory Bowel Disease
Characteristic
Ulcerative Colitis
Crohn’s Disease
Autoimmune disease
Th2 mediated
Th1 mediated
T cell expansion/apoptosis
Normal
Florid expansion + defective
apoptosis
Gut layers affected
Mucosa + submucosa
All layers
Regions of the gut affected
Colon
Any region
Inflammation
Continuous
Patchy
Fistulae/fissures/abscesses
Not present
Present
Surgery
Curative
Not always curative
Treatment falls into 2 parts: the treatment of active disease and the
maintenance of remission. These then are put into 3 categories:
• Supportive therapies – acute treatment + nutrition-based therapies to
maintain remission
• Treatment to reduce inflammation + relief of symptoms – glucocorticoids,
aminosalicylates, immunosuppressives
• Curative therapies – anti-TNFalpha antibodies
Drug
Mesalazine
Class
Aminosalicylate
Pharmacodynamics (MOA)
Anti-inflammatory action: reduces free radicals, upregulates
endogenous anti-oxidants, reduces leukocyte infiltration
Clinical Uses
Treatment of ulcerative colitis + maintenance of remission
Pharmacokinetics
Oral administration (pH dependent capsules)
Absorbed in small bowel and colon
Side Effects
Nausea, diarrhoea, abdominal pain/cramps, urticaria
Other relevant information
No immuno-supressive action
Innefective in Crohn’s
Drug
Sulfasalazine
Class
Aminosalicylate
Pharmacodynamics (MOA)
Anti-inflammatory action: reduces free radicals, upregulates
endogenous anti-oxidants, reduces leukocyte infiltration
Clinical Uses
Treatment of ulcerative colitis + maintenance of remission
Pharmacokinetics
Oral administration (pH dependent capsules)
Absorbed in colon
Metabolised by colonic flora
Side Effects
Anorexia, nausea, agranulocytosis, hypospermia
Other relevant information
No immuno-supressive action
Innefective in Crohn’s
Drug
Prednisolone
Class
Glucocorticoid
Pharmacodynamics (MOA)
Cortisol-derived agonist of glucocorticoid receptors. Then act
as:
• Anti-inflammatories – positive transcription factors for
anti-inflammatory genes + negative transcription factors
for pro-inflammatory factors
• Immunosuppressives: reduce antigen presentation, cell
proliferation and clonal expansion
Clinical Uses
Inducing remission in Crohn’s disease
Pharmacokinetics
Administered topically (oral if severe)
Side Effects
Related to effects of cortisol: osteoporosis, suppression of
HPA axis, T2DM, hypertension, infection susceptibility, skin
thinning, bruising, proximal myopathy, buffalo hump
Other relevant information
Strategies for minimising unwanted effects include use of
tapered doses, use of drugs with high therapeutic index,
topical administration
Drug
Fluticasone
Class
Glucocorticoid
Pharmacodynamics (MOA)
Cortisol-derived agonist of glucocorticoid receptors. Then act
as:
• Anti-inflammatories – positive transcription factors for
anti-inflammatory genes + negative transcription factors
for pro-inflammatory factors
• Immunosuppressives: reduce antigen presentation, cell
proliferation and clonal expansion
Clinical Uses
Inducing remission in Crohn’s disease
Pharmacokinetics
Administered topically (oral if severe)
Side Effects
Related to effects of cortisol: osteoporosis, suppression of
HPA axis, T2DM, hypertension, infection susceptibility, skin
thinning, bruising, proximal myopathy, buffalo hump
Other relevant information
Strategies for minimising unwanted effects include use of
tapered doses, use of drugs with high therapeutic index,
topical administrationn
Drug
Budesonide
Class
Glucocorticoid
Pharmacodynamics (MOA)
Cortisol-derived agonist of glucocorticoid receptors. Then
act as:
• Anti-inflammatories – positive transcription factors for
anti-inflammatory genes + negative transcription factors
for pro-inflammatory factors
• Immunosuppressives: reduce antigen presentation, cell
proliferation and clonal expansion
Clinical Uses
Inducing remission in Crohn’s disease
Pharmacokinetics
Administered topically (oral if severe)
Side Effects
Related to effects of cortisol: osteoporosis, suppression of
HPA axis, T2DM, hypertension, infection susceptibility, skin
thinning, bruising, proximal myopathy, buffalo hump
Other relevant information
Strategies for minimising unwanted effects include use of
tapered doses, use of drugs with high therapeutic index,
topical administratiopn
Drug
Azathioprine
Class
Immunosuppressive
Pharmacodynamics (MOA)
Pro-drug activated by gut flora to 6-mercaptopurine – this
interferes with purine biosynthesis and hence dna
synthesis/replication. Effects include:
• Impaired acquired immune response, lymphocyte
proliferation, mononuclear cell infiltration, antibody
synthesis
• Enhanced T cell apoptosis
Clinical Uses
Maintaining remission of UC
Inducing + maintaining remission of CD
Enabling reduction of glucocorticoid dose
Pharmacokinetics
Metabolised by xanthine oxidase
Side Effects
Bone marrow suppression
Contraindications
Co-administration with drugs that inhibit xanthine oxidase, eg
allopurinol, as lead to build up of 6-mercaptopurine > blood
disorders
6. Antimicrobials
Antimicrobials
• These should be toxic for the pathogenic cell but
innocuous for the host. This selective toxicity depends
on the existence of exploitable biochemical differences
between the pathogen and host cell, which in turn
depends on how far apart the cells are in terms of
evolutionary development
• These include:
–
–
–
–
Anti-bacterial agents
Anti-mycobacterial agents
Anti-fungals
Anti-virals
Antibacterials
• These exploit the differences between
prokaryotic bacterial cells, and eukaryotic host
cells.
• Targets for antibacterial agents include:
– Folate
– Peptidoglycan
– Ribosomes
Drug
Co-trimoxazole
Class
Combined folate synthesis inhibitor (sulphonamide) + folate
antagonist (trimethoprim) = sequential blockade
Pharmacodynamics (MOA)
Sulphonamide – structural analogue of P-aminobenzoic acid
(required for folate synthesis); competes for dihydropteroate
enzyme therefore interfering with DNA/RNA synthesis –
BACTERIOSTATIC
Trimethoprim – folate antagonist that inhibits dihydrofolate
enzyme action; interferes with use of folate for DNA/RNA
synthesis
Sulphonamides potentiate the action of trimethoprim
Clinical Uses
Pneumonia (AIDs patients) – infection with pneumocystis
carinii
Pharmacokinetics
Oral administration
Half excreted within 34 hours
Side Effects
Nausea/vomiting
Skin rashes
Hypersensitivity reactions
Drug
Penicillin
Class
Beta-lactam Antibiotic
Pharmacodynamics (MOA)
Beta lactam ring interferes with peptidoglycan synthesis,by
inhibiting the transpeptidation enzyme that cross-links the
peptide chains with the backbone of the peptidoglycan
• preventing formation of bacterial cell wall > bacterial burst
= BACTERIOCIDAL
Pharmacokinetics
Oral administration – depends on acidity of stomach (empty
stomach)
Widely bio-distributed; crosses placenta but lipid insoluble
therefore doesn’t cross BBB
Mainly renal excretion
Side Effects
Relatively free from toxic effects, but hypersensitivity
reactions are common:
• Skin rashes, fever
• Anaphylaxis
GI tract disturbances also common
Other relevant information
Resistance mechanisms:
• Production of B-lactamases
• Reduction in permeability of outer bacterium membrane
• Occurrence of modified penicillin-binding sites
Drug
Cefotaxime
Class
Beta-lactam antibiotic (part of cephalosporin family)
Pharmacodynamics (MOA)
Interfere with peptidoglycan synthesis = BACTERIOCIDAL
Clinical Uses
Crosses BBB therefore first line treatment for bacterial
meningitis
Pharmacokinetics
IV/IM administration
Renal excretion
Side Effects
Hypersensitivity
Nephrotoxicity
Diarrhoea
Contraindications
10% of people with penicillin hypersensitivity will be
cefotaxime sensitive
Other relevant information
Resistance (wide-spread)
• Gene encoding beta lactamase – more active in
hydrolysing cephalosporins than penicillins
• Decreased penetration of drug due to mutations in outer
membrane proteins or binding site proteins
Drug
Tetracycline
Class
Antibiotic (inhibitor of ribosome function)
Pharmacodynamics (MOA)
Binds to + actively transported into bacteria to interrupt
protein synthesis via competitive binding for A binding site
on 502 subunit = BACTERIOSTATIC
Clinical Uses
Wide spread of bacterial infections (both gram +ve and –ve)
Pharmacokinetics
Absorption is irregular + incomplete – chelation of iron +
calcium
Wide bio-distribution
Excretion by bile and glomerular filtration
Side Effects
GIT disturbances
Chelated calcium deposits in growing bone > deformity
Contraindications
Children, pregnant women, nursing mothers
Other relevant information
Resistance mechanisms:
• Development of energy dependent efflux mechanisms
• Mutations of ribosome structure to prevent binding
Drug
Chloramphenicol
Class
Antibiotic (inhibitor of ribosome function)
Pharmacodynamics (MOA)
Binds to 50s subunit of ribosome, inhibiting transpeptidation
and therefore protein synthesis = BACTERIOSTATIC
Clinical Uses
Wide spread (gram +ve and –ve infections)
Pharmacokinetics
Oral or parenteral administration
Complete absorption
Half life 2 hours
Distribution includes CSF
Excretiion: 10% unchanges in urine, 90% metabolised in liver
and then excreted via kidneys + bile
Side Effects
Pancytopenia (decrease in all blood cells due to bone
marrow suppression)
Grey baby syndrome – vomiting, diarrhoea. Flaccidity, low
temp, ash grey colour in newborns
GI disturbances
Other relevant information
Resistance mechanism: R plasmid mediated transfer of
chloramphenicol acetyl-transferase.
Solution: replacing terminal OH on side-chain by fluorine
reduces susceptibility to acetylation
Drug
Gentamicin
Class
Antibiotic (aminoglycoside)
Pharmacodynamics (MOA)
Binds to 30s subunit of bacteria > anticodon-codon misread >
translation of defective protein = BACTERIOCIDAL
Second mechanism unknown
Clinical Uses
Aerobic gram –ve infection
Infection causes by streptococcus, listeria, pseudomonas aeruginosa
(in conjunction with penicillin)
Pharmacokinetics
Highly polar – not absorbed in GIT therefore IV/IM adminstration
Not widely distributed
Half life 2-3 hours
Elimination entirely by kidney
Side Effects
Ootoxicity (damage to sensory cells in cochlea and vestibular organ)
Nephrotoxicity
Contraindications
Renal impairement
Chloramphenicol (blocks oxygen-dependent active transport of
gentamicin into bacterial cell)
Other relevant information
Resistance mechanisms:
Inactivation by microbial enzymes
Failure of penetration – overcome with penicillin
Mutations – alter 30s binding site
Anti-mycobacterial agents
• Used to treat infections caused by
mycobacterium tuberculosis and leprae
– Main problem with infection is that micro-organisms
can survive inside macrophages unless they are
activated by T-cell lymphokines > latent infection
• 6 month drug combination therapy is used to
manage high incidence of drug resistance (6
month treatment minimum – poor compliance)
– 1st phase = 2 months (isoniazid, rifampicin +
pyrazinamide)
– 2nd phase = 4 months (isoniazid + rifampicin)
Drug
Isoniazid
Class
Anti-mycobacterial
Pharmacodynamics (MOA)
Bacteriostatic on resting mycobacteria
Bacteriocidal on dividing mycobacteria (extracellular and
intracellular)
MOA not fully understood – inhibition of cell wall synthesis?
Clinical Uses
TB + leprosy
Pharmacokinetics
Oral administration
Readily absorbed from GIT
Widely distributed (CSF)
Metabolism = acetylation.
Other relevant information
Therapeutic response dependent on whether patient is fast
or slow acetylator (slow = better because slower
metabolism)
Drug
Rifampicin
Class
Anti-mycobacterial agent
Pharmacodynamics (MOA)
Inhibits prokaryotic DNA-dependent RNA-polymerase =
BACTERIOCIDAL
Effective for both extracellular and intracellular organisms
Clinical Uses
TB + leprosy
Pharmacokinetics
Oral administration
Widely distributed
Excreted in bile + urine – undergoes enteroheptic recycling
Progressive metabolism: deacetylation – metabolite less well
absorbed
Side Effects
Infrequent – skin rashes, fever, GIT disturbances
Drug
Pyrazinamide
Class
Anti-mycobacterial
Pharmacodynamics (MOA)
tuberculoSTATIC at acidic pH, like that of the macrophage
environment. Therefore effective against the intracellular
organism in macrophage
Clinical Uses
TB
Pharmacokinetics
Oral administration
Good absorption
Widely distributed (inc meninges)
Excretion via glomerular filtration
Side Effects
Arthralgia, GIT disturbance, malaise + fever
Anti-fungals
• Fungal infections are termed mycoses; these
may be systemic (rare) or superficial (more
common)
• Superficial mycoses may be dermatomycoses
(commonly tinea infections) or candidiasis
(yeast infections of mucous membranes)
Drug
Nystatin
Class
Anti-fungal
Pharmacodynamics (MOA) Polyene macrolide that binds to ergosterol (within cell
membrane), forming a transmembrane ion channel that
disrupts permeability and transport function
Clinical Uses
Fungal infections of skin + GI tract
Pharmacokinetics
No absorption through mucous membranes
Side Effects
Rare; nausea and vomiting
Very rare; rash
Drug
Miconazole
Class
Anti-fungal
Pharmacodynamics (MOA)
Azole group of synthetic anti-mycotic agent that blocks the
synthesis of ergosterol, altering the fluidity of fungal
membrane and interfering with the action of membraneassociated enzymes – results in inhibition of replication
Clinical Uses
Wide spectrum of systemic and superficial infection
Pharmacokinetics
IV administration for systemic
Oral administration for superficial
Short plasma half life
Side Effects
Infrequent; GIT disturbance
Rare; blood dyscrasias
Anti-Virals
• Viruses: small intracellular parasites consisting
of nucleic acids (RNA or DNA) enclosed by a
protein coat/capsid
• Obligate intracellular parasites therefore use
host cell machinery for replication; poses
challenge for selective drugs
– Virus-specific enzymes potential targets
• Difficulty is that clinically detectable infection
is usually far advanced so treatment difficult
Drug
Acyclovir
Class
Anti-viral
Pharmacodynamics (MOA)
Guanosine derivative that is converted to monophosphate
form by thimidine kinase (viral thymidine kinase much more
effective at doing this). Host cell kinases then convert
monophosphate form to triphosphate form, and this then
inhibits DNA viral-polymerase, terminating chain reaction and
thus inhibiting nucleic acid synthesis
Clinical Uses
HSV infection
Pharmacokinetics
Oral (20% absorbed) or IV
Widely distributed; crosses BBB
Rapidly broken down within host cells by cellular phosphatases
(need frequent application)
Excreted by kidneys
Side Effects
Rare with oral administration, more common in intravenous
administration:
Local inflammation, renal dysfunction, nausea, headache
Other relevant information Resistance occurs due to changes in viral genes coding for
thymidine kinase or DNA polymerase
Drug
Zidovudine (AZT)
Class
Anti-RETROviral
Pharmacodynamics (MOA)
Analogue of thymidine (activated by cellular enzymes to triphosphate
form) acts as competitive inhibitor of reverse transcriptase;
incorporation into growing viral DNA strand results in chain
termination preventing DNA synthesis
Clinical Uses
AIDS – reduces opportunistic infections, thrombocytopenia,
dementia + viral load
HIV+ve – prolongs life expectancy
HIV+ve mothers – reduces chance of transmission to fetus
Pharmacokinetics
Oral administration
Undergoes extensive first pass metabolism
Widely distributed – enters cells by passive diffusion
Metabolised by liver to inactive glucuronide
20% active form excreted in urine
Side Effects
Common = anaemia, neutropenia
Rare = GIT disturbance, skin rash, insomnia, fever, headache
Other relevant information
Therapeutic response wanes with long term use – development of
resistance:
• Mutations in viral reverse transcriptase accumulate progressively
• Decreased activation to triphosphate form
7. Cytotoxics
Cytotoxics
• Definition: “drugs that modify the growth of
cells and tissues”
• Challenges with cytotoxics: It is difficult to find
exploitable differences, they need to produce a
near total cell kill, have no effect on resting cells
(which means relapse likely)
• Cytotoxics tend to be antiproliferative, with no
effect on tendency to metastasize or invade –
effect on rapidly dividing normal tissues therefore
result in multiple adverse effects
Drug
Cyclophosphamide
Class
Alkylating agent (interferes with DNA
transcription/replication)
Pharmacodynamics (MOA)
Ethylene immonium derivative – substrate for cytochrome
P450, when oxidised becomes extremely reactive and
carbonium ion binds irreversibly with cell macromolecules
including RNA, proteins and DNA, causing intra/inter chain
cross-linking
• This interferes with transcription and replication
• Most common targets N7 guanine, N1/N3 adenosine
Clinical Uses
Cancer treatment
Immunosuppession following allogenic tissue
transplantation (at low dose)
Pharmacokinetics
Rapidly metabolised, but metabolites also have cytotoxic
action
Side Effects
Myelotoxicity - damage bone marrow lead to reduced
lekukocyte production. Impaired wound healing. Depression
of growth. Sterility (because gonadal tissues are highly
active). Teratogenicity - cross placenta. Loss of hair. Nausea
and vomitting. GI tract epithelia, hair and nails
Drug
Methotrexate
Class
Antimetabolite (interferes with DNA base synthesis)
Pharmacodynamics (MOA)
Interferes with thymidylate synthesis (folate synthesis), thus
preventing purine (adenine + guanine) synthesis > interfering
with DNA synthesis
Clinical Uses
Cancer treatment
Immunosuppression following allogenic tissue transplant (at
low doses)
Side Effects
Myelotoxicity - damage bone marrow lead to reduced
lekukocyte production. Impaired wound healing. Depression
of growth. Sterility (because gonadal tissues are highly
active). Teratogenicity - cross placenta. Loss of hair. Nausea
and vomitting. GI tract epithelia, hair and nails
Drug
Doxorubicin
Class
Cytotoxic antibody (inhibits DNA/RNA chain synthesis)
Pharmacodynamics (MOA)
Antibody complexes with DNA, preventing the
topoisomerase from “zipping up” DNA therefore inhibiting
DNA and RNA synthesis
Clinical Uses
Cancer treatment
Side Effects
Myelotoxicity - damage bone marrow lead to reduced
lekukocyte production. Impaired wound healing.
Depression of growth. Sterility (because gonadal tissues are
highly active). Teratogenicity - cross placenta. Loss of hair.
Nausea and vomitting. GI tract epithelia, hair and nails
Drug
Bleomycins
Class
Cytotoxic antibody
Pharmacodynamics (MOA)
Metal-chelating glycopeptide antibody that degrades DNA
Clinical Uses
Cancer treatment
Pharmacokinetics
Administered intravenously
Side Effects
Myelotoxicity - damage bone marrow lead to reduced
lekukocyte production. Impaired wound healing.
Depression of growth. Sterility (because gonadal tissues are
highly active). Teratogenicity - cross placenta. Loss of hair.
Nausea and vomitting. GI tract epithelia, hair and nails
Other relevant information
Active against non-dividing cells, therefore very toxic and
high chance of pulmonary toxicity
Drug
Etoposide
Class
Plant alkaloid
Pharmacodynamics (MOA)
Inhibition of topoisomerase II inhibits DNA synthesis > cell
cycle block at G2 phase
Clinical Uses
Cancer treatment
Side Effects
Myelotoxicity - damage bone marrow lead to reduced
lekukocyte production. Impaired wound healing.
Depression of growth. Sterility (because gonadal tissues are
highly active). Teratogenicity - cross placenta. Loss of hair.
Nausea and vomitting. GI tract epithelia, hair and nails
Drug
Vincristine
Class
Plant alkaloid (spindle cell poison)
Pharmacodynamics (MOA)
Binds to tubulin, inhibiting its polymerisation to form
microtubules necessary for spindle formation. This therefore
prevents cell division and thus successful replication
Clinical Uses
Cancer treatment
Side Effects
Myelotoxicity - damage bone marrow lead to reduced
lekukocyte production. Impaired wound healing. Depression
of growth. Sterility (because gonadal tissues are highly
active). Teratogenicity - cross placenta. Loss of hair. Nausea
and vomitting. GI tract epithelia, hair and nails
Drug
Cisplatin
Class
Miscellaneous cytotoxic
Pharmacodynamics (MOA)
Interacts directly with DNA causing guanine intrastrand
cross-linking > interference with transcription and
replication
Clinical Uses
Cancer treatment
Side Effects
Myelotoxicity - damage bone marrow lead to reduced
lekukocyte production. Impaired wound healing. Depression
of growth. Sterility (because gonadal tissues are highly
active). Teratogenicity - cross placenta. Loss of hair. Nausea
and vomitting. GI tract epithelia, hair and nails
Drug
Procarbazine
Class
Miscellaneous cytotoxic
Pharmacodynamics (MOA)
Alkylates DNA, interfering with DNA/RNA synthesis and
mitosis at interphase
Clinical Uses
Cancer treatment
Side Effects
Myelotoxicity - damage bone marrow lead to reduced
lekukocyte production. Impaired wound healing. Depression
of growth. Sterility (because gonadal tissues are highly
active). Teratogenicity - cross placenta. Loss of hair. Nausea
and vomitting. GI tract epithelia, hair and nails
Other relevant information
Activated by cytochrome P450 and MAO
8. Drugs of Abuse
Drugs of Abuse
• MOA: artificially hijack the natural reward pathway; DA
release from ventral tegmental area into the nucleus
accumbens > euphoria
• Classification of drugs:
– Narcotics (painkillers) are opiate like drugs, eg heroin and
morphine
• Opitaes bind to u opiate receptors on the GABAergic neuron cell body
to suppress them, therefore suppressing GABA release > more
dopamine release
– Depressants are ‘downers’, which slow down the CNS. These
include alcohol, benzodiazepines (valium), and barbiturates
– Stimulants are ‘uppers’, and are probably the largest class of
addictive drugs, which tend to speed everything up in the CNS,
eg cocaine + nicotine
– Miscellaneous drugs have several effects and properties (e.g.
stimulant as well as hallucinogenic), and these drugs include
cannabis and ecstasy (MDMA).
Drug
Cannabis
Class
Miscellaneous drug of abuse
Origin
Genus of flowering plant. > 60 Cannabinoids (active component) found in all parts of the plant,
eg tetrahydrocannabinol (THC – most potent).
• Marijuana = crushes dried leaves
• Resin/Hashish = cannabinoid secreted from glandular trichomes
• Hash oil = solvent extracted hashish (concentrated)
Pharmacodynamics
(MOA)
Analogue of endogenous cannabinoid (eg anadamide – generated from arachidonic acid), which
binds to endogenous CB1 receptors in brain and CB2 receptors on WBC. Binding > downregulation of adenylyl cyclase > inhibition of GABA secretion > increased DA secretion
Clinical Uses
In disease: upregulating CB receptors used to mitigate disease eg MS, as well as having an effect
on fertility, obesity
In pharmacology: targeting the cannabinoid system can be used to increase appetite in AIDs
patients, decrease appetite in obese patients and treat neuropathic pain in MS
Pharmacokinetics
Administration:
• Smoking > 50% absorption but rapid onset of action
• Eating > 10% absorption (first pass metabolism), delayed onset of action but prolonged effect
Duration of action is dependent on adipose tissue. Cannabis is very lipid soluble, therefore sits in
fat cells for long periods of time before returning to the circulation (unusual)
Hepatic metabolism
25% excreted unmetabolised, 65% undergoes enterohepatic recycling. Metabolism forms 11hydroxyTHC = active metabolite > increased intoxication
Side Effects
Psychosis + schizophrenia (anterior cingulate cortex), munchies (hypothalamus), amnesia (limbic
regions), effect on psychomotor performance (cerebral cortex), immunosuppressant (B2
receptors on WBC), reddening conjunctivae (vasodilation)
Drug
Cocaine
Class
Stimulant drug of abuse
Origin
Erythroxylum coca plant. Can extract up to 0.9% of drug from plant; different forms:
• Paste
• Cocaine HCl (paste dissolved in acid)
• Crack cocaine (Cocaine HCl precipitated in alkaline solution)
• Freebase cocaine (crack dissolved in ammonia)
Pharmacodynamics
(MOA)
Binds to da transporter present on terminals of DA neurons and prevents reuptake,
therefore prolonging DA effect > euphoria
Pharmacokinetics
Administration
• Paste + cocaine HCl – IV, oral , intranasal
• Crack + freebase – inhalation
Onset of action: within seconds following smoking/injection
Metabolised by liver + plasma cholinesterases
Half life < 20 mins
Side Effects
Local anaesthesia – blocks Na+ channels, inhibits monoamine transporters (a2
adrenoceptors)
Irratibility, anxiety, hostility – CNS stimulation
Other relevant
information
Risk of sudden death: increased endothelin 1 (vasoconstriction), decreased NO
production (increased platelet activation), increased SNS activation
Drug
Nicotine
Class
Plant-derived alkaloid
Pharmacodynamics
(MOA)
Acts on nicotinic acetylcholine receptors (especially alpha 4 and beta 2 subunits)
on the cell bodies of dopaminergic neurones > DA release into nucleus accumbens
> euphoria
Clinical Uses
Suggestive protection against Parkinson’s and Alzheimer’s
Pharmacokinetics
Administration
• Intranasal spray – 20-50% absorbed
• Gum – 50-70% absorbed (slow onset)
• Cigarettes – 20% absorbed (rapid onset)
• Transdermal patch – 70% absorbed
Spray, gum + patch aim to remove spike which encourages addiction
Pka of 7.9. smoke is relatively acidic therefore is ionised; spray, gum and patch aim
to buffer to maximise absorption
Half life – hours
Hepatic metabolism by cytochrome P2A6 and cotidine
Renal excretion
Side Effects
CVS effects (due to Ach agonistic action)
• Increased HR, SV, coronary vasoconstriction, skeletal vasodilation, increased
platelet activity (increased ThA2 + decreased NO)
Metabolic effects: increase BMR, appetite suppressant
Drug
Alcohol
See lecture 15 (too much detail for slide)
Disulfram
Alcohol dehydrogenase inhibitor = Ethanol
aversion drug; leads to build up of toxic
metabolite acetylaldehyde which leads to
horrible feeling when drinking
9. Opiates + Opioids
Pain Pathway
• Ascending pathways - perception of pain
• Descending inhibitory pathways – pain tolerance
–
–
–
–
PAG = peri-aqeductal grey area (midbrain)
NRM = nucleus raphe magnus (medulla)
NRPG = nucleus reticularis paragigantocellularis
LC = locus coeruleus (brainstem)
Drug
Morphine
Class
Opiate
Structure
Natural opiate; alkaloid derivative of papaver somniferum poppy (tertiary amine with hydoxyl groups at positions 3 and 6)
Pharmacodynam
ics (MOA)
Act via endogenous opioid receptors (endogenous opioid peptides inc endorphins, enkephalins and neoendorphins).
Binding to u, d or k G-protein linked receptors > decreased adenylate cyclase > decreased cAMP > increased capacity for
K+ efflux + decreased Ca2+ influx > decreased action potential generation = DEPRESSANT
•
Analgesia: huge concentration of receptors in SC – depress afferent pathways > reduced perception + activate
descending inhibitory pathway > increased tolerance
•
Euphoria: Suppress GABA release from mesolimbic dopamine neurones into nucleus accumbens > increased DA
•
Antitussive: inhibit seratonin receptor activation in cough centre + suppress release of Ach and neurokinins in airways
Clinical Uses
Analgesic
Antitussive (usually codeine)
Pharmacokinetic
s
Oral administration (40-50% bioavailability) or IV administration
Metabolised in liver > morphine-6-glucuronide. Then either excreted by kidney or active metabolite secreted in bile to
undergo enterohepatic recycling
Complex pharmacokinetics as largely ionized at physiological pH
Side Effects
SHORT TERM:
•
Respiratory depression: desensitizes chemoreceptors > loss of response to arterial CO2 + medullary action to control
resp (main COD in overdose)
•
Nausea/vomiting: depresses natural inhibition of chemoreceptor trigger zone > activation of vomiting centre
•
Miosis: stimulation of occulomotor nerve > ciliary ganglion > iris > constriction (unconscious + pinprick pupils = heroin
overdose)
•
Constipation: depress gastric emptying and GI motility > increased water absorption
•
Allergy: G-protein mediated activation of mast cells > histamine release > pruritus (itching), urticaria, hypotension
LONG TERM:
•
Tolerance: increased arrestin production > receptor internalisation > decreased response
•
dependence: withdrawal > upregulation of adenylate cyclase system > craving, tremor, diarhoea
Other relevant
information
Treatment for overdose is opioid receptor antagonist NALOXONE (iv administration)
Drug
Codeine
Class
Opiate
Structure
Natural opiate (methyl-morphine) – tertiary amine with methyl group at position 3
Pharmacodynami
cs (MOA)
Act via endogenous opioid receptors (endogenous opioid peptides inc endorphins, enkephalins and neoendorphins).
Binding to u, d or k G-protein linked receptors > decreased adenylate cyclase > decreased cAMP > increased capacity for K+
efflux + decreased Ca2+ influx > decreased action potential generation = DEPRESSANT
•
Analgesia: huge concentration of receptors in SC – depress afferent pathways > reduced perception + activate
descending inhibitory pathway > increased tolerance
•
Euphoria: Suppress GABA release from mesolimbic dopamine neurones into nucleus accumbens > increased DA
•
Antitussive: inhibit seratonin receptor activation in cough centre + suppress release of Ach and neurokinins in airways
Clinical Uses
Analgesic
Antitussive
Pharmacokinetics
Oral administration (5-10% bioavailability)
Side Effects
SHORT TERM:
•
Respiratory depression: desensitizes chemoreceptors > loss of response to arterial CO2 + medullary action to control
resp (main COD in overdose)
•
Nausea/vomiting: depresses natural inhibition of chemoreceptor trigger zone > activation of vomiting centre
•
Miosis: stimulation of occulomotor nerve > ciliary ganglion > iris > constriction (unconscious + pinprick pupils = heroin
overdose)
•
Constipation: depress gastric emptying and GI motility > increased water absorption
•
Allergy: G-protein mediated activation of mast cells > histamine release > pruritus (itching), urticaria, hypotension
LONG TERM:
•
Tolerance: increased arrestin production > receptor internalisation > decreased response
•
dependence: withdrawal > upregulation of adenylate cyclase system > craving, tremor, diarhoea
Other relevant
information
Treatment for overdose is opioid receptor antagonist NALOXONE (iv administration)
Drug
Heroin
Class
Opiate
Structure
Di-acetyl-morphine – acetylated > acetyl groups at position 3 and 6 > increased potency
Pharmacodynamics
(MOA)
Act via endogenous opioid receptors (endogenous opioid peptides inc endorphins, enkephalins and neoendorphins). Binding to
u, d or k G-protein linked receptors > decreased adenylate cyclase > decreased cAMP > increased capacity for K+ efflux +
decreased Ca2+ influx > decreased action potential generation = DEPRESSANT
•
Analgesia: huge concentration of receptors in SC – depress afferent pathways > reduced perception + activate descending
inhibitory pathway > increased tolerance
•
Euphoria: Suppress GABA release from mesolimbic dopamine neurones into nucleus accumbens > increased DA
•
Antitussive: inhibit seratonin receptor activation in cough centre + suppress release of Ach and neurokinins in airways
Clinical Uses
Analgesic
Antitussive (usually codeine)
Pharmacokinetics
Intravenous administration
Hepatic metabolism (like morphine) + plasma esterases > shorter half life > more addictive
Side Effects
SHORT TERM:
•
Respiratory depression: desensitizes chemoreceptors > loss of response to arterial CO2 + medullary action to control resp
(main COD in overdose)
•
Nausea/vomiting: depresses natural inhibition of chemoreceptor trigger zone > activation of vomiting centre
•
Miosis: stimulation of occulomotor nerve > ciliary ganglion > iris > constriction (unconscious + pinprick pupils = heroin
overdose)
•
Constipation: depress gastric emptying and GI motility > increased water absorption
•
Allergy: G-protein mediated activation of mast cells > histamine release > pruritus (itching), urticaria, hypotension
LONG TERM:
•
Tolerance: increased arrestin production > receptor internalisation > decreased response
•
dependence: withdrawal > upregulation of adenylate cyclase system > craving, tremor, diarhoea
Other relevant
information
Treatment for overdose is opioid receptor antagonist NALOXONE (iv administration)
Drug
Methadone
Class
Opiate
Pharmacodynamics
(MOA)
Act via endogenous opioid receptors (endogenous opioid peptides inc endorphins, enkephalins and neoendorphins).
Binding to u, d or k G-protein linked receptors > decreased adenylate cyclase > decreased cAMP > increased capacity for
K+ efflux + decreased Ca2+ influx > decreased action potential generation = DEPRESSANT
•
Analgesia: huge concentration of receptors in SC – depress afferent pathways > reduced perception + activate
descending inhibitory pathway > increased tolerance
•
Euphoria: Suppress GABA release from mesolimbic dopamine neurones into nucleus accumbens > increased DA
•
Antitussive: inhibit seratonin receptor activation in cough centre + suppress release of Ach and neurokinins in
airways
Clinical Uses
Morphine/heroin replacement to wean off addicts
Analgesic
Antitussive (usually codeine)
Pharmacokinetics
Lipid-soluble + efficient distribution
Long half-life, therefore low dose for long time
Side Effects
SHORT TERM:
•
Respiratory depression: desensitizes chemoreceptors > loss of response to arterial CO2 + medullary action to control
resp (main COD in overdose)
•
Nausea/vomiting: depresses natural inhibition of chemoreceptor trigger zone > activation of vomiting centre
•
Miosis: stimulation of occulomotor nerve > ciliary ganglion > iris > constriction (unconscious + pinprick pupils =
heroin overdose)
•
Constipation: depress gastric emptying and GI motility > increased water absorption
•
Allergy: G-protein mediated activation of mast cells > histamine release > pruritus (itching), urticaria, hypotension
LONG TERM:
•
Tolerance: increased arrestin production > receptor internalisation > decreased response
•
dependence: withdrawal > upregulation of adenylate cyclase system > craving, tremor, diarhoea
Other relevant
information
Treatment for overdose is opioid receptor antagonist NALOXONE (iv administration)
10. Drugs and the CNS
Anxiolytics, Sedatives + Hypnotics
• These drugs all affect GABA transmission (principal
inhibitory NT of the CNS), and tend to act on the GABAA receptor complex
• GABA-A complex consists of Cl-, GABA, BDZ + BARB
receptor proteins
• GABA binds to receptor, activating GABA modulin (link
between GABA + BDZ protein) > opening of Cl- channel
• Anxiolytics remove anxiety WITHOUT impairing mental
or physical activity
• Sedatives reduce mental and physical activity
WITHOUT producing loss of consciousness
• Hypnotics induce sleep
Drug
Amobarbitol
Class
Barbituate
Structure
Classic 6-membered ring with number of additional groups
Pharmacodynamics
(MOA)
BARBs bind to their own receptor; enhance GABA action + binding
(not reciprocated by GABA) + direct effect on Cl- channel > increased
DURATION of Cl- ion channel opening
BARBs also appear to act as non-selective glutamate antagonists >
decreased excitatory transmission (use for induction of anaesthesia)
Clinical Uses
Sedative, hypnotic
Side Effects
Depress respiration, “hangovers” (alter natural sleep + REM),
tolerance (severe; pharmacokinetic + tissue tolerance),
dependence/withdrawal (insomnia, anxiety, tremors)
Contraindications
Interact with co-administered drugs, as are enzyme inducers
Potentiate other CNS depressants eg alcohol
Benzodiazepine
ure
3 ring structure; lots of variations > large changes in pharmacokinetic activity
acodynamics
BDZ bind to their own receptor; enhance GABA action + GABA binding (reciprocrat
GABA) > increased FREQUENCY of Cl- ion channel opening
Uses
Anxiolytic
acokinetics
Oral administration
Peak plasma within hour
Bind pp and highly lipid soluble – well distributed
Hepatic metabolism (glucuronidation)
Renal excretion
Duration of action = long acting (t ½ = 32 hours); metabolism via active metabolite
fects
Sedation, confusion, ataxia
Tolerance (< than BARBs; only tissue)
Dependence + withdrawal
Increase in free plasma concentrations of other drugs eg aspirin
indications
Potentiates other CNS depressants eg alcohol
dynamics
ses
Benzodiazepine
3 ring structure; lots of variations > large changes in pharmacokinetic activity
BDZ bind to their own receptor; enhance GABA action + GABA binding (reciprocrated b
increased FREQUENCY of Cl- ion channel opening
Sedative
Hypnotic
Anxiolytic (in hepatic impairment as alternative to diazepam)
kinetics
Oral administration (IV for status epilepticus)
Peak plasma within hour
Bind pp and highly lipid soluble – well distributed
Hepatic metabolism (glucuronidation)
Renal excretion
Duration of action = short acting (t ½ = 8 hrs)
ts
Sedation, confusion, ataxia
Tolerance (< than BARBs; only tissue)
Dependence + withdrawal
Increase in free plasma concentrations of other drugs eg aspirin
ications
Potentiates other CNS depressants eg alcohol
e
3 ring structure; lots of variations > large changes in pharmacokinetic activity
codynamics
BDZ bind to their own receptor; enhance GABA action + GABA binding (reciprocrated
increased FREQUENCY of Cl- ion channel opening
Uses
Sedative
Hypnotic
cokinetics
Oral administration (IV for status epilepticus)
Peak plasma within hour
Bind pp and highly lipid soluble – well distributed
Hepatic metabolism (glucuronidation)
Renal excretion
Duration of action = short acting (t ½ = 8 hrs)
ects
Sedation, confusion, ataxia
Tolerance (< than BARBs; only tissue)
Dependence + withdrawal
Increase in free plasma concentrations of other drugs eg aspirin
ndications
Potentiates other CNS depressants eg alcohol
levant
Advantages over BARBs:
Drug
Chloral Hydrate
Pharmacodynamics (MOA)
not known
Clinical Uses
Sedative/hypnotic in children/elderly (wide margin of safety)
Pharmacokinetics
Metabolised in liver to trichloroethanol = active component
Drug
Busipirone
Class
5HT-1A agonist
Pharmacodynamics (MOA)
Interacts with seratonin transmission (not
fully understood)
Clinical Uses
Anxiolytic
Pharmacokinetics
Slow onset of action
Side Effects
Few
Anti-convulsants
• Epilepsy: the tendency to recurrent, unprovoked
seizures
– Cause: symptomatic (structural/metabolic brain injury
– either acquired or inherited) or idiopathic (either
mendelian or polygenic)
– Classification: focal or generalised (tonic-clonic or
absence)
• AED act by 3 mechanisms:
– Enhancing GABA mediated transmission
– Inhibiting fast excitatory NT transmission – glutamate
– Inhibiting neuronal AP generation – blocking NA
voltage channels
Phenytoin
Anti-convulsant
dynamics
Blockade of voltage-dated Na+ channels > reduced AP generation
es
Partial epilepsy
Status epilepticus (prolonged seizure)
kinetics
Hepatic metabolism: oxidation, hydroxylation then conjugation (large variation)
Renal excretion
Saturable kinetics; dosing very important
Elimination t ½ 20 hours – monitoring requires at least 5 half lives
Highly pp bound
s
Allergy: rash, vasculitis, fever, hepatitis
Toxic: ataxia, sedation
Chronic: folate deficiency, Vit K deficiency, peripheral neuropathy, myopathy
vant
n
P450 enzyme inducer, therefore large number of drug interactions
• Amiodarone + isoniazid – inhibit metabolism
• Aspirin – disaplaces from PP
• Valproate – displaces + inhibits
• Cyp450 > reduced warfarin, estrogen containing OCP
Drug
Carbazepine
Class
Anti-convulsant
Pharmacodynamics
(MOA)
Blockade of Na+ voltage-gated channels
Clinical Uses
Partial seizures
Secondary generalized seizures
Pharmacokinetics
Half-life 5-26 hours
Hepatic metabolism: oxidation then conjugation. Active metabolite
= carbazepine epoxide
Side Effects
Hypersensitivity: rash, hepatitis, nephritis
Dose-related: ataxia, dizziness, sedation
Chronic: Vit K deficiency, depression
Other relevant
information
Potent hepatic enzyme inducer
Complex drug interaction profile
Drug monitoring useful
Drug
Sodium valproate
lass
Anti-convulsant
harmacodynamics
MOA)
Mechanism not known, but enhances GABA via number of mechanisms
linical Uses
Partial seizures
Generalised seizures
harmacokinetics
Half life 4-12 hours
Metabolism by hepatic oxidation and conjugation – no active metabolites
Renal excretion
ide Effects
Severe adverse drug reactions: Severe hepatic toxicity, pancreatitis,
encephalopathy, tremor, blood dyscrasias
ontraindications
Co-administration with penytoin, phenobarbitol + carbazemazepine
Other relevant
nformation
Potent inhibitor of hepatic enzymes > important drug reactions
Drug
Vigabatrin
Class
Anti-convulsant
Pharmacodynamics (MOA)
Irreversible inhibition of GABA transferase
(involved in metabolism of GABA to SCA)
Clinical Uses
Partial epilepsy
Pharmacokinetics
Half life 7 hours
Side Effects
Visual field constriction
Other relevant information
May worsen some generalized seizures
Drug
Lamotrigine
Class
Anticonvulsant
Pharmacodynamics (MOA)
Unknown
Clinical Uses
Partial epilepsy
Generalised epilepsy
Pharmacokinetics
Half life 8 hours
Side Effects
Well tolerated
Anti-Parkinsonians + Neuroleptics
• Parkinson’s affects the Nigrostriatal dopaminergic
pathway (projected from substantia nigra to striatum) –
involved in control of movement
– Neuropathology: nigrostriatal pathway degeneration,
accumulation of Lewy-Bodies (containing toxic proteins),
cell loss > 85% dopaminergic neuron loss + 70% striatal DA
depletion
• Schizophrenia affects the Mesolimbic dopaminergic
pathway (projected from ventral tegmental area to
nucleus accumbens etc) – involved in emotion
– Neuropathology: excessive dopamine transmission
through mesolimbic region (DA action on D2 receptors) >
positive symptoms (delusions, hallucinations, etc), and
dopamine deficit in pre-frontal regions (D1 mediated) >
negative symptoms (withdrawal, flattening of emotional
responses)
Drug
L-DOPA
Class
Anti-parkinsonian
Pharmacodynamics (MOA)
Dopamine replacement therapy. DOPA doesn’t cross BBB, but
L-DOPA can cross BBB and be centrally converted to DOPA.
This occurs if peripheral conversion of L-DOPA to DOPA does
not occur (involving DOPA-decarboxylase)
Clinical Uses
Hypokinesea, rigidity + tremor associated with Parkinson’s
Pharmacokinetics
Start with low dose; response decreases with disease
progression
Side Effects
Acute:
• Nausea (prevents by Domperidone)
• Hypotension
• Psychological (schizophrenia-like effects)
Chronic:
• Diskinesias
• Rapid fluctuations in clinical state
Drug
Domperidone
Class
Anti-parkinsonian drug
Pharmacodynamics (MOA)
DOPA-decarboxylase antagonist– inhibits peripheral
conversion of L-DOPA > DOPA, therefore increasing quantity of
L-DOPA crossing BBB
Clinical Uses
Administered with L-DOPA; allowing lower dose of L-DOPA to
be used, and boosting its effect
Side Effects
Chronic:
• Diskinesias
• Rapid fluctuations in clinical state
Drug
Carbidopa
Class
Anti-parkinsonian drug
Pharmacodynamics (MOA)
Inhibits DOPA-decarboxylase action in periphery, so more LDOPA reaches the CNS
Clinical Uses
Treatment of bradykinesias, tremors and rigidity associated
with Parkinsons
Pharmacokinetics
Administered in conjunction with L-DOPA
Side Effects
Chronic:
• Diskinesias
• Rapid fluctuations in clinical state
Drug
Bromocriptine
Class
Anti-parksinonian drug
Pharmacodynamics (MOA)
DA (esp D2) receptor agonist
Clinical Uses
Used in conjunction with L-DOPA (to treat bradykinesias etc)
when L-DOPA becoming less effective
Pharmacokinetics
Oral administration
Crosses BBB
Longer duration of action than L-DOPA, therefore less
diskinesias
Side Effects
Common – confusion, dizziness, nausea/vomiting,
hallucinations
Rare – constipation, headache, dyskinesias
Contraindications
Ergot ring structure can cause problems with heart valves
Drug
Deprenyl
Class
Anti-parkinsonian drug
Pharmacodynamics (MOA)
Selective MAO-B inhibitor; prevents central breakdown of DA,
therefore prolonging action
Clinical Uses
Preservation of naturally synthesised DA in early Parkinson’s
Administration in conjunction with L-DOPA to reduce dose
Pharmacokinetics
Side Effects
Rare – hypotension, nausea/vomiting, confusion, agitation
Drug
Entacapone
Class
Anti-parkinsonian drug
Pharmacodynamics (MOA)
COMT inhibitor; prevents peripheral conversion of L-DOPA to
3-0methylDOPA, thus increasing the bioavailability of L-DOPA
Clinical Uses
To reduce L-DOPA dosage
To boost response to L-DOPA in patients starting to show
tolerance
Side Effects
Marked side effect profile – CVS effects
Drug
Chlorpromazine
Class
Neuroleptic
Pharmacodynamics
(MOA)
Dopamine receptor antagonists (particular D2 + D4) > reduce
dopamine transmission through mesolimbic region > reduction in
positive symptoms
Clinical Uses
Treatment of schizophrenia
Pharmacokinetics
Initially compensatory mechanisms to increase DA synthesis, but
these decline with therefore slow onset of action
Side Effects
Effects due to non-selectivity of antagonists:
Blocking receptors in chemotactic trigger zone > anti-emetic
Blocking of DA in tuberoinfundular pathway (endocrine) > excess
prolactin > lactation
Blockade of AChM receptors > blurring of vision, increased intraocular pressure, dry mouth, constipation (typical anti-muscarinic
effects)
Blockade of DA receptors in nigrostriatal pathway > Parkinsonian-
Drug
Haloperidol
Class
Neuroleptic
Pharmacodynamics
(MOA)
Dopamine receptor antagonists (particular D2 + D4) > reduce
dopamine transmission through mesolimbic region > reduction in
positive symptoms
Clinical Uses
Treatment of schizophrenia
Pharmacokinetics
Initially compensatory mechanisms to increase DA synthesis, but
these decline with therefore slow onset of action
Side Effects
Effects due to non-selectivity of antagonists:
Blocking receptors in chemotactic trigger zone > anti-emetic
Blocking of DA in tuberoinfundular pathway (endocrine) > excess
prolactin > lactation
Blockade of AChM receptors > blurring of vision, increased intraocular pressure, dry mouth, constipation (typical anti-muscarinic
effects)
Blockade of DA receptors in nigrostriatal pathway > Parkinsonian-
Drug
Sulpride
Class
Neuroleptic
Pharmacodynamics
(MOA)
Dopamine receptor antagonists (particular D2 + D4) > reduce
dopamine transmission through mesolimbic region > reduction in
positive symptoms
Clinical Uses
Treatment of schizophrenia
Pharmacokinetics
Initially compensatory mechanisms to increase DA synthesis, but
these decline with therefore slow onset of action
Side Effects
Effects due to non-selectivity of antagonists:
Blocking receptors in chemotactic trigger zone > anti-emetic
Blocking of DA in tuberoinfundular pathway (endocrine) > excess
prolactin > lactation
Blockade of AChM receptors > blurring of vision, increased intraocular pressure, dry mouth, constipation (typical anti-muscarinic
effects)
Blockade of DA receptors in nigrostriatal pathway > Parkinsonian-
Drug
Clozapine
Class
Neuroleptic
Pharmacodynamics
(MOA)
Dopamine receptor antagonists (particular D2 + D4) > reduce
dopamine transmission through mesolimbic region > reduction in
positive symptoms
Clinical Uses
Treatment of schizophrenia
Pharmacokinetics
Initially compensatory mechanisms to increase DA synthesis, but
these decline with therefore slow onset of action
Side Effects
Effects due to non-selectivity of antagonists:
Blocking receptors in chemotactic trigger zone > anti-emetic
Blocking of DA in tuberoinfundular pathway (endocrine) > excess
prolactin > lactation
Blockade of AChM receptors > blurring of vision, increased intraocular pressure, dry mouth, constipation (typical anti-muscarinic
effects)
Blockade of DA receptors in nigrostriatal pathway > Parkinsonian-
11. Anaesthetics
General Anaesthetics
• Common property: inducing loss of consciousness at
low concentrations
• Desirable effects:
– loss of consciousness (propofol) – depression of
thalamocortical neurons + RAS
– analgesia (opiates)
– suppression of reflex responses (enflurane) – depression
of reflex pathways in spinal cord
– muscle relaxation (NM blockers)
– amnesia (benzodiazepines) – decreased synaptic
transmission in hippocampus + amygdala
• May be gaseous or intravenous
• The more lipid-soluble, the more rapid the onset of
action. For inhaled GAs, a lower blood-gas partition coefficient means more lipid-soluble and remains
gaseous for longer.
Drug
Propofoll
Class
General anaesthetic
Pharmacodynamics (MOA)
Binds to GABA-a receptor to facilitate
opening + GABA-mediated inhibition
• B3 subunit = anaesthetic effect
• A5 subunit = amnesia effect
Clinical Uses
Inducing loss of consciousness
Pharmacokinetics
Intravenous administration
Fast recovery
Drug
Etomidate
Class
General anaesthetic
Pharmacodynamics (MOA)
Binds to GABA-a receptor to facilitate opening + GABAmediated inhibition
• B3 subunit = anaesthetic effect
• A5 subunit = amnesia effect
Pharmacokinetics
Intravenous administration
Fast recovery
Drug
Nitrous oxide
Class
General anaesthetic
Pharmacodynamics (MOA) Blocks excitatory NMDA-type glutamate receptors
Neuronal nicotinic Ach receptor antagonists
TREK (background leak) K+ channel agonists > increase
hyperpolarisation
Pharmacokinetics
Gas administration
Fast recovery
Drug
Halothane
Class
General anaesthetic
Pharmacodynamics (MOA)
Potentiate GABA-A receptor function (no subunit specificity)
Blocks excitatory NMDA-type glutamate receptors
Neuronal nicotinic Ach receptor antagonists
TREK (background leak) K+ channel agonists > increase
hyperpolarisation
Pharmacokinetics
Gas administration
Medium recovery )higher blood-gas partition coefficient)
Side effects
Rare liver toxicity
Drug
Enflurane
Class
General anaesthetic
Pharmacodynamics (MOA)
Potentiate GABA-A receptor function (no sub-unit
specificity)
Blocks excitatory NMDA-type glutamate receptors
Neuronal nicotinic Ach receptor antagonists
TREK (background leak) K+ channel agonists > increase
hyperpolarisation
Clinical Uses
Suppression of reflex responses and maintenance of
anaesthesia
Pharmacokinetics
Gas administration
Medium recovery (higher blood-gas partition coefficient)
Local Anaesthetics
• Definition: drugs which reversible block neuronal
conduction when applied locally
• Structural group areas: aromatic benzene-like ring,
basic amine side chain (usually tertiary amine) +
bridging group (ester linkage eg cocaine, amide linkage
eg lidocaine)
• Different routes of administration:
–
–
–
–
–
–
Surface
Infiltration (subcutaneous)
Intravenous regional
Nerve block
Spinal
Epidural
Drug
Cocaine
Class
Local anaesthetic (ester)
Pharmacodynamics (MOA)
Unionised basic structure diffuses inside sensory axon and
then is ionized (to reach equilibrium). Ionized cation binds to
voltage-sensitive Na+ channels, preventing rapid
depolarisation by blocking the flow of ions = HYDROPHILIC
PATHWAY
Pharmacokinetics
Surface administration
Good mucuous membrane absorption
Pka 8-9
90% plasma protein bound
Metabolized in liver + plasma (non-specific esterases)
T ½ 1 hour
Side Effects
CNS stimulation: restlessness, confusion, tremor (paradoxical)
CVS: myocardial depression, vasodilation, hypotension
Drug
Lidocaine
Class
Local anaesthetic (amide)
Pharmacodynamics (MOA)
Unionised basic structure diffuses inside sensory axon and
then is ionized (to reach equilibrium). Ionized cation binds to
voltage-sensitive Na+ channels, preventing rapid
depolarisation by blocking the flow of ions = HYDROPHILIC
PATHWAY
Pharmacokinetics
Various routes of administration
Hydrolysed in liver, then undergoes n-dealkylation
70% plasma protein bound
T ½ 2 hours
Side Effects
CNS: euphoria and excitation
CVS: increased cardiac output, vasoconstriction, hypertension