Pharmacology Key Notes
Session 1 - How do Drugs Work



Compliance
o Reasons for non-compliance - no symptoms felt, worries about dependency, side
effects, price of prescriptions
o Improve compliance - patient education, simple regimes, reduce SE’s
Pharmacokinetics - what the body does to a drug - ADME
o Absorption - how drugs get in - Sublingual (GTN), PR (diazepam - status epilecticus),
 First pass metabolism - extent of metabolism occurring before the drug enters
the systemic circulation. Mainly due to breakdown by the liver (affects oral and
PR drugs)
 Bioavailability (F) - fraction of administered drug that reaches circulation
unaltered (For IV, F = 100%; For oral F = % unaltered after first pass of gut and
liver)
o Distribution - some drugs bind to proteins, decreased proteins  more unbound active
drug
o Metabolism - hepatic drug metabolism. Either phase 1, phase 2 or both can happen to a
molecule
 Phase 1 - addition of a functional group to allow conjugation if the drug cant
already
 Phase 2 - conjugation, which adds a heavy, polar, biologically inactive group
o Excretion - Kidneys (main route - CKD!!), bile, lungs. Kidneys
 Glomerular Filtration - only unbound drugs
 Passive Tubular reabsorption - affected by pH and the formation of conjugate
acids/bases (charged molecules cant cross)
 Active Tubular Secretion - proximal tubule
 CKD  ↑ drug levels, anaemia, vit D def (osteoporosis), poor BP control
 Peripheral Swelling causes- HF, LF, CKD, local infection, lymph block
 Kidney is likely to be the first organ to fail due to high blood demand required to filter blood; needed to supply high ATP demand of channels
o Definitions
 Zero order kinetics - rate of elimination is constant - PEA, Phenytoin, Ethanol,
Aspirin
 First order kinetics - metabolic rate  to amount of drug (fraction eliminated is
constant). Half-life exhibits this property
 Volume of Distribution - relates the amount of drug in the body to the amount
in the serum = vol body/vol serum
 Clearance - relates rate of elimination to plasma concentration
 Loading Dose - initial large bolus of a drug to help get to equilibrium steady
state levels faster (usually takes 5 half lives to get there) - shots of alcohol!
Pharmacodynamics - what the drug does to the body
o Efficacy - the maximum effect a drug can have
o Potency - amount of drug needed to give this effect (high potency requires ↓ dose)
o Therapeutic Window - measure of drug safety (mortality or morbidity)
1|Page


= (median lethal dose/median effective
dose) - higher is better!
o Receptors - see molecules
The terms therapeutic and toxic are arbitrary and simply
two ends of a spectrum
Session 2b - Drug Metabolism in the Liver





The Liver structure - lobules (hexagonal functional units) with portal triads at the each corner
and a central vein in the middle taking venous blood back to the heart. Contains hepatocytes
with the basolateral surface facing the sinusoids (mixed venous and arterial blood towards the
central vein - for kidney excretion) and the apical surface facing the bile canniculi (for liver
excretion)
o Functions (lots!) - Drug metabolism! Plasma protein synthesis (clotting factors),
Metabolism (interconversion and storage of glucose), Bile excretion
o Has three functional zones
 Zone 1 (periportal) - involved in oxidative metabolism
 Zone 2 (Intermediat zone)
 Zone 3 (centrilobular zone) - P450 system, senstive to toxic injury, affected first
by ischaemia, alcoholic hepatitis
Drug Metabolism in the liver
o Phase 1 reactions (cytochrome P450 reactions) - oxidation, reductions and hydrolysis introduces functional groups for reaction in phase 2 reactions
 CYP3A (does lots) - Ca blockers, statins, antihistamines
 CYP2D6 (converts codeine and diamorphine  morphine)
o Phase 2 - conjucation (adding large, polar, biologically inactive groups). Adds GAS Glucuronyl, Acetyl, Sulfate
Paracetamol - narrow therapeutic window - Usually conjugated in Phase 2 metabolism with
glutathione. In overdose glutathione is depleted and paracetamol undergoes P450 Phase 1
reaction to toxic metabolite NAPBQI which causes hepatic necrosis. Antidote is through Nacetylcysteine which regenerates glutathione
P450 interactions (CYP3A)
o Inducers - speed up metabolism of P450 and reduce drug effects - Quinidine,
Barbituates, St. Johns Wort (importance of a full drug history), Rifampacin,
Carbamazepine, Chronic Alcohol use
o Inhibators - slow down metabolism - MAGIC RACKS - Macrolides, Amiodarone,
Grapefruit Juice, Itraconazole, Cimetidine, Ritonavir, Acute Alcohol abuse, Ciprofloxacin,
Ketoconazole, Sulfonamides - check with english drugs!
Liver Disease - cirrhosis - diffuse fibrousis and nodular regeneration of hepatocytes  decreased
metabolic capacity  increased bioavailability and decreased protein binding
2|Page
Reproductive System
Session 2a - Hormone Replacement






Properties of Oestrogen - (from granulosa cells after stimulation by FSH)
o Many sub types of oestrogen receptors which are tissue dependent and specific
 can be targeted with selective oestrogen receptor modulators (SERMs) to have
antagonistic effects at one site but agonistic affect at another
o Allows Sexual characteristics to form
o Structural - proliferation in Endometrium, myometrium, bone, breast, skin - link to
endometrial and breast cancer
o Coagulation - Thromboembolic effects of pregnancy and birth control - links to CV
disease
o Lipid - Higher levels of HDL which is the good cholesterol
o Suppression of HPO axis
Properties of Progesterone (from corpus luteum (maintained by hCG from syncytiotrophoblast))
o Structural - stabilizes structures that oestrogen has built up (Endometrium,
Myometrium, Breast)
o Affects lipid ratio - less lipid benefit
o GI delays - Smooth muscle relaxant, leads to constipation in pregnant women
o HPO Suppression
Other Menstrual cycle hormones
o FSH - stimulates follicle development (stimulates granulosa cells)
o LH - stimulates ovulation/ development of corpus luteum (secretes progesterone when
stimulated by hCG from syncytiotrophoblast placenta)
o Inhibin - stops FSH secretion (but not LH). In men it is involved in spermatogenesis
Inadequate sex hormone secretion - occurs due to:
o Adolescence (androgen insensitivity) - give oestrogen (no uterus to worry about
proliferating), allows 2O sexual characteristics to form
o Chemotherapy - can start the menopause due to ovary damage - P and O
o Menopause - P and O levels decrease due to reduced synthesis in ovaries
 Triad of symptoms - hot flushes, night sweats (can lead to poor sleep  poor
concentration and memory etc), vaginal dryness
 Other symptoms - UTI’s osteoporosis
 Treat with O (relieves symptoms, slows bone loss, lipid benefit) or P + O
(relieves symptoms and has endometrial protective effect (but not breast))
Oestrogen Receptor (ER) - some tumours have this receptor and can be attacked using hormone
manipulation. The receptors are tissue dependent and tissue specific meaning that the act
differently in different tissues
Inappropriate response to sex hormone dependent tissues
o Breast cancer - if expresses ER then give SERM. Tamoxifen - antagonist to breast but
agonist to endometrium (check for adenocarcinoma in uterus)
o Endometriosis - endometrial tissue outside the endometrium.
 Tx - GnRH agonist, GnRH needs to be pulsatile to work therefore induces
menopause (risk of menopause symptoms)
 Add-back therapy (little bit of Oest) to protect against osteoporosis
o Fibroids - non cancerous tumours in or around the uterus
 Tx - GnRH agonist + add-back therapy - as above
3|Page


Dysfunction of HPO axis
o Infertility
o PCOS (polycystic ovarian syndrome) - insulin resistance  hyperinsulaemia  ovary
production of androgens  male sex steroid effects (hair, baldness)
Don’t use HRT for osteoporosis alone due to increase in CV risk (stroke, MI, clots) and breast
cancer, even though it lowered risk of hip fractures and colon cancer
o Still use it for menopause symptoms
Contraception

See Repro session 6b
4|Page
Cardiovascular System


Angina - pain or discomfort in the chest when blood supply to part of the myocardium is
temporarily inadequate for its needs. Central heavy/crushing chest pain radiating to neck, jaw
or arms. Usually caused by coronary atheroma
o Comes with exercise, meals, cold weather (increased TPR), goes with rest (<10mins)
o Tx - lifestyle, statins, GTN’s
ACS - Unstable Angina, NSTEMI, STEMI
o Unstable Angina - as angina but comes with progressively less exercise or at rest. Lasts
10-20 mins, No troponin T levels. Tx
 Tx - Send to hospital, see below
o NSTEMI - As above + sympathetic NS activation. Lasts > 30 mins. Troponin T positive.
ST depression
 Tx - MONA + cyclizine + urgent PTCA (72 hours) or thrombylsis if PTCA not
available
o STEMI - as above but with ST elevation. Tx involves:
 Pre-hospital - MONA + cyclizine + have defib ready
 Acute - PTCA
 Further Management - CABS - Clopidogril, ACEi/ARB, -blocker, Statins
Session 3a - Angina


There are three strategies for treating Angina Pectoris:
o Reduce CV risk factors - Aspirin, Statins
 Reversible Risk Factors - BP, cholesterol, smoking
o Decrease metabolic demand of LV
 Reduce heart rate - -blocker, Ivabradine (If channel blocker)
 Reduce arterial pressure - afterload reduction - Calcium Channel blockers Nifedipine (only works on arteries), Verapamil, Diltiazem
 Reduce ventricular size - preload reduction - GTN
o Increase coronary blood flow (GTN achieves this a bit)
Aspirin - Anti-coagulant, anti-inflammatory, annipyretic, analgesic
o Antiplatelet treatment via COX inhibition (AATA2 and prostacyclins)  ↓ risk of MI,
stroke and peripheral vascular damage
o TA2 (causes platelet aggregation and vasoconstriction) vs Prostacyclin’s (antiaggregation and vasodilation) - TA2 made in platelets with no nucleus therefore useless.
Prostacyclin produced in epithelium which has a nucleus therefore function
regenerates. Therefore process favours anti aggregation
o SE - General NSAID side effects. Action is different because it is irreversible
 GI issues (N&V, peptic ulcers (prostaglandin inhibition)
 Increased Bleeding
 Rashes
 Salicylate Toxicity - tinnitus (usually the first sign), vertigo, renal failure,
insomnia, tachycardia, pulmonary oedema, depression, seizures, coma
 Tx - fluid replacement with bi-carb. Sever cases - Haemodialysis
 Reye’s Syndrome - liver and brain disorder triggered by aspirin in children under
16
o Selective COX-2 inhibitors - see later
5|Page






Ivabradine - inhibits If channel in SA node to slow influx of Na and K  reduced chronotropy
o SE - Heart failure, increased ventricular dimensions
-blocker (bispr-olol) - reduces sympathetic drive - stops GDP  GTP and activating adenylyl
cyclase converting ATP  cAMP. Reduces Inotropy and Chronotropy. Ideally want 1-receptors
blockers
o SE - Ivabradine + cold periphery, wheeze (2 effects)
o CI - don’t use in heart failure, bradycardia or asthma
Calcium Channel Blockers - reduces Ca2+ in peripheral vasculature  relaxation and ↓ TPR
o SE - flushing, headaches, ankle swelling
o Dihydropyridines (nifedipine) - only affects arteries
 SE - reflex tachycardia
o Diltiazem and Verapamil - affects the heart too - reduces Ca2+ in cardiomyocytes
 SE - bradycardia, heart failure, oedema
Nitrovasodilators - preferential action to cause venodilation  ↓ preload
o NO  guanylate cyclase  cGMP MLCK phosphosphatase phosphorylation? …… see
molecules  fall in [Ca2+]I  vasodilation
o GTN - taken under tongue to avoid first pass metabolism
o Isoorbide mononitrate - take orally - long lasting GTN
o SE - Tolerance, Vascular headache, Reflex tachycardia, Steal Syndrome
NICE guidance - Beta-blocker or calcium antagonist as first line. Switch them around. Use
together. Add long-acting nitrate OR ivabradine OR nicorandil (opens K+ channels in coronary
arteries) OR ranolazin (affects Na+ dependent Ca2+ channels. SE - inhibits CYP 2D6, increases QT
interval)
Unstable angina
o Antiplatelet ASAP - aspirin, clopidogrel, glycoprotein IIb/IIIa inhibitor (Eptifibatide)
o Anti-thrombin - Heparin or Bivalirudin (direct thrombin inhibitor)
o Nitrates
Session 6a - Acute Myocardial Infarction (MI)





Diagnosis - ECG, Bloods (Troponin T), CXR (?)
Immediate Treatment - MONA - Morphine (+ anti-emetic),
Oxygen, Nitrates, Aspirin
Revascularisation - PCTA is gold standard if can’t get then use
thrombolysis (clot busters)
Late Treatement - CABS - Clopidogrel, ACEi/ARB, -blocker,
Statins
Thrombolysis - breaks down clots (clot lysis)
o Streptokinase - from bacteria - complexes with
plasminogen to make plasmin which causes fibrinolysis
 SE - allergic reaction, Reperfusion arrythmia
 CI - recent use (5 days to 1 year) or infection
o Urokinase - c.f. to sterptokinase
o tPA - selective for fibrin-bound plasminogen,
activating it to plasmin
o CI - Depends on risk vs benefits
 Risks of immune response
 Risk of serious bleeding:
6|Page

 previous haemorrhagic stroke
 any stroke within 6 months
 recent arterial/other major surgery
 peptic ulceration/internal bleeding
 oesophageal varices
 pregnancy
 severe proliferative retinopathy
 PE’s or DVT’s?
o Others - Reteplase, APSAC
Complications of MI - FARMTAP - Failure, Arrhythmia, Rupture, Mural thrombosis,
Thromboembolus, Aneurysm, Pericarditis
Session 3b - High Blood Pressure




Mean arterial Pressure  TPR x CO - to change
Category
Systolic (mmHg) Diastolic (mmHg)
BP you need to change one of these two things
< 90
< 60
TPR - affected by constriction of blood vessels - Hypotension
Normal
< 130
< 85
blood flow is regulated by:
High normal
130-139
85-89
o Metabolic activity - pH, pCO2, pO2
(20’s)
(10’s)
o Neural Regulation - Vasoconstrict (α-1 Hypertension
Adrenoceptors);
Vasodilate
(β-2 Mild
140-159
90-99
Adrenoceptors) - noradrenaline mediated Moderate
160-179
100-109
o Humoral Control - RAAS (↑BP), ANP/BNP Severe
180-209
110-119
(↓BP)
Very severe
> 210
> 120
o Autocrine - NO, Ang II
RAAS - Renin-Angiotensin Aldosterone System - increases blood pressure. (see urinary)
o Activated by decreased perfusion (low Na)
o Pathway - look up
o Angiotensin II actions - increases sympathetic activity, Na absorption, K secretion,
Arteriole vasoconstriction, ADH secretion (post. pit.), Aldosterone secretion (adrenal
gland). Breaks down bradykinin (build up causes a dry cough)
o Aldosterone actions - ↑ Na retention ( oedema and HF), ↓ K (arrythmias)
ANP (atrial natriuretic peptide) - from atria (due to ↑BP), Brain NP - from ventricles (due to ↑
stretch) - Leads to reduced blood pressure by:
o Inhibiting - Na+ reabsorption, renin secretion, ADH release  ↓ Na reabsorption
o Vasodilating afferent arterioles  ↑ GFR
Treatment
 Non Pharmaceutical Tx - Weight, Diet (Dash diet - less Na more K), SMOKING!, lipids (makes Ang
II), Exercise (↑ capillaries in smooth muscle  ↓ TPR)
 Pharmacological - counteract CO and TPR
o Reduce CO
 -blockers (aten-olol) - cardio selective
 Ca Channel Blocker (nifedipine) - vasodilation of arteries
o Effects CO and TPR
 Inhibit RAAS (ACEi (Rami-pril)/ARB (Lo-sartan)) - see HF
 Ca Channel Blocker (Verapamil, Diltiazem) - vasodilation of arteries + decreased
Ca in cardiac myocytes
7|Page


-blockers - non-cardio selective - bronchospasm, increases TPR
Diuretics
 Thiazides
(Bendroflumethiazide)
increase
Na
excretion.
Hyperkalaemia!
 K+ sparing - counteracts K loss of thiazides  High K, Low Na
o Spironolactone (aldosterone receptor blocker) - gynacomastia
 Can treat Conns (primary hyperaldosteronism) - Na
retention and K excretion
o Amiloride (ENaC blocker)
 Can treat Liddle’s (high activity ENaC)
Session 4a - Pharmacology of Blood
Haemostasis - Clotting and Anti-clotting
 Thrombosis - formation of a thrombus (a blood clot within the circulation)  4 B’s (cf to
atheroma 5 B’s - block, blood clot block, break of block, bulge (aneurysm), burst (haemorrhage))
o Note - can occur in arteriole or venous system, not to be confused with atherosclerosis
(an arterial disease) which is thickening of the vessel wall
 Anti-thrombilytic therapy - antiplatelet, anticoagulation, thrombolysis
 Haemostasis
o Vascular Constriction - immediate reaction of vessel
o Platelet Plug - formed by activation of platelets due to exposure to vWF. Activated
platelets release more activators (e.g. TA2 and ADP). Antiplatelets:
 Aspirin - COX inhibitor stops TA2 (also stops prostacyclin’s (stops platelet
aggregation and vasodilation) for a short period but this can regenerate)
 Clopidogril - inhibits ADP
 GP IIb/IIIa inhibitors - fibrinogen receptor - stops cross linking between
platelets
8|Page
o
Clot Formation - extrinsic (fast) and intrinsic (slow) clotting cascades lead to Factor 10a
 active factor 5a  converts prothrombin to thrombin  converts fibrinogen
(incorporated into platelet plug and soluable) to fibrin (insoluable). Anticoagulation:
 Warfarin - PET - Prothrombin Time, Extrinsic. Oral
PET A PITT bull
 Use - DVT, AF, mechanical heart valves, post-MI
 Action - Inhibits Vit K epoxide reductase which affects factors 1972
 CI’s - Pregnancy, Significant bleeding, Haemorrhagic strokes, Severe
hepatic or renal impairment
 Interactions - p450 breaks it down and can be effected by:
o Potentiate - cranberry juice, aspirin, intoxication, cimetidine
o Attenuate - Barbituates, Cholestyramine (lipid lowerer)
 SE’s - Haemorrhage, Alopecia, Purpura, Skin necrosis (protein C and S)
 Reverse - Lower dose, Vit K, Fresh Frozen Plasma
Used for early prophylaxis
whilst Warfarin starts to take Heparin - A PITT - Activated Partial Thromboplastin Time, Intrinsic. Intravenous
 Use - Rapid anticoagulation in PE, MI, Storke; surgery prophylaxis
effect
 Action - binds to antithrombin, increasing its activity in inactivating
Can be used for pregnancy as
thrombin. Needs to be given IV?
doesn’t cross the placenta
 CI’s - Significant bleeding, imminent labour (can be used in pregnancy
though)
 SE’s - haemorrhage, Heparin induced thrombocytopaenia (HIT)
 Reverse - Protamine Sulphate 1%
o Clot Lysis - see thrombolysis for MI above
 Thrombocytopaenia - decrease of platelets in the blood
o Causes - decreased production, Increased destruction (SLE), Iatrogenic (methotrexate,
interferon, heparin)
o HIT - type 1 (normalises with continued therapy, 2 days), type 2 (immune-mediated, 410 days, Tx - lepirudin)
o Tx - platelet transfusion, Destruction causes (corticosteroids, immunosuprresants,
MABs)
Anaemia - find and treat the cause!
 Normocytic, Normochromic - acute blood loss, ACD (anaemia of chronic disease - e.g. CKD),
Haemolytic disease (sickle cell)
o Reticulocytes - immature RBC’s - high count indicates hypergeneration of RBCs - Acute
blood loss or Haemolytic disease
o Transfusions - use for acute blood loss and symptomatic chronic anaemia. Can use
crystalloid/colloid or RBC’s. Replaces lost volume.
 RBC transfusions are a last resort if no other alternatives exist! Issues with
Blood transfusion:
 Allergic/Anaphylaxis, Allo-immune (Graft vs Host), Transfusion
transmitted infection, transfusion associated circulatory overload
 Haemosiderosis (transfusion acquired iron overload) - Tx = Iron chelator
o Recombinant EPO - chronic blood loss or ACD (e.g. CKD) - stimulates RBC’s
 Microcytic, Hypochromic - Iron deficiency (chronic blood loss, malnutrition, menstruation),
Thalassemia (genetic disorders in globin chain production)
o Iron Replacement - Iron deficiencies
 Ferrous sulphate (oral) - risk of overdose! Nausea, diarrhoea, constipation
9|Page


 Iron Dextrin (parenteral) - if intolerant to Oral. Can cause anaphylaxis
 If Iron overload occurs use iron chelators (desferriozamine)
Macrocytic, Normochromic
o Megaloblastic - Vit B12 deficiency (Dietary, Pernicious Anaemia), Folate Deficiency
 Vit B12 (can cause low folate) and folate supplements
 Enzymatic processes - succynal CoA Activation, Produces DNA and RBC,
Methylation of homocysteine (HCY)
o Non-Megaloblastic (Liver Disease, Hypothyroidism, Drug induced)
Crystaloids vs Colloids - Colloids (e.g. blood) contain large particles which can’t be filtered across
a membrane. Crystalloids contain salts.
Session 5a - Arrhythmias




Pacemaker Action Potential (have automaticity - determine their own rate of depol)
o Pacemaker potential - slow diastolic depolarisation due to If channels (Na+) and T-type
Ca2+ channels. Working against efflux of K+
o Depolarisation - once threshold is reached VGCC open causing Ca2+ influx
o Repolarisation - Ca2+ Influx channels close and K+ efflux channels open
Ventricular Action Potential
o Phase 0 - Rapid depolarisation - due to Na+ influx
o Phase 1 - Initial repolarisation - due to inactivation of Na+ influx and initial K+ efflux
o Phase 2 - Plateau - Ca2+ influx counteracts K+ efflux. Ca2+ influx triggers Ca2+ release from
sarcoplasmic reticulum and contraction
o Phase 3 - Rapid depolarisation - opening of slow K+ channels leads to large efflux and
closure of Ca2+ influx
o Phase 4 - Resting potential - Na+ and K+ exchange
Causes of Arrhythmias
o Re-entry - most common cause - needs unidirectional
conduction block, Multiple pathways for impulse conduction,
Critical slowing of conduction to allow re-entry into previously
refractory tissue
o Triggered activity - EAD, DAD (early/delayed after
depolarisation)  tachcardia
Antiarrythmics - work by changing the rate of depolarisation/repolarisation of cells. Naughty
Boys Kick Cats
o Na+ channel blockers - affect Phase 0
 Class 1a - Quinidine - ↑ AP duration by binding to inactive Na+ channels
 Uses - Atrial and ventricular arrhythmias
 SE’s - headaches and tinnitus
 Class 1b - Lignocaine - ↓ AP duration by binding to depolarised Na+ channels
 Uses - Acute ventricular arrhythmias (post-MI)
 SE’s - local anaesthetic
 Class 1c - Flecainide - no affect on AP duration.
 Use - VT and VF
 CI - 1C is Contraindicated post-MI - pro-arrhythmic
o -blockers (Bisopr-olol) - reduces chronotropy and inotropy (decreased cAMP 
decreased [Ca2+]i) - reduces sympathetic drive
 Uses - AF, atrial flutter, VT, SVT
10 | P a g e


SE’s - Impotence, Bradycardia, HF, Bronchospasm, cold periphery, claudication,
worsens lipid profile, weight gain
+
o K channel blockers (amiodarone (40% iodine!), sotalol) - ↑ AP by delaying
repolarisation (K+ efflux)
 Use - safest short term (not good long term!), SVA, VA
 SE’s - pulmonary fibrosis, hepatotoxicity, thyroid dysfunction, potentiates
(warfarin and digoxin), peripheral neuropathy, corneal deposits
2+
o Ca channel blockers (Verapamil, Diltiazem) - affects Ca2+ influx in pacemaker cells and
reduces amplitude in myocytes
 Use - SVT, antihypertensive, anti-angina
 SE’s - reduced inotropy, constipation, flushing, oedema
Other drugs
o Cardiac Glycosides (Digoxin) - inhibits Na+:K+ exchange  indirect inhibition of Na+: Ca2+
exchanger  ↑ [Ca2+]I  positive inotrope. Stimulates the Vagus  ↓ HR
 Uses - HF, AF
 SE’s - hyperkalaemia, arrythmias
o Adenosine - ↑ K+ out of cells  hyperpolarised cell  blocked AVN for ~15 secs. Used
to diagnose or abolish (AVN dependent) supraventricular tachycardia
 SE - Flushes, hypotension, chest pain (warn patient)
o Atropine - inhibits M2 receptors (Ach) therefore stops parasympathetic system (↑ HR) no effect on arrhythmias - Use for bradycardia and MI
o If Channel Blockers (ivabradine)- stops Na+ influx in SA node therefore slows HR
Session 5b - Heart Failure




Heart Failure - The inability of the heart to pump adequate blood. Vicious cycle
o Decreased CO  Fall in BP  Detected in baroreceptors and increased sympathetic
activation  Vasoconstriction  Increased afterload  Decreased CO
o Also leads to activation of RAAS
ACEi (Rami-pril) - stops RAAS - 1st line
o SE
dry
cough
(bradykinin),
hypotension, hyperkalaemia, bilateral
renal stenosis
ARB (Lo-sartan) - stops RAAS - if ACEi intolerant
o SE - c.f. to ACEi, NO dry cough
o CI - pregnancy, bilateral renal artery
stenosis
-blockers - Inhibit SA node, AV node,
myocardial contractility  ↓HR, reduce
afterload, ↑ coronary flow by increasing
diastolic filling time, reduce cardiac work and
↑CO
o Bisprolol, metoprolol, carvedilol - 1
selective (SA, AV, myocardium affects only)
o SE - see arrhythmias
Acute HF Tx - Loop diuretics, opioids, GTN, ACEi
Chronic HF Tx - diuretics, ACEi/ARB, Cardiac glycosides
11 | P a g e




Diuretics
o Loop Diuretics (furosemide) - inhibits Na:K:2Cl reabsorption in ascending loop of henle.
Leads to Na and water excretion. Get some Na exchange in the collecting duct for H+ or
K+
 SE - metabolic alkalosis, hypokalaemia, hyponatraemia, hypovolaemia, ototoxic
(THINK OF ACTION OF DRUG)
 Bumetanide - more nephrotoxic less ototoxic
o Thiazide (bendrofluazide) - inhibits NaCl reabsorption in distal convoluted tubule leads
to Na and water excretion. Get some Na exchange in the collecting duct for H+ or K+
 SE - see loop diuretics (no ototoxic), Gout (thiazides compete for uric acid
secretion)
 Metolazone (thiazide like) - more powerful
o K+ sparing - works in the collecting duct, counteracts effects of other diuretics
 Spironolactone - aldosterone antagonist - also used for Conn’s Syndrome
(primary hyperaldosteronism)
 Amiloride - ENaC blocker - also used for Liddle’s Syndrome (overactive ENaC)
Nitrovasodilators (GTN, Isoorbide mononitrate) - reduce preload (see angina)
Cardiac Glycosides (digoxin) - see arrythmias
Arteriole Dilator (Hydralazine) - unknown mechanism
12 | P a g e
Session 4b - Thyroid




Thyroid hormones (affects the B’s) - BMR, Bone growth, Brain maturation, Beta-androgenic
effects. Calcitonin (calcium regulation)
o Hyperthyroidism (thyrotoxicosis) - too much thyroid hormones
 Caused by - Grave’s (autoimmune activation of TSH receptors  myxoedema,
Goitre, Exopthalmos), MNG (multinodular Goitre), Hormone secreting tumours
 Signs/symptoms - think of hormone function (hot, weight loss, hyperactive,
tachycardia); Graves (goitre, exopthalmus, myxoedema); moist skin
 Treatment
 Thioamid (carbimazole, propylthiouracol) - inhibits TPO and PTU also
inhibits peripheral conversion. 2 week lag due to lack of effect on
stored hormones
o SE - Rashes, agranulocytosis (↓WBC), Necrosis
 Iodine - paradoxical inhibition of synthesis, variable length of effect
 Radioactive Iodine - preferred to surgery - partial destruction o the
gland
o SE - hypothyroidism, cancer risk to nearby children and
pregnant women
 Thyroid Storm - medical emergency - V. high levels of T3/T4  HF, AF, coma,
hyperthermia
 Treatment - IV steroids, propranolol (blocks T4 - T3 conversion),
Amiodarone (K+ antiarrhythmic - messes up thyroid), PTU
(propylthiouracil)
o Hypothyroidism- too little thyroid hormones
 Caused by - autoimmune (Hashimoto’s), previous anti-thyroid treatment
(thyroidectomy, radiation damage), iodine deficiency
 Signs/Symptoms - think of hormone function (cold, weight gain, hypoactive,
bradycardia); myxoedema (dry firm waxy swelling of skin); dry, cool skin;
course, brittle hair; Goitre
 Tx - Levothyroxine (synthetic T4 with long half life), Liothyronine (synthetic T3
short half life and rapid effect)
 SE - sympathetic activation (palpitations, tachycardia, arrhythmias),
cardiotoxicity (build up dose slowly)
Impaired peripheral conversion of T3 to T4 is caused by:
o Fasting, propranolol, acute trauma, systemic illness, amiodarone, PTU,
glucocorticosteroids
Thyroid Tumours - Papillary adenocarcinoma (80%), Follicular adenocarcinoma (10%), Medullary
adenocarcinoma (5%), Anaplastic carcinoma
Thyroid Hormone Synthesis - controlled by TSH from anterior pit. in response to TRH from
hypothalamus. Somatostatin inhibits the process
o Iodine transported in by Na:I symporter (powered by Na:K ATPase) (stim by TSH)
o Thyroglobulin (Tg) synthesis by RER and secreted into follicle (stim by TSH)
o Tg iodination by thyroid peroxidase (TPO)  MIT DIT, T3 (triiodothyronine), T4
(thyroxine) (stim by TSH)
o Endocytosis and hydrolysis of T3, T4 from Tg (rest is recycled) (stim by TSH)
o Secretion of T3/T4 (stim by TSH)
13 | P a g e
Session 6b - Cancer (links to Molecules, MoD + systems)

Benign
Malignant
Tumour = a swelling. Neoplasm = abnormal growth of cells which persists after the initiating
stimulus has been removed (it has escaped normal regulation). Benign (-oma) = compact mass
that hasn’t passed through the basement membrane. Malignant (-sarcoma, -carcinoma) =
spreads into surrounding tissue and metastasises. Metaplasia - a reversible change from one
cell type to another. Dysplasia = a premalignant conditions with increased cell growth, cellular
atypia and altered differentiation.
Behaviour
Macroscopic
Microscopic
 No invasion
 Capsule
 Nuclear variation in size, chromasia and shape is
enclosed
minimal – mostly normal
 No metastasis
 Well defined
 Low mitotic count, normal mitoses
 Retain function
edge
 Retention of specialization
 Variable growth
rate, often slow
 Structural differentiation retained
 Organized
 Expansile cohesive growth
 Invade
 Ill-defined
 Nuclear variation in size, chromasia and shape
margin
minimal to marked, often variable
 Metastasise
 Low to high mitotic count, abnormal mitoses
 Cells lose function  Haemorrhage
 Necrosis
 Loss of specialization
 Variable growth
rate, may be fast
 Structural differentiation shows a lot of changes
 Not organized
 Local invasion beyond normal boundaries
 Carcinogenesis - transformation from normal to neoplastic cells through genetic alterations by
carcinogens (environmental agent that precipitates tumour causation) Carcinogens:
o Radiation - UV, ionising
o Chemicals - polycyclic aromatic hydrocarbons (soot), aromatic amines (dyes)
o Occupational exposure - asbestos (mesothelioma), dyes, soot
o Viruses - Hep B (hepatocellular carcinoma), HPV (cervical), EBV (Burkitt lymphoma)
o Micro-organisms - bacteria (H.pylori - gastric lymphoma), Fungi (aspergillus flavus liver), parasites (schistosoma - SSC of bladder)
o Exogenous Hormones - oestrogens (endometrial cancer)
 Essential Alterations for Malignancy (The Magnificent seven) - GMAILED
o Growth Factors Self Sufficiency - proto-oncogenes (GOF oncogenes)
o Metastasis
o Angiogenesis (sustained)
o Insensitivity to Negative Growth Signals - LOF TSGs - Rb (E2F)
o Limitless Replicative Potential (GOF telomerase)
o Evasion of Apoptosis
o Defects in DNA Repair (p53)
 Metastasis - the ability to distant, non-contiguous sites.
o Spread - via blood, lymphatic’s, transcoelomicly, iatrogenically.
 To Bone - BLT KP - breast, lung, thyroid, kidney, prostate (oseteosclerotic,
others are osteolytic)
 To Lung - all sorts due to large venous vascular supply. kidney = cannoball
 To Liver - GI cancers, bronchial, breast
 To Brain - Lung, Breast, Kidney, Melanoma
o Mechanisms
14 | P a g e







Altered cell-cell adhesion - discohessive due to ↓ expression of cadherins
Altered cell-stromal interactions - ↓ expression of integrin’s (attachment to
stroma)
 Altered Enzyme synthesis - Malignant cells stimulate stromal fibroblasts to
synthesise more MMP enzymes (Collagenases, Gelatinases, Stromelysins) that
break down the BM
 counteracted by TIMPs (Tissue Inhibitors of Matrix MetalloProtinases)
 Spread and growth at Distant sites
 Invade through the BM (MMP vs TIMP)
 Pass through the extracellular matrix (MMP vs TIMP)
 Intraversion (MMP vs TIMP)
 Immune interaction (↓ MHC-1)
 Platelet adhesion (GF release) - thrombotic effects
 Adhesion to endothelium (CD44)
 Extraversion (MMP vs TIMP)
 Angiogenesis (VEGF, BFGF - fibrosis, healing, blood supply)
Oncogenes - an activated proto-oncogene whose presence predisposes to malignancy, usually
by eliciting a continuous and unregulated growth signal. Examples:
o Ras - activation causes cell growth. It is a G protein which is active when bound to GTP,
can’t hydrolyse itself to switch off when mutated therefore permanently on
 RAS  RAF  MEK-P  MAPK-P
o HER-2 - tyrosine kinase receptor - an abnormal epidemial growth factor receptor (EGFR)
found in breast cancer (AD). Tx - Herceptin
o Myc
Tumour Suppressor Genes (TSG) - genes that inhibit tumour formation because their protein
product inhibits mitosis. Both copies of a gene need to be mutated to predispose to malignancy.
Examples:
o Rb - AD; normally inhibits E2F growth factor, phosphorylation leads to deregulation of
E2F; two hit hypothesis
o p53 - G1/S checkpoint; induces repair or apoptosis as necessary),
o SMAD, Wnt-APC, BRCA1
Genetics
o Susceptibility
 Xeroderma pigmentosum (AD) - limited repair of UV dmg  melanomas
 Ataxia Telangiectasia (AR) - susceptible to ionising radiation and low ATM
(activates p53)
o Inheritance
 Familial adenomatous polyposis (AD, APC gene - TSG),
 Breast cancer - HER-2 (AD, oncogene) and/or BRCA1 (TSG)
 Neurofibromatosis (AD)
 Rb (TSG, AD)
Medical conditions predisposing to cancer - anything with prolonged inflammation
o UC, cirrhosis, Hashimoto’s thyroiditis, Coeliacs, Barrett’s Oesophagus
Symptoms
o Local affects - Pressure (atrophy), obstruction (of hollow viscera) , invasion (into local
tissue), ulceration ( haemorrhage) - latter 2 only for malignant
o Systemic effects - para-neoplastic syndromes
15 | P a g e










Endocrine effects of excess secretion due to local growth of glands or ectopic
production (small cell lung carcinoma  ACTH (Cushings) or ADH (SIADH))
Haematological - anaemia, thrombosis (procoagulant)
Cachexia, Malaise, Pyrexia (pyrogens = IL1, IL2, IL6 and TNF-)
Pigmentation, Pruritis
Stage
o TNM - tumour (size 1-4), nodes (0-1), metastasis (0-1)
o Dukes - A (confined to bowel wall), B (through bowel wall), C (lymph nodes), D (met)
o Ann Arbour - for Hodgkins lymphoma (Reed-Sternberg Cells - binucleate B-cells)
 I (single lymph node), II (2 or more LN, same side of diaphragm), III (LN both
sides of diaphragm, IV (metastatic spread
 B symptoms - fever, drenching night sweats, weight loss
Grade - degree of tumour differentiation (well, moderate or poor)
o look for tubule formations, nuclear pleomorphism, mitotic rate
Nottingham Prognostic index - stage + grade + size for breast cancer - score of 2-9
Tumour Markers Screening criteria - SEE PINK! for emotional effects of screening (Wilson and Junger)
o Cervical, breast, colorectal
Cell Cycle - G1 (synthesis of components for DNA synthesis)  G1/S checkpoint (size,
components, environment)  S (synthesis of DNA) G2 (synthesis of components for mitosis)
 G2/M checkpoint (size, components, environment)  mitosis (IPMAT)
Treatment
Principles
 Kill all cancer cells - cytotoxic drugs have 1st order kinetics therefore need multiple doses
 Use combinations to minimise resistance - each drug is: anti-neoplastic, a different mechanism
of action (different cancer cell target site), have a different site for organ-specific toxicity
o Surgery + Radio ± Chemo-Therapy
 Spare host cells - target rapidly dividing cells (SE’s - GI, hair, bone marrow, sterility), target
specific mechanisms of growth, local drug administration, local drug targeting
 Tumour resistance
o Increased rate of DNA repair (alkylating agents; cisplatin)
o Formation of trapping agents for reactive oxygen species
o Change in target enzymes (dihydrofolate reductase and methotrexate)
o Reduced pro-drug activation (6-mercapto-purine (comes from azathioprine))
o Drug inactivation (purine/pyrimidine anti-metabolites)
o P-glycoprotein transporter (out of cancer cells)
Classes - CHAVMAT - see p402 for toxicity diagram - guess leukaemia and lymphoma for uses
 Cytotoxic Abx (-cin)- inhibits preformed DNA
o Doxorubicin - cardiotoxic
 Hormone Antagonists - mainly to do with sec hormone cancers
o Prednisolone - ACTH issues  cortisol (diabetes, osteoporosis)
o Herceptin - HER2, breast cancer
 Antimetabolism (think folate) - prevents DNA synthesis (S phase)
o Methotrexate - tetrogenic due to folate (NTD), pulmonary fibrosis (tx - folinic acid)
o Azathioprine - interacts with allopurinol (↑ levels!)
16 | P a g e




Vinca Alkaloids - prevents microtubule formation (M phase)
o Vincristine - neurotoxic
MABS’s - retiximab
Alkylating Agents - cross links DNA (G0/G1 phase)
o Cyclophosphamide - haemorrhagic cystitis (via acrolein, ihibit this with mesna)
Taxanes - stabilises microtubules (G2 phase)
o Paclitaxel - neuropathy
17 | P a g e
Session 7a - Respiratory Drugs
Asthma and COPD are both chronic obstructive disorders of the airways.
Conditions
Asthma
A chronic inflammatory disorder of the airways with symptoms associated with widespread but variable
airflow obstruction and an increase in airway response to a variety of stimuli. Obstruction is often
reversible with a diurnal pattern









Classic triad of symptoms - expiratory wheeze, cough, SOB (dysnpnoea) especially at night
Can be caused by allergies (atopic asthma - type 1 hypersensitivity) and can occur alongside hay
fever and eczema.
o Common allergies - 4 legged animals, bakers (yeast), Health care (latex), lab animals (rat
urine), woodworkers (plicatic acid)
Non-specific triggers (occurs in all types of asthma) - smoke, cold, exercise, URTI
Pathogenesis - Hypersensitivity type 1 reaction - allergen  dendritic cell  CD4 (Th2
pathway) which secretes cytokines which cause:
o Th2 activates B-cells to form IgE  attaches to mast cells causing sensitisation 
immediate degranulation on allergen exposure  histamine release  bronchospasm
(+ air trapping), vasodilation, increased capillary permeability
o Th2 activates eosinophil’s  mucous secretion, vascular leakage, infiltration 
oncoming inflammation and sensitisation of sensory nerve endings  hyper-reactivity
(parasympathetic mediated constriction)
Pathophysiology
o Smooth muscle dysfunction (2 agonists bronchodilators) - airway hyper-reactivity and
bronchoconstriction
o Airway inflammation (Corticosteroids - antiinflammatory agents) - eosinophils  mucosal
oedema, mucus hyper-secretion
o Airway remodelling (no treatment) - airways become thick and rigid due to smooth
muscle proliferation, epithelial damage, smooth muscle and epithelial hyperplasia and
basement membrane thickening
Long term complications of asthma - Smooth Muscle Hypertrophy, Bronchial Hyperplasia,
angiogenesis and subepithelial fibrosis
History - occupation, atopy, smoking, pets! QoL (sleep, reliever use)
Examination - eczema, vital signs (for attacks), wheeze vs silent chest, nasal polyps (other cause
of obstructive breathing)
Investigation - PEF diary (worse in morning - due to parasympathetic drive), Spirometry
(reversible change with 2 agonists), bronchoprovocation test, immunology tests, ABG’s (acute)
Management
 Non pharmacological - education (avoid smoking, avoid allergens) weight loss, breast feed
 5 step approach
o Step 1 - As needed short acting 2-agonists (salbutamol)
o Step 2 - Add low dose Inhaled corticosteroids (beclomethasone, budesonide)
o Step 3 - Add long acting 2-agonists (salmeterol)
18 | P a g e

o Step 4 - Increase Inhaled corticosteroids to high dose
o Step 5 - Add on therapies including oral corticosteroids
Acute attack - ABC, O2, nebulised bronchodilators (-agonists and anticholinergics), systemic
steroids, magnesium sulphate (bronchodilator)
COPD (chronic obstructive pulmonary disease)
COPD is a disease state characterized by airflow obstruction
that is not fully reversible. The airflow limitation is usually
both progressive and associated with an abnormal
inflammatory response of the lungs to noxious particles or
gases (SMOKING). It is an umbrella term covering the
“irreversible” aspect of chronic bronchitis, emphysema and
asthma.





Symptoms
o Chronic bronchitis (Blue bloaters) - productive cough for >3 months in two consecutive
years  productive cough, sputum
o Emphysema (pink puffers) - enlarged air spaces distal to the terminal bronchioles
accompanied by destruction of the walls (with or without fibrosis)  SOB. Two types:
 Centriolobular - centre of a resp lobular
 Panacinar - diffuse damage across the lobule. MORE SEVERE
 Paraseptal - ??
Risk factors - SMOKING! SES, infections, occupational chemicals
Pathophysiology
o Large Airways  squamous metaplasia; goblet cell and submucosal gland hyperplasia;
CD8 infiltration the wall; neutrophils infiltrate the lumen
o Small Airways  airway wall thickening, lumen filled with inflammatory exudate,
smooth muscle hypertrophy and fibrosis
o Changes to lung parenchyma (alveoli)  wall destruction, lose elastic recoil
History - SMOKING (pack years), symptoms, age (>35)
Diagnosis - BODE index (BMI, obstruction, dysnpoea, exercise), spirometry
o Spirometry - FEV1/FVC <0.7 = obstructive, FEV1 < 80% predicted (based on age etc)
o Classification
Severity of COPD
Stage I: Mild
FEV1/FVC
< 0.70
Stage II: Moderate
Stage III: Severe
< 0.70
< 0.70
Stage IV: Very Severe
< 0.70
FEV1
FEV1 > 80% predicted
MedResCouncil dyspnoea grades
1. Not troubled except in strenuous
exercise
50% < FEV1 < 80% predicted
2. SOB when walking up slight hills
30% < FEV1 < 50% predicted
3. Walks slower than others on
level ground due to breathlessness
FEV1 < 30% predicted, or
4. Stops for breath after walking
FEV1 < 50% predicted plus chronic 100m
respiratory failure
5. Too breathless to leave house
Management
 Non pharmacological - exercise training programmes (improves exercise tolerance), pulmonary
rehabilitation (MDT programmes tailored to patient - exercise, education, nutrition, breathing
techniques), palliative care (expectations, pain)
19 | P a g e



Treatment based on stage
o Stage 0: At risk - avoid risk factors (smoking), flu vaccine
o Stage 1: Mild - add short acting bronchodilator (2-agonists, anticholinergics,
theophylline)
o Stage 2: Moderate - add long-acting bronchodilator + rehabilitation
o Stage 3: Severe - add inhaled glucocorticoidsteroids
o Stage 4: Very Severe - add long-term O2 (if chronic resp failure)
Long Term Oxygen Therapy (LTOT) - indicated if patient is on full treatment and PaO2 < 7.3kPa
or patients with PaO2 between 7.3-7.8 kPa and who exhibits signs of hypoxia (pulmonary
hypertension, cor pulmonale, oedema)
Exacerbations - worsening SOB, increased sputum volume (± more purulent)
o Increase frequency of bronchodilators, Oral Abx (if purulent), Prednisolone
COPD vs Asthma
Cause
Other cells
T cell
Granulocyte
Affect
Pathophysiology
Clinical Picture
Full Reversibility
Symptoms under 35
Chronic productive cough
Breathlessness
Night time waking with SOB
and/or wheeze
Significant diurnal or day to
day variability of symptoms
Asthma
Allergens
Mast Cells
CD4 (Th2)
Eosinophils
Bronchoconstriction
BM thickening in large airways
COPD
Smoking! (nearly all!)
Macrophages
CD8 (Tc)
Neutrophils
Small airways narrowing and
alveolar destruction
BM thickening in small airways
Yes
Often
Uncommon
Variable
Common
No
Rare
Common
Persistent and Progressive
Uncommon
Common
Uncommon
Respiratory Failure
 Type1: Hypoxic Failure: PaO2 low (<8KpA); PCO2 normal/low
o Asthma, Pneumonia, Pulmonary Embolism, Interstitial Lung Disease
 Type 2: Ventilatory Failure: PaO2 low, PCO2 high (>6.5KpA)
o COPD, Opioid Overdose, Severe Obesity
o Giving O2 will stop breathing due to lack of hypercapnic drive (relying on hypoxic drive
but high conc O2 will remove this!)
Respiratory Drugs
Bronchodilators
 2-agonists (sympathetic) - Ligand (drug or NA)  GPCR  adenylate cyclase  ↑ cAMP 
PKA activation  smooth muscle relaxation
o Actions of PKA
 Phosphorylates MLCK (inactivates it) preventing contraction
20 | P a g e




Opens K+ channels  hyperpolarisation (less chance of contraction)
Inhibits IP3  ↓Ca release from ER  contractility (synergistic affect with antiach drugs)
o Other effects -decrease plasma exudation, increase mucocillary escalator
o SE’s - fine tremor, headache, muscle cramps, palpitations, tachycardia, hypokalaemia WHY if it causes K efflux ????????, sleep disturbance
o Types of
 Short term - salbutamol, terbutaline (blue) - fast acting
 Long term - salmeterol - slow acting
 Formoterol - fast acting, long lasting
Methylxanthines (theophylline, aminophylline) - phosphodiesterase inhibitors (PDEi) prevent
the breakdown of cAMP (see 2-agonists)
o SE’s - NARROW therapeutic window! - too high  seizures; cardiac arrhythmias
o Lots of drug interactions
Anti-cholinergics (parasympathetic) - works synergistically with 2-agonists. COPD
o Blocks Ach normal action (which is: Ligand (drug or Ach)  GPCR PLC which converts
PIP2 to IP3  release of Ca2+ from ER  Ca2+calmodulin  MLCK  (P)Myosin 
muscle contraction
o SE’s - anti para symptoms (anti-SLUD - Salivation, Lacrimation, Urination, Defecation),
URTI, SVT, AF
o Types of receptor M1, M2, M3.
 M2 is involved in ACh reuptake therefore want to leave this one alone in order
to reduce synaptic Ach
 M3 selective would be ideal
o Main types (-tropium)
 Ipratropium (M1-M3) - short term
 Tiptropium - (M1-M2) - long acting
Glucocorticoid Steroids (anti-inflammatories)
 Increased expression of anti-inflammatory genes 
decrease in all inflammatory processes (especially
eosinophils)
 Mainly used for asthma
 SE’s
o Fluid retention, diabetes, capillary fragility,
hypertension, osteoporosis, weight gain,
Psychosis!
o Negative feedback on the pituitary  ↓ACTH
 Addisons disease (on withdrawal)
 Types
o Inhaled - beclometasone, budesonide - less systemic effects than oral!
o Oral - prednisolone
Note on Steroids (adrenal glands)
Generally used to reduce inflammation but inhibits the immune system!
 Corticosteroids - mineralocorticoid steroids (aldosterone and RAAS), glucocorticoid steroids
(Prednisolone)
 Catecholamines - NA, A, (cortisol - catecholamine mimetic)
21 | P a g e
Other drugs
 Omalizumab - complexes IgE preventing mast cell sensitisation
 TB - can be primary TB (asymptomatic and chon focus), post-primary TB (any TB after 2 weeks of
infection) or millary TB (wide spread dissemination from an existing focus via the blood)
o Diagnosis
 History - cough, haemoptysis, weight loss, drenching night sweats, fever
 Microbiological - Ziehl-Neelson stain, need cultures for sensitivities!
 Tests - Mantoux test, interferon Gama Release Assay
 Rapid techniques - PCR
o Treatement - RIPE
 Rifampacin (red urine), Isoniazid, Pyrazinamide, Ethambutol
 RIP - rash, liver toxicity  hepatitis (yellow sclera), irreversible  STOP Tx!
 R - p450 inducer  lowers the effects of steroids
 E (eyes) - optic neuritis, colour blindness
 Pneumonia - See Resp
o CAP causes - Strep pneumonia, Haemophilus influenza, S. Aureus, Chlamydia Pneumonia
o Nosocomal Causes - Gram negative bacteria (klebsiella, pseudomonas, E.coli), S. Aureus
o CURB-65 - severity scoring
 Confusion
 Urea > 7 mmol/l
 Resp Rate ≥ 30/min
 BP - SBP <90 or DBP < 60mmHg
 Age ≥ 65yrs
 Score: 2+ send to hospital, 3+ manage as severe, 4+ (ICU)
o Diagnosis
 Symptoms of acute LRTI - cough, sputum production, SOB, chest
pain/discomfort
 New focal signs on examination - crepitation’s, bronchial breathing
 At least one systemic feature - i.e. fever
o Tx - 7 days amoxicillin or clarithromycin
 PDE inhibators
22 | P a g e
GI drugs
Session 7b - Motility Drugs







GI innervation - myenteric plexus (smooth muscle contraction) and submucosal plexus
(secretions), parasympathetic (motility)
GI coordination - slow waves (from BER) regulate frequency of contractions, number of action
potentials per slow wave gives the strength of contraction
Colonic motility - Haustral contractions (mixing), mass movements (propulsion)
Constipation - infrequent (<2 a week) or difficult evacuation of faeces (1 or 2 on the Bristol stool
chart), tenesmus, can have obstruction and paradoxical diarrhoea if severe
o Causes - colon cancer (weight loss and anaemia), IBS (alternating constipation and
diarrhoea), Anorectal disease (haemorrhoids/anal fissures - painful defecation),
medications
o Treatment - change diet, purgatives
Cathartic Colon - stimulant laxative abuse (>3 times per week for a year)  loss of basal tone 
fluid an electrolyte imbalance, steatorrhoea, vit and mineral deficiencies
Diarrhoea - frequent, watery, loose bowel movements. Several types (MOIST)
o Motility-related - ↑ motility  lack of absorption. (Diabetic neuropathy)
o Osmotic - heavy osmotic load due to malabsorption. (Coeliacs)
o Inflammatory - damage to the mucosal lining  less absorption. (infections,
autoimmune (IBD))
o Secretory - increased active secretions, no structural damage. (Cholera)
o Treatment - maintenance of fluid and electrolytes (especially Na+ and K+), anti-diarrheal,
anti-infective
Nausea and Vomiting (emesis) - causes - CNS, GI, Vestibular, Toxins (drugs (chemo), Abx, LDopa, Digoxin, opiate analgesics, NSAIDs, Iron
Purgatives (laxatives) - accelerate transit through intestines for constipation (BOSS)
 Bulk Laxatives (methyl cellulose) - increase volume of non-absorbable residue  retained water
in lumen, softening and increased bulk. Acts in 1-3 days. Used for constipation and IBS
 Osmotic Laxatives (saline, lactulose) - poorly absorbed solutes draw water into lumen
o Magnesium Sulphate (saline purg) - Acts in 1-2 hours for bowel operations. SE dehydration and electrolyte depletion
o Lactulose - disaccharide  fructose and galactose  lactic and acetic acid. Acts in 1-3
days. For opioids. SE - cramping, gas, borborygmus
 Faecal Softeners - acts like detergents to produce softer faeces. Acts in 3-5 days. For
fissures/piles
 Stimulant Laxative - increase GI motility. Senna - Anthracene derivatives absorbed and
stimulate myenteric plexus. Acts in 8 hrs (take it over night). SE - can appear in breast milk, abdo
pain, potential for abuse (cathartic colon)
Anti-Diarrhoeal
 Oral Rehydration Therapy - isotonic solution containing glucose and NaCl - exploits ability of
glucose to enhance Na transport and hence water
 Anti-infective - often viral (resolves itself). Bacterial (Abx). Campylobacter infections
(ciproflocacin, erythromycin)
 Anti-motility (loperamide) - a unique opioid as it can’t cross the BBB. Act on μ-opioid receptors
in the myenteric plexus. Increase tone and rhythmicity of the colon but reduces propulsion,
23 | P a g e

contracts sphincters  more fluid absorption. SE - chronic use  constipation, abdo cramps,
dizziness, paralytic ileus
Anti-spasmodics (atropine, hydroscine) - muscarinic antagonists inhibits parasympathetic
activity. Used for bowel colic, IBS, abdo cramps. SE - anti parasympathetic!!! CI’s - yasthenia
Gravis, UC, pyloric stenosis, GORD
Anti-Emetics
 Anti-muscarinic - atropine, cyclizine
 Dopamine receptor antagonists - metoclopromide
 5HT3 receptor antagonists - ondansetron
 Corticosteroids - dexamethasone
Session 8a - Acid Secretion






Acid secretion by parietal cells - H2O + CO2  HCO3- + H+; H+ goes into
lumen by a by H+/K+ ATPase; bicarb removed by HCO3-/Cl- antiporter; Clpassively diffuses into lumen
Acid secretion control (diagram also shows drugs)
o Stimulated by Gastrin, Ach and Histamine
o Inhibited by Somatostatin, Prostaglandins (also stimulates mucus, both functions
inhibited by NSAIDs) and Enteric Hormones
Mucous - stimulated by prostaglandins (produced due to local irritation to mucosa) + the stimuli
of acid secretion
Reflux Oesophagitis - inflammation of lower oesophagus due to GORD  heartburn,
haematemesis, peptic stricture, Barrett’s
o Tx - antacids, H2-receptor antagonists, PPI (monitor to avoid hypocholorohydria)
Zollinger-Ellison Syndrome - increased levels of gastrin  ↑ acid secretion, can be due to a
gastrinoma of duodenum or pancreas. Leads to peptic ulcers, parietal cell hyperplasia.
o Tx - PPI and H2-R antagonist (tumours surgically removed if possible)
Peptic Ulcers - duodenum mainly, usually caused by H.pylori - secretes urease which gets
converted into CO2 and NH3  neutralise the gastric acid and lets the organism penetrate the
mucosal barrier (along with acid)  NH3 and acid damage to epithelial cells
o Other causes - NSAIDs, Crohn’s, Z-E syndrome, malignant tumours
o H. Pylori treatment (ACE) - 2Abx (Amoxicillin + Clarithromycin) + PPI (Esomeprazole)
o Can also use bismuth chelates
24 | P a g e
Antacids
 Substances that counteract stomach acidity, usually used as a combo o Magnesium hydroxide (causes diarrhoea)
o Aluminium hydroxide (causes constipation)
 Also inhibits pepsin activity (it is inactivated in pH’s above 5
Drugs that protect the Mucosa
 Bismuth Chelate - coats the mucosa, absorbs pepsin, enhances local PGE synthesis, stimulates
HCO3- secretion, mild antibiotic. Used in combination treatments for H.pylori
o H. pylori treatment (ACE) - Amoxicillin, Clarithromycin, Esomeprazole
o SE’s - N & V, reversible blackening of tongue and faeces
 Misoprostol - PGE anologue - binds to PGE-R on parietal cell. Used to counter NSAID effects
o SE’s - Diarrhoea and stomach cramps, uterine contractions
o CI’s - women of child bearing age - PGE  contractions  miscarriage
 Histamine (H2-receptor) antagonists (cimi-tidine) - competitively inhibits histamine action (v.
specific to parietal cells)
o SE’s - diarrhoea, dizziness, muscle pain, rashes, impotence
o Drug interactions - inhibitor of P450  ↑ warfarin, propranolol, ethanol, sulfonylureas
 Proton Pump Inhibators (Esomeprazole, ome-prazole) - irreversibly inhibits H+/K+ ATPase - gold
standard! They are only active in acidic environment
o SE’s - headache, diarrhoea, rash, dizziness, confusion, impotence, hypochlorohydria
(deficiency of HCl in gastric juice impaired digestion/absorption (Fe, Vit B), increased
vulnerability of GI tract to bacterial infections
Session 8b - IBD (Irritable Bowel Disease)


Covers Crohns, UC and microscopic colitis (rare and often mistaken for IBS)
Diarrhoea is often the presenting complaint. Need to check for other causes of diarrhoea:
25 | P a g e
o




Infective - Virus (norovirus, rotavirus), Bacteria (C.diff, Salmonella, Shigella, Cholera),
Protozoan (Hx of travel - Giardia)
o Non-infective - iatrogenic (laxitives, Abx, chemo), paradoxical diarrhoea (colon cancer,
constipation), endocrine (VIPoma (vasoactive intestinal peptide), diabetic autoimmune
neuropathy)
Aetiology - unknown - genetic predisposition, environmental factors and host immunity
Pathophysiology - exaggerated inflammatory and immunological response
Crohns Disease - Mouth to anus (mainly transition zones - will occur at surgery sites), skip
lesions, transmural inflammation (fistulas), granulomas, goblet cells present
Ulcerative collits - colon only with no anal involvement, continuous, superficial inflammation
Comparing and
contrasting
Crohn’s disease
Ulcerative colitis
(smoking reduces incidence)
Coeliac disease
Autoimmune reaction to
Prolamin (comes from gluten)
All of GI tract, Mouth
Distal colon and
Duodenum / Jejunum
to anus
rectum
Bowel wall thickened,
Macroscopic
Skip lesions,
Area affected
appearance of
Cobblestone
continuous, inflamed,
Smooth mucosa
mucosa
appearance,
contact bleeding
Strictures
Microscopic
Transmural.
Superficial crypt
appearance of
Granulomas, Goblet
abscesses, Goblet cell
Partial / Total absence of villi
mucosa
cell present
depletion
Abdo cramping,
Diarrhoea with blood
Malabsorption, Anaemia (Fe
Common presenting
Diarrhoea, Weight
and mucus, malaise
or B12 deficiencies), Gas and
symptoms
loss, Steatorrhorea
lethargy
bloating
Cancer Risk
No
Yes
 Extra-intestinal features (both UC and Crohns)
o Joints: sacroileitis, peripheral joints, arthritis (can be the main presenting
complaint)
o Eyes: uveitis (inflammatory changes in the eye, needs aggressive
treatment), conjunctivitis
o Skin:
 Erythema nodosum (more common) - can also be caused by
sarcoidosis (resp) therefore check by xray
 Pyoderma gangranosum (skin “rots”, hard to treat!). Most likely cause is
UC (50%)
 Treat with corticosteroids +/- immunosuprresants
o Liver: gall stones, sclerosing cholangitis
o Renal: amyloid
 Investigations
o Blood tests - Anaemia (FBC); Inflammation (CRP, ESR); Malnutrition (albumin)
o Imaging - MRI enterography, Enteroclysis
o Endoscopy - colonoscopy, sigmoidoscopy, capsule endoscopy (for SI)
Affected Region:
26 | P a g e
Steroids
 Used for short periods to initiate remission by suppressing humoral and cell mediated
immunological activity
o don’t use long term in order to avoid side effects
 Hydrocortisone, prednisolone, budesonide (designer steroid - can be used longer)
 Usually given orally or IV, only give topically for proctitis if extremely mild! (otherwise just gets
washed away)
 SE’s of long term steroid useo Osteoporosis (steroids compounded with poor nutrition) - Tx with bisphosphonates
o Iatrogenic Cushing’s Syndrome (most common cause of Cushing’s)  too much cortisol
(even though low ACTH)
o Addison’s on withdrawal - ↓levels of ACTH due to long term use  too little cortisol
o Diabetogenic
o Redistribution of body fat
o Psychiatric problems
Aminosalicylates
 Used long term to maintain remission by: affecting arachidonic acid metabolism (Leukotriene
inhibition, Prostaglandin stimulation); free radical scavenging; inhibiting cytokine (IL-1) release
 Me-salazine, Balsalazine, Sulphosalazine
 SE’s - dyspepsia, headaches, rash, fever, pancreatitis, pericarditis, pneumonitis, aplastic anaemia
Immunomodulators (lots of patients on these)
 Azathioprine (Maintains remission in UC and crohns) - purine antimetabolite.
o Is a purine itself therefore allopurinol causes these drugs to accumulate in the body
 Thiopurine methyl transferase (TPMT) - is the rate limiting enzyme in purine
metabolism - 1:300 people are missing this  can’t give them Azathioprine as it
will destroy their bone marrow!
o SE’s - Bone marrow suppression, N&V, Pancreatitis, Hepatitis
 Methotrexate (maintains crohns remission) - folic acid antagonist
o SE’s - Bone marrow suppression, Megaloblastic anaemia, Nausea and vomiting,
Pneumonitis, Tetrogenic  Abortion and foetal malformation (not for women of child
bearing age!),
 Infliximab (severe crohns/perianal disease) - anti TNF-
 Cyclosporin (Severe UC) - inhibits IL2 & interferon-
o SE’s - nephrotoxic, hypertension, neurotoxic, hair growth
27 | P a g e
Urinary System
Session 9a - Diuretics







Diuresis - excretion of water (main areas of H2O regulation are descending loop of Henle and
CCD)
Natriuresis - excretion of sodium (main areas of Na regulation are Ascending loop of Henle,
distal nephron and CCD)
Diuretics are used to treat fluid overload - oedema (HF, LF, CKD, local infection, lymph drainage
blockage), congestive heart failure, hypertension
RAAS - don’t want RAAS to be activated if trying to reduce fluid overload (switch on by low Na or
low flow in tubule)
Loop Diuretics (furosemide) - the most powerful diuretics, act in the Ascending Loop of Henle
by inhibiting Na:K:2Cl co-transporter through competitive binding at the Cl site.
o It has 2 mechanisms
 Abolishes hypertonicity of the medulla  preventing osmotic drag out of the
tubule
 Stops Na reabsorption  hypertonicity in the tubule  osmotic drag into the
tubule
 Get down stream effects of Na+ exchange for K+ or H+ in principle cells some
SE’s. Same occurs for thiazides
o Uses - Oedema (CHF, cirrhosis, pulmonary oedema, nephrotic syndrome),
hypercalcaemia (promotes calcium excretion?) , hypertension
o SE’s - OH DANG - Ototoxicity, Hypokalaemia/calcaemia, Dehydration, Allergy, Nephritis,
Gout
Thiazide (bendroflumethiazide) - works in the distal tubule by inhibiting NaCl co-transporter
and therefore increasing osmotic drag into the tubule
o Uses - Oedema, Hypertension, CHF, Nephrogenic Diabetes insipidus (paradoxical!)
o RAAS activation - due to normal Na levels at macula densa but ↓ in systemic volume 
systemic activation of RAAS - DON’T WANT THIS
o CI - freely filtered so not good in renal impairment
o SE’s - Hypokalaemia, hyponaturaemia, metabolic alkalosis, HyperGLUC:
 HyperGlycaemia - due to hypokalaemia  ↓ insulin release (see mechanisms)
 HyperLipideamia  HyperUricaemia - thiazides compete with uric acid for secretion  Gout
 HyperCalcaemia?
Potassium Sparing - inhibit the action of principle cells in CCT
o Uses - Hypokalaemia (i.e. counteract other diuretics), Hyperaldosteronism (Conn’s),
o SE’s - Hyperkalaemia ( arrhythmias; CI with ACEi/ARBs due to Na:K exchange),
metabolic acidosis
o ENaC Blockers (Amiloride) - stops exchange of Na for K  higher tubule Na conc
 Use - as above + Liddle’s syndrome (genetically over active ENaC - Na lecture)
o Mineralcorticoid Receptor Blockers (Spironolactone) - competitive aldosterone
receptor antagonist  reduced action of aldosterone
 Normal action of aldosterone  migration of ENaC to apical membrane,
activation of basolateral Na:K antiporter, activation of apical K+ channel
 Use - as above + hyperaldosteronism (Conn’s)
 SE - as above + gynecomastia
28 | P a g e


Other Diuretics
o Carbonic Anhydrase (acetazolamide)- blocks tubule CA in PCT  inhibited HCO3-/Na+
reabsorption
 Use - intraocular pressure (glaucoma), altitude sickness
 SE’s - Metabolic acidosis (lower bicarb and retained H)
o Osmotic Diuretic (Mannitol) - increased solutes in tubule  osmotic drag. C.f to
diabetes
 Use - intraocular pressure (glaucoma)
o ADH antagonist - used for SIADH
Diuretic Combinations - Loop/thiazide + K sparing
Session 9b - Calcium Metabolism




Hypocalcaemia - due to deficiency.
o Symptoms - seizures, muscle cramps (tetany), prolonged QT interval
o Management - IV calcium gluconate (acute), oral calcium and vitamin D (chronic)
Hypercalcaemia - due to parahypothyroidism
o Symptoms - Stones (real or billary), Bones (pain), Groans (abdo pain, N&V), Thrones
(polyuria  osmotic drag), Psychiatric overtones (depression, anxiety, confusion)
o Management - >3mmol/l is an emergency  loop diuretics, fluids, calcitonin,
bisphosphonates, parathyroid gland surgery
Bone - Type 1 collagen (B(ST)CRB) and hydroxyapatite. Can be either cortical (hard) or
trabecular (soft) bone. Types of formation
o Intra-membranous Osteogensis - no cartilage precursor - mesenchyme cells
differentiate into osteoblasts  secretes osteoid  osteoblasts are trapped and
differentiate into osteocytes  woven bone  reorganises into lamellar (layered) bone
o Endochondrial Ossification - cartilage precursor - chondrocytes undergo hypertrophy
and secretes ECM  calcifies and chondrocyte death  osteogenic buds invade dead
cartilage bringing blood supply with it osteoblast development  see intramembranous
o Bone repair - haematoma  granulation tissue  callus formation  woven bone 
lamellar bone  remodelling
Osteoporosis (MSK) - loss of bone density (ineffective osteoblasts & structure  fractures 
mortality
o Bone measures
 Biochemical - calcium homeostasis (PTH, vit D, urinary calcium), bone turnover
(alkaline phosphatase)
 Imaging (X-ray, CT, radionucleotide scans, DEXA scan (bone mineral density)
 Biopsy - last resort!!
o Causes - Age, post menopause, cushings, lack of activity/weight, vit D/ calcium def.
o Risk Factors - alcohol (>4 units per day), family history, RA, low BMI, Crohn’s,
menopause
o Managemet
 Tx - bisphosphonates, SERMs, PTH (give cyclically ↑ bone density, given
continuously decreases it), Strontium Ranelate, Vit D + Calcium (needed for
others to work)
 Prevention - improve life style (diet, exercise), early detection (DEXA), prevent
fractures (reduce falls, lessen impact). Use the above treatments as prophylaxis
29 | P a g e






Osteomalacia/Rickets - inadequate bone mineralisation due to vitamin D deficiency/lack of
minerals. In children it is characterised by elongated growth plates. Signs - bilateral leg bowing
Paget’s Disease - increased osteoclast activity and compensatory osteoblast activity  large
amounts of woven bone (weak). Usually occurs locally and doesn’t spread (unilateral)!
o Symptoms - local fractures, pain, increased bone size (i.e. skull),, arthritis,
deafness/blindness, cardiac and neurological complications
o Tx - Bisphosphonates
Osteogensis imperfect - genetic type 1 collagen defect. Blue sclera, battered baby syndrome
Renal Osteodystrophy - several causes see urinary
Hyperparathyroidism - continuous PTH secretion bone loss, hypercalcaemia
Hypoparathyroidism - caused by surgical resection of the glands
o Tx - lifelong treatment of Vit D, high Ca diet
Calcium homeostasis is regulated by:
 Parathyroid glands - sense low Ca and produce PTH which causes Vit D Activation
o Calcium Receptor Agonists (CaR agonist) - regulate PTH production by parathyroid gland
by increasing CaR sensitivity to Ca  reduced PTH secretions
 Use - 2O hyperparathyroidism (renal osteodystrophy)
 Kidneys - Vitamin D is activated here
 Intestines - site of Ca uptake and regulated by activated vit D
o Vit D + Calcium supplements - given orally for Hypocalcaemia, Rickets/Osteomalacia, 2O
hyperparathyroidism, Vit D deficiency, kidney disease
 Cholecalciferol (unactivated Vit D) - for normal kidneys
 Calcitriol (activated Vit D) - for kidney failure as won’t be able to convert Vit D
to active form
 Don’t give to people with functioning kidneys as they will become
hypecalcaemic
 Can also give alfacalcidol - which is prehydoxylated (what the kidney
does) therefore it only needs liver conversion
 Bone - stores Ca and PO4. Formed from trabecular (metabolically active) and cortical (strength)
bone. Constantly remodelling due to osteoblast and osteoclast activity.
o Calcitonin - made in C cells of thyroid. Prevents osteoclast action in bones and
decreases PO4 and Ca2+ reabsorption in the PCT.
 Regulation - opposite to PTH! increased or decreased with high/low plasma Ca
levels respectively
 Uses - Paget’s (pain relief), Osteoporosis, Hypercalcaemia
o HRT - oestrogen is required for normal bone development (involved in osteoblast/clast
formation). Only used for osteoporosis in exceptional circumstances!
 SE - CV events, breast cancer, side effects of the pill (LOOK UP)
o SERMs (Specific Oestrogen Receptor Modulators) - Raloxifene specifically targets bone
oestrogen receptors, not breast or endometrium
o Bisphosphonates (Zole-dronate (yearly), Alendronate (weekly)) - most important antiosteoporotic drug! Slows the rate of bone remodelling down by interfering with
osteoclast function. Can do this by either inhibiting mevalonate or forming toxic ATP
analogues.
 Uses - osteoporosis, hypercalcaemia, Paget’s (controls pain and turnover)
30 | P a g e


Administration - very specific - 30 mins pre meal (uptake inhibited by calcium),
sitting up to avoid irritation. Better having weekly or yearly dose
 Issues - loose function after long term use, long half life (6 months)
 SE’s - asymptomatic hypoglacaemia, GI issues, affects healing of bone
(osteonecrosis of the jaw, teeth - tell your dentist!)
o Stontium Ranelate (protelos) - increase bone formation (stimulates osteoblasts) and
inhibits bone reabsorption (inhibits osteoclasts)  decreases fracture risk and increases
bone mineral density!
o Clinical PTH (preotact) - given cyclically it can increase BMD by stimulating osteoblast
development, inhibiting osteoblast apoptosis and inhibiting osteoclasts from
producing sclerostin (inhibits bone formation by antagonising the WNT signalling
pathway)
 Use - hypoparathyroidism, osteoporosis
Denosumab - inhibits RANK Ligand which is required for osteoclast activation
o Use - bone mets
o SE - osteonecrosis of the jaw, infections, unusual fractures
31 | P a g e
Diabetes and Hyperlipidaemia
Session 10a - Glucose Lowering Agents

Type 1 Diabetes Mellitus - autoimmune destruction of -cells by T-cells that presents at a young
age, often following an infection  ↓insulin production  unable to utilise glucose 
increased production of glucose + getting energy from other sources (ketones)
o Symptoms - polyuria (osmotic drag of glucose  UTI), polydipsia, lethargy (no glucose in
cells), weight loss (starving in the midst of plenty), ketoacidosis (ketones)
o Complications
 Atherosclerosis (macrovascular damage)  CHD/TIA/Strokes
 Microvascular damage  diabetic retinopathy, diabetic nephropathy
 Diabetic neuropathy - glove and stocking distribution (peripheral neuropathy?)
 Diabetic emergencies
 Diabetic ketoacidosis - occurs in severe insulin deficiency  acidic
ketone production from adipose tissue. Gives pear drop smell on breath
and Kussmaul breathing (deep hyperventilation - for acidosis)
 Hypoglycaemia - get sympathetic activation symptoms followed by GCS
decrease
 Lactic Acidosis - due to anaerobic respiration
 Treatment - insulin, potassium (is taken in by cells with glucose
therefore give to prevent hypokalaemia  cardiac arrest), bicarbonate
and IV saline (fluid)
o Treatment - lifestyle (diet (low glycaemic index), exercise), insulin, Islet transplantation

Type 2 Diabetes Mellitus - long term hyperglycaemia causes insulin insensitivity 
hyperinsulinaemia  -cell burnout. Usually occurs at older age (after 40)
o Symptoms - initially weight gain followed by type 1 symptoms,
o Complications - don’t get DKA have some insulin, can progress to type 1
o Treatment
 Life style - diet and exercise
 Glucose modifying drugs - metformin, gliclazide, proglitazone
 Insulin (± oral agents)
Other types of diabetes
o MODY - maturity onset diabetes of the young - an inherited form of NIDDM, early onset

32 | P a g e




o Gestational DM - any degree of glucose intolerance first observed during pregnancy
o LADA - latent autoimmune diabetes of adults, c.f. to type 1
GLUT transporters
o GLUT 1 - insulin independent - found in the brain and RBC’s
o GLUT 2 - insulin dependent - bidirectional transporter found in liver (glycolysis and
gluconeogenesis)and pancreas (glucose sensing and insulin regulation)
o GLUT 3 - brain - high affinity form allowing transport even if glucose conc is low
o GLUT 4 - insulin dependent - uptake into muscle and adipose
Diagnosis of Diabetes
o By HbA1c - over 6.5% (48mmol/mol)
 6.0-6.4% - indicates high risk of DM - give lifestyle advice
 < 6.0% - could still have risk (if clinically indicated then treat as high risk)
o By Glucose - diabetes symptoms + either:
 random venous plasma glucose ≥ 11.1 mmol/l
 fasting plasma glucose ≥ 7.0mmol/l
 two hour plasma glucose ≥ 11.1 mmol/l after a 75g Oral Glucose Tolerance Test
Incretin effect overview - levels of insulin are much higher in response to oral glucose (than IV)
due to endocrine secretions from the gut.
o Glucagon-like peptide (GLP-1) and Glucose-dependent insulinotropic peptide (GIP) 
increase in insulin release, decrease in glucagon release, slows rate of gastric emptying,
↑ saity, reduces gluconeogenesis
o GLP -1 and GIP are rapidly degraded by Dipeptidyl peptidase-4 (DPP-4)
Alphabet strategy
o Advice
- Smoking, diet, exercise
o Blood pressure
- < 140/80
o Cholesterol
- TC ≤ 4, LDL:HDL ≤ 2
o Diabetes control
- HbA1c ≤ 7%
o Eye examination
- Annual examination
o Feet examination
- Annual examination
o Guardian drugs
- Aspirin, ACEi, statins
Treatments
 Oral Hypoglycaemic Drugs (OHDs)
o Biguinides (Metformin) - ↑insulin sensitivity, suppresses hepatic glucose output and ↓
glucose uptake from gut. First line treatment, can have slow release form. Take with
insulin
 SE’s - lactic acidosis, GI issues, vit B12 malabsorption (wernickes
encephalopathy?), no weight gain!
 CI - liver, kidney, heart or resp failure, pregnancy
o Sulfonylureas (Glizlazide, Glimepiride) - increase insulin output by closing K ATPase in cells  depolarisation  opening of VGCC  exocytosis of insulin. Need -cells, 2nd line
Tx
Weight Gain
 SE’s - hypoglycaemia  weight gain, GI issues, allergic rash, bone marrow suppr
Gliclazide
 CI - obese patients
Nateglinide
o Meglitinides (Nateglinide) - cf to sulfonylureas but has a different binding site to ATPase
Pioglitazone
 Acts rapidly! gives meal time flexibility (Ramadan)
33 | P a g e
Acarbose - delays digestion and absorption of carbohydrates by inhibiting -glucosidase
 SE’s - lots of flatulance (GI) therefore poorly tolerated, no weight gain!
Glitazones/Thiazolidinedion (Pioglitazone) - increases insulin sensitivity by acting on PPAR
receptor  transcription of more insulin sensitive genes
o SE’s - fluid retention (Oedema, HF), anaemia, hypoglycaemia  weight gain
o CI’s - Oedema, HF, anaemia
GLP-1 receptor agonists (Exenatide) - incretin mimetics. SE’s - no weight gain (loss), nausea
DPP-4 inhibitors (Sitagliptin) - incretin enhancer. Use if glitazones is CI’d. SE’s - no weight gain,
nausea
o



Session 10b - Insulin






Give to IDDM and NIDDM (to improve metabolic control) - mimics insulin action
SE’s - hypoglycaemia  weight gain, lipohypertropy (local fat deposits), lipoatrophy (large No.s
of Ab’s  degeneration)
o Transient deterioration of retinopathy and neuritis (eyes used to high blood flow due to
high glucose, insulin stops this)
Control vs hypos - need to find the correct balance for the patient
o poor control  ↓hypo’s and ↑risk of retinopathy
o good control  ↑ hypo’s and ↓ risk of retinopathy
IDDM treatment - all of the above drugs apart from SFU and glitazones can be used
Types of Insulin
o Short acting insulin - has a rapid onset (30 mins), use before meals or in hyperglycaemia
 Human - actrapid, humulin S
 Analogue - Humalog, Novorapid - meal times or emergencies
o Intermediate acting insulin - slower onset, BD, usually combined with fast acting
 Isophane = Humulin N = NPH (Neutral Protamine Hagedorn)
o Long acting insulin - analogues, often combined with fast acting insulin for best control
 Glargine, Detemir (levemir)
o Premixed Insulin’s - any combination of above
 Novomix 30 = 30% novarapid, 70% isophane
Regimes - once daily, basal bolus, 4 x basal bolus,
Insulin Actions
Liver cells
Fat cells
Carbohydrate
metabolism
↑Glycolysis
↑Glycogenesis
↓Glycogenolysis
↓Gluconeogenesis
↑Glucose uptake
Fat metabolism
(makes it hard to
lose weight)
↓Lipolysis
↑Lipogenesis
↑Synthesis of
triglycerides and fatty
acids
↓Lipolysis
Protein metabolism
↓Protein breakdown
-
Muscle cells
↑Glucose uptake
↑Glycolysis
↑Glycogenesis (storage)
-
↑amino acid uptake
↑protein synthesis
34 | P a g e
Session 10c - Cholesterol Lowering Drugs






Hyperlipidaemia - 3.5 < Cholesterol < 6.5 mmol/l, ideally 5
o CHD mortality is proportional to total cholesterol
o LDL:HDL ratio is most important factor for MI’s (followed by smoking, DM,
hypertension, diet and exercise)
Dietary lipids are emulsified by bile and form chylomicrons which are absorbed out of the GIT.
These are then repackaged by the liver into VLDL  LDL  cells as a source of cholesterol
o LDL can also be trapped in arterial walls  formation of atherosclerotic plaques. Plaque
rupture leads to acute vascular events (more likely if smoke, DM, high BP)
Atheroma formation
o Local injury of endothelial cells  inflammation  local angiotensin II production 
promotes endothelial dysfunction
 LDL’s can enter tunica intima which are oxidised by free radicals
o Monocytes  macrophages which engulf LDL’s  foam cells  cytokine release
bringing other inflammatory mediators
o Platelets adhere to injury and release PDGF  smooth muscle migration  intimal
plaque formation
o Smooth muscle cells calcify, when they die this causes extracellular calcium deposits
which reduces artery compliance
Atheroma  fatty steaks  fibro-fatty plaques (fibrous plaque with central necrosis) 
complicated plaques
Anti-athrogenic actions of HDL
o inhibits oxidation of LDL, promotes efflux of cholesterol, inhibits experession of
endothelial cell adhesion molecules
Lipid lowering therapy - used for MI patients, CHD or atheromatous disease and primary
prevention in high risk patients (DM patients over 40)
Treatments
 Statins (atorvastatin) - inhibits HMG-CoA reductase in the liver therefore stops cholesterol
production. Lowers total cholesterol and LDL  better lipid profile. Indicated as said above
o SE’s (rare) - myalgia, nausea, headache, insomnia
o Note - Nystatin isn’t a statin, it’s an antifungal treatment
 Fibrates (fenofibrate) - PPAR- agonist (see glitazones)  increases lipase activity, increased
HDL, increased clearance of LDL favourable HDL:LDL ratio
o Indications - hyperlipidaemia, low HDL, statins CI’d
o SE’s - myalgia, gallstones, nausea
 Nicotinic Acid - inhibits lipolysis in adipocytes, reducing release of FFA’s  less TAG synthesis.
Also promotes reverse cholesterol transport  ↑ HDL
o SE’s - Flushing, headaches
 Ezetimibe - prevents cholesterol uptake
 Orlistat - inhibits pancreatic lipases  decreased fat absorption
 Omega-3 - reduces TAGs - use post MI
35 | P a g e
Neuro Drugs
Session 11a - NSAIDs and Narcotic Analgesia





Gate Control Theory of Pain
o C/A carry pain input from nociceptors to excite
projection neurons (P) and inhibit the substantia
gelatinosa (SG) which usually inhibits pain transmission
o The SG is stimulated by cutaneous stimulation (A) which is why rubbing the skin
doesn’t hurt - can use rubbing a wound to make it feel better
o Descending inhibition serotoninergic pathways also activate the SG to inhibit pain
WHO ladder of pain
o Non opioid analgesic (paracetamol, aspirin) + adjuvant
o Mild opioid analgesic (codeine) ± non-opioid ± adjuvant
o Strong opioid (morphine) ± non-opioid ± adjuvant
Paracetamol - good antipyretic but no anti-inflammatory effect
o Toxicity - see page 2 about glutathione
NSAIDs - anti-inflammatory, anti-pyretic, analgesic, anticoagulant. Work by blocking
prostaglandin (pro-inflammatory) synthesis by inhibiting COX (cyclo-oxygenase enzymes). Also
stop thromboxane A2 (platelet aggregation) and leukotrienes (chemoattractant). ↓ prostacyclin
levels  ↓ sensitivity of bradykinin and prostanoid receptors which are involved in pain
transmission
o Three types of COX enzyme
 COX-1 - normal tissue functions
 COX-2 - activated by interleukins and has inflammatory and pyretic functions
 COX-3 - involved in fever
o 6 classes of NSAIDs - Salicylates (aspirin), Pyrazolones (Diclofenac), Propionic acids
(ibuprofen)
o SE’s - GI issues (N&V, diarrhoea), rashes, renal impairment
 Aspirin - see earlier (p5) for salicylate poisoning and Reye’s Disease. It works
slightly differently to other making its action irreversible
 Selective COX-2 (-coxib) - decreased normal SE’s but increased risk of CV and
thrombotic events
o Interactions
 Don’t use different NSAIDs together (up the dose or add paracetamol)
 Increased bleeding risk with SSRI’s (anti-depressants)
 Increased risk of nephrotoxicity with ACEi and diuretics
 Can enhance anti-coagulant effect of drugs used in CV disorders (Warfarin etc)
 Can antagonise hypotensive drugs (alpha and beta blockers and nitrates)
Opioid analgesics - acts in central and peripheral nervous system to excite descending inhibition
and inhibit ascending pain pathways
o 3 classes of opioid
 Pure agonists
 Strong - morphine, diamorphine,
 Weaker - codeine, methadone - less likely to result in dependence and
resp effects but less effective
 Partial agonists - buprenorphine, pentazocine
36 | P a g e

o
o
o
o
o
o
o
o
o
Antagonists - naloxone and naltrexone - inhibits the action of opioids
(addiction!)
Uses - analgesia (chronic and acute but not neuropathic), anaesthesia, antitussive (stop
coughing), antidiarrhoeal (codeine)
Mechanism for ascending inhibition - activate μ, κ, δ and ORL1 (orphan receptors)
receptors  GPCR  inhibits adenylate cyclase   opening of K+ channels
(hyperpolarisation)  less likely to depolarise  decreasing levels of Ca2+  inhibition
of neurotransmitter release
Route of admin - depends on severity of condition and side effects
Metabolism - diamorphine and codeine are converted to morphine by CYP2D6 (5% of
population don’t have this therefore won’t respond to these treatments.
Interactions - drugs that alter its rate of metabolism
 β-blockers (↓ sympathetic activity), slow metabolism and vascular flow, leading
to increased levels of circulating opioid.
 Antibacterials and other cP450 inducers lead to a more rapid metabolism of
opioids, decreasing analgesic effects.
 Treatments for psychological disorders, such as antidepressants (↑
transmission) and antipsychotics (↓ transmission), lead to increased
excitability, or enhanced central depression, e.g. Pethidine and MAOIs
coadministration is linked to increased excitability and occurrence of seizures.
SE’s - respiratory depression, N&V, diarrhoea, anaphylaxis, depression and altered
mood
 Vomiting - will happen therefore give anti-emetic (cyclizine)
Overdose - respiratory depression, Miosis (diagnostic as other coma causes lead to
pupil dilation!), confusion, coma
 Tx - naloxone and naltrexone, if within 1 hr of OD give charcoal
 Coma cocktail - naloxone, O2, glucose, thiamine, flumazenil
Addiction - Tolerance and dependency lead to withdrawal symptoms on termination
(symptoms opposite to the effect of the opioid)
 Tolerance - decreasing effect of drug following repeat admin
 Dependancy - psychological and physiological components due to
reinforcement of positive effects (euphoria and sedation which occurs due to
dopaminergic pathways c.f. to alcohol)
 Symptoms - Dysphoria, N&V, muscle cramps, lacrimation, rhinorrhea, pupillary
dilation, diarrhoea, fever, insomnia, tachycardia
 Tx - Buprenorphine, Methadone, Lofexidine, Naltrexone (removes positive
reinforcement)
 Improve compliance with random urine analysis, daily prescriptions, titrate dose
against symptoms, psychological support
Legal aspects - record keeping! Two nurses measure dose
Session 11b - Parkinsonism an Schizophrenia

Neurotransmitters associated in disease:
o Parkinson’s - Dopamine (too little)
o Schizophrenia - Dopamine (too much), Glutamate…
o Depression - 5HT, NA
o Epilepsy - GABA and Na+ levels
37 | P a g e



o Alzheimer’s - ACh
o All transmitters have a knock on effect on each other!
Dopamine - involved in Parkinsomism and Schizophrenia (2 conditions at the opposite ends of a
scale)
o Pathways - nigrostriatal (SN to striatum - motor control), mesolimbic (reward),
mesocortical (higher senses), tubero-hypophyseal (pit and hypothalamus regulation)
Parkinsonism - too little dopamine due to damage of the substantia nigra - leads to lack of
stimulation of the direct pathway which usually disinhibits the thalamus  hypokinesia
o 3 types of parkinsonism
 Pure parkinsonism (idiopathic, iatrogenic (drug induced), post-encephalitic)
 Parkinsonism + (parkinsonism with additional neurodegenerative disorders
 Pseudoparkinsonism - don’t respond well to typical treatment
 Benign essential tremor - slow tremor at rest. Tx - alcohol (2 units)
 Wilson’s Disease - cooper deposits in liver, basal ganglia and eye
(kayser-Fleischer rings) - has a hypo and hyperkinetic form
 Atherosclerotic disease (vascular) parkinsonism
o Symptoms - TRAmP - Tremor at rest (pill roling), Rigidity (cog wheel), Akinesia,
micrographia, Postural instability, festinating gait
o Diagnosis - symptoms, challenge test with levodopa, MRI/CT to eliminate other causes
o Management
 Pharmacological (as late as possible as it only works for so long and can’t be
stopped). Gradually titrated up against symptoms
 Physiotherapy, speech, occupational therapy, dietry etc
 Iastrogenic - stop drugs (schizophrenic drugs) and switch to an alternative
Parkinsonism Treatment - Ropinirole, Entacapone, Rasagiline, Levodopa, Apomorphine
o Dopamine Replacement - redresses the dopamine imbalance. Dopamine doesn’t cross
the blood brain barrier therefore use Levodopa which does. However levodopa is
broken down in the periphery therefore need to use a peripheral dopamine
decarboxylase inhibitor (benserazide, carbidopa)
 Can be used as co treatments - Co-Beleldopa, co-carbidopa
o COMTi (entacapone) - COMT metabolises levodopa, therefore inhibition of this prolongs
its action
o MAOI-B (rasagiline) - MAO-B also metabolises L-dopa, therefore prevent this
o Dopamine receptor agonists (Ropinirole) - synthetic agonists acting on D2 receptors used mainly for younger patients as can delay the need for L-dopa
 Has fewer moor complications long term but more psychiatric SE’s
o Side Effects of dopamine based treatments:
 Peripheral effects - N&V, anorexia, drowsiness, hypomania, psychosis, sudden
onset sleep, hypotension, tachycardia, arrhythmias
 On/Off effect - occurs in later stages due to long term use (>2 years)
 Drugs less effective and take longer to act
 Dyskinesias - due to too much dopamine!
 Can be reduced by combination therapies
 Apomorphine - “fills in the gaps” of off periods - self administered when
signs of approaching off period occur (requires domperidone first to
prevent N&V)
38 | P a g e
o


Anticholinergics (Benzatropine) - required due to raised levels of Ach which is caused by
decreases in dopamine levels. Use for iatrogenic parkinsonism (which doesn’t need Ldopa?)
 SE’s - similar to dopamine treatments, psychiatric SE’s (drowsiness, confusion,
agitation), unopposed sympathetic activation (as it affects the parsympathetic
pathway more)
o Glutamate Antagonists (amantadine) - may reduce dyskinesias, an NMDA-r antagonist
o Adenosine Antagonists (caffeine) - neruo protective?
Schizophrenia - too much dopamine in the mesolimbic pathways (dopamine hypothesis) 
anatomical abnormalities - thinning of grey matter (medial temporal lobe) and enlarged
ventricles and sulci. Symptoms include:
o Positive (manic)
 Delusions (paranoia, being told what to do)
 Hallucinations
 Bizarre Behaviour
 Thought Disorders (lack of insight)
o Negative (depressive) - the 4 A’s
 Affective blunting - mood depressed
 Ahedonia and Associality - inability to experience pleasure
 Alogia - poverty of speech (lack of additional unprompted info)
 Apathy/avolution - no motivation
o Disorganisation syndromes - speech, thought and behaviour
Schizophrenia Treatment - Dopamine (D2) receptor antagonists
o Classical (haloperidol, chlorpromazine) - Dopamine (D2) receptor antagonist. Low
efficacy. Affects other neurotransmitters
 Extrapyramidal signs (c.f. to parkinsonism) - dystonia, parkinsonism, akathisia
(motor restlessness) - STORM Babi
 Tardive Dyskinesia - disabling involuntary movements - tongue
protruding, choreiform movements, grimacing and twisting
o Often irreversible once it has started - occurs in 25% cases of
long term treatment. Stop anticholinergics? immediately and
switch to atypicals
o Atypicals (clozapine (last resort as lots of CV SE’s), risperidone) - has multiple actions 5HT (also has a role in depression), DA and others. Higher efficacy and fewer SE’s
 SE’s - similar to Classical but with fewer EPS + cholinergic SE’s
Session 12b - Affective Disorders and Epilepsy


Affective disorders - disorders of mood (syndromes rather than diseases), includes depression,
schizophrenia, mania, psychotic disorders, anxiety and stress
Depression - a syndrome consisting of a cluster of symptoms (behavioural, physical, cognitive
features and changes in mood)
o ABC Symptoms
 Affect - persistent low mood
 Behavioural - not eating/sleeping, social withdrawal
 Cognitive - depressive ideology, suicidal thoughts
o Two groups - unipolar, bipolar (has manic phases - opposite end of the scale)
o Diagnosis - 5 or more, every day for >2 weeks
 Low/depressed mood
39 | P a g e




Anhedonia (no pleasure)
Suicidal thoughts
Others - low energy/fatigue, sleep disturbances, confusion/cognitive deficits,
low self eseem, weight changes
o Monoamine hypothesis - low levels of NA and 5HT  depression
 Complicated by fact that NA and 5HT interact with other pathways (5HT and DA)
 Pharmacological treatments target this
o Serotonin (5HT) - produced in Raphe Nuclei, in the medulla. We require tryptophan
(marmite and cheese) to make it. Involved in:
 mood, agitation, OCD, anxiety, appetite, insomnia, sexual function, N&V
o Noradrenaline (NA) - main CNS production site is the Locus Coeruleus from the
breakdown of dopamine. Involved in:
 depression, attention, energy, homeostasis, agitation, emotions, BP, HR,bladder
o Management
 Pharmacological - main antidepressants aim to increase NA and 5HT via:
 Reuptake inhibition
 Receptor Blocking
 Enzyme Inhibition
 CBT (cognitive behavioural therapy) - first line unless severely depressed
 ECT (electroconvulsive therapy) - very affective! (takes days rather than
months!) Unfortunately has a huge stigma, now down with muscle relaxants so
patient doesn’t shake around
Depression Drugs
o SSRI’s (selective serotonin re-uptake inhibitors) - first line! Stops 5HT being brought
back into synapses. Fluoxetine (Prozac), paroxetine, sertaline
 SE’s - N&V, insomnia, anorexia, takes 2 weeks to increase 5HT levels (therefore
patients will feel worse before they feel better, explain this to them!!!)
 Serotonin Syndrome - adverse drug reaction due to OD or combination with
other meds  high 5HT hyperthermia, aggression, tremor, rigidity, CV issues
o Tricyclic Antidepressants (TCA’s) - second line, also used for neuropathic pain. E.g.’s
Amitriptyline, Imipramine or -pramines?
 Has 5 mechanisms of action (2 desired and 3 that cause side effects)
 NA reuptake blocker - main effect
 5HT reuptake blocker - variable effect
 α1 adrenoreceptor antagonist
 H1 receptor antagonist
 M1 receptor antagonist - anti-parasympathetic therefore  dry mouth
and eyes?
 SE’s - sedation (H1), postural hypotension, confusion, visual problems, cardiac
dysrhthythmias, mania
o MAOI-A (phenelzine, moclobemide) - increases NA/5HT levels by inhibiting enzymatic
breakdown
 DO NOT USE WITH SSRI’s OR TCA’s - due to drug interactions
 MAO-A (brainstem), MAO-B (brain - parkinsons)
 SE’s - postureal hypotension, restlessness, convulsions, insomnia
 Cheese Reaction - MAOIs interact with food containing tyramine (a
sympathomimetic) as they stop its metabolism  overactive SNS!
40 | P a g e
o

Lithium - a mood stabiliser (last resort!), mechanism not understood
 SE’s - very toxic at high levels!
o Atypical Depression Drugs
 NRI’s (NA reuptake inhibators) - NA reuptake inhibator - reboxetine
 SNRI’s - 5HT and NA reuptake inhibitor - venlafaxine
 5HT1A partial agonists - reduce activity to increase transmitter levels  slowly
balances levels therefore has less SE’s - buspirone
 -adrenoreceptors - presynaptic modulation of NA and 5HT by blocking 2
adrenoreceptor (acts as a brake to release)
 SE’s - decreased vascular flow in extremities, postural hypotension,
fatigue, bronchoconstriction, cardiac failure, bradycardia
Epilepsy - sudden transient changes in neuronal activity
o Diagnosed - symptoms + EEG/MRI/CT
o Main categories - partial and generalised
o Cause - excitatory changes in neuronal activity is brought about by:
 Reduction in GABA (inhibitor that usually codes information)
 Increase in Ach transmission
 Increase in Na+ transmission
 Decrease in K+ transmission
o Clinical correlations
 Use Carbamazepine and sodium valproate for everything apart from absence
seizures (see below)
 Partial Seizures
 Simple Partial Seizures - no loss of consciousness or post-ictal
confusion, symptoms depend on the focal site
o Jacksonian Seizure - where a simple partial seizure progresses
distil limb through to ipsilateral face
 Complex Partial Seizures - alterend consciousness but maybe fully
aware. May have aura, automacities, lasts a few minutes and can have
post-ictal confusion
 Partial seizures with 2O generalised - affects the whole brain once the
thalamus is involved
 Generalised Seizures
 Tonic-Clonic (grand mal) - whole brain involved, followed by
unconsciousness, muscle relaxation and slow regain of consciousness
(confusion, sleepy, headaches), no recall of the episode
o Tonic Phase - whole body stiffness, breathing may stop, loss of
bladder
o Clonic phase - muscle jerks
 Absence Seizures (petit mal) - whole brain is involved. Patient “switches
off” and cannot be alerted or woken. Occurs more in girls than boys
between 6-12
 Status epilepticus - I.V lorazepam after 5 and 10 mins
 NEAD (non-epilectic attack disorders) - psychogenic seizures, don’t give the antiepilectic drugs
 Tx - remove AED’s and give antidepressants/psychotherapy
41 | P a g e



Antiepilectic hypersensitivity syndrome - fever, rash and swollen lymph nodes
within 8 weeks of starting treatment - withdraw drugs (be aware of risk of
rebound seizures though)
o Management
 Pharmacological - first line
 Surgical - removal of aberrant areas (scar tissue)
 Implants - vagal nerve stimulation
Epilepsy Treatment
o Na+ channel blockers (carbamazepine, sodium valproate) - blocks inactivated VDNaC
 SE’s - CNS (cognitive and visual impairment), osteomalacia (vit D reduction),
peripheral neuropathy, skin issues, gum hyperplasia, anaemia
 Tetrogenicity - be careful with child bearing age. issues with neural tube
formation - can use folate supplements if have to give them to women!
o GABA agonist
 Benzodiazepines (lorazepam) - rapid treatment of individual fits (status
epilecticus) - potentiates GABA action by increasing activity of ion channels
 SE’s - short term use only (<12 weeks), tolerance and dependency,
withdrawal on termination!
o others - impaired motor coordination (decreases muscle tone),
impaired cognition, sedation, disturbed sleep, retrograde
amnesia
 Barbiturates - (Pentobarbital) - same as benzos just on a different GABA subunit
o Inhibition of GABA breakdown (vigabatrun)
o Inhibition of GABA uptake (tiagabine)
 SE’s of vigabatrun and tiagabine - CNS effects (visual and confusion), sedation,
dizziness and fatigue, weight gain
o GABA mimetics (GABApentin) - used for neuropathic pain
o Ethosuximide - Ca+ channel blocker - use for absence seizures (only affective treatment)
 SE’s - gastric, CNS, allergic
Neuropathic Pain - treat with antiepileptic’s and antidepressants
o Tx - GABApentin, TCA, carbamazepine
42 | P a g e
Infections





SIRS - a dysregulated host inflammatory response. Characterised by:
o Temperature
> 38.5ºC or <35ºC
o Heart rate
> 90 bpm
o Respirations
> 20 / min
o White blood cell count
> 12,000/mm3 or less than 4000/mm3
Sepsis - SIRS + a known primary site of infection - Consequences of sepsis lead to hypoperfusion
of body tissues! Leads to lactic acidosis and declining GCS
o Severe Sepsis - sepsis + organ dysfunction
o Septic shock - sepsis + hypotension (SBP <90mmHg) + hypoperfusion
o Septic six management
Give to patient
Monitor from patient
High Flow Oxygen
Measure FBC (serum lactate)
Give IV Fluid
Measure Urinary Output
Give Empirical Abx Take blood cultures
CNS infections - fever, headache, neck stiffness, photophobia, rash (purpuric), ↓GCS
o Meningitis - infection of meninges, bacterial causes are serious
 Kernigs sign (stiff neck), Brudzinski sign (neck pain on flexed hip)
 Neisseria Meningitidis - sudden onset, purpuric rash - ceftriaxone
 Others - TB (v serious - RIPE), strep pneumonia
o Encephalitis - infection of brain, viral causes are very serious
 Herpes (HSV), HIV, rabies - IV acyclovir, high dose
 Others - strep (abscess), toxoplasmosis (cysts)
o Investigations - blood cultures and PCR, serology, Head CT (if ICP indicated), LP
o Treatment - Septic six treatment on top of Abx/antivirals
o Prophyaxis for meningitis
 Chemoprophylaxis - household and kissing contacts - ciprofloxacin
 Immunoprophylaxis - meningococcus A and C (N. menigitidis)
Malaria - hot/cold sweats, headache, D&V, anaemia, arthralgia and myalgia
o Falciparum (severe type) - hypoglycaemia, haemorrhage, renal failure, sepsis, ↓GCS
 Tx - quinine followed by doxycycline
o Risk assessment - travel Hx
HIV (human immunodeficiency virus) leads to AIDS (acquired immunodeficiency syndrome).
Occurs due to a progressive loss of CD4 cells  unusually infections
o Transmission - sex, transfusions, needle stick (0.3% chance, negligible if take three
antivirals ASAP)
o Symptoms - opportunistic infections, TB, oral candidiasis, karposis sarcoma,
pneumocystic pneumonia jerovicii (PCP)
o Treatment - PCP occurs once CD4 count is below 200/ml therefore start treatment at a
count of 350/ml
 Highly Active Anti-Retroviral Therapy (HAART) - 2 NRTIs and 1 NNRTI
 PCP prophylaxis if CD4 count < 200/ml - co-trimoxazole
43 | P a g e
Antibiotics







Inhibit cell wall synthesis (bacteria lytic) - PGCC (teaching, pens), (PCC - beta lactam based know for allergies)
o Penicillin - amoxicillin (1st line for chest), flucloxicillin (skin infections -S. Aurius)
 10% of people have an allergy
 Clavulonic Acid - inhibits beta-lactamases
 Co-Amoxiclav - broad spec!!- GI, Chest, skin
o Glycopeptides - Vancomycin (poorly absorbed from the gut  C. diff Tx)
o Cephalosporins - ceftriaxone (meningitis)
o Carbapenems - resistant to beta lactamases
Inhibits protein synthesis (bacteria static) - ATM (teach to get money)
o Aminoglicosides - Gentamicin (MRSA)
o Tetracyclines
o Macrolides - Erythromycin (for people with penicillin allergies)
Inhibits DNA synthesis (bacteria static) - SAQ (short answer questions)
o Suphonamides - trimethoprim
o Azoles
o Quinolone - ciprofloxacin
Damages DNA
o Imisazoles - Metronidazole (GI infections (anaerobes) - gastric enteritis, ascending
cholangitis, pancreatitis) - tetrogenic
Specific treatments
o H.pylor - ACE
 Amoxicillin, Clarithromycin, Esonoprazole?
o TB - RIPE
 Rifampacin (red urine), Isoniazid, Pyrazinamide, Ethambutol
 RIP - liver toxicity (yellow sclera stop!!!!!)
 E - renal failure
o UTI - often caused by E.coli, Tx - trimethoprim
SILLY SODS GUIDE TO ABX
SE’s?
Other Bits and Pieces



Corticosteroids - inhibit the immune system
Types of beta receptors
o B1 - heart - atenolol, metaprolol, bisprolol?
 Tinolol, mestoprolol?? - used for glaucoma
o B2 - bronchi
o B3 - adipose tissue
Methods of increasing signal transmission at synapses
o More presynaptic release
o Less breakdown (acetylcholinesterase inhibitor)/ less reuptake of transmitter (????)
o More post synaptic receptors
44 | P a g e