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 (AATA2 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