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Pharmacology Topic Drug Actions CHOLINOMI METIC Directly ACh Muscurinic: i) CVS: HR, CO ( as Atrial contracn and vasodilation (NO on endothelium) = BP Choline Ester Mimic the actions of Ach by binding to and stimulating ACh receptors Muscarinic receptors (i) all effector organs innervated by postgang para (ii) sweat glands (iii) endothelial cells (non-innervated) where they mediate NO-dependent vasodilation. (iv) CNS ii) Non Vascular SM: a Lungs – bronchoconstriction GI - motility (peristalsis) and secretion Bladder – contracn of detrusor; relaxatn of trigone and sphincters s iii) Exocrine Secretions: Salivation GI secretions Sweating bronchial Secretions iii) Eye: Contracn of ciliary body = fat lens accommodation for near vision Contracn of Sphincter Pupillae (circular muscle of the iris) = constricts pupil (miosis) improves drainage of aq fliud, intra-ocular P Lacrimation Applications Unwanted Effects Does not differentiate between muscurinic and nicotinic e.g. skeletal muscle contracn and symp activity b) Indirectly (Anticholinest erase) Bethanechol – mildly modified from ACh – Choline Ester Pilocarpine (Pilocarpus - shrub growing in SA Alkaloid Selective Agonist at muscurinic Not a substrate for cholinesterase enzyme Physostigmine Carbamyl Ester Muscurinic Dose related – ACh activity at all musc Competes w/ Ach for active site on enzyme, CNS: tertiary gp enter Sp to Muscurinic – selective to M3 Limited access to CNS Resistive to degradation LOW dose - Reversible Donates carbamyl gp to enzyme, Reactivated by slow hydrolysis /neostigmine musc Excitabily w/ possible convulsions Oral 3-4 hrs Muscurinic CO, HR = BP nausea, vomiting colic, sweating impaired vision glaucoma -miosis, local Xerotosma (dry mouth) 1) Glaucoma: IOP drainage by miosis Local- eye drops Local muscle twitiching 2) Atropine Poisoning: Overcomes musc effects, iv CNS effects MODERATE - + effect at all ANS, Symp effect HIGH – toxic dose: dep block at gang Depression, unconsciousness, R failure, death Weak neuromuscular effects - greater effect on ANS Ecothiopate Irreversible Organo-P Has labile gp F/ organic, inactivates enzyme by Phosphorylation = same 1) Glaucoma local Local muscle twitching 1) Organophosp poisoning if protective clothing not 2) worn: a agriculture –insecticides Musc activity, brady, 3) hypo, brochocons, sweat, biological warfare – nerve gases saliva, miosis, fixed for near stable Recovery –synthesis: wks vision Neuromusc juncs effect: muscle twitching, dep block, paralysis of diaphr / DYFLOS Highly lipid solubleEasily absorbed thru skin, nasal mucosa, lungs die of CNS effects – R failure Treatment: atropine iv, artificial resp, pralidoxime iv which reactives plasma chlolinesterase 2) peripheral nerve demyelination = weakness and sensory loss Bind with high affinity CHOLINOCE PTOR ANTAGONIS T Nicotinic/gang lion blocking Activity depends on pre-existing stimulation: level of tone Hexamethonium / Trimetaphan Block transmission at all ANS Except skeletal neuromuscular i) CVS – BP –Impaired postural reflexes – renin secretion ii) Non-vascular SM –GI tract – motility –Bladder – impaired emptying –Urinogenital - impotence –Lungs – bronchodilation iii) Eyes – •dilated pupil, •accommodation fixed for far vision, •impaired light reflex •Inhibition of exocrine glands Trimetaphan: controlled short lasting (2 3 minutes) hypotension in surgery; iv Hexamethonium No longer clinically used –Sweat, –Salivary, –GI –Bronchial –Lacrimal Muscarinic Cholinoceptor Antagonists Atropine –Derived from deadly nightshade –Belladona alkaloid i) CVS –Initial in HR (CNS effect) –Subsequent mild tachycardia –Cutaneous flushing (histamine effect) –No change in BP •Hyoscine ii) Inhibition of exocrine glands Block receptors: iii)Eye –Dilated pupil (mydriasis) –Impaired light reflex –Accommodation fixed for far vision – IOP i) Post-gang para ii) Post-gang symp, that use Ach Block "muscarinic" the CNS. iv) smooth muscle –Bronchodilation – contracn of ureter and bladder – contracn of gallbladder and bile ducts –Little effect on the uterus GI tract: –Difficulty swallowing – motility v) CNS –Initial excitation (atropine only)– Depression –tranquility, amnesia –Overdose :Coma, Resp depression, Death NEUROMUS CULAR BLOCKING DRUGS •Dont Affect Consciousness •Dont Affect Pain Sensation Assist Resp (Until Drug Inactive Or Antagonised) Atropine i.v. –Sinus brady –oral, i.m. Well distributed Metabolism: Hepatic–t1/2: 23h Atropine Dry mouth Blurred vision Urinary retention –Tropicamide local, short acting – dilate the pupil to view the retina young children who eat deadly nightshade berries. Atropine poisoining Characterised by hyperactivity CNS Hyoscine, transdermal depression –Prevention of motion sickness body temperature periph musc block – i.e. dry –Parkinson’s mouth, etc. Ipatropium inhalation Asthma Obstructive airways disease –Peptic ulcer disease –Irritable bowel syndrome –Facilitate endoscopy Treated anti-cholinesterase drugs which penetrate the CNS, e.g. physostigmine • Diazepam / Baclofen: (Central Processes ) / Dantrolene: (Propagn Of AP Along Muscle Fibre + Muscle Contracn) Spasmolytics : •Local Anaesthetics Conduction Of Nerve Ap In Motor Neurone •Hemicholinium •Ca2+ Entry Blockers •Neurotoxins Ach Release Non Deoplarising Tubocurarine (Prototype) Depolarisation Of Motor End-Plate A AP Initiation Relaxation Of Skeletal Muscles During Surgery (= Less Anaesthetic) Competitive Post Synaptic Competitive nAChr Antagonist • 4° Ammonium Compound (Alkaloid) 70 - 80% Block Necessary Found In S. American Plant (Arrow Poison) •Graded Block = Different Proporn Of Fibres Blocked Pancuronium leads to: Flaccid Paralysis of 1. Extrinsic Eye Muscles (Double Vision) 2. Small Muscles Of Face, Limbs, Pharynx 3. Resp Muscles Gang Block ( TPR) Histamine Release From Mast Cells Permit Artificial Ventilation Hypotension Iv- highly charged Doesnt Cross Bbb / Placenta Onset: 2 - 3 Min Actions Reversed By Anticholinesterases e.g. Neostigmine (+ Atropine) Tachycardia (Arrhythmias ??): Reflex Blockade Of Vagal Ganglia 40 - 60 Min (Long) Bronchospasm Not Metabolised excrete 70%Urine; 30% Bile (Care If Renal Or Hepatic Function Impaired) Apnoea (Always Assist Respiration) Secretions: Bronchial & Salivary) Depolarising (Agonists) SYMPATHO MIMETICS Suxamethonium ( Succinylcholine) Adrenoreceptors A1, a2, b1, b2, b3 all organs: by post-gang symp, bronchial SM, CNS A1: w/ imp of adrenergic activity vasoconstricn: skin, mucous memb, salivary, abdo sweating – thick and viscous male genitalia: ejaculation Constricn of iris radial muscles = mydriasis bladder: constricts trigone and sphincter ureter: motility and tone stimulates tears saliva Liver: glycogenolysis, gluconeogenesis = G lipolysis GI: motility and tone, contacn of sphincters A2: Inhibition of transmitter release, contraction of vascular SM, CNS. B1: HR and contractility lipolysis renin secretion relaxation of GI B2: Glycogenolysis, gluconeogenesis Skeletal muscles vasodilation Bladder: Relaxes detrusor Dilate trachea and bronchioles Relaxation of uterus relaxation of visceral SM β3- Lipolysis •G-protein coupled : –type 2 receptor –response slow: sec - min •2nd messenger: – a1 coupled to the PLC / IP3 – a2, b1, b2 aden cyc ( cAMP) Directly acting symp Mimic actions of NA/A by binding to and stimulating adrenoceptors Adrenalineemergency hormone CVS HR and contractility B1- b1=b2>a1=a2 a1vasoconstricn greater b2 vasodiln = peripheral resistance ( blood supply to skeletal muscle and lood supply to skin, g.i.t., mucusa) = CO BP SM •Lungs – Relaxation of tracheal and bronchial SM =Opens up airways Metabolism - Increases energy supply – blood levels G (glycogenolysis and gluconeogenesis in muscle and liver) – blood levels of free fatty acids 1. Acute allergic reactions and anaphylactic shockType 1 hypersensitivity reactions (i.v.) Inhibits release and opposes the inflammatory mediators which cause a fall in BP and breathing difficulties. i) CVS: tachycardia, arrythmias, cold extremities, severe hypertension ii) Reduced and thickened mucous secretions (dry mouth) ii) Tremor due to effects on skeletal muscle 2. As a cardiac stimulant (overdose) = to cerebral (i.v.) in: haemmorhage and e.g. acute manage heart block pulmonary oedema. 3. To maintain BP during spinal anaesthesia (i.v.). 4. To prolong the duration of (lipolysis in adipose tissue) local anaesthetics eye Constricts the radial muscle–Mydriasis (pupillary dilatation) 5. To treat glaucoma (eye drops): prodn of aq humour 6. COPD Phenylephrine a1 1. stop superficial bleeding from skin and mucous memb same as adrenaline; more resistant to COMT but not MAO. 2. dilate pupil (eye drops) without cycloplegia (loss of accommodation for near vision) or loss of light reflex. 3.nasal decongestant (nose drops; vasoconstrictor Clonidine a2 adrenoceptor mediated presynaptic inhibition of NA release Isoprenaline B1 = B2 Less susceptible to Uptake 1 and MAO than adrenaline; Symp oral hypertension ·a2 migraine ·central action in brainstem within baroreceptor pathway to symp oral/ iv heart block (cardiogenic shock, acute heart failure or myocardial infarction); i.v asthma discontinued plasma t ½ 2 hrs Dry mouth, Sedation, dizziness bradycardia, nausea, constipation. Tachycardia (reflex), dysrhythmias Dobutamine B1 > B2 heart block •(Lacks isoprenaline’s reflex tachycardia) i.v. t ½ 2 mins (rapid metabolism by COMT) Salbutamol (ventolin) B2>B1 asthma : (inhalation) - relaxation of bronchial SM - inhibition of the release of bronchoconst subs from mast cells. synthetic catecholamine •Reflex tachycardia •tremor •caution with cardiac patients, hyperthyroidism and diabetes (i.v.use) threratened uncomplicated premature labour: iv resistance to MAO and COMT INDIRECTL Y ACTING SYMP Cocaine A2 : prevents uptake by MAO so A/NA Tyramine: cheese reacn’ false’ neurotransmitter dietary aa (cheese, red wine and soy sauce SYMP ANTAG Problems: MOAs inhibited (antidepressant drugs eg. phenelzine) = ingestion of foods containing tyramine cause a hypertensive crisis. Not a problem when normal mechanisms for degradation of monoamines are in operation Hypertension �Cardiac Arrhythmias �Angina �Modify Plasma Lipid levels �Glaucoma Blocks presynap β- NA Kidney : blood vol and renin. heart: HR and CO Arterioles- peripheral resist due to less renin & pre-synapt β block CNS- controls BP B antagonist 1) Hypertension: sustained diastolic arterial pressure greater than 90 mmHg Bronchoconstriction – (β2− lungs) Caution: asthmatics pts, bronchitis. 2) Anxiety states - to control somatic symptoms eg palpitations and tremor. � Cardiac Failure – Pts w/ heart dis need some symp for normal CO 3)Migraine prophylaxis. 4)Benign essential tremor. � Hypoglycaemia - G controlled by liver β2warning diabetic (sweating, palpitations, tremor) of G Use B1 . � Fatigue - CO and muscle perfusion. � Cold Extremities - no βvasodilat in skin � Bad Dreams Propranolol Β1+ Β2− Non-Selective at rest, causes little change in HR, CO or arterial pressure, but effect of exercise or excitement on arrhythmia's that occur during exercise or mental stress 1st clinical βantagonists � maintains Reflex vasoconsn so postural hypotension /exercise less problematic. refractory period of the AVN = thus interfering with AV conducn in arterial tachycardias, and to slow ventricular rate. Class II Antiarrhythmics Atenolol Β1−Selective antagonise NA on heart but also any tissue β1. cardio-selective drugs � Less effect on airways than non-selective drugs, but not safe w/ asthmatic Labetalol Dual acting β1 and α1 antagonists, β1 : α1 (4:1) BP by via peripheral resis – via block of α1 in blood vessels & β1 effects on renin/neurotransmitter release. � No change in HR and CO metoprolol β1- HR � systolic blood pressure. � cardiac contractile activity. without affecting bronchial smooth muscle. (low dose) ANGINA- myocardial oxygen demand. higher dose selectivity is lost and resembles propranolol � Carteolol hydrochloride, timolol, maleate. � rate of aq humor prodn by blockthe receptors on the ciliary body. Which normally respond to symp and A Glaucoma � betaxolol hydrochloride : β1 antagonists � in arterial pressure (α- = periph resis � Postural hypotension. � Cardiac output/heart rate – reflex response to fall in arterial pressure (β- A adrenorecepto r antagonist Non-selective Phentolamine � vasodilan and � GIT motility BP due to block α1 � not clinically used diarrhoea concomitant α2 block tends to NA = reflex tachycardia occurs with any BP lowering agent Prazosin A1 Methyldopa False Transmitter released like NA � less active than NA on α1-= less vasoconstrictn � more active on presynaptic (α2), autoinhibitory feedback mechanism operates more strongly, release below normal α1-antagonists Plasma Lipid Levels- � Vasodilatn and arterial P. � Less tachycardia than non-selective as don’t NA �veins dilate, venous P, CO �less Hypotensive. � LDL , HDL � antihypertensive � postural hypotension is troublesome. � Taken up by NA neurons. � Decarboxylated and hydroxylated to = false transmitter, α-methyl-NA. � Not deaminated within neuron by MAO and so accumulate in larger quantities than NA , and displaces NA from synaptic vesicles. hypertensive patients with renal insufficiency or cerebrovascular disease. Dry mouth � Sedation � Postural hypotension (particularly in elderly) � Male sexual dysfunction � Parenchymal injury in the liver resembling viral hepatitis. hypertensive pregnant women, has no adverse effects on foetus Renal blood flow is well maintained, widely despite crossing bloodplacenta barrier � CNS effects, stimulates vasopressor centre in brain stem to inhibit symp � used very infrequently. �LDL and (VLDL) levels and total triglyceride levels. (HDL) risk factors for coronary artery dis. DRUGS AFFECTING THE HEART Symp: •inc force of contraction (+ve inotropic) •inc HR (+ve chronotropic ) •inc automaticity •red cardiac efficiency (i.e. cardiac O2 consumption inc > cardiac work) •activate B1: stimulate adenyl cyclase = inc prodn of cAMP from ATP, intracellular messenger = inc Ca – effect on L-type channels and sarcoplasmic reticulum and stimulate Na-K ATPase in cardiac myocyte Changes in preload and afterload •Inc preload (venous return) inc force of contraction (Frank Starling effect) •Inc afterload dec stroke vol Heart failure: serious condn w/ high mort heart does not adequately perform funcn as a pump (or only does so at elevated filling pressures). = fluid retention, oedema and fatigue. •due to ischaemic heart disease, hypertension, cardiomyopathy of a combination of these conditions •ACEI (ARB), beta-blockers and spironolactone have been shown to improve survival. Para: Cardiac slowing and dec automacity Inhibiton of AV condn inhibit symp stimulation of heart 1. Angina 2. Post myocardial infarction 3. Cardiac dysrhythmias 4. Hypertension 5. Chronic heart failure 6. thyrotoxicosis, glaucoma, anxiety states, migraine prophylaxis, benign essential tremor 7. improve post MI 1. 2. 3. 4. Organic Nitrates glyceryl trinitrate isosorbide mononitrate, Affect the preload Predominantly venodilators, dec venoreturn and cardiac work, release NO in SM and relaxes them, inc in venous capacitance –antiplatelet agents –coronary artery vasodilators –reduce systemic arterial tone (afterload). Caused by vasodilation • hypotension, headaches and flushing •Excessive/prolonged use: tolerance – i.e. a loss of effect and benefit. nicorandril open K (ATP) B-Blockers competitive antag badrenoceptors propranolol (non-selective), atenolol (B1 selective) Longer acting; transdermal patch first pass’ metabolism by liver. sublingual tablet or spray: rapid relief Bronchoconstriction Worsening of cardiac failure Bradycardia (heart block) Hypoglycaemia (diabetics on insulin) 5. Fatigue 6. Cold extremities and worsening of peripheral arterial dis 7. CNS effects (lipophilic agents) e.g. nightmares of angina short t ½ (~5 mins). Vasodilation affects the arterial circ Calcium antagonist 1) Cardiac and Verapamil (and diltiazem less) affect L-type channels in SM actions heart and blood vessels. a) bind to L-type calcium channels and reduce Ca2+ entry Phenylalkylami into cardiac and SM - relax nes (e.g. verapamil - -ve ionotropic and chronotropic actions Verapamil) b)Benzothiazepi nes (e.g. Diltiazem) 1. Hypertension 2. Angina 3. Anti-dysrrhythmics (verapamil > diltiazem, ) 4. Negative inotropic effect (verapamil > diltiazem, Verapamil: heart block, heart failure and constipation Longer acting Flushing headaches, hypotension, ankle swelling Antidysrhythm endogenous mediator produced by the metabolism of adenosine triphosphate (ATP). ic agents A1: hyperpolarize cardiac tissue and slow conduction Adenosine through AVN. Iv: terminate superventricular tachyarrhythmias (SVT). short-lived (20-30s) safer than verapamil. •Chest pain, shortness of breath, dizziness and Verapamil Calcium antagonist Inhibits AV-node conduction Paroxysmal SVT atrial fibrillation (no abnorm conducn pathways). Amiodarone Complex action probably involving multiple ion channel block and possibly anti-thyroid action Antidysrhythmic: superventricular and ventricular tachyarrhythmias accumulates in the body (t½ 10 100days) Cardiac ionotrpes Dobutamine b1 agonist inc force contraction w/out any major effect on heart rate. acute heart failure e.g. after cardiac surgery or in cardiogenic or septic shock 2) SM actions Dihydropyridin es (e.g. amlodipine) dec Ca2+ entry into SM only affect blood vessels. •Inhibitors of phosphodiesterase: inhibit breakdown of cAMP in cardiac myocytes. 1. 2. 3. 4. 5. 6. photosensitive skin rashes hypo- or hyper-thyroidism pulmonary fibrosis corneal deposits neurological, GI disturbances nausea impair survival in chronic heart failure and are rarely used. milrinone Cardiac glycosides Digoxin DRUGS AND VASCULATU RE ACE Inhibitors inhibit Na-K-ATPase (Na/K pump). Accumulate Ca2+: dec Na+ release and inc Na+/Ca2+ exchange = inc force of contraction dec rate of conduction through the AVN (result of central vagal stimulation) slows ventricular rate in atrial fibrillation and relieves symptoms in chronic heart failure (common and severe) •dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity) •Clinically imp interactions w/ drugs that reduce digoxin excretion and tissue binding (e.g. amiodarone, verapamil) or agents that reduce plasma [K+] (e.g. diuretics). prevent the conversion of ang I to ang II by ACE 1. 2. 3. 4. 5. 6. 1. Cough (ACEI) 2. Hypotension 3. Urticaria / Angioedema (ACEI - v. rarely) 4. Hyperkalaemia (care with K supplements or K sparing diuretics) 5. Fetal injury 6. Renal fail:pts w/ renal art stenosis prevent the degradation of bradykinin (and other kinins) enalapril hypertension heart failure post-myocardial infarction diabetic nephropathy progressive renal insufficiency pt: high risk of cardio disease Ang receptor blockers ARB or AIIA non-comp antag of type 1 (AT1) receptors AngII losartan •Clinical experience less extensive than ACEI Both inhibit the hypertensive and Na+ retaining effects of angII Aldosterone antagonist Spironolactone inhibits the Na retention heart failure resistant cases of hypertension. limited diuretic effects B Blockers Comp antag breceptors b1 antagonists: hypotensive action not understood do not dec peripheral resistance (PVR) (except partial agonists / vasodilatory beta blockers). 1. 2. 3. 4. Hypertension alternative for ACEI in pt who cannot tolerate ACEI (e.g. Chronic heart failure). Same inc angII levels and do not prevent actions on AT2 Angina Post myocardial infarction Cardiac dysrhythmias Chronic heart failure hyperkalemia steroid-like effects: gynaecomastia, menstrual probs, testicular atrophy. Atenolol B1 5. Hypertension 6. thyrotoxicosis, glaucoma, anxiety states, migraine prophylaxis, benign essential tremor Calcium Blockers 1. dec renin release by the kidney 2. dec NA release by symp 3. lipophilic: exert central sympatho-inhibitory actions: less marked rise in PVR on chronic as opposed to acute administration. reduce Ca2+ entry into cardiac and smooth muscle cells Verapamil & diltiazem Dihydropyridines: Vasodilators Hydralazine dilates arteries/arterioles. Consequently it induces reflex tachycardia. Rarely used except in pre-eclampsia / pregnancy-associated hypertension Organic nitrates nitroprusside nitric oxide (NO) donors and vasodilate arteries, esp veins. Propranolol lipophilic angina Nicorandil NO donor and KATP channel opener. A blockers and sympatholytics antag a1 doxazosin competitive Arterial vasodilat that inhibit vasoconstrict effects of symp on blood vessels clonidine - Centrally acting antihypertensive penoxybenzamine irreversible combined w/ antihypertensives in resistant hypertension long-lasting a-blockade in pheochromocytoma (combined with a beta blocker). Use often limited by adverse effects a-methydopa (a2-adrenoceptor agonists), moxonidine (imadazoline agonist) Reserpine depletes neuronal NA. trimetaphan Short acting ganglion blockers, anaesthesia to dec BP Vasoconstricto rs Sumitriptan constricts large arteries and inhibits trigeminal nerve migraine attacks, Sympathomim etic Adrenaline: catecholamine, produced by the adrenal gland ergot alkaloids Agonist at 5HT1D recep cardiac arrest anaphylactic shock contraindicated in pt with coronary dis. usefulness is limited by side effects. HAEMOSTAT arrest of blood loss from damaged blood vessels. a rapid, potent, localized response to vascular damage. SIS 1. Vasoconstriction 2. Platelet aggregation (clumping) 3.Coagulation to produce a fibrin clot cofactor in synthesis of clotting factors: fibrinogen – fibrin Vit K Synth by bact in mesh GI + w/ carboxyglutamic acid inc modification of factors Promote Coag THROMBOSI S In vivo Clot: in vitro pathological formn of haemostatic plug w/in vasculature in the absence of bleeding Virchow’s Triad 1) Injury to the vessel wall e.g. rupture of athero plaque 2)Stasis e.g. atria of heart during atrial fibrillation, veins of the legs following restricted movement on long flights. 3)Abnormal coaguability of the bloode.g. late stages of preg, during treatment w/ certain oral contraceptives Arterial (white thrombus) atherosclerosis. platelets and leukocytes in a fibrin mesh. Interrupts blood flow= ischemia/ infarcn of tissue beyond. Venous (red thrombus) blood stasis. Small platelet component large fibrin component. break away= embolus wh/ lodges in lungs or (if it comes from the left heart or carotid) the brain. 1. 2. 3. 4. promote coag: haemophilia staunch haemorrhage following surgery after anti-coagulant Therapy 1. Newborn babies to prevent haemorrhagic dis 2. stop bleeding in excess anticoag Haemophilia – lack of factor VIII = fresh plasma, conc factor 8 and 9 Drug therapy used to treat or prevent thombosis (or thromboembolism) acts in 3 distinct ways antiplatelet anticoagulant fibrinolytic form in heart in pt w/ atrial fib Treatment – antiplatelet drugs and fibrinolyitic dugs anticoagulants Anticoagulants Natural 1) Warfarin 2) Heparin 3) Low Molecular Weight Heparin (LMWH) Anti Platelet Aspirin 1.TFPI – tissue factor pathway inhibitor 2. Protein C – activated by thrombin, inactivates factors VII and V 3. Antithrombin III – activated by heparin inactivates thrombin - prevents the activation of vitamin K drug interactions: 1) inhibit cyt P450- antibact– erythromycin - antifungal– fluconazole 2)induce cyt P450: -Anticonvulsants – Phenobarbital 3) drugs which inhibit platelet function: - aspirin 4)drugs which displace warfarin from plasma proteins -aspirin -activates anti-thrombin III which inhibits factor Xa and thrombin by binding to the active serine sites. LMWH same effect on Xa but less on thrombin. Reversal: Stop IV . Give IV protamine - binds to heparin to produce an inactive complex Irreversibly inhibits COX-1. Inhibits the production pf TXA2 in platelets -oral, absorbed quickly from GI, peak blood conc:1h, pharmaco effect delayed:12 – 16h, peak after 48h and last 4-5 days – slow turnover of clotting factors binds strongly to plasma prot (99% albumin): small vol of distribn. Metab: hepat mixed funcn cytP450 1. haemorrhage (especially into the brain or bowel 2. teratogenicity (not given to pregnant mothers reverse effects: Low doses of vitamin K - Fresh frozen plasma or prothrombin complex concentrate can be infused if a rapid reversal Anticoag act monitored by International Normalised Ratio (measures prothrombin time) oral - Poorly absorbed subcut: delayed 1 hour iv: Imm onset Short t½ . saturation kinetics (t½ inc w/ inc dose). Anticoag act measured. longer t½ , exhibits 1st order kinetics, act does not require monitoring. oral Highly plasma protein bound 1) Bleeding 2) Thrombocytopenia 3) Osteoporosis :(assoc with long term therapy over 3 months) 4) Hypersensitivity: chills, fever, urticaria and even anaphylaxis GI sensitivity Clopidrogel pro-drug inhibits fibrinogen binding to glycoprotein IIb/IIIa receptors =In aspirin sensitive pt Amciximab Streptokinase Non-enzymatic protein. Alteplase recombinant tPA. Fibrinolytic Antag of the glycoprotein IIb/IIIa receptor. This is a hybrid murine/human monoclonal Ab wh/ : use in acute coronary syndromes- in combination w/ heparin and aspirin- to prevent ischemia in pts w/ unstable angina Derived from culture of B-hemolytic streptococci. Binds to plasminogen causing a conformational change exposing the active site, causing plasmin activity. Activated plasmin degrades fibrin. works better on plasminogen bound to fibrn that to soluble plasminogen in the plasma : clot sensitive. It activates plasmin that then degrades fibrin and dissolving the clot. Oral Peak plasma conc: 4hrs after a single dose but inhibitory effect on platelt not seen until after 4 days of regular dosing Iv Binds rapidly to platelets. Cleared with platelets. Antiplatelet effect persists for 24-48hrs IV – 30 –60 min infusion Bleeding GI haemorrhage, diarrhea, rash In some patients neutropenia Bleeding May potentially be immunogenic Bleeding May potentially be antigenic Rapidly cleared t1/2 12-18 mins Iv 30min infusion Rapidly cleared t1/2 12-18 mins 1) Acute MI admin w/in 12h or onset of sympt dec the mortality rate 2)Acute thrombotic stroke- w/in 3h 3)Deep vein thrombosis, pulmonary embolus, acute arterial thromboembolism, local thromboembolism in the anterior chamber of the eye. bleeding LIPID LOWERING DRUGS “ Atherosc is an inflamm fibroploriferative disorder” LDL:Assoc w/ atherosc and CHD events •10% incr = 20% incin CHD. main target to prevent CHD • risk factors: –low HDL–smoke –hypertension –diab increase pancreatitis risk HDL :protective effect •lower HDL, the higher the risk •HDL low when triglycerides high •HDL lowered by smoking, obesity and physical inactivity TRIGLYCERIDES: incr risk of CHD –? low HDL and more atherogenic LDL (small dense ) •Normal triglyceride levels <200mg/dl (2.3mmol/l) •Very high triglycerides (>1000mg/dl, 11.3mmol/l) CHOLESTROL – A Modifyable risk factor •USA, 37% (102 million): high(>200 mg/dL, 5.2mmol/L)1 •EUROASPIRE II, 58% pts w/ CHD had high cholesterol (³5 mmol/L, 190 mg/dL)2 10% dec in total cholesterol: –15% dec in CHD mort (p<0.001) –11% dec in total mort (p<0.001)3 Statins Simvastatin dec LDL by 25%-35% = dec CHD morbidity/mortality • dec in all-cause mort in 2° prevention and in cardiovasc mort in 1° prevention (clinical trials and regression studies) support treatment in various pt gps: – women –elderly –diab dec inflamm response Fibrates activation of PPAR (peroxisome proliferator activated receptors) alpha and gamma receptors Ezetemibe Inhibits cholesterol absorpn Absorbed then activated as glucuronide thiazolidinediones (glitazones) used in diab NON STEROIDAL ANTI INFLAMMAT ORY DRUGS - inhibit rate limiting enzyme, cyclo-oxygenase (COX) -inhibit synthesis of Prostanoids: no effect on the act of preformed, pre-released or exogenously admin prostanoids 24 million prescriptions/pa in UK Average prescribing rates, 246 scripts/1000 pop in UK 1. Analgesic (relieve pain): •Toothache, headache, backache -taken occasionally •Some postoperative pain •Dysmenorrhea (menstrual pain) –dec fever e.g.Influenza prostanoids: Prostaglandins and thromboxanes e.g. PGE2 –Dec inflamm e.g.Rheumatoid Lipid mediators from arachidonic acid arthritis •Osteoarthritis • musculo • in most tissues •Are not stored preformed, but are made •Soft tissue injuries (strains and and released imm • many prostanoid receptors •many sprains) •Gout actions, not all pro-inflamm: 2. Antipyretic (reduce temp) 1.Hyperalgesic (enhances sensitivity to pain): 3. Anti-inflamm: peripheral nociceptors more sens to chemical and thermal -high doses and long periods stimuli wh/ cause pain 4. Closure of ductus arteriosus in the NSAID prevents PG synthesis: prevents stimulation of PG newborn receptors on nerve endings= Nociceptors not sensitized and 5. Prolongation of gestation and the perception of pain is reduced = Pain relief labour 6. Management of Familial 2.Pyretic (raises temp) by “re-setting” hypo thermostat. Adenomatous Polyposis stimulates hypothal neurones: inc body temp 7. Prevent Alzheimer’s dementia Normalised temperature by correction of the hypothalamic thermostat NSAIDS dec raised temp 8. Aspirin: anti platelet 3. Immune and Inflamm pathways:inc prodn of proinflamm cytokines: IL-23, IL-6 –Th2 cytokines IL4, IL5 –granulocyte-macrophage colony-stimulating factor •inhibits prodn: –Th1 cytokines such as IFNg and IL2 NSAIDS inhibit PGE2 and other prostanoids 4. Vasodilator (inc oedema): dilates precapillary arterioles –Synergises w/ other vasodilators eg histamine and bradykininns •Indirectly inc perm of post-capillary venules nsaids: dec dilatation, Red inflamm (dec oedema) 5. gastric cytoprotecn: Inhibits acid secretion and inc mucus secretion in stomach nsaids prevent: inc HCL = gastric ulceration 6. Modulate glomerular blood flow and Na+ and water reabsorn in the kidney - PGE2 enhances renal blood flow and therefore GFR NSAIDS : red GFR = renal ischaemia, and salt and water retention Cox-1 made all the time •Ubiquitous •Physiological Cox-2 •Inducible (in response to sp stimuli) by leucocytes •pro-inflamm • physiological funcn: –regulate ovulation, parturition Ibuprofen typical NSAID inhibits COX-1 and COX-2 reversibly (short lasting) Celecoxib Selectively inhibits COX-2 • less effect on the GI –dec risk of hospitalisation for serious GI effects –dec need for additional drugs to prevent GI side-effects •No effect on nephrotoxicity • NICE recommendations: used in pts at high risk of GI side effects, –history of ulcers/GI bleeding –over 65 –Pts taking other drugs wh/ inc GI side-effects –Patients needing maximal doses of NSAIDS long-term Aspirin Binds more to COX-1 irreversibly inhibits COX enzymes •Acetylates an aa in active site = actions long-acting –reversed by de novo synthesis of new cox Physiological side effects rofecoxib (trade name: Vioxx) discont: inc risk of CVD if long-term (>18 months). therapeutic doses: irreversibly 1.Gastric irritation and ulceration: dec cytoprotection of the stomach 2.Nephrotoxicity: dec renal blood flow 3.Bronchospasm in sens asthmatics 4.Prolonged bleeding times due to inhibition of platelet aggregation Covalent binding of Aspirin confers its anti-aggregatory property which is unique among NSAIDS serious effects in overdose Paracetamol No anti-inflamm not an NSAID inhibits prostanoid synthesis in brain but not in periphery •may work by inhibiting a novel isoform of cyclooxygenase (COX-3) good analgesic for mild-to-moderate pain • anti-pyretic very safe drug overdose : irreversible liver failure –reactive, but minor metabolite (Nacetyl-p-benzoquinoneimine) normally safely conjugated w/ glutathione. –If glutathione is depleted the metabolite oxidises thiol groups of key hepatic enzymes = cell death DIURETICS 1) Osmotic Mannitol Drugs that act on the renal tubule to promote the excretion of Na+, Cl- and H2O. 1. Inhibit reabsorpn Na+ and Cl- = promote excretion 2. Inc osmolarity of tubular fliud delivered to collecting duct = dec osmotic gradient across the epithelia prevent reabsorption of water 1) Hypertension 2) Salt and water overload due to •Acute pulmonary oedema •Chronic heart failure •Liver cirrhosis plus ascites •Nephrotic syndrome •Renal failure 3)Acute hypercalcaemia Filtered by the glomerulus but not reabsorbed 1)Inc osmolarity of tubular fluid = dec H2O reabsorpn where the nephron is freely permeable to water, i.e. –prox tubule –descend loop –collecting duct =Inc H2O excretion, 2)Small inc in Na+/Cl- loss Iv Pharmacologically inert 1) Cerebral oedema 2) Raised intraocular pressure 3) Prevent acute renal failure Weak diuretics on proximal tubule 1) Prevent the reabsorption of HCO3- and Na+ 2) dec H2O reabsorption + + Acetazolamide 3) Inc Na to distal tubule: inc K loss 4) Inc tubular fluid osmolarity : dec H2O reabsorpn in collecting duct. • inc urine vol , Na+, HCO3 -( an alkaline urine) K+ loss 2) Carbonic Anhydrase Inhibitors 3) Loop Frusemide (furosemide) Powerful diuretics – promote the excretn of 30% of the filtered Na+ load ascending loop 1) Inhibit co-transporter system = inhibit Na+ and Clreabsorption = dec osmolarity of the medullary interstitium 2) Assoc inhibition Ca2+ & Mg2+ reabsorption 3) Inc Na+ to distal = incr Na+/K+ exchange =inc K+ loss 4) Inc osmolarity of tubular fluid delivered to collecting duct + dec osmolarity of the medullary interstitium = dec H2O reabsorption inc: urine vol •loss of Na+, Cl- and K+ •loss of Ca2+ and Mg2+ • Hypovolaemia • Metabolic alkalosis prompt short-lasting, powerful diuresis •Sometimes called a ‘high ceiling’ diuretic Glaucoma 1) Acute pulmonary oedema 2) Oedema due to heart, liver or renal disease if refractory to other diuretics 3)Acute treatment of hypercalcaemia 4) Hyperkalaemia 5)Acute renal failure 6)Hypertension if assoc w/ renal failure (piretanide: gd vasodilator) oral or i.v. Distribution – strongly bound to plasma proteins Clearance – secreted into the renal tubular fluid, excreted unchanged Transient expansion of ECF vol and associated hyponatraemia Headaches, nausea and vomiting 1) K+ loss 2) Mild metabolic acidosis 3) Self-limiting action 1. Hypokalaemia 2. Metabolic alkalosis 3. Loss of Ca2+ and Mg2+ 4. Hypovolaemia and hypotension, particularly in the elderly 5. Nausea 6. Allergic reaction 7. Deafness (rare) t ½ : – short – 1-2h Duration – short – 3-6h max 5) Thiazides bendrofluazide (bendroflumet hiazide) early distal tubule: block electroneutral Na+/Cl- co-transp 1) Impaired reabsorpn of Na+ and Cl2) Inc Na+ late distal: inc Na+/K+ exchange, inc K+ loss 3)Dec Mg2+reabsorpn 4)Inc Ca2+ reabsorption 5)Incr osmolarity of tubular fluid entering the collecting duct: dec epithelial osmotic gradient = impaired H20 reabsorpn = inc urine vol a) Hypochloraemic alkalosis b) Vasodilation c) Inhibition of insulin secretion - diabetogenic due to opening of K+ channels d)Inhibition of uric acid secretion Diazoxide nondiuretic thiazide, 6) K+ Sparing vasodilator and diabetogenic actions. Weak diuretics late distal tubule block Na+/K+ exchange max of 5% of filtered Na+ load is excreted. 1) Hypertension – initial action due to dec blood volume but long-term effects due to vasodilation 2) Mild heart failure 3) Severe resistant oedema 4) Prevent recurrent stone formn in idiopathic hypercalciuria 5) Nephrogenic diabetes insipidus (paradoxical oral, well absorbed Distribution –bind to plasma prot •Clearance – compete w/ uric acid for secretion into the renal tubule •Excreted unchanged via the urine •Onset of action: 1-2h •Duration of action –‘Short acting’ – 12-24h (e.g. bendrofluazide) –‘Long acting’ - >24h (e.g. chlorthalidone 1) control K+ levels 1) Inhibit Na+ and K+ secretion in the late distal tubule 2) Inc osmolarity of tubular fluid entering the collecting duct: reduced reabsorption of water 3) Dec H+ secretion into the tubular fluid 4) Dec uric acid secretion (competes with uric acid for secretion into the tubular fluid) amiloride, Inhibitors of aldosterone-sensitive Na+ channels 1) Hypokalaemia 2) Metabolic alkalosis 3) Hyperglycaemia – exacerbation of diabetes mellitus 4) Uric acid retention – possibility of gout 5) Rarely. hypersensitivity reactions (rashes, blood dyscrasias) 6) Rarely, hyponatraemia better tolerated –Poorly absorbed orally –Competes with uric acid for secretion into the renal tubule –Slow onset of action (4-6h) –Duration 24h –Excreted unchanged via the urine Spironolactone and amiloride –Hyperkalaemia –Metabolic acidosis spironolactone Aldosterone receptor antagonists Primary and Secondary hyperaldosteronism –Well absorbed orally –Promptly converted to active metabolite, canrenone –Onset of action slow (several days) Actions on other steroid receptors: •Gynaecomastia •Menstrual disorders •Testicular atrophy ANTI INFLAMMAT ORY BOWEL DRUGS •Pathogenesis not completely understood •Probably due to defective interaction between mucosal immune system and gut flora •2 x 1014 bacteria in gut •genetic factors are important 1. Supportive therapies - Fluid/electrolyte replacement - Blood transfusion/ oral iron - Antibiotics Immune system distinguish between pathogenic and nonpathogenic, excessive response = inflamm 2. Possible curative therapies Treatment of symptoms: a) treatment of active disease -Glucocorticoids eg Prednisolone ulcerative colitis: more common •Th2- mediated autoimm reacn •Th2 cytokines esp IL-13 •T cell clones limited capacity to expand •No defect in T cell apoptosis •Confined to mucosa and submucosa •Begins in rectum •May spread proximally, but remains confined to colon •Inflamm is continuous •Surgery is curative crohns (more extensively studied) •Th1-mediated dis •Th1 cytokines imp e.g. IFNg, TNFa •Florid T cell expansion •Defective apoptosis of T cells •Not confined to mucosa and submucosa •affect any part of small or large intestine •Inflamm may be patchy and discontinous •Abcesses, fissures and fistulae are common •Less responsive than UC to drugs •May recur after resection b) prevention of relapse or remission - Aminosalicylates eg Mesalazine - Immunosuppressives eg azathioprine 3. Possible Curative Therapies: - Anti-TNFa eg Infliximab IBD Inc:10 - 20 new cases/100,000 pop/yr •Peak inc 20 – 40 yr Prev: 100 - 200 /100,000 pop •More common in women •Inc incidence in first degree relatives •diff between ethnic groups •Severity of sympt depends on extent and location of dis •rectal bleeding w/ mucous discharge, diarrhoea, abd pain, anorexia, Wt loss, fever, other extra-GIT symptoms •Rarely fatal, due to modern therapy, dec quality of life Glucocorticoid s Prednisolone, Fluticasone, Powerful anti-inflamm and immunosuppressive •Activate intracell Glucocorticoid Recept = +ve/ -ve transcription factors •Dec influx and activate pro-inflamm cells Before GCs, IBD had a high mort 1) reduces/delays need for surgery 2) treatment of severe active IBD. •However, better to use other drugs to 1)Osteoporosis : inc osteoclast dec osteoblast Inc risk of Gastric ulceration - dec prostaglandins in stomach budesonide Derived from cortisol –Dec adhesion molecules on endothelial cells and leukocytes –Dec synthesis of some chemokines •Dec prodn of mediators causing signs of inflamm by dec synthesis of: –cytokines and their receptors (IL-1, TNFa) –Proteolytic enzymes (e.g. elastase) –Enzymes catalysing mediator synthesis (eg COX) –Eicosanoids (eg prostaglandins and leukotrienes) –Nitric oxide maintain remission •Start w/ high dose and taper down •Use drug with high therapeutic index (e.g. fluticasone) •topically •use oral or topically (fluid or foam enemas or suppositories) wh/ is degraded locally e.g.Budesonide imuunosurppressive: •Dec Ag presentn •Dec prodn of mediators (e.g IL-2, IL-4, IFNg): •Dec cell proliferation and clonal expansion Suppression of HPA axis -ve fdback on pit & hypo 2) Type II D : oppose acn of insulin; inc gluconeogenesis inc glycogenolysis Hypertension: cause Na+, Cl-, water retention, inc receptors response to catecholamine 3) Susceptibility to inf immunosupp 4)Skin thinning, bruising and slow wound healing: dec connective tissue turnover and repair 5) Muscle wasting and buffalo hump: dec storage of G in muscle, inc fat deposn Aminosalicylat es Sulfasalazine (first), Mesalazine, olsalazine Anti-inflamm •dec synthesis of eicosanoids •dec free radical levels •dec inflamm cytokine prodn •Dec leukocyte infiltration •No immunsuppress effects • aminosalicylate = sulfasalazine: split by colonic flora into: 5-ASA (therapeutic) and Sulfapyridine maintain remission and prevent relapse 5 aminosalicylic acid (5-ASA) Mesalazine (–33% released in upper SI, remainder in distal ileum and colon Absorbed: Small bowel and colon 1) Olsalazine(2x5-ASA molecules linked by azo bond) Colon, Metab by colonic flora and liver 2) Balsalazide ( 5-ASA linked to carrier molecule) Colon metab by colonic flora Controlling absorption: = gradual release Topical (suppositories, enemas) •pH-dependent release capsules ( SI) •Slow release microspheres ( small and large bowel) Limited use in the treatment of active IBD Sulfapyridine causes most of the sideeffects Azathioprine pro-drug: degrades spontaneously in vivo= active form 6mercaptopurine by gut flora Immunosuppressive interferes w/ purine biosynthesis, wh/ interferes with DNA synthesis and cell replication •It impairs: –cell- and Ab-mediated immune responses –lymphocyte proliferation –mononuclear cell infiltration –synthesis of Ab •It enhances: –T cell apoptosis 1) Crohn’s disease 2) maintaining remission 3) May induce remission in some cases of active disease 4) May dec glucocorticoid dose or postpone colostomy 1)Bone marrow suppression 2) If admin w/ drugs wh/ inhibit xanthine oxidase e.g. allopurinol, ( treatment of gout), 6 –Mercaptopurine levels rise and blood dyscrasias may result Infliximab Crohn’s: Th1-mediated autoimm response and TNFa plays imp role in dise pathogenesis •Anti- TNFa dec activation of TNFa receptors in gut •Dec Prodn of cytokines, infiltration and activation of leukocytes •Also binds to memb assoc TNFa •Mediates complement activation and induces cytolysis of cells expressing TNFa •Promotes apoptosis of activated T cells ANTI EMETIC DRUGS only when cause of the nausea/vomiting is known, otherwise they mask the diagnosis of potentially serious conditions, e.g. digoxin excess, diabetic ketoacidosis. Promethazine comp antag at histaminergic (type H1), cholinergic (muscarinic, M) and dopaminergic (type D2) receptors. Order of potency of antag act: H1> M > D2 receptors Acts centrally (labyrinth, NTS, vomiting centre) to block activation of vomiting centre. Anti Tumour Necrosis Factor phenothiazine derivative c.f. other phenothiazines, wh/ are used as neuroleptic drugs, have a different order of potency with greater antagonistic effects at D2 receptors. Orally , Onset of action 1-2 hrs Max effect circa 4 hrs Duration of acn 24 hours Metocloprami de dopamine receptor antagonist. Order of antag potency: D2 >> H1 >>> Musc receptors Acts centrally, especially at CTZ Acts in the GI : -inc SM motility (oesophagus to SI - accelerated gastric emptying note: care must be taken with the bioavailabilty of coadministered drugs eg. - adsorption and effectiveness of digoxin reduced - nutrient supply compromised; imp in DM 1) CD: Successful in pts w/ refractory dis and fistulae Curative rather than palliative •iv •Very long half-life (9.5 days) •Benefits can last for 30 wks after a single infusion •Most pts relapse after 8 – 12 wks •repeat infusion every 8 weeks •4x - 5x inc inc of TB and other inf •not be used if evidence of sepsis (eg an abcess): risk of septicaemia •Worsening of heart failure •Can be immunogenic – therefore given with azathioprine • used by specialists where adequate resuscitation facilities available because of the risk of anaphylaxis 1. Motion sickness – prophylactically, but some benefit if taken after the onset of nausea and vomiting 2. Disorders of labyrinth eg, Meniere’s dis 3. Hyperemesis gravidarium 4. Pre- and post-operatively (sedative and anti-muscarinic). 5. Relief of allergic symptoms 6. Anaphylactic emergency 7. Night sedation; insomnia Dizziness Tinnitus Fatigue Sedation (‘do not drive or operate machinery') Excitation in excess Convulsions (children more susceptible) Antimuscarininc side-effects Used to treat nausea and vomiting In CNS assoc w/: drowsiness 1.uraemia (severe renal failure) dizziness 2.radiation sickness anxiety 3.GI disorders - accelerates transit of intestinal contents (from duodenum to ileo-coecal valve) extrapyramidal reacns; children 4.cancer chemotherapy (high doses) more susceptible (Parkinsonian-like eg. cisplatin (intractable vomiting) syndrome: rigidity, tremor, motor restlessness) orally / i.v.; rapidly absorbed; note: No anti-psychotic actions extensive first pass metabolism In the endocrine system crosses BBB, placenta hyperprolactinaemia galactorrhoea disorders of menstruation Hyoscine, antimuscarinic drug Ondansetron, 5HT3 receptor antagonist Order of antagonistic potency: Muscarinic >>>D2 = H1 receptors Acts centrally, especially in the vestibular nuclei, NTS, vomiting centre to block activation of vomiting centre. Atropine is less effective orally (peak effect in 1-2 hours), i.v., transdermally Acts to block transmission in visceral afferents and CTZ. 1. prevent anticancer drug-induced vomiting, esp cisplatin 2.radiotherapy-induced sickness 3.post-operative nausea and vomiting orally; well absorbed, excreted in urine ANTI ULCER DRUGS 1.Prevention of motion sickness 2.Has little effects once nausea/emesis is established 3.In operative pre-medication integrity of GI mucosal barrier is imp: to maintain a dis free state. protective factors lubricate ingested food and protect stomach from attack by acid and enzymes: 1.mucus from gastric mucosa creates GI mucosal barrier 2.hco3- ions trapped in mucus generate a pH of 6-7 at mucosal surface 3.locally prod prostaglandins stimulate mucus and HCO3prodn (paracrine action) and inhibit gastric acid secretion factors wh/ convert food into a thick semi-liquid paste (chyme) have potential to damage the mucosal barrier: 1.acid secretion from parietal cells of the oxyntic glands in the gastric mucosa 2.pepsinogens from chief cells wh/ can erode mucus layer imbalance of the protective and damaging factors: peptic, duodenal and gastric ulcer disease helicobacter pylori inf= damage to mucosal GI barrier –inc acid and/or dec HCO3- prodn –dec thickness of mucus layer –inc pepsin type I –decr mucosal blood flow cause: not fully understood risk factors: genetic predisposition, stress, smoking prevalence: 1:10 of the pop in dev countries eliminate cause of mucosal damage - promote ulcer healing - gastric ulcers duodenal ulcers Typical anti-muscarinic side-effects: drowsiness dry mouth, cycloplegia mydriasis constipation (not usually at antiemetic doses) headache sensation of flushing and warmth increased large bowel transit time (constipation) •gastroesophageal disease (gerd) stomach and duodenal contents reflux into oesophagus (oesophagitis) - occasional and uncomplicated gerd - heart burn, may treat by self medication w/ antacids and h2 antag - progress to premalignant mucosal cells and potentially oesophageal adenocarcinoma •treat w/ PPIs (drugs of choice) or H2 antag (less effective) •combine w/ drugs that inc gastric motility and emptying of the stomach eg. DA2 receptor antag(metoclopramide A) antibiotics eliminate helicobacter pylori (gram -ve bacterium –50-80% pop worldwide are chronically inf (low grade inf cause gastritis) –10-20% develop peptic ulcer dis or neoplasia (mechanisms unknown - genetic/virulence of strain) –100% of pts w/ duodenal ulcer and 80-90% with gastric ulcer are infected •compliance •dev of resistance •adverse response to alcohol, especially with metronidazole (interferes with alcohol metabolism •risk factors for acquiring infection–unknown •methods of transmission – uncertain –socioeconomic condns –contact with animals and contaminated faeces •success of eradication (aim for 90% eradication within 714 days) –inf may be difficult to eradicate –if eradication is part of treatment recurrence of duodenal ulcer after healing falls from 80% to 5% eg2 1)h2 receptor antag 2) clarithromycin 3) bismuth B) inhibitors of gastric acid secretion 1. omeprazole, proton pump inhibitors triple therapy” best practice in treating peptic ulcer : single not effective, dev resistance 1) metronidazole (active against anaerobic bact and protozoa) or amoxycillin (broad spectrum antibiotic), depending on pattern of local resistance 2) clarithromycin AB w/ a macrolide structure; inhibits translocation of bacterial tRNA) 3) proton pump inhibitor (ppi) :–improves AB efficiency by inc gastric ph which improves stability and absorption inhibit basal and stimulated gastric acid secretion from the parietal cell by >90% 1–triple therapy 2–peptic ulcers resis to h2 antag 3–reflux oesophagitis • irreversible inhibitors of the h+/k+ atpase •oral ; as enteric coated slow-release • inactive at neutral ph •weak base: accumulates in the cannaliculi of parietal cells; formulations concentrates its action there and prolongs its duration of action (2-3 days) and minimises its effect on ion pumps elsewhere in the body rare •oral , well absorbed less effective at healing ulcers than ppis 2. cimetidine, ranitidine histamine type 2 recep antag 3. antimuscarinic inhibit gastric acid secretion by approximately 60% C) cytoprotective enhance mucosal protection mechanisms and/or build a physical barrier over the ulcer 1. sucralfate polymer containing aluminium hydroxide and sucrose octasulphate acquires a strong -ve charge in acid environment •binds to positively charged groups in large molecules (proteins, glycoproteins) resulting in gel-like complexes •these coat and protect the ulcer, limit h+ diffusion and pepsin degradation of mucus •inc pg, mucus and hco3- secretion and red h. pylori oral remains in g.i.t 2. bismuth chelate acts like sucralfate used in triple therapy (resistant cases) 3. misoprostol stable prostaglandin analogue mimics acn of locally produced pg to maintain the gastroduodenal mucosal barrier 4. antacids DRUGS OF ABUSE • - rare •relapses likely after withdrawal of treatment little use as anti-ulcer drugs co-prescribed with oral nsaids when used chronically •nsaids block the cox enzyme required for pg synthesis from arachidonic acid therefore, reduction in the natural factors that inhibit gastric acid secretion and stimulate mucus and hco3- prodn mainly salts of al3+ and mg2+ •neutralises acid, raises gastric ph, reduces pepsin activity 1)Narcotics/Painkillers – opiate like drugs e.g. heroin 2) Depressants – ‘downers’ e.g. alcohol, benzodiazepines (valium), barbiturates 3) Simulants – ‘uppers’ e.g. cocaine, amphetamine (‘speed’), caffeine metamphetamine (‘crystal meth’) 4)Miscellaneous – e.g. Cannabis, Ecstasy (MDMA) • constipation •reduces absorption of some other drugs (eg. antibiotics and digoxin •diarrhoea, abdominal cramps, uterine contractions •do not use in pregnancy • non-ulcer dyspepsia effective in dec duodenal ulcer recurrence rates Snort’ – Mucous membranes of nasal sinuses, Slow absorption Eat’ – GI tract, Very slow ‘Smoke’ – Small airways and alveoli ; Rapid apsorption Inject’ – Veins ; Rapid Mesolimbic dopamine system – Central ‘reward’ pathway Ventral tegmental area → Nucleus Accumbens (VTA) (NAcc) NAcc → Dopamine = Reward (End pt for drugs of abuse) → Oral < Intranasal < Intravenous < Inhalational Cannabis Cannabis/Marijuana; Hashish/Resin; Hash Oil – Main active ingredient that acts on thbrain <>9-THC (Tetrahydrocan nabinol): Dronabinol Nabilone CB1 receptors- brain: Hippocampus/cerebellum/cerebral cortex /basal ganglia D9-THC + CBD: Sativex Cannabis Sativa = <>9-THC (inc potency) Cocaine Erythroxylum coca CB2 receptors - periphery:Immune cells ; Endogenous Anandamide Pharmacodynamics : 1. Psychosis, Schizophrenia!! 2. Food intake – Hypothalamus 3. Memory loss – Limbic regions 4. Psychomotor performance – Cerebral cortex 5. Peripheral effects; 6. Immunosuppressant 7. Tachycardia/vasodilation Paste’~ 80% (Cocaine sulphate) Extracted using an organic solvent. Impure! Iv, oral, intranasal: absorbed through mucous memb lining the sinuses = slower absorption - 100–500 ng/mL. Cocaine HCl – Passed through an acidic aqueous solution (HCl); the solution is neutralized and the cocaine is extracted by recrystalization. heat labile. Iv( rapid absorp), oral, intranasal Crack –precipitate out cocaine using an alkaline solution (e.g. sodium bicarbonate). Inhalation: rapid absorption plasma concentration = 500–1000 ng/mL. Cocaine freebase - dissolve in a non-polar solvent e.g. diethyl ether. inhalation reward pathway: Inhibit reuptake of dopamine in NAcc. neuropharmacology: blocks plasma memb transporter for dopamine (DA) (and has less potent effects on the norepinephrine (NE), and serotonin (5HT) transporters). Local anaesthetic effect – blocks sodium channels Pharmacokinetics; Inhalation – 50% Oral – 10-15% Onset = Seconds - Minutes Tissue t1/2 = 7 days Metabolised: Liver - 11-hydroxy-THC Excreted: GIT – 65% Urine – 25% Inc regulation of CB receptors: 1)Multiple sclerosis/pain/schizophrenia – regulatory 2)Fertility/obesity/stroke – pathology ‘Autoprotection’ – Dronabinol, Sativex ‘Autoimpairment’ - Rimonabant 75-90% - ecgonine methyl ester benzoylecgonine - liver Onset = Seconds T1/2 - 20-90min renally excreted. 1)Cardio: MI Inc symp: Platelet aggregation: vasoconstriction And inc HR 2) dec in cerebral blood flow 3)inflammation in the walls of the brain vessels (vasculitis). Nicotine Volatile: (95%) Nitrogen, Carbon Monoxide/Dioxide, Benzene, Hydrogen Cyanide Particulate: (5%) Alkaloids, Tar Pharmacodynamics Low dose – Symp via peripheral receptors (or direct effect on brain) → ↑ HR and BP. Higher doses - Binds to nicotinic receptors. Ganglionic stimulation and catecholamine release from adrenals. Very high dose – Ganglionic block and vagal stimulation. Effects on reward pathway: nicotinic located somatodendritically on dopaminergic VTA neurones – directly ↑ firing rate. Chronic smokers – Plasma nicotine levels between 2040ng/ml Nicotine spray – 1mg20-50% Particulate droplets reach the small airways and alveoli. Rapid absorption from the lung (faster than i.v.). Distributes rapidly to different tissues, incl the brain (within 10-20s). Nicotine Gum – 2-4mg 50-70% Cigarettes – 6-11mg 20% Nicotine Patch – 15-22mg/day 70% Hepatic CYP2A6: 70-80% to conitine (lung and brain) Elimination half life – 2-3h. Onset = Seconds Tissue t1/2 = 2-3h CVS effects: ↑ blood coagulation. ↑ myocardial work: inc HR and SV ↓ oxygen carrying capacity of blood (due to carbon monoxide) Coronary and peripheral vasoconstriction ↑ LDL and VLDL, FFA and ↓ HDL ↑ risk for atherosclerosis, myocardial infarction, cardiovascular disease Metabolic effects: ↑ metabolic rate ↓ appetite lipolysis, FFA, VLDL, dec HDL, Inc TXA2, dec NO Parkinson’s; - brain CYPs Alzheimer’s: dec b-amyloid toxicity Dec amyloid precursor protein (APP) Endocrine: ↑ACTH/cortisol OPIATES AND OPIODS alkaloid derived from the poppy, Papaver somniferum specific ‘opioid’ receptors used by the endogenous opioid peptides: –Endorphins –Enkephalins –Dynorphins/neoendorphins Located CNS: Presynaptic inhibitory function G-protein •Activation = dec cAMP Three main types u, k and d 1.analgesia: •Dec pain perception •Inc pain tolerance 2.Depression of respiration (medulla) 3.Sedation 4.Euphoria 5. Dysphoria 6.Depression of cough centre (anti-tussive) 7.Stimulation of chemoreceptor trigger zone •They are used clinically as analgesics •They are potentially fatal in overdose •They are drugs of abuse •Morphine •Heroin •Codeine •Methadone ••Naloxone - antagonist• tolerance –Pharmacokinetic – not a problem ––Tissue tolerance – principal cause dependence–Withdrawal assoc w/ •Psychological craving •Physical withdrawal (like flu) –Rarely occurs in pts taking morphine long-term for analgesia Receptor-selective ligands do not differentiate between the wanted and unwanted effects of opioids Overdose: 1. Coma (nausea/vomiting) 8.Stimulation of the oculomotor nucleus = miosis 9.GI tract: dec gastric emptying, decGI motility, inc water absorpn = constipation 10. inc histamine release; Suppression of medulla =dec BP 2. Respiratory depression 3. Pin-point pupils 4. Hypotension Treatment: Naloxone (opioid antagonist) i.v. Morphine Acute or chronic pain • oral (high first pass), i.m. or i.v. •Distribution: wide •Metab: hepatic – conjugation •Duration: - 3-6 h Heroin (diamorphine) Similar to morphine but– Enters brain more quickly = greater ‘rush’ –Shorter acting Codeine (3-Methyl Morphine) 1. Mild pain (weak analgesic vs. morphine) 2. Anti-tussive at sub-analgesic doses Oral, converted to morphine Causes severe constipation Pethidine (Meperidone) Weak agonist Used in obstetrics as excreted without conjugation orally or i.m. Methadone •Weak agonist •Little euphoric action •Used in chronic pain and substitution therapy orally, long duration of action (24h) Fantanyl •Highly potent, u –selective •Used in anaesthesia (intra-thecally) also in acute pain i.v., epidurally or transdermally Short-acting ADDICTION AND COMPULSIV E BEHAVIOUR GP 200 pts suffer • 1/5 hospital beds alcohol related conditions. • 50% in An E in the evenings or at weekends probs assoc w/ alcohol or drugs Addictive substances and processes are a significant contributory factor to many major illnesses. 1. Cancer of the lung: nicotine addiction. 2. Heart attacks: nicotine addiction, alcoholism, compulsive overeating, drug addiction. 3. Liver disease: alcoholism, compulsive overeating, drug addiction. Dis of human spirit • Abstinence = ‘dry drunk’ • affects abstract qualities such as syndrome: mood disturbance and the hope, trust, beauty, honour, innocence. resulting blame and self-pity. These are not intellectual characteristics. The disease of the • mood altering process of reaching human spirit requires the spiritual out to help others within the treatment of the Twelve Step Anonymous Fellowships. A.A. is the Programme. primary treatment, not an add-on extra.When A reaches out to help B • Given appropriate continuing anonymously it is A who feels better. treatment, the mood disorder resolves • 4. Accidents: alcoholism, drug addiction 5. Diabetes: compulsive overeating. and the long term consequences are avoided. • Emotional probs factor to the body/mind interrelationship and affect a wide range of clinical conditions. managed by doctor rather than referred to psychiatrists or counsellors. • In GP, 20% of all consultations are primarily emotional. is primarily a disease of feeling rather than of thought. • From one of the most devastating clinical conditions of all, patients can get into full remission provided that they continue the spiritual treatment on a daily basis. Assessing ‘why?’ – Preoccupation. – Use alone. – Use primarily for mood altering effect. – Use as a medicine. – Protection of supply. – Using more than planned. – Higher capacity than others. – Continuing despite damage. – The tendency to cross addict. – Drug seeking behaviour. – Drug dependent behaviour. – Continuing despite repeated concern of others. consequences – Emotional. – Behavioural. – Social. – Marital. – Professional. – Intellectual. – Educational. – Financial. – Legal. – Spiritual. – Physical. Shorter PROMIS Questionnaire: addicts to be distinguished from the normal pop and medical students. • same ten questions are asked on sixteen different • An addictive nature is a chronic illness and therefore requires life-long treatment by attending an appropriate Anonymous Fellowship and working the Twelve Step Programme. Inappropriate treatments: • Medicinal treatment (antidepressants, tranquilisers, sleeping tablets, mood altering painkillers, Methadone etc): alternative addictions. • Naltrexone and other antieuphoriants, or antabuse and other deterrents, • Psychotherapy as an adjunct to the Twelve Step Programme. Emotional trauma does not appear to lead to addictive behaviour in the absence of genetic predisposition (assumed from the Shorter PROMIS Questionnaire). • Inpatient or outpatient treatment in a Minnesota Method (Twelve Step) Treatment Centre may be helpful if patients find it impossible to maintain recovery in the community. Research: • Project MATCH compare the long term outcome of alcoholic patients treated with Cognitive Behavioural Therapy, Motivational Therapy and Twelve Step approaches. The initial results: all 3 equally successful but addictive behaviours. Answers given on a range 0- 5, depending upon relevance and intensity. • The clinical cut-off point is a score of 20 out of 50 on any individual outlet. Clusters of addictive behaviour 1. Hedonistic’: alcohol, recreational drugs, prescription drugs (antidepressants, tranquilisers, sleeping tablets and mood altering pain killers), nicotine, caffeine, gambling and risk taking, sex and love addiction. 2. Nurturant of self: food (binging, vomiting, starving, purging) stimulated primarily by refined carbohydrates (sugar and white flour), exercise, work, shopping and spending. 3. Relationship addiction (using other people as if they were drugs) and compulsive helping (using oneself as a drug for other people). • indicates spread of someone’s addictive behaviour • Pts need to be abstinent from all addictive substances and behaviours in a cluster a genetic predisposition. Perhaps each addictive cluster is determined by a separate gene. • evolutionary advantage of a hedonistic gene • all addictive behaviour originates in a defect in the neurotransmission systems in the mood centres of brain. • Pts discover for themselves the mood altering effects. The inner sense of emptiness (involutional melancholia) should be distinguished from sadness, (which is a response to distressing circumstances) and is relieved so that patients feel normal when they take a mood altering substance or process. The effect wears off in time and therefore the process is repeated. i) all therapy was given 1 to 1 but Twelve Step approaches are essentially a group process. ii) some patients in the CBT and ME groups also went to AA Dual diag: • Depression and addiction are synonymous and should not be treated medicinally. • Sadness is a normal human response to distressing circumstances and should also not be treated medicinally. • Attention Deficit Hyperactivity Disorder (ADHD) early signs of an addictive nature. Current recommended treatment is with Ritalin (an amphetamine). Cocaine or Heroin would probably be equally effective and equally damaging. • Compulsive helping is the mirror image of primary addiction. • The addict wants to be fixed and the addictive behaviours are blame and self-pity. • The compulsive helper needs to be needed and the addictive behaviours are care-taking (far beyond normal helping) and self denial. • The two fit together in a mutually destructive relationship. • Professional helpers need to understand the boundaries between normal helping and compulsive helping so that they do not make matters worse. • Addicts need to be confronted (politely and with understanding for their illness) on their behaviour and not enabled to carry on with it without getting the consequences. ADVERSE DRUG REACTIONS AND INTERACTIO NS: Classify; A) Onset Acute: Within 1 hour Sub-acute: 1 to 24 hours Latent : > 2 days B) Severity Mild: requires no change in therapy Moderate: requires change in therapy, additional treatment, hospitalisation Severe: disabling or life-threatening , = death Requires or prolongs hospitalization, Causes disability Causes congenital anomalies, Requires intervention to prevent permanent injury C)Type A Augmented pharmacological effect • extension of pharmacologic effect • usually predictable and dose dependent • responsible for at least two-thirds of ADRs • e.g., atenolol and heart block, anticholinergics and dry mouth, NSAIDS and peptic ulcer B • • • Bizarre: idiosyncratic or immunologic reactions includes allergy and “pseudoallergy” rare (even very rare) and unpredictable e.g., chloramphenicol and aplastic anemia, ACE inhibitors and angioedema Epidem substantial morb and mort incidence vary w/ study methods, population, and ADR definition 4th to 6th leading cause of death among hospitalized patients* 6.7% inc of serious ADRs* 0.3% to 7% of all hosp admiss annual costs in the billions (?$120 billion in US) 30% to 60% are preventable 1. 2. 3. 4. 5. 6. 7. 8. Causes: Antibiotics Antineoplastics* Anticoagulants Cardiovascular drugs* Hypoglycemics Antihypertensives NSAID/Analgesics* CNS drugs* • • – – • • Detection: Subjective report: pt complaint Objective report: direct observation of event abnormal findings physical examination laboratory test C Chronic: assoc with long-term use • involves dose accumulation • e.g., methotrexate and liver fibrosis, antimalarials and ocular toxicity • diagnostic procedure yellow card scheme • 1964 after thalidomide • run by the Committee on Safety of D Delayed: delayed effects (largely dose independent) Medicines (part of the • carcinogenicity (e.g. immunosuppressants) Medicines Control Agency) • teratogenicity (e.g. thalidomide) • entirely voluntary • used by docs, dentists, nurses, E End-of-treatment coroners and pharmacists • includes blood products, vaccines, Withdrawal reacn: Opiates, benzodiazepines, contrast media corticosteroids • for established drugs only report Rebound reactions: Clonidine, B-block, corticosteroids serious adverse reactions “Adaptive” reactions: Neuroleptics (major (fatal, life-threatening, needing tranquillisers) hospital admission, disabling) • for “black triangle “ drugs (newly allergic reactions licensed, usually <2 years) • Type I - immediate, anaphylactic (IgE) report any suspected adverse e.g., anaphylaxis with penicillins • Type II - cytotoxic antibody (IgG, IgM) Incidence of drug drug interactons: e.g., methyldopa and hemolytic anemia • True incidence difficult • Type III - serum sickness (IgG, IgM) • Data for drug-related hospital antigen-antibody complex admissions do not separate out drug e.g., procainamide-induced lupus interactions, focus on ADRs • Type IV - delayed hypersensitivity (T cell) • Lack of availability of e.g., contact dermatitis comprehensive databases • Difficulty in assessing OTC and pseudoallergies: herbal drug therapy use Aspirin/NSAIDs – bronchospasm • Difficulty in determining ACE inhibitors – cough/angioedema contribution of drug interaction in complicated patients • Sometimes principal cause of ADRs with specific drugs drug interactions: eg statins A)Pharmacodynamic drug’s effects in the body • Receptor site occupancy – Synergistic actions of antibiotics – Overlapping toxicities - ethanol & benzodiazepines – Antagonistic effects - anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors) Deliberate interactions: • levodopa + carbidopa • ACE inhibitors + thiazides • penicillins + gentamicin • B) Pharmacokinetic body’s effects on the drug i)Absorption, • Chelation – Irreversible binding of drugs in the GI tract – Tetracyclines, quinolone antibiotics - ferrous sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy products (Ca+2) ii) Protein binding effects • Comp for protein or tissue binding sites – Inc in free (unbound) conc = inc pharmacological effect • Many interactions previously thought to be PB interactions, were found to be primarily metabolism interactions • PB interactions are not usually clinically significant but a few are (with warfarin) iii)Changes in drug metabolism Phase 1 and 2 • inhibited or enhanced by coadmin of other drugs • CYP 450 system has been the most extensively studied – CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and others • Phase 2 metabolic interactions (glucuronidation, etc.) occur, research in this area is increasing Cyp450 subs: • Metabolism by a single isozyme (predominantly) – Few egs of clinically used drugs – Egs of drugs used primarily in research • Metabolism by multiple isozymes • Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19 – If co-admin with CYP450 inhibitor, some isozymes may “pick up slack” for inhibited isozyme Cyp450 inhibitors: very rapid – Cimetidine, Erythromycin, Ketoconazole, Ciprofloxacin – Ritonavir etc, Fluoxetine etc, Grapefruit juice salbutamol + ipratropium Cyp450 inducers: takes hours/days – Rifampicin Carbamazepine (Phenobarbitone) – (Phenytoin) St John’s wort (hypericin) vi) Alteration in elimination: renal tubule - probenecid and penicillin (good) - lithium and thiazides (bad) • Pharmaceutical - drugs interacting outside the body (mostly IV infusions) ALCOHOL ethanol (c2h5oh) soluble in water i.e. mix with water & drink % ABV x 0.78 = g alcohol/100ml (abv = alcohol by volume) absolute amount of alcohol in a drink can be calculated 1 unit = 10ml or 8g of absolute alcohol 1 unit = ½ pint/1 glass of wine/single measure spirits nb – no consistency!! longer carbon chain = inc lipid solubility = inc potency sniffed %abv x volume (ml) / 1000 number of units in a given volume of beverage methanol is too dangerous safe? men < 21 units/week women < 14 units/week -exceed these levels – 27% men & 13% women (-) Uncharged and \highly lipid soluble Rapidly absorbed from the mucous membranes of the stomach and gut (Slowed by First-pass hepatic metabolism i.e. rapidly cleared from portal vein blood However, saturation kinetics at low alcohol concentrations = rapid absorption (e.g. empty stomach/drinking games!) = high portal vein conc =liver enzyme saturation =ethanol escapes into systemic circulation approx 400,000 people in uk with alcohol related problems (5% men, 2% women) impt. – alcohol has low pharmacological potency = large amounts required to produce effects and little selectivity minimal effects at 20-40mg/100ml (10-20 x can be lethal) however; effects generally occur between 40-100mg/100ml General 5-10% excreted unchanged in the urine (variable) and expired air (constant) - breathalyser test (80mg/ml blood @ 35mg/100ml expired air) Current research; Phosphatidyl ethanol (PEth) – Detectable in blood for 3 wks (3 units/day) Fatty acid ethyl esters (FAEEs) –Long term detection in hair. Can distinguish between light and heavy drinkers hangover: 1. nausea: alcohol irritates the stomach lining → vagus and sympathetic stimulation → vomiting center of the medulla 2. headache: vasodilation effect of alcohol → ↑ pressure in the cranial cavity. (may also ↑ histamine and serotonin levels 3. fatigue: major cause = sleep deprivation. "rebound effect" → lose depressive effect as BAC (blood alcohol conc) ↓ = overstimulation 4. minor cause = alcohol ↓ blood sugar levels 5. restlessness and muscle tremors: cns excitation exists during the hangover phase e.g. tremors, ↑ h.r., and ↑ bp 6. polyuria and polydipsea ↓ ADH secretion symptoms commence hrs after the last ingestion of alcohol (peak as BAC → 0) cause: food) Rapidly distributed throughout body water (dependent on tissue blood flow) Depressant effect (primary effect ) (cns agitation) degree of cns excitability: environment, personality a)non-social – excitation ↓ \ sedation/drowsiness b)social setting – huge sensory input. loss of inhibition enhances effects A) cns effects: acute 1. complex = relationship between behaviour of cells and organ as a whole is unclear 2.ethanol has low potency = low selectivity and = all regions of cns are affected Theories inc gaba inhibition (- cl- flux)(?? sedative/anxiolytic effects) inhibit ca2+ entry through voltage gated ca2+ channels (inhibits transmitter release) inhibit NMDA receptor function (dec effect of glutamate)(?? loss of memory – amnestic effects) enhance 5-HT-meditated effects (?? mood control, inhibition of pain pathway, hallucinogenic) cortical region : impairs – (a) sensory function i.e. mood changes e.g. inc self confidence, euphoria, dec powers of discrimination and concentration, memory loss (b) motor function i.e. slurred speech, prolonged reaction time, loss of coordination corpus collosum - passes info from left brain (rules, logic) to R (impulse, feelings) and vice versa. hippocampus - memory. hypothalamus - controls appetite, emotions, temperature, and pain sensation. cerebellum - controls movement and coordination basal ganglia – perception of time blood levels – - likelihood of car accident 20-40mg/ml (minimal effects 50mg/ml 80mg/ml (legal driving limit) x 4 up to 150mg/ml (90% - gross intoxication) x 25 300mg/ml (coma – via reticular activating region) 4-500mg/ml (death –depression of resp control center) beneficial effects – 2. dec mortality from coronary artery disease (men 2-4 units/day); 3. inc HDL 3. inc tPA levels /dec platelet aggregation (i.e. antithrombotic effects) (nb presence of polyphenols in red wine may produce superior effect) 1.dehydration – liver/kidney need water to process alcohol 2.toxic metabolites – direct effects 3.sleep deprivation 4.congeners – toxic effects cure: don’t drink!! replace water/vitamins; bed rest pharmacological intervention = disulfiram (aversion therapy) inhibits aldehyde dehydrogenase acetaldehyde accumulation high levels of acetaldehyde flushing, tachycardia, hyperventilation, panic/distress useful in discouraging recovering alcoholics from drinking (no ffect without alcohol present) genetic polymorphisms (within asian population); common variation in enzyme aldehyde dehydrogenase = alcohol intolerance rarer variation in enzyme alcohol dehydrogenase = prone to alcoholism tolerance to effects of ethanol occurs rapidly (1-3 weeks with continuing ethanol administration) due to: pharmacokinetic tolerance, tissue tolerance cellular adaptation, ?? others dependence = overpowering craving for alcohol physical withdrawal characterized by; tremor, hallucinations, convulsions, behaviour disturbances, nausea, fever reticular activating system – consciousness chronic effects – 1. dementia – cortical atrophy/dec vol cerebral white matter 2. ataxia – cerebellar cortex degeneration 3. wernicke-korsakoff syndrome (thiamine def) 4. wernicke’s encephalopathy(degeneration in structures around 3rd ventricle & aqueduct): confusion, eye signs, ataxia 6. korsakoff’s psychosis - memory impairment – 8. (changes in dorsomedial thalamus) 9. sensory-motor peripheral neuropathy – affects lower limbs B) liver: chronic alcohol = hydrogen and acetaldehyde = impairment = mitochondrial fatty acid oxidation triacylglycerol glycerol + = / cell (adipose tissue)=blood= fatty acids mitochondria = triacylglycerol hepatitis: – blood + hepatic cytokine changes (e.g. - il-6 and tnf-a) liver tissue regenerates after alcohol induced damage cirrhosis: hepatocytes cannot regenerate fast enough! fibroblasts (connective tissue cells) overproduce = dec in active liver tissue fat accumulation (fatty liver) liver inflammation (hepatitis) irreversible hepatic necrosis/fibrosis (cirrhosis) (diversion of portal blood flow around fibrotic liver can cause oesophageal varices to develop which can bleed suddenley and catastrophically) cause - release of fatty acids from adipose tissue (due to sympathetic discharge) impaired fatty acid oxidation (due to metabolic load imposed by alcohol) contributory factor = chronic malnutrition C) cardio- acute: 1. cutaneous vasodilation: i.e flushing (causes warm feeling but - heat loss) 2. central depression of sympathetic outflow chronic: atrial arrythmias; prolong conduction times and heterogeneous inc in refractory period, acute negative inotropic effect mediated by direct interaction with cardiac muscle cells alcoholic cardiomyopathy: myocyte and nuclear hypertrophy, interstitial fibrosis, and myocyte necrosis D) gi tract: acute– inc salivary and gastric acid secretions reflex – taste - salivary secretions irritant effect i.e. - histamine release ® - hcl (nb may be due to fermentation products) stimulation of sensory nerve endings chronic: direct effect damaging the gastric mucosa ( prop to dose) inc gastric bleeding (?? gastritis or gastric ulcers) E) endocrine: acute– dec vasopressin: direct effect at hypo = polyuria (i.e. diuresis) \water & electrolyte loss = dehydration (hangover!!) chronic– inc acth /impairment of hydrocortisone metabolism = pseudo-cushing’s syndrome (e.g. fat redistribution) - direct action at anterior pituitary - dec testosterone secretion/ inc inactivation = feminisation/impotence (impaired testicular steroid synthesis, enhanced testosterone inactivation by liver enzymes) F) lipid metabolism/platelet formation – in small doses - thrombosis formation risk of atherosclerosis/ ischaemic heart disease cause - hdl cholesterol esterification plaque formation thromboxane a2 platelet aggregation G) foetal development – foetal alcohol syndrome; (mothers drink at least 4 units/day) abnormal facial development (+ other anatomical abnorms) growth retardation, mental retardation (smaller degrees of ethanol-related abnormality may occur very frequently) cause - inhibition if cell division/migration?? GABA-ERGIC TRANSMISSI ON •gaba (γ-aminobutyric acid), glycine = neutral aa inhibitory i) motor activity [cortex, cerebellum, •glutamate, aspartate = acidic aa excitatory cord] (l-homocysteate?) ii)extrapyramidal activity [basal ganglia] distribution: cortex, cerebellum, Hippocampus, corpus iii) emotional behaviour [limbic striatum, hypothalamus system] Ø dorsal horn of sp. cord v) endocrine function [hypothalamus] Ø little in pns •most neurones respond (» 30% of synapses) •short inhibitory interneurones •some longer tracts (striato-nigral;cerebellar) widespread inhibitory action in cns (both pre and post synaptic) neurotransmission 1) synthesis: glutamate = (gad) = gaba •gad immunohistochemical labelling 2) storage & release: nerve terminals (vesicles), exocytosis 3) receptors: gabaa & gabab 4) inactivation: reuptake (neuronal & glial) na+ - dependent; energy dependent; saturable 5) metabolism: GABA= gaba-t = succinic semialdehyde = SS Dehydrgoenase = Succinic Acid mitochondrial enzymes inhibitors of gaba metabolism: large inc brain gaba - eg •sodium valproate (epilim) – both gaba-t and SSDH •vigabatrin (sabril): gaba-t gabaa receptors: postsynaptic •cellular moa: Cl-, hyperpolarisation(IPSP), inhibit firing •agonists: gaba, muscimol, benzodiazepines, barbiturate •antagonists: bicuculline (competitive) picrotoxin (non-competitive) Øconvulsants Ø important experimental tools gabab receptors: presynaptic •inhibit NT release: autoreceptors, heteroreceptors (dec DA release) •cellular moa: g-protein-linked, dec ca2+ conductance, = dec NT release / inc k+ conductance = hyperpolarisation •agonists: gaba, baclofen muscle relaxant (sp. cord) = spasmolytic drug •antagonists: phaclofen, saclofen (competitive) ANXIOLYTIC S, SEDATIVES AND HYPNOTICS bzs & barbs :-i)no activity alone (allosteric action) ii)different binding sites and different mechanisms Ø bzs - frequency of openings Ø barbs - duration of openings 7. naesthetics (barbs only : thiopentone) 2. anticonvulsants (diazepam; clonazepam; phenobarbital) 3.anti-spastics (diazepam) iii)barbs less selective than bzs dec excitatory transmission other membrane effects = may explain: induction of surgical anaesthesia Ølow margin of safety 4. anxiolytics 5. sedatives / hypnotics anxiolytics: remove anxiety without impairing mental or physical activity (“minor tranquillisers”) sedatives: reduce mental and physical acitvity w/out producing loss of consciousness hypnotics: induce sleep ideally: i) have wide margin of safety ii) not depress respiration iii) produce natural sleep (hypnotics) iv) not interact with other drugs v) not produce ‘hangovers’ vi) not produce dependence Barbiturates non-selective cns depressants Phenobarbiton e Pentobarbiton e Thiopentone largely superseded (sed/hyp) by bzs (1960’s) CCl3CH(OH)2 1. GAs (thiopentone) 2. anticonvulsants (phenobarbital) 3. sedative / hypnotics: Øamobarbital – severe intractable insomnia t½: 20-25 hrs ® CCl3CH2OH chloral hydratetone benzodiazepine »20 available; all act at gabaa receptors s •all similar potencies & profiles anxiolytics: (‘long-acting’) diazepam (valium), admin.:well absorbed p.o. peak [plasma] » 1h (oxazepam i.v. V status epilepticus •distn: bind plasma prot strongly (not drugs of 1st choice) 1. low safety margins: depress resp, overdosing lethal (use forced alkaline diuresis) 2. alter natural sleepØ(dec REM)= severe hangovers/ irritability 3. enzyme inducers 4. potentiate effect of other cns depressants (e.g. alcohol) 5. tolerance (p’kinetic & tissue) 6. dependence: withdrawal syndrome (insomnia, anxiety, tremor, convulsions, death) •sedation, confusion, ataxia (impaired manual skills) slower) •potentiate other cns depressants (alcohol; barbs) chlordiazepoxide (librium), nitrazepam short acting: oxazepam - hepatic impairment, t ½ 8hrs highly lipid soluble = wide distn •metabolism: usually extensive (liver) •excretion: urine - glucuronide sedative / hypnotics: (‘short-acting’) temazepam, conjugates oxazepam, lorazepam •duration of acn: varies long acting: nitrazepam- day, anxiolytic effect,t½ 28hrs i) short-acting ii) long-acting: slow metabolism •wide margin of safety: overdose- prolonged sleep rousable and / or - flumazenil active metabolites •mild effect on REM sleep •do not induce liver enzymes liver = trichloroethanol other sedative/hypno •moa unknown •wide margin of safety (children and elderly) tics chloral hydrate other anxiolytics propranolol improves physical symptoms tachycardia (b1), tremor (b2), ‘stage fright’ buspirone•5HT1a agonist slow onset of action (days / weeks) •few side-effects DOPAMINER GIC PATHWAYS OF THE BRAIN dopaminergic pathways 1) nigrostriatal - control of movement: cell bodies originate in the substantia nigra zona compacta and project to the striatum 2) mesolimbic: emotion - cell bodies originate in the ventral tegmental area and project to the nucleus accumbens, frontal cortex, limbic cortex and olfactory tubercule 3) tuberoinfundibular system:regulate hormone secretion - short neurones running from the arcuate nucleus of the hypothalamus to the medial eminence & pituitory gland “d1 like family”: • d1 & d5 • 2nd messenger - inc in camp, • postsynaptic •tolerance (less than barbs; ‘tissue’ only) •dependence: withdrawal syndrome similar to barbs (less intense) - withdraw slowly •inc free [plasma] by e.g. aspirin, heparin • found mainly in nigrostriatal & limbic system “d2 like family” • d2, d3 & d4 • second messenger - dec in camp or inc in k+ • pre & postsynaptic • limbic - d2, d3, d4 • nigrostriatal - d2 • pituitary - d2 PARKINSON’ rest tremor, rigidity, bradykinesia, poverty of blinking, S DISEASE impassive face, dribbling, swallowing diff, monotony of speech and loss of volume of voice Degeneration of disorder of posture:- flexion of neck and trunk, lack of dopaminergic arm swing nigrostratal depression, taste disturbance/ parosmia, pain neurones autonomic dysfuncn: constipation, postural hypotension, urinary frequency, urgency, impotence, inc sweating, seborrheic dermatitis = loss of pigmented cells of pars compacta of substantia nigra, locus coeruleus (ascending na neurons) but to a lesser degree. • other areas affected but not in all cases: dorsal vagus nucleus, neuleus basalis of mynert, other subcortical nuclei biochemical changes: marked dec in caudate nucleus /putamen dopamine content • need to loose 80-85% of the dopaminergic neurons and deplete 70% of the striatal dopamine before symp appear L- DOPA Enzyme DOPA decarboxylase also present in peripheral tissues. • 95% of admin L-DOPA metabolised to dopamine in the periphery - major side effects of nausea & vomiting. • Peripheral DOPA decarboxylase inhibitor + L-DOPA. • Preparations:- Sinamet (Carbidopa + L-DOPA) Madopar (Benserazide + L-DOPA) Effectiveness of L-DOPA declines with time! • After 6 years of therapy • Dyskinesias (54%) • On-off oscilations (64%) • Visual hallucinations & other psychological probs (17%) =Hypokinesia, rigidity & tremor Start w/ low dose of drug and inc dose until max benefit w/out side effects chronic • Dyskinesias – Abnorm movements of limbs & face. Occur w/in 2 yrs of treatment. Disappear if reduce dose but clinical symptoms reappear! • “On-Off” effects – Rapid fluctuations in clinical state. Off periods may last from mins to hrs. Occurs more with L-DOPA Dopamine Agonists Bromocriptine • Lisuride • Pergolide • Ropinirole • Cabergoline • Apomorphine MAO Inhibitors Deprenyl (selegiline) • Act on D2 receptors • Longer duration of action than L-DOPA • Smoother & more sustained response • Actions independent of dopaminergic neurons • Incidence of dyskinesias is less COMT Inhibtors Tolocopone (peripheral) Entacapone (peripheral + CNS) • CNS - Prevents breakdown of dopamine in the brain • Peripheral - COMT in the periphery converts L-DOPA to 3-0-methyl-DOPA (3-0MD). 3-OMD and L-DOPA compete for same transport system into the brain. COMT inhibitors stop 3-OMD formn = incr bioavailability of L-DOPA, Thus more L-DOPA converted to dopamine in CNS = dec L-DOPA dosage! SCHIZOPHR ENIA 1 % of pop • Positive symptoms - Delusions, hallucinations, Thought Onset - Adolescence or young adult. disorders. Two types: • Negative symptoms - Withdrawal, Flattening of emotional A) Relapsing and remitting • Selective for MAO-B, predominates in dopaminergic areas of CNS. Actions are w/out peripheral side effects of none-selective MAO-I’s Acute: • Nausea - prevented by Doperidone (peripheral acting antag) • Hypotension • Psychological effects Schizophrenia like syndrome w/ delusions, hallucinations, confusion, disorientation & nightmares • Common - Confusion, dizziness, nausea/vomiting • Rare - Constipation, headache, dyskinesias, drowsiness & hallucinations Can be given alone in the early stages rare - hypotension, nausea/vomiting, of the disease. confusion and agitation. Or in combination with L-DOPA, reduce the dose of LDOPA by 30-50% Strong hereditary t • First degree relatives (10%) , monozygotic twins, one of whom has schizophrenia (50%) responses. B) Chronic and progressive. Dopamine hyperactivity underlies at least +ve symptoms • Dopamine agonists e.g bromocriptine can induce various psychotic reactions. • anti-schizophrenic drugs are dopamine receptor antag. • In drug naïve patients PET scans show inc dopamine receptor numbers. • 6 fold inc in number of D4 receptors Aetiology - Unknown but several theories. • Slow viral linked with auto-immune process • Developmental abnormality ~ anatomical changes in the temporal lobes & amygdala (Mesolimbic system) Neuroleptics antagonists at dopamine “D2 like” receptors. • block other receptors e.g. 5-HT, = side effects. • Clozapine: not selective between D1 and D2 receptors but does have a high affinity for D4 receptors that have been shown to be inc in schizophrenia. • Drugs treat positive symptoms but not the negative ones! • Delayed effects, takes weeks to work. Initially neuroleptics induce an increase in DA synthesis and neuronal activity. This declines with time. Endocrine Effects - DA is involved in the Tuberoinfundibular system that regulated prolactin secretion. Neuroleptics inc serum prolactin= breast swelling (men & women) and lactation in women. • Block muscarinic receptors: e.g blurring of vision, inc intra-ocular pressure, dry mouth, constipation, urinary retention. Anti-emetic effect – Block DA receptors in the chemoreceptor trigger zone. Phenothiazine: control vomiting and nausea induced by drugs (e.g chemotherapy), renal failure. –Block histamine receptors = control motion sickness. Extrapyramidal - Block of dopamine receptors in nigrostriatal system= “Parkinson” like side effects. • Acute dyskinesias - inc in cholinergic function. Develop at onset, reversible on drug withdrawal or anti-cholinergic drugs. • Tardive dyskinesias - Involuntary movements, often involving the face & tongue. 20% pts after several months or years of therapy. Made worse by drug withdrawal or anti-cholinergics. May be related to proliferation in pre-synaptic DA receptors or drug toxicity. Incidence is less with atypical drugs. GENERAL ANAESTHETI CS 1. Induce a loss of consciousness at low conc 2.Induce an inc in lack of responsiveness at higher conc’ ranging from simple chemically inert gases to complex barbiturates inhalation vapours :ether, chloroform), Halothane/ Enflurane gases:cyclopro pane, Nitric oxide • Intravenous Thiopental • Etomidate Loss of consciousness Suppression of reflex responses Analgesia (relief of pain) Muscle relaxation Amnesia ‘The potency of G.A. inc in propn to its oil:water partition coefficient’ – site was lipid bilayer portion of nerve memb But;How does a change in the lipid bilayer result in a dysfunctional membrane protein? Effects are produced by ; 1. Reduced neuronal activity 2. Altered synaptic function vary greatly in their ability to induce analgesia, muscle relaxation and amnesia. Therefore, other drugs are used! • Relief of pain (analgesia) – Opioid (e.g. i.v. fentanyl) • Muscle relaxation – Neuromuscular blocking drugs (e.g. suxamethonium) • Amnesia – Benzodiazepines (e.g. i.v. midazolam) • Inhibit synaptic transmission by: dec transmitter release • dec postsynaptic response. Anatomically in the thalamus, cortex and hippocampus. Anaesthetics solubility in different media is expressed as “partition coefficients”, : ratio of conc of agent in two phases at equbm. blood:gas partition coefficient main factor that determines the rate of induction and recovery from an inhalation anaesthetic. lower coefficient, faster induction and recovery. oil:gas partition coefficient measure of fat solubility and determines potency of anaesthetic, influencing the kinetics of distribution in body. high oil:gas partition coefficient (i.e. High lipid solubility), delayed recovery 1. poteniate GABAA receptor funcn (and glycine receptors). Less potent than iv and show no subunit selectivity (altered synaptic function). 2. Inhibits nACh (altered synaptic function) 3. Facilitate TREK (background leak) potassium channel opening (reduced neuronal excitability). Dec NMDA receptor funcn (altered synaptic function). • Potentiate GABAA receptor funcn (altered synaptic function) – most abundant, fast inhibitory, ligand-gated ion channel in CNS Propofol Ketamine Midazolam At a cellular level at synapses either pre or post synaptically. • Rapid induction and recovery: flexible control over the depth of anaesthesia. • Agents with high lipid solubility (eg. Halothane) accumulate gradually in body fat to produce a prolonged hangover effect. Local Anaesthetics Drugs which reversibly block neuronal conduction when applied locally 1. Prevent generation and conduction of APs 2. Don’t influence resting membrane potential 3. influence:Channel gating, 4. Selectively block: Small diameter fibres Non-myelinated fibres Surface tension LAs are weak bases (pKa 8-9) Infected tissue 2. Infiltration anaesthesia Directly into tissues → sensory nerve terminals, Minor surgery Adrenaline co-injection (NOT extremities) 5. Spinal anaesthesia Sub-arachnoid space – spinal roots Abdominal, pelvic, lower limb surgery ↓ b.p.; prolonged headache 3. IV regional anaesthesia i.v. distal to pressure cuff Limb surgery Systemic toxicity of premature cuff release 6.Epidural anaesthesia Fatty tissue of epidural space – spinal roots Uses as for 5) and painless childbirth Slower onset – higher doses Lidocaine amide 1. Surface anaesthesia Mucosal surface (mouth, bronchial tree), Spray (powder) High conce → systemic toxicity 4.Nerve block anaesthesia Close to nerve trunks e.g. dental nerves Widely used – low doses – slow onset Vasoconstrictor co-injection i. CNS stimulation restlessness, confusion tremor ii.CVS myocardial depression vasodilatation ↓ b.p. Paradoxical Na+ channel blockade Cocaine ester i.CNS: euphoria, excitation ii. CVS: Symp ↑ C.O. vasoconstriction ↑ b.p. ANTI CONVULSAN TS epileptic seizure: manifestation of an abnormal and excessive synchronised discharge of a set of cerebral neurones syndrome, not a disease (cf. Anaemia) Seizures are sudden and transient (“paroxysmal”) Benefits: Seizure suppression (dec in Sz-related harm) Harms: Psychosocial consequences (illness status, selfesteem, education, employment) phenytoin Partial epilepsy and and status epilepticus Effect of other drugs on PHT • Amiodarone, cimetidine, Isoniazid - Potent inhibitors of PHT metabolism, with increased levels • Aspirin - displaces PHT from protein binding – • Valproate - displaces PHT and also inhibits PHT metabolism = toxicity Mechanism:Blo ckade of vgated Na channels Factors influencing decision to treat • Number of seizures at presentation • 1 seizure – risk of further 50% • >2 seizures – risk of further seizures 80% • Seizure type and severity • Cause of seizure Factors influencing AED choice • Personal preference • Dogma rather than scientific knowledge • Partial epilepsy - CBZ first line • Generalized epilepsy - VPA first line (LTG in woman of childbearing age) • Many are “broad spectrum” & used in both generalized and partial epilepsy: e.g., VPA, TPM, LTG • ESM - childhood absence epilepsy only • CBZ, VGB, GPT may worsen generalized epilepsy (absence and myoclonic seizures) Pharmacokinetic variation • Bio-availability: age, gender, generic formulations • Distribution:Vd (muscle, fat), Protein binding (hepatic/renal disease, pregnancy, age) • Metabolism:Biotransformation (Phase I & II enzymes) • Excretion: Renal disease, age • Drug interactions: Induction/inhibition of liver enzymes Pharmacodynamic: Genetic variation drug receptors e.g., polymorphic variation GABAA receptor sub-units and BDZs • T ½ :Mean 20 hours – Hepatic metabolism: oxidation (CYP2C9 >2C19), hydroxylation, conjugation Potent hepatic enzyme inducer , P450 enzyme inducer - D/Is renal excretion of non-active Effect of PHT on other drugs metabolites • warfarin- Complex pharmacokinetics, w/ an initial inc in – Saturable kinetics: conc dependent. anticoagulation, after wh/ conc dec. Monitor INRs i.e., non-linear kinetics (rising quickly • CBZ, LTG, TPM, corticosteroid, cyclosporin, after point of enzyme saturation) praziquantel levels all lowered – Highly (70-90%) protein bound so • Estrogen containing OCP efficacy reduced Vit K free PHT levels helpful in some deficiency (pregnancy) circumstances (displacement Idiosyncratic & dose-related ADRs Teratogenicity • Background risk MCM = 1.5% • Risk 1 AED = 3-5% • Risk 2 AEDs = 5-10% • Risk of individual drugs not clear • Background risk NTD=0.2 - 0.5% • Risk VPA = 1 -2% • Risk LTG/CBZ = 0.5 - 1% • Weigh up risks from Szs (accident, injury, death), against risk of teratogenicity • Book early (AFP and high res US • FA 5mg daily, dec risk of NTD • Vit K in enzyme inducing AEDs Wrong AED, poor control, worsening of epilepsy Ataxia, dizziness, sedation, hypersensitivity, rash, fever, gingival hypertrophy, folate deficiency, megaloblastic anaemia, vit K deficiency, depression, hirsutism, peripheral neuropathy, osteomalacia, reduced bone density, hypocalcaemia, hepatitis, vasculitis, myopathy, coagulation defects, bone marrow hypoplasia Avoid combination where possible. Start low, unless urgent, when can load IV carmazepine Partial and secondary generalized seizures Mechanism:Blo ckade of vgated Na channels • (auto-induction): Steady state reached at about 1/12 • t ½ : 5-26 hours • Metabolism: Hepatic oxidation then conjugation. Potent hepatic enzyme inducer Active metabolites: carbamezepine epoxide Ataxia, dizziness, sedation, hypersensitivity, rash, fever, diplopia, vit K deficiency, depression, impotence, osteomalacia, reduced bone density, hyponatraemia, hepatitis, bone marrow dyscrasias, nephritis lamotrigine Partial and generalized epilepsy - wide spectrum Mechanism:Blo ckade of vgated Na channels Effect of other drugs on LTG • Enzyme inducing drugs dec half-life and lower levels (e.g., CBZ, PB, PHT) • VPA inc half-life tob60 hours, doubling levels and can precipitate toxicity/severe rash • C-OCP can lower levels by 1/3 (as can pregnancy) • dosage modified according to co-medication (introduction and withdrawal). Eg, adding to valproate comedication, initiate drug at very low doses and incrementing the dose very slowly will lower the incidence of rash. If adding valproate to LTG, then half dose of LTG. • t ½ : 29 hrs (monoPx), 15 hrs (enzyme inducing co medication), 60 hrs (valproate co-medication) • Metabolism: Hepatic glucuronidation (no phase 1 metabolism). No hepatic enzyme induction. Main advantage is that it is usually well tolerated, but high incidence of rash (2%), sometimes severe. Effect of LTG on other drugs does not inhibit or induce hepatic enzymes, so does not alter metabolism of OCP or warfarin if rash develops, stop AED immediately valporate Partial or generalized epilepsy - wide spectrum Mechanism:inc GABA by a variety of mechanisms Effect of VPA on other drugs • potent inhibitor of both oxidation and glucuronidation • PHT, PB, LTG levels all inc • CBZ-epoxide levels increased T ½ : 4-12 hrs (tds dosing) Severe hepatic toxicity (especially young), pancreatitis, drowsiness, encephalopathy (ammonia driven), tremor, blood dyscrasias, hair thinning and loss, weight gain, endocrine (PCO). viagabatrin Mechanism: Irreversible inhibition of GABA Transaminase Partial epilepsy (partial or secondary generalized Szs) infantile spasms (esp in TS) Effect of other drugs on CBZ • PHT, PB induce CBZ metabolism • VPA 4x inc in CBZ-epoxide levels - inhibits epoxide hydrolase. LTG inc epoxide levels to a lesser extent. • Macrolide AB (e.g., erythromycin) inhibit CBZ metabolism: can inc levels 2-3X (avoid!) Effect of CBZ on other drugs • Ca2+ channel blockers (diltiazem/verapamil) can double • Dec (e.g., PHT, VPA, LTG) CBZ levels (nifedipine has no effect) • OCP - inform patients • Fluoxetine may increase CBZ levels • Warfarin • Metabolism: Hepatic oxidation, conjugation. Potent inhibitor of hepatic enzymes Effect of other drugs on VPA • Levels dec by hepatic enzyme inducers (PHT, PB, CBZ) • Antacids may impair absorption Some NSAIDs, aspirin, phenylbutazone displace VPA from its albumin binding sites and may result in toxicity Elimination half-life: 4-7 hours Metabolism: Renal excretion without metabolism headache, blood dyscrasia, ataxia, diplopia and dizziness, sedation, insomnia, mood disturbance. Visual field constriction in 30% limits it use. Neuro-psychiatric D/I with PHT (dec level ANTI MICROBIALS should be toxic for the parasitic cell but innocuous for the host. Selective toxicity depends on the existence of exploitable biochemical differences between the parasite and host cell wh/ depends on how far apart the host and parasite are in evolutionary development. e.g. Prokaryotes (cells w/out nuclei - bact) - easier to kill. Eukaryotes (cells with nuclei - protozoa) - more similar biochemically to cells of the host, more difficult to kill. Affect folate Folate is required for DNA/RNA synthesis in both Man and bacteria. • Bact synthesise folate: P-aminobenzoic acid • Sulphanilamide: structural analogue of P-aminobenzoic acid and competes for enzyme dihydropteroate wh/ is involved in the synthesis of folate. Interfere w/ bact metabolism and are bacteriostatic : (arrest growth of bact but do not kill them, allows host defence to increase) • Peptidoglycan: cell wall of bact • Some bact cell wall is many layers thick. Each layer consists of multiple backbones of amino sugars – alternating N-acetyl-glucosamine and N-acetylmuramic acid residues – later of which have short peptide side chains which cross-link to form a lattice. = wall very strong and can resist high osmotic pressures. • b-Lactam antibiotics e.g. penicillin inhibits the formation of peptidoglycan. Bacteriocidal •Tetrahydrofolate: co-factor in thymidylate synthesis (pathway which has a differential sensitivity of human and bact enzymes to drugs) •pathway is identical in M and man - key enzymes, dihydrofolate reductase , is more sensitive to folate antagonist trimethoprim in bacteria than in man • human enzyme is very sens to effects of the folate analogue methotrexate • sulphonamides affect earlier stage in same metabolic pathway i.e. folate synthesis, they potentiates acns of trimethoprim. Folate antagonist Sequential blockade Combination - Diff between bact and eukaryotes 1. Cell Wall –peptidoglycan: supports the underlying memb wh/ is subject to osmotic pressure. 2. Genetic – No nucleus, genetic material forms a single chromosome wh/ lies loose in cyto 3. Plasma memb – Bact memb contain no sterols : differential penetration to chemicals. 4. Protein synthesis – Bact ribosome’s consist of 50s and 30s subunits, whilst mammalian ribosome’s consist of 60s and 40s subunits • Readily absorbed in GI • max plasma conc 4-6 hours. • Side Effects: •oral •absorbed from GI tract •widely distributed throughout the tissues and body fluids. • Reaches high conc in the lungs and kidney. •uses: - urinary tract and resp inf • 2/3 of each drug is protein bound • half of each is excreted w/in 24 hrs • • • Mild/moderate (do not warrant withdrawal) nausea & vomiting, headache, mental depression. • Severe (warrant withdrawal) hepatitis, hypersensitivity reactions, bone marrow suppression. • Wide spread resistance but imp since gave rise to diuretics (acetazolamide & Thiazides), tuberculostatic agents, oral hypoglycaemics (sulphonylureas) • nausea/vomiting and skin rashes. • small dose of sulphonamide wh/ is used in co-trimoxazole has serious side effects e.g. hypersensitivity reacns, wh/ are not dose related. • co-trimoxazole sulphamethazo le and trimethoprim B lactam antag Penicillin cephalosporins carbapenems • effective at 1/10 / < of needed if given on its own. • uses: - inf w/ pneumocystis carinii: pneumonia in pts w/ AIDS, high doses. •The basic nucleus of penicillin is 6-aminopenillanic acid, which consists of a thiazolidine ring linked to a b-lactam ring. Penicillin’s may be destroyed by enzymes - amidases and b-lactamases. •Interfere w/ synthesis of bact wall peptidoglycan - inhibit transpeptidation enzyme that cross links the peptide chains attached to the backbone of the peptidoglycan. • Benzylpenicillins:active against a wide range of bact, • poorly absorbed (injection) and susceptible to blactamases. Synthetic penicillin’s have been produced to try and overcome these problems (over 50 types). Resistance: 1) Prodn of b-lactamases by bact e.g. staphylococci. genetically controlled and can be transferred from one bacterium to another. Solution - use b-lactamase inhibitors e.g. clavulanic acid: covalently binds to enzyme at or close to its active site. 2) dec in perm of outer memb dec ability of drug to penetrate to target site. 3) The occurrence of modified penicillin-binding sites. • Same as penicillin’s, interfere with peptidoglycan cephalosporin synthesis. Cephalexin (oral), • Resistance to this group of drugs has increased. Gram Cefuroxime & ve bact have the gene encoding for b-lactamase wh/ is more active in hydrolysing cephalosporins than penicillin. Cefotaxime (parenteral) Resistance also occurs if there is dec penetration of drug due to alterations to outer memb proteins or mutations of the binding site proteins. They are bactericidal. • orally,: absorbed to differing degrees depending on stability in acid and adsorption to food. • widely distributed in body fluids, passing into joints, pleural and pericardial cavities, into the bile, the saliva and the milk and across the placenta. lipid insoluble they do not enter mammalian cells= do not cross readily BBB unless meninges are inflamed,( reach effective therapeutic conc). Elimination is renal and occurs rapidly, 90% being by tubular secretion. • Relatively free from direct toxic effects. • hypersensitivity reacns: breakdown products of penicillin combine w/ host protein and become antigenic. E.g. skin rashes and fever, acute anaphylactic shock. • broad spectrum penicillin’s: gut bacterial flora : GI tract disturb. • orally but mostly parenterally, i.m. or i.v. • Widely distributed, passing into the pleural, pericardial and joint fluids and across the placenta. Some cross BBB (e.g. cefoperazone, cefotaxime): bacterial meningitis. • Excretion:kidney, by tubular secretion, but 40% of ceftriaxone and 75% of cefoperazone is eliminated in the bile. • different b-lactam AB bind to diff binding proteins: combine two or even more of these agents and achieve synergistic action Hypersensitivity reactions, Some cross reaction occur, about 10% of penicillin sensitive individuals will also be allergic to cephalosporins. Nephrotoxicity (esp w/ cephradine). Diarrhoea; with oral cephalosprins. Affect protein • Active transported into bact and interrupt protein synthesis. Compet w/ tRNA for the A binding site. sysnthesis Bacteriostatic, not bactericidal. Tetracycline’s broad-spectrum • Spectrum: - Very wide Gram +ve and Gram -ve, antibiotics that mycloplasma, Rickettsia, Chlamydia, some spirochaetes have a and some protozoa (e.g. amoebae). polycyclic • resistance : development of energy-dependent efflux structure. mechanisms which transport the tetracycline’s out of bact, but alterations of the target, the bacterial ribosome also occur. • orally , parenterally. • absorption from gut is irregular and incomplete, and is improved by the absence of food. • Since tetracycline’s chelate metal ions (e.g. iron)= non-absorbable complex, absorpn dec by presence of milk, certain antacids and iron preparations. • wide distribution, entering most fluid compartments. • Excretion: bile and by glomerular filtration in the kidney. accumulate if renal funcn impaired. • Doxycycline exception, excreted into GI via the bile. •orally , parenterally chloramphenic • binds to 50S subunit of ribosome and inhibits transpeptidation. ol •absorbed Inhibition of • Spectrum: - Wide spectrum of activity, including Gram - •max conc in plasma w/in 2 hours. protein ve and Gram +ve bact. bacteriostatic •widely distributed through tissues and synthesis . Resistance: prodn of chloramphenicol acetyl-transferase body fluids includ the CSF. and is plasmid mediated. R plasmids containing •30-50% plasma protein bound determinants for multiple drug resis for chloramphenicol, • t½: 2 hrs. streptomycin, tetracycline’s, etc. may be transferred from •10% excreted unchanged in urine one bacterial species to another by 'promiscuous plasmids'. •inactivated in the liver. Derivatives of chloramphenicol w/ terminal OH on the •Metabolite being excreted via the side-chain replaced by fluorine are likely not to be kidney and the bile. susceptible to acetylation and thus to retain antibacterial activity. •polycations & highly polar; not aminoglycoside •inhibit bact protein synthesis by binding to the 30S subunit of the ribosome = alteration in codon:anticodon absorbed in GI tract. s - e.g. recognition = misreading of mRNA and producn of gentamicin • i.m. or i.v. defective bact proteins. • Binding to plasma proteins is minimal. •penetration through cell memb of the bact depends on oxygen-dependent active transport system, wh/ •do not enter cells, nor cross the BBB chloramphenicol can block. into the CNS. •Bactericidal, enhanced by agents that interfere w/ cell •Plasma t ½ 2-3 hrs. wall synthesis. • Elimination: glomerular filtration in Resistance: - inactivation by microbial enzymes, the genes kidney. for which are carried on plasmids. •Tissue conc inc during treatment and • GI disturb: direct irritation and later to modification of the gut flora. • Because they chelate Ca: deposited in growing bones and teeth, = staining and bone deformities. • not given to children, pregnant women or nursing mothers. • Phototoxicity (sensitisation to sunlight) with Demeclocycline. Minocycline:vestibular disturb (dizziness and nausea), freq of dose related. • High doses of tetracycline’s dec protein synthesis in host cells - an anti-anabolic effect. •depression of bone marrow: pancytopenia - dec in all blood cell elements - occur in very low doses and rare •new-borns: inadequate inactivation and excretion = 'grey baby syndrome' vomiting, diarrhoea, flacidity, low temp and an ash-grey colour - 40% mortal •Hypersensitivity, GI disturbances and other alteration of the intestinal microbial flora. • Ototoxicity:progressive damage to and destruction of the sensory cells in the cochlea and vestibular organ of the ear. • Nephrotoxicity - damage to kidney tubules . reversed if use of the drug is stopped. Since elimination is renal, their nephrotoxic action can impair their own excretion and a vicious cycle can be set up. =,Plasma conc monitored regularly. failure of penetration (overcome by concomitant use of penicillin and/or vancomycin which synergies with aminoglycosides) lack of binding of drug due to mutations that alter the binding-site on the 30S subunit. can reach toxic levels after about a week of unmodified dosage. antimycobacte rial TB (Mycobacteriu m tuberculosis) & and leprosy (leprae) isoniazid prob : after phagocytosis, the M can survive inside macrophages, unless 'activated' T cell lymphokines. rifampicin most active antituberculosis agents •Binds to and inhibits DNA-dependent RNA polymerase in prokaryotic but not eukaryotic cells. •active against other Gram +ve and many Gram -ve species. • enters phagocytic cells and can kill intracellular M •Pharmacokinetics: - Rifampicin is given 1st phase 2 months three drugs used concomitantly: isoniazid, rifampicin, pyrazinamide (plus ethambutol if the org is resistant). 2nd:, continuation 4 months, two drugs: isoniazid and rifampicin; • Readily absorbed from the GI • • parenteral injection • widely distributed: tissues, body fluids, CSF. • penetrates into necrotic tuberculous lesion. • Metabolism:acetylation, depends on genetic factors that determine whether a person is a slow (t1/2=3hours): better therapeutic response. • rapid(t1/2= 1.5 hours) acetylator •orally • infrequent, fewer than 4% e.g. skin •widely distributed in tissues and body eruptions, fever, GI tract disturbances. fluids. •excreted partly in urine and bile, undergoing enterohepatic cycling. •progressive metabolism: deacetylation during repeated passage through liver. metabolite retains antibact act but less well absorbed from GI tract. pyrazinamide •inactive at neutral pH but tuberculostatic at acidic pH. •effective against intracellular org in macrophages, since after phagocytosis the org contained in phagolysosomes in wh/ pH is low. TBw/ HIV. =combination drug therapy: dec the emergence of resistant org, • activity limited to mycobacteria. bacteriostatic on resting org and can kill dividing bacteria. passes freely into mammalian cells : effective against intracellular org inhibits the synthesis of mycolicacids, imp constituents of the cell wall and peculiar to mycobacteria. • well absorbed , oral • widely distributed, penetrating into meninges • excreted:kidney- glomerular filtrate Spectrum: - effective against many aerobic Gram -ve and Gram +ve bact. They may be given together with penicillin in infections caused by Streptococcus, Listeria or Pseudomonas aeruginosa. • longer treatment is needed in some situations e.g. meningitis, bone/joint involvement, drug resistant cases. • arthralgia (assoc w/ high conc of plasma urates). • GI tract upsets, malaise and fever are reported. ANIT FUNGAL DRUGS Fungal inf: are termed mycoses nystatin fungal inf of the skin and GI tract. miconazole Azole gp of synthetic antimycotic agents with a broad spectrum of activity ANTI VIRAL • virus-specific enzymes: targets for drugs. • antiviral agents effective while virus is replicating. acyclovir Inhibiton of nucleic acid 1)Superficial - Affecting skin, nails, scalp, mucosal memb. •Dermatomycoses - inf of skin, nails and hair caused by dermatophytes. commonest due to Tinea orgae.g. Tinea pedis - causing 'athlete’s foot'. •Candidiasis - yeast like org wh/ infect the mucous memb of the mouth (thrush), or vagina, or skin. 2)Systemic inf - Affecting deeper tissues and organs. • polyene macrolide. no absorption from mucous memb of the body • Binds to cell memb and interferes w/ perm and w/ transport funcn. • forms a pore in memb, the hydrophilic core of the molecule = transmemb ion channel. • selective acn, binding to memb of fungi and some protozoa, less avidly to mammalian cells and not at all to bact. block synthesis of ergosterol, by interacting w/ enzyme for conversion of lanosterol to ergosterol= resulting depletion of ergosterol alters fluidity of memb and interferes w/ acn of memb assoc enzymes. = inhibition of replication, inhibition of the transformation of candidal yeast cells into hyphae - the invasive and pathogenic form of the parasite. •Primary systemic fungal inf rare and occur in defined endemic areas of the world. •UK commonest is candidiasis - inf w/ a yeast like orr • • smallest infective agent, w/ nucleic acids (either RNA or DNA) enclosed in a protein coat or capsid. DNA viruses: poxvirus (smallpox), • viruses share many metabolic herpes viruses (chicken pox, shingles, processes w/ host cell: diff to find herpes and glandular fever), drugs that are selective for the adenoviruses (sore throat, pathogens. conjunctivitis), and papillomaviruses • Problem:by the time a viral inf (warts). becomes clinically detectable, the RNA Viruses: orthomyxoviruses process of viral replication is usually (influenza), paramyxovirus (measles, far advanced and chemotherapeutic mumps), picornaviruses (colds, intervention is very difficult. meningitis, poliomyelitis), retroviruses (AIDS), arenavirus (meningitis, Lassa fever). • intracellular parasites w/ no metabolic machinery • replicate: attach to and enter a living host cell and use its metabolic processes. The receptor on host cell to wh/ virus attaches are normal memb constituents( e.g. ion channels, neurotransmitter receptors, integral memb glycoproteins) = receptor/virus complex enters cell by endocytosis:virus coat may be removed nucleic acid of virus then uses cell's machinery for synthesising nucleic acid and protein and the manufacture of new virus particles. • guanosine derivative w a high sp for herpes simplex: more sensitive than other herpes viruses: glandular fever or shingles. • • specificity for fungi; due to drugs • Rare. Limited to nausea and greater avidity for ergosterol (fungal vomiting when high doses are taken membrane sterol) than cholesterol, the by mouth. V.rare - Rash. main sterol in the plasma membrane in animal cells. It is effective against most fungi and yeast’s. • • • • iv systemic infections orally for GI infections short plasma t ½ given every 8 hours. Orally: 20% of dose is absorbed peak plasma conc in 1-2 hrs, i.v; plasma conc 10- to 20- x • Relatively infrequent, most commonly being GI tract disturbances, blood dyscrasias. • minimal. • Local inflammation can occur during i.v. if there is extravasation of syntheis against cytomegalovirus (CMV): glandular fever in adults or severe disease e.g. retinis, resulting in blindness in individuals with AIDS. • converted to monophosphate by thymidine kinase - the virus sp form of this enzyme being very much more effective in carrying out the phosphoylation than the host cells' thymidine kinase = triphosphate by host cell kinases. • only activated in infected cells. • Acyclovir triphosphate inhibits viral DNA-polymerase, terminating the chain. 30x more potent against the herpes virus enzyme than host enzyme. • Acyclovir triphosphate is fairly rapidly broken down within the host cells by cellular phosphatases. AZTazidothymidin e Zidovudine analogue of thymidine. •retroviruses -HIV- active inhibitor of reverse transcriptase. •phosphorylated by cellular enzymes to triphosphate form, where it competes w/ equivalent cellular triphosphates wh/ are essential substrates for formn of proviral DNA by viral reverse transcriptase (viral RNA-dependant DNA polymerase); •its incorporation into the growing viral DNA strand = in chain termination. •Mammalian alpha DNA polymerase is resistant. However, gamma DNA polymerase in the host cell mitochondrion is fairly sensitive to the compound and this may be the basis of unwanted effects. 1. In pts w/ AIDS: dec incidence of opportunistic inf (Pneumocystis carnii pneumonia), stabilises wt, reverses HIV-associated thrombocytopenia, stabilises HIV assoc dementia and dec viral load. 2. HIV +ve before onset of AIDS in combination wi/ other drugs: prolong life expectancy. 3. HIV +ve mothers dec risk of transmission of virus to the foetus by 66%. 4. subjects who have been accidentally exposed to HIV e.g. hospital worker, rape victims, condom problems etc topically. widely distributed: conc in CSF 50% of plasma. excreted in kidneys by glomerular filtration and by tubular secretion. the solution, which is very alkaline. • Renal dysfunction when i.v.; slow infusion dec risk. • Nausea and headache •Resistance due to changes in the viral genes coding for thymidine kinase or DNA polymerase has been reported and acyclovir-resistant herpes simplex virus:pneumonia, encephalitis in immunocompromised pts. orally, bio-availability 60-80 % due to first pass metabolism, peak plasma conc30 mins. i.v. •little plasma protein binding so no drug interactions due to displacement by other drugs. • mammalian cells by passive diffusion -passes to CSF and brain. •metabolised to inactive glucuronide in the liver, • 20% of active form excreted in urine. • Common: anaemia and neutropenia. • Uncommon: GI disturbances, skin rash, insomnia, fever, headache, abnorms of liver function, and myopathy. Confusion, anxiety, depression, and a flu-like sy. • Resistance: In most pts therapeutic response wanes w/ long-term use, esp in late-stage. virus dev resis to drug due to mut = aa subs in viral reverse transcriptase and these genetic changes accumulate progressively. Thus, virus is a constantly moving target. Resistant strains can be transferred between individuals. • loss of efficacy due to: dec activation of zidovudine to triphosphate, inc virus load due to dec in immune mechanisms and inc virulence of the pathogen. Cytotoxic drugs drugs that modify the growth of cells and tissues. Anti-cancer agents: To eradicate disease Induce a remission Control symptoms Control of immune responses in organ transplantation Management of autoimmune disease Neoplasia (new growth) Neoplasm,: uncontrolled proliferation only – benign Neoplasm,: uncontrolled proliferation, invasiveness and metastases – malignant. The Cancer Cell Phenotype Disregard of signals to stop proliferating. Disregard of signals to differentiate. Capacity for sustained proliferation. Evasion of apoptosis. Ability to invade. Ability to promote angiogenesis. Alkylating agents Interfere with transcription and replication. Anti metabolites Block or antiproliferative. Do not affect invasiveness and tendency to metastasise. used as combinations to dec chances of drug resistance. Will affect all rapidly dividing normal tissues as well as tumour. 1. Alkylating agents and related compounds. 2. Antimetabolites 3. Cytotoxic antibiotics 4. Plant derivatives 5. Miscellaneous agents Fast growing cells immunopharm Azathioprine, methotrexate and Inhibit cell division cyclophosphamide Cell cycle specific drugs: Bone Primary funcn of immune system: protect host from marrow, GI tract epithelium,Hair & invasion. nails, Spermatogonia system is responsible for causing autoimmune disease and rejecting allogenic tissue grafts after transplantation. Slow growing cells Cytotoxic drugs:used as immunosuppressants, but at Introduce DNA mutations much lower doses than used to treat cancer. selective action on lymphocytes which drive the immune Cell cycle independent (alkylating agents) response. Secondary tumours Covalently bond with nucleophiles. Nitrogen mustards Reactive group is a carbonium ion. cyclophosphamide bifunctional. Guanine N7 is main target, also N1 and N3 of adenine and N3 of cytosine. Can cause intra- or interchain crosslinks. Folate antagonists e.g. methotrexate,:interfere with thymidylate synthesis. Pyrimidine analogues e.g. fluorouracil : interfere with Difficult to find differences between cancer cells and normal Need to produce a near total cell kill. far advanced before diagnosis. Tumour cells can be: Dividing (sensi to anticancer treat) No longer able to divide (not a problem) Resting in G0 phase (insensitive to anticancer treatment and could start dividing again after chemotherapy). 1. 2. 3. 4. 5. 6. 7. Myelotoxicity. Impaired wound healing. Depression of growth (children) Sterility. Teratogenicity. Loss of hair. Nausea and vomiting subvert pathways in DNA synthesis. 2’-deoxythymidylate synthesis. Purine analogues e.g. Azathioprine inhibits purine synthesis. Actinomycin D (Dactinomycin) intercalates DNA and Cytotoxic AB Direct interferes with topoisomerase II. interaction with Doxorubicin inhibits DNA and RNA synthesis. DNA. Bleomycins metal-chelating glycopeptide Ab: degrade DNA. active against non-dividing cells. podophyllotoxins e.g.etoposide, inhibit DNA synthesis. Plant Causes cell cycle block at G2. derivatives The vinca alkaloids e.g. vincristine,:binding to tubulin and inhibiting polymerisation into microtubules. prevents spindle formation. miscellaneous 1. Hydroxyurea inhibits ribonucleotide reductase. 2. Cisplatin interacts with DNA causing guanine intrastrand cross-links. 3. Procarbazine inhibits DNA and RNA synthesis and interferes with mitosis at interphase. Metabolically activated by cytochrome P450 and monoamine oxidase to alkylate DNA (N7 and O6 of guanine). hormones Can inhibit tumours in hormone-sensitive tissues. Gonadotrophin-releasing hormone analogues e.g. Goserelin iv. chemotherapy but are not technically cytotoxic. RESPIRATOR Ventolin). selective β 2-adrenoceptor agonist. Y Salbutamol, salmeterol aminophylline ( symptomatic relief of asthma. an increase in camp PDE inhibitor), ipratropium bromide muscarinic antagonist metacholine , stable analogue of ACh, on airways conductance (Conductance : opposite of resistance – the more conductance decreases, the harder it is to breathe Leukotriene C4 is a locally produced bronchoconstrictor, enyzme 5-lipo-oxygenase (5-LO or 5-LOX) is the rate limiting enzyme Histamine bronchoconstrictor. released in airways as part of an allergic response, for example in patients with asthma (anticholinergic inhaled