Drug List 3

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) aall effector organs innervated by postgang para (ii) ssweat glands (iii) endothelial cells (non-innervated) where they mediate NO-dependent vasodilation. (iv) CNS

ii) Non Vascular SM: • Lungs – bronchoconstriction • GI - motility (peristalsis) and secretion • Bladder – contracn of detrusor; relaxatn of trigone and sphincters 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

Reversible Donates carbamyl gp to enzyme, Reactivated by slow hydrolysis

/neostigmine

Sp to Muscurinic – selective to M3 Limited access to CNS Resistive to degradation

LOW dose -

musc

Excitabily w/ possible convulsions MODERATE - + effect at all ANS, Symp effect

• 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

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 worn: 2) aagriculture – • Musc activity, brady, insecticides hypo, brochocons, sweat, 3) saliva, miosis, fixed for near biological warfare – nerve gases vision

stable Recovery –synthesis: wks

•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

CHOLINOCE PTOR ANTAGONIS T Nicotinic/gang lion blocking

Bind with high affinity 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 –Sweat,

Trimetaphan: • controlled short lasting (2 3 minutes) hypotension in surgery; iv Hexamethonium No longer clinically used

–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

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

 young children who eat deadly nightshade berries.

– dilate the pupil to view the retina

Characterised by hyperactivity → CNS depression Hyoscine, transdermal  body temperature –Prevention of motion sickness  periph musc block – i.e. dry mouth, etc.

–Parkinson’s Treated Ipatropium anti-cholinesterase drugs inhalation which penetrate the CNS, Asthma e.g. physostigmine Obstructive airways disease

– 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 poisoining

–Peptic ulcer disease –Irritable bowel syndrome –Facilitate endoscopy •

• 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 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

• Relaxation Of Skeletal Muscles During Surgery (= Less Anaesthetic) • Permit Artificial Ventilation Iv- highly charged Doesnt Cross Bbb / Placenta Onset: 2 - 3 Min

Gang Block (

TPR)

Histamine Release From Mast Cells Hypotension Tachycardia (Arrhythmias ??): • Reflex • Blockade Of Vagal Ganglia

40 - 60 Min (Long) Bronchospasm

3. Resp Muscles Actions Reversed By Anticholinesterases e.g. Neostigmine (+ Atropine)

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) =

BP

CO

1. Acute allergic reactions and anaphylactic shockType 1 hypersensitivity reactions (i.v.)

i) CVS: tachycardia, arrythmias, cold extremities, severe hypertension

ii) Reduced and thickened mucous secretions (dry Inhibits release and opposes mouth) the inflammatory mediators which cause a fall in BP and ii) Tremor due to effects on breathing difficulties. skeletal muscle

SM •Lungs – Relaxation of tracheal and bronchial SM =Opens up airways

(overdose) = to cerebral 2. As a cardiac stimulant haemmorhage and (i.v.) in: pulmonary oedema. e.g. acute manage heart block

Metabolism - Increases energy supply

3. To maintain BP during spinal anaesthesia (i.v.).

– blood levels G (glycogenolysis and gluconeogenesis in muscle and liver) – blood levels of free fatty acids (lipolysis in adipose tissue)

4. To prolong the duration of local anaesthetics 5. To treat glaucoma (eye drops): prodn of aq humour

eye Constricts the radial muscle –Mydriasis (pupillary dilatation)

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

Symp

hypertension

·a2

migraine

·central action in brainstem within baroreceptor pathway to symp

oral/ iv

oral Dry mouth, Sedation, dizziness bradycardia, nausea, constipation.

Isoprenaline B1 = B2

 heart block (cardiogenic shock, acute heart failure or myocardial infarction); i.v

Less susceptible to Uptake 1 and MAO than adrenaline;

Tachycardia (reflex), dysrhythmias

asthma discontinued plasma t ½ 2 hrs

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

Not a problem when normal mechanisms for degradation of monoamines are in operation 

Problems: MOAs inhibited (antidepressant drugs eg. phenelzine) = ingestion of foods containing tyramine cause a

hypertensive crisis.

SYMP ANTAG

B antagonist

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

1) Hypertension: sustained diastolic arterial pressure greater than 90 mmHg 2) Anxiety states - to control somatic symptoms eg palpitations and tremor.

3)Migraine prophylaxis.

4)Benign essential tremor.

Bronchoconstriction – (β2− lungs) Caution: asthmatics pts, bronchitis.  Cardiac Failure – Pts w/ heart dis need some symp for normal CO  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.

 betaxolol hydrochloride : β1 antagonists

 rate of aq humor prodn by blockthe receptors on the ciliary body.

Which normally respond to symp and A

Glaucoma

A adrenorecepto r antagonist

 in arterial pressure (α- = periph resis  Postural hypotension.  Cardiac output/heart rate – reflex response to fall in arterial pressure (β-

Non-selective Phentolamine

 vasodilan and

BP due to block α1

 not clinically used

 GIT motility

Prazosin A1

Methyldopa False Transmitter released like NA  less active than NA on α1-= less vasoconstrictn  more active on presynaptic (α2), autoinhibitory feedback mechanism

diarrhoea concomitant α2 block tends to NA = reflex tachycardia occurs with any BP lowering agent

 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.

Renal blood flow is well maintained, widely  CNS effects, stimulates vasopressor centre in brain stem to inhibit symp

hypertensive pregnant women, has no adverse effects on foetus despite crossing bloodplacenta barrier  used very infrequently.

operates more strongly, release below normal

α1-antagonists Plasma Lipid Levels-

DRUGS AFFECTING THE HEART

LDL and (VLDL) levels and total triglyceride levels.

(HDL) risk factors for coronary artery dis.

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 Para: Cardiac slowing and dec automacity Inhibiton of AV condn

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.

B-Blockers

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. Bronchoconstriction 2. Worsening of cardiac failure 3. Bradycardia (heart block) 4. Hypoglycaemia (diabetics on insulin) 5. Fatigue 6. Cold extremities and worsening of peripheral arterial dis 7. CNS effects (lipophilic agents) e.g. nightmares

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)

competitive antag badrenoceptors propranolol (non-selective), atenolol (B1 selective)

Longer acting; transdermal patch

Calcium Vasodilation affects the arterial circ 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) 2) SM actions Dihydropyridin es (e.g. amlodipine)

dec Ca2+ entry into SM only affect blood vessels.

first pass’ metabolism by liver. sublingual tablet or spray: rapid relief of angina short t ½ (~5 mins).

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 ic agents adenosine triphosphate (ATP).

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 milrinone

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

Cardiac glycosides Digoxin

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. hypertension 2. heart failure 3. post-myocardial infarction 4. diabetic nephropathy 5. progressive renal insufficiency

1. Cough (ACEI) 2. Hypotension 3. Urticaria / Angioedema (ACEI - v. rarely) 4. Hyperkalaemia (care with K

DRUGS AND VASCULATU RE ACE Inhibitors

•Inhibitors of phosphodiesterase: inhibit breakdown of cAMP in cardiac myocytes.

prevent the degradation of bradykinin (and other kinins) enalapril

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.

6. 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

Hypertension alternative for ACEI in pt who cannot tolerate ACEI (e.g. Chronic heart failure).

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).

Atenolol B1 Propranolol lipophilic

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.

1. Angina 2. Post myocardial infarction 3. Cardiac dysrhythmias 4. Chronic heart failure 5. Hypertension 6. thyrotoxicosis, glaucoma, anxiety states, migraine prophylaxis, benign essential tremor

Calcium Blockers

reduce Ca2+ entry into cardiac and smooth muscle cells Verapamil & diltiazem Dihydropyridines:

Vasodilators Hydralazine

dilates arteries/arterioles. Consequently it induces reflex tachycardia.

Organic nitrates nitroprusside

nitric oxide (NO) donors and vasodilate arteries, esp veins.

Nicorandil

NO donor and KATP channel opener.

A blockers and sympatholytics

doxazosin competitive

supplements or K sparing diuretics) 5. Fetal injury 6. Renal fail:pts w/ renal art stenosis Same

inc angII levels and do not prevent actions on AT2

hyperkalemia steroid-like effects: gynaecomastia, menstrual probs, testicular atrophy.

Rarely used except in pre-eclampsia / pregnancy-associated hypertension

angina

combined w/ antihypertensives in resistant hypertension

Use often limited by adverse effects

antag a1

penoxybenzamine irreversible

Arterial vasodilat that inhibit vasoconstrict effects of symp on blood vessels

clonidine - Centrally acting antihypertensive

long-lasting a-blockade in pheochromocytoma (combined with a beta blocker).

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

cardiac arrest anaphylactic shock

HAEMOSTAT SIS

arrest of blood loss from damaged blood vessels. a rapid, potent, localized response to vascular damage.

1. Vasoconstriction 2. Platelet aggregation (clumping) 3.

Coagulation to produce a fibrin clot

1. promote coag: haemophilia 2. staunch haemorrhage 3. following surgery 4. after anti-coagulant Therapy

ergot alkaloids

Agonist at 5HT1D recep

Vit K cofactor in synthesis of clotting factors: fibrinogen – fibrin Synth by bact in mesh GI + w/ carboxyglutamic acid inc modification of factors Promote Coag

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

contraindicated in pt with coronary dis. usefulness is limited by side effects.

THROMBOSI S In vivo

Arterial (white thrombus)

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 blood e.g. late stages of preg, during treatment w/ certain oral contraceptives

Venous (red thrombus)

atherosclerosis. platelets and leukocytes in a fibrin mesh.

Interrupts blood flow= ischemia/ infarcn of tissue beyond.

Clot: in vitro

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

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.

Anticoagulants

1.TFPI – tissue factor pathway inhibitor

Natural

2. Protein C – activated by thrombin, inactivates factors VII and V 3. Antithrombin III – activated by heparin inactivates thrombin

1) Warfarin - 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 2) Heparin 3) Low Molecular

-activates anti-thrombin III which inhibits factor Xa and thrombin by binding to the active serine sites.

-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 .

1) Bleeding 2) Thrombocytopenia 3) Osteoporosis :(assoc with long

Weight Heparin (LMWH)

Anti Platelet Aspirin

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

saturation kinetics (t½ inc w/ inc dose). Anticoag act measured.

term therapy over 3 months) 4) Hypersensitivity: chills, fever, urticaria and even anaphylaxis

longer t½ , exhibits 1st order kinetics, act does not require monitoring. oral Highly plasma protein bound

GI sensitivity

Clopidrogel pro-drug

inhibits fibrinogen binding to glycoprotein IIb/IIIa receptors =In aspirin sensitive pt

Oral Peak plasma conc: 4hrs after a single dose but inhibitory effect on platelt not seen until after 4 days of regular dosing

Bleeding GI haemorrhage, diarrhea, rash In some patients neutropenia

Amciximab

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

Iv Binds rapidly to platelets. Cleared with platelets. Antiplatelet effect persists for 24-48hrs

Bleeding May potentially be immunogenic

Streptokinase Nonenzymatic protein.

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.

IV – 30 –60 min infusion

Bleeding May potentially be antigenic

Alteplase recombin ant tPA.

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.

Iv 30min infusion Rapidly cleared t1/2 12-18 mins

Fibrinolytic

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 LOWER ING 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 STEROI DAL ANTI INFLAM MATOR Y 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 Adenomatous Polyposis thermostat. 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 3.

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: 4.

Inhibits acid secretion and inc mucus secretion in stomach

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 Covalent binding of Aspirin confers its anti-aggregatory property which is unique among NSAIDS

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 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

DIURETICS

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) 4) Acute hypercalcaemia

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

1) Osmotic

Filtered by the glomerulus but not reabsorbed

Mannitol

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

2) Carbonic Anhydrase Inhibitors

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

Iv Pharmacologically inert 1) Cerebral oedema 2) Raised intraocular pressure 3) Prevent acute renal failure

Glaucoma

Transient expansion of ECF vol and associated hyponatraemia Headaches, nausea and vomiting

1) K+ loss 2) Mild metabolic acidosis 3) Self-limiting action

3) oop Frusemide (furosemide)

L Powerful diuretics – promote the excretn of 30% of the filtered Na+ load ascending loop 1) Inhibit co-transporter system = inhibit Na+ and Cl- reabsorption = 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

1) Acute pulmonary oedema 2) O edema due to heart, liver or renal disease if refractory to other diuretics 3) 3) Acute treatment of hypercalcaemia 11) 4) Hyperkalaemia 5) 12) Acute renal failure 6) 4) 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 t ½ : – short – 1-2h Duration – short – 3-6h max

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)

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) 4) Dec Mg2+reabsorpn 8) 12) 4)

Diazoxide nondiuretic thiazide,

5) 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 vasodilator and diabetogenic actions.

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) 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

6) K+ Sparing

Weak diuretics late distal tubule block Na+/K+ exchange max of 5% of filtered Na+ load is excreted.

1) control K+ levels

Spironolactone and amiloride –Hyperkalaemia –Metabolic acidosis

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

spironolactone Aldosterone receptor antagonists

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 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 INFLAM MATOR Y 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 Immune system distinguish between pathogenic and nonpathogenic, excessive response = inflamm 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 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

1. Supportive therapies - Fluid/electrolyte replacement - Blood transfusion/ oral iron - Antibiotics 2. Possible curative therapies Treatment of symptoms: a) treatment of active disease -Glucocorticoids eg Prednisolone b) prevention of relapse or remission - Aminosalicylates eg Mesalazine - Immunosuppressives eg azathioprine 3. Possible Curative Therapies: - Anti-TNFa eg Infliximab

Glucocorticoid s Prednisolone, Fluticaso ne, budesoni de Derived from cortisol

Powerful anti-inflamm and immunosuppressive •Activate intracell Glucocorticoid Recept = +ve/ -ve transcription factors •Dec influx and activate pro-inflamm cells –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

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 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

1)Osteoporosis : inc osteoclast dec osteoblast Inc risk of Gastric ulceration - dec prostaglandins in stomach Suppression of HPA axi s -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 Sulfasala zine (first), Mesalazi ne, 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 Limited use in the treatment of active IBD

Sulfapyridine causes most of the sideeffects

5 aminosali cylic 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) Azathioprine pro-drug: degrades spontaneo usly in vivo= active form 6mercapto purine 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

Anti Tumour Necrosis Factor 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.

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

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

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

•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

• • • • • • •

Dizziness Tinnitus Fatigue Sedation (‘do not drive or operate machinery') Excitation in excess Convulsions (children more susceptible) Antimuscarininc side-effects

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

- accelerates transit of intestinal contents (from duodenum to ileo-coecal valve) note: care must be taken with the bioavailabilty of coadministered drugs eg.

- adsorption and effectiveness of digoxin reduced - nutrient supply compromised; imp in DM

Hyoscine, antimuscarini c drug

• •

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

Ondansetron, Acts to block transmission in visceral afferents and CTZ. 5HT3 receptor antagonist orally; well absorbed, excreted in urine

Used to treat nausea and vomiting assoc w/: 1.uraemia (severe renal failure) 2.radiation sickness 3.GI disorders 4.cancer chemotherapy (high doses) eg. cisplatin (intractable vomiting) orally / i.v.; rapidly absorbed; extensive first pass metabolism crosses BBB, placenta

1.Prevention of motion sickness 2.Has little effects once nausea/emesis is established 3.In operative pre-medication orally (peak effect in 1-2 hours), i.v., transdermally 1. prevent anticancer drug-induced vomiting, esp cisplatin 2.radiotherapy-induced sickness 3.post-operative nausea and vomiting

In CNS • drowsiness • dizziness • anxiety • extrapyramidal reacns; children more susceptible (Parkinsonian-like syndrome: rigidity, tremor, motor restlessness) note: No anti-psychotic actions In the endocrine system • hyperprolactinaemia • galactorrhoea • disorders of menstruation 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)

ANTI ULCER DRUGS

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

eliminate cause of mucosal damage - promote ulcer healing -

- gastric ulcers duodenal ulcers

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 •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 • inactive at neutral ph

•oral ; as enteric coated slow-release formulations

rare

•weak base: accumulates in the cannaliculi of parietal cells; concentrates its action there and prolongs its duration of action (2-3 days) and minimises its effect on ion pumps elsewhere in the body

2. cimetidine, ranitidin e histamine type 2 recep antag 3. antimusc arinic

inhibit gastric acid secretion by approximately 60%

C)

enhance mucosal protection mechanisms and/or build a physical barrier over the ulcer

cytoprote ctive 1. sucralfate polymer containin g aluminiu m hydroxide and sucrose octasulphate

•oral , well absorbed less effective at healing ulcers than ppis

• - rare •relapses likely after withdrawal of treatment

little use as anti-ulcer drugs

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 prostaglan din analogue

mimics acn of locally produced pg to maintain the gastroduodenal mucosal barrier 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

• constipation •reduces absorption of some other drugs (eg. antibiotics and digoxin

•diarrhoea, abdominal cramps, uterine contractions •do not use in pregnancy

4. antacids

mainly salts of al3+ and mg2+ •neutralises acid, raises gastric ph, reduces pepsin activity

• non-ulcer dyspepsia effective in dec duodenal ulcer recurrence rates

DRUGS OF ABUSE

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)

• Snort’ – Mucous membranes of nasal sinuses, Slow absorption • Eat’ – GI tract, Very slow

Mesolimbic dopamine system – Central ‘reward’ pathway Ventral tegmental area → Nucleus Accumbens (VTA) (NAcc) NAcc → Dopamine = Reward (End pt for drugs of abuse)

• ‘Smoke’ – Small airways and alveoli ; Rapid apsorption • Inject’ – Veins ; Rapid → Oral < Intranasal < Intravenous < Inhalational

Cannabis Main active ingredient that acts on thbrain <>9-THC (Tetrahydrocan nabinol): Dronabinol Nabilone D9-THC + CBD: Sativex Cannabis Sativa = <>9-THC (inc potency)

Cannabis/Marijuana; Hashish/Resin; Hash Oil – CB1 receptors- brain: Hippocampus/cerebellum/cerebral cortex /basal ganglia 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

Pharmacokinetics; Inhalation – 50% Oral – 10-15% Onset = Seconds - Minutes Tissue t1/2 = 7 days Metabolised: Liver - 11-hydroxy-THC Excreted: GIT – 65% Urine – 25% ‘Autoprotection’ – Dronabinol, Sativex ‘Autoimpairment’ - Rimonabant

Inc regulation of CB receptors: 1)Multiple sclerosis/pain/schizophrenia – regulatory 2) Fertility/obesity/stroke – pathology

Cocaine Erythroxylum coca

• Paste’~ 80% (Cocaine sulphate) Extracted using an 75-90% - ecgonine methyl ester

benzoylecgonine - liver organic solvent. Impure!

Iv, oral, intranasal: absorbed through mucous memb lining the sinuses = slower Onset = Seconds T1/2 - 20-90min absorption - 100–500 ng/mL. • Cocaine HCl – Passed through an acidic aqueous renally excreted. 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

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.

2.

3.

4.

5.

6.

•They are used clinically as analgesics •They are potentially fatal in overdose •They are drugs of abuse •Morphine •Heroin •Codeine •Methadone • •Naloxone - antagonist•

analgesia: •Dec pain perception •Inc pain tolerance Depression of respiration (medulla) Sedation Euphoria

Overdose: 1. Coma 2. Respiratory depression 3. Pin-point pupils 4. Hypotension Treatment: Naloxone (opioid antagonist) i.v.

Dysphoria

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

1. Mild pain (weak analgesic vs. morphine)

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

6.

Depression of cough centre (anti-tussive) 7.

Stimulation of chemoreceptor trigger zone (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

Codeine

tolerance –Pharmacokinetic – not a problem – –Tissue tolerance – principal cause

Oral, converted to morphine

Causes severe constipation

(3-Methyl Morphine)

2. Anti-tussive at sub-analgesic doses

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.

4. Accidents: alcoholism, drug addiction 5. Diabetes: compulsive overeating.

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 • and the long term consequences are • An addictive nature is a chronic avoided. illness and therefore requires life-long treatment by attending an appropriate • From one of the most devastating Anonymous Fellowship and working clinical conditions of all, patients can the Twelve Step Programme. get into full remission provided that they continue the spiritual treatment Inappropriate treatments: on a daily basis.

• Medicinal treatment (antidepressants, tranquilisers, sleeping tablets, mood altering painkillers, Methadone etc): alternative addictions.

• 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.

Assessing ‘why?’

– Preoccupation.

– Use alone.

– Use primarily for mood altering effect.

– Use as a medicine.

• Naltrexone and other antieuphoriants, or antabuse and other

– – – – – – – –

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 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

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 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.

spending.

• 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.

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

• Compulsive helping is the mirror image of primary addiction.

a genetic predisposition. Perhaps each addictive cluster is determined by a separate gene.

• evolutionary advantage of a hedonistic gene

• The addict wants to be fixed and the addictive behaviours are blame and self-pity.

• all addictive behaviour originates in a defect in the neurotransmission systems in the mood centres of brain.

• The compulsive helper needs to be needed and the addictive behaviours are care-taking (far beyond normal helping) and self denial.

• 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.

• 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

Classify; A) Onset − Acute: Within 1 hour − Sub-acute: 1 to 24 hours

Epidem − substantial morb and mort − incidence vary w/ study methods, population, and ADR definition

− Latent : > 2 days

INTERACTIO NS:

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

C Chronic: assoc with long-term use • involves dose accumulation • e.g., methotrexate and liver fibrosis, antimalarials and ocular toxicity

− 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 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)

− allergic reactions • Type I - immediate, anaphylactic (IgE) e.g., anaphylaxis with penicillins • Type II - cytotoxic antibody (IgG, IgM) e.g., methyldopa and hemolytic anemia • Type III - serum sickness (IgG, IgM) antigen-antibody complex e.g., procainamide-induced lupus • Type IV - delayed hypersensitivity (T cell) e.g., contact dermatitis pseudoallergies: Aspirin/NSAIDs – bronchospasm ACE inhibitors – cough/angioedema

drug interactions: 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) 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

hospital admission, disabling) • for “black triangle “ drugs (newly licensed, usually <2 years) report any suspected adverse Incidence of drug drug interactons: • True incidence difficult • Data for drug-related hospital admissions do not separate out drug interactions, focus on ADRs • Lack of availability of comprehensive databases • Difficulty in assessing OTC and herbal drug therapy use • Difficulty in determining contribution of drug interaction in complicated patients • Sometimes principal cause of ADRs with specific drugs eg statins Deliberate interactions: • levodopa + carbidopa • ACE inhibitors + thiazides • penicillins + gentamicin • salbutamol + ipratropium

• 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 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 food) Rapidly distributed throughout body water (dependent on tissue blood flow)

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 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

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 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 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)

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: 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,

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 • 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

beneficial effects – 2. dec mortality from coronary artery disease (men 2-4 units/day); 3. inc 4. HDL 3. inc 5. tPA levels /dec platelet aggregation (i.e. antithrombotic effects)

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

6. (nb presence of polyphenols in red wine may produce superior effect)

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

5.

6.

7.

8.

9.

around 3rd ventricle & aqueduct): confusion, eye signs, ataxia korsakoff’s psychosis memory impairment – (changes in dorsomedial thalamus) 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: 2. i.e flushing (causes warm feeling but heat loss) 2.

3. 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 • glutamate, aspartate = acidic aa excitatory (l-homocysteate?) distribution: cortex, cerebellum, Hippocampus, corpus striatum, hypothalamus Ø dorsal horn of sp. cord Ø little in pns •most neurones respond (» 30% of synapses) • short inhibitory interneurones •

i) motor activity [cortex, cerebellum, cord] ii)extrapyramidal activity [basal ganglia] iii) emotional behaviour [limbic system] v) endocrine function [hypothalamus]

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 iii)barbs less selective than bzs dec excitatory transmission other membrane effects = may explain: induction of surgical anaesthesia Ølow margin of safety 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

7. naesthetics (barbs only : thiopentone) 2.

20) anticonvulsants (diazepam; clonazepam; phenobarbital) 3.anti-spastics (diazepam) 4. anxiolytics 5. sedatives / hypnotics

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)

1. GAs (thiopentone) 2. anticonvulsants (phenobarbital) 3. sedative / hypnotics: Øamobarbital – severe intractable insomnia t½: 20-25 hrs Ø severe intractable insomniaØ t½ 20-25h

CCl3CH(OH)2 ® CCl3CH2OH

chloral hydrate tone benzodiazepine s »20 available; all act at gabaa receptors • all similar potencies & profiles

admin.:well absorbed p.o. peak [plasma] » 1h (oxazepam slower) i.v. V status epilepticus •distn: bind plasma prot strongly anxiolytics: (‘long-acting’) diazepam (valium), highly lipid soluble = wide distn chlordiazepoxide (librium), nitrazepam •metabolism: usually extensive (liver) short acting: oxazepam - hepatic impairment, t ½ 8hrs • excretion: urine - glucuronide sedative / hypnotics: (‘short-acting’) temazepam, conjugates oxazepam • , lorazepam duration of acn: varies long acting: i) short-acting nitrazepam- day, anxiolytic effect,t½ 28hrs ii) long-acting: slow metabolism and / or •wide margin of safety: overdose- prolonged sleep rousable active metabolites - flumazenil

(not drugs of 1st choice) 1. low safety margins: depress resp, overdosing lethal (use forced alkaline diuresis) 2. alter natural sleep (dec REM)= 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) •potentiate other cns depressants (alcohol; barbs) •tolerance (less than barbs; ‘tissue’ only) •dependence: withdrawal syndrome similar to barbs (less intense) - withdraw slowly •inc free [plasma] by e.g. aspirin, heparin

•mild effect on REM sleep •do not induce liver enzymes other sedative/hypno tics chloral hydrate

liver = trichloroethanol • moa unknown •wide margin of safety (children and elderly)

other anxiolytics

propranolol improves physical symptoms tachycardia (b1), tremor (b2), ‘stage fright’

DOPAMINER GIC PATHWAYS OF THE BRAIN

buspirone •5HT1a agonist slow onset of action (days / weeks) • few side-effects 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 • 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%)

Dopamine Agonists Bromocriptine • Lisuride • Pergolide • Ropinirole • Cabergoline • Apomorphine MAO Inhibitor s Deprenyl (selegilin e) COMT Inhibtors Tolocopone (peripheral) Entacapone (peripheral + CNS)

• 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

• Selective for MAO-B, predominates in dopaminergic areas of CNS. Actions are w/out peripheral side effects of none-selective MAO-I’s • 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!

=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

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%

SCHIZOPHR ENIA 1 % of pop Strong hereditary t • First degree relatives (10%) , monozygotic twins, one of whom has schizophrenia (50%)

• Positive symptoms - Delusions, hallucinations, Thought Onset - Adolescence or young adult. disorders.

Two types: • Negative symptoms - Withdrawal, Flattening of emotional A) Relapsing and remitting 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

• 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 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).

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.

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.

• Intravenous Thiopental • Etomidate

• Potentiate GABAA receptor funcn (altered synaptic

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

function) – most abundant, fast inhibitory, ligand-gated ion channel in CNS Propofol Ketamine Midazolam

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

ANTI CONVUL SANTS epileptic seizure: manifestati on of an abnormal and excessive synchronise d 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)

i.CNS: euphoria, excitation ii.

CVS: Symp  ↑ C.O.  vasoconstriction  ↑ b.p.

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

praziquantel levels all lowered • Estrogen containing OCP efficacy reduced Vit K deficiency (pregnancy)

– Highly (70-90%) protein bound so free PHT levels helpful in some circumstances (displacement

Avoid combination where possible.

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).

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!)

• Ca2+ channel blockers (diltiazem/verapamil) can double CBZ levels (nifedipine has no effect) • Fluoxetine may increase CBZ levels

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

Start low, unless urgent, when can load IV

Effect of CBZ on other drugs • Dec (e.g., PHT, VPA, LTG) • OCP - inform patients • Warfarin

• Metabolism: Hepatic oxidation, conjugation. Potent inhibitor of hepatic enzymes

headache, blood dyscrasia, ataxia, diplopia and dizziness, sedation, insomnia, mood disturbance.

toxicity viagabatrin

Mechanism: Irreversible inhibition of GABA Transaminase Partial epilepsy (partial or secondary generalized Szs) infantile spasms (esp in TS) ANTI Selective toxicity depends on the existence of exploitable MICROBIALS biochemical differences between the parasite and host should be toxic cell wh/ depends on how far apart the host and parasite for the parasitic are in evolutionary development. cell but e.g. Prokaryotes (cells w/out nuclei - bact) - easier to kill. innocuous for Eukaryotes (cells with nuclei - protozoa) - more similar the host. biochemically to cells of the host, more difficult to kill.

Affect folate Folate is required for DNA/RN A synthesis in both Man and bacteria.

Folate antagonist

• 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,

Elimination half-life: 4-7 hours Metabolism: Renal excretion without metabolism 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.

Visual field constriction in 30% limits it use. Neuro-psychiatric D/I with PHT (dec level •

• 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

Sequential blockade Combination co-trimoxazole sulphamethazo le and trimethoprim B lactam antag Penicillin cephalosporins carbapenems

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.

•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. cephalosporin • Same as penicillin’s, interfere with peptidoglycan Cephalexin synthesis. (oral), • Resistance to this group of drugs has increased. Gram Cefuroxime & -ve bact have the gene encoding for b-lactamase wh/ is Cefotaxime more active in hydrolysing cephalosporins than penicillin. (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.

• 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 •

• 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.

• 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

reacns, wh/ are not dose related.

•

•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.

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 sysnthesis synthesis. Compet w/ tRNA for the A binding site.

Tetracycline’s Bacteriostatic, not bactericidal. 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.

• binds to 50S subunit of ribosome and inhibits transpeptidation.

• Spectrum: - Wide spectrum of activity, including Gram -ve and Gram +ve bact. bacteriostatic Resistance: prodn of chloramphenicol acetyl-transferase and is plasmid mediated. R plasmids containing determinants for multiple drug resis for chloramphenicol, streptomycin, tetracycline’s, etc. may be transferred from one bacterial species to another by 'promiscuous plasmids'. Derivatives of chloramphenicol w/ terminal OH on the side-chain replaced by fluorine are likely not to be susceptible to acetylation and thus to retain antibacterial activity. aminoglycoside •inhibit bact protein synthesis by binding to the 30S s - e.g. subunit of the ribosome = alteration in codon:anticodon gentamicin recognition = misreading of mRNA and producn of defective bact proteins.

•penetration through cell memb of the bact depends on chloramphenic ol Inhibition of protein synthesis .

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 • 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 •absorbed •max conc in plasma w/in 2 hours.

•widely distributed through tissues and body fluids includ the CSF. •30-50% plasma protein bound • t½: 2 hrs.

•10% excreted unchanged in urine •inactivated in the liver.

•Metabolite being excreted via the kidney and the bile.

•polycations & highly polar; not absorbed in GI tract.

• i.m. or i.v.

• Binding to plasma proteins is minimal.

• 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 antianabolic 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

oxygen-dependent active transport system, wh/ chloramphenicol can block.

•Bactericidal, enhanced by agents that interfere w/ cell wall synthesis.

Resistance: - inactivation by microbial enzymes, the genes for which are carried on plasmids. 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.

•do not enter cells, nor cross the BBB into the CNS. •Plasma t ½ 2-3 hrs.

• Elimination: glomerular filtration in kidney.

•Tissue conc inc during treatment and 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

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.

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.

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.

from GI tract. pyrazinamide

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

•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.

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.

• well absorbed , oral • widely distributed, penetrating into meninges • excreted:kidney- glomerular filtrate •Primary systemic fungal inf rare and occur in defined endemic areas of the world.

•UK commonest is candidiasis - inf w/ a yeast like orr •

• arthralgia (assoc w/ high conc of plasma urates).

• GI tract upsets, malaise and fever are reported.

•

• specificity for fungi; due to drugs •Rare. Limited to nausea and vomiting greater avidity for ergosterol (fungal when high doses are taken by mouth. membrane sterol) than cholesterol, the 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.

•Relatively infrequent, most commonly being GI tract disturbances, blood dyscrasias.

ANTI VIRAL • virus-specific enzymes: targets for drugs.

• antiviral agents effective while virus is replicating.

acyclovir Inhibiton of nucleic acid syntheis

• smallest infective agent, w/ nucleic acids (either RNA or DNA) enclosed in a protein coat or capsid.

• 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. 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.

DNA viruses: poxvirus (smallpox), herpes viruses (chicken pox, shingles, herpes and glandular fever), adenoviruses (sore throat, conjunctivitis), and papillomaviruses (warts).

RNA Viruses: orthomyxoviruses (influenza), paramyxovirus (measles, mumps), picornaviruses (colds, meningitis, poliomyelitis), retroviruses (AIDS), arenavirus (meningitis, Lassa fever).

•viruses share many metabolic processes w/ host cell: diff to find drugs that are selective for the pathogens.

•Problem:by the time a viral inf becomes clinically detectable, the process of viral replication is usually far advanced and chemotherapeutic intervention is very difficult.

Orally: 20% of dose is absorbed peak plasma conc in 1-2 hrs, i.v; plasma conc 10- to 20- x topically. widely distributed: conc in CSF 50% of plasma. excreted in kidneys by glomerular filtration and by tubular secretion.

• minimal.

• Local inflammation can occur during i.v. if there is extravasation of 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

• 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

•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.

diffusion -passes to CSF and brain.

•metabolised to inactive glucuronide in the liver, • 20% of active form excreted in urine.

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 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. immunopharm Azathioprine, methotrexate and cyclophosphamide  Primary funcn of immune system: protect host from invasion.  system is responsible for causing autoimmune disease

 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  Inhibit cell division  Cell cycle specific drugs: Bone marrow, GI tract epithelium,Hair & nails, Spermatogonia

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.

 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

Alkylating agents Interfere with transcription and replication.

Anti metabolites Block or subvert pathways in DNA synthesis.

and rejecting allogenic tissue grafts after transplantation.  Cytotoxic drugs:used as immunosuppressants, but at Slow growing cells much lower doses than used to treat cancer.  Introduce DNA mutations  selective action on lymphocytes which drive the immune  Cell cycle independent (alkylating response. agents) 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 2’-deoxythymidylate synthesis.  Purine analogues e.g. Azathioprine inhibits purine synthesis.

Cytotoxic AB  Actinomycin D (Dactinomycin) intercalates DNA and 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.

Plant  podophyllotoxins e.g.etoposide, inhibit DNA synthesis. derivatives Causes cell cycle block at G2.  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).



iv.

hormones

 Can inhibit tumours in hormone-sensitive tissues.  Gonadotrophin-releasing hormone analogues e.g. Goserelin

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



chemotherapy but are not technically cytotoxic.

inhaled