year 2 pharmacology & therapeutics essential drug list alexandra burke-smith

YEAR 2 PHARMACOLOGY & THERAPEUTICS

ESSENTIAL DRUG LIST Alexandra Burke-Smith

1. Drugs and the Autonomic Nervous System

Overview of the ANS Sympathetic NS = “fight or flight”, Parasympathetic NS = “rest + digest”• NT = Ach + NA • Ach Receptors: nicotinic + muscarinic cholinoceptors

• Nicotinic = ionotrophic (ligand-gated ion channel)• Muscarinic – metabotrophic (G-protein)• Muscarinic subtypes:

• M1 – neural (excitatory)• M2 – cardiac (inhibitory)• M3 – exocrine (excitatory)

• NA receptors: adrenoceptors• A1 > PLC > IP3 + DAG > PKC + Ca2+

• A2 > cAMP > PKA• B1 > cAMP > PKA • B2 > cAMP > PKA

Cholinomimetics

• “drugs which mimic the action of Acetylcholine (Ach agonists)” – Principally mimic parasympathetic NS – Directly acting: choline esters + alkaloids that have

agonistic action at Ach receptors – Indirectly acting: anticholinesterases that potentiate

the action of Ach; preventing its breakdown by inhibiting acetylcholinesterase and/or butyrylcholinesterase (plasma ezyme)• Reversible = alkaloid carbamyl esters • Irreversible = organophosphate compounds

Drug Acetylcholine (choline ester; neurotransmitter)

Class Directly acting cholinomimetic

Pharmacodynamics (MOA) Agonist at nicotinic + muscarinic Ach receptors (parasympathetic + sympathetic action)

Pharmacokinetics Metabolism: cholinesterasesDuration of action: seconds

Notes: No therapeutic use as non-selective and quickly degraded

Drug Pilocarpine

Class Directly acting cholinomimetic (alkaloid)

Pharmacodynamics (MOA) Partial agonist at muscarinic Ach receptors (parasympathetic activation)

Clinical Use Treat glaucoma (contraction of ciliary muscle + sphincter pupillae > miosis + improved drainage of aqueous humour)

Pharmacokinetics Administration: locally as eyedropsHalf-life: 3-4 hours

Side Effects Predicted by PNS actions:Blurred vision, sweating, GI disturbance, hypotension, respiratory distress

Drug Bethanechol (choline ester)

Class Directly acting cholinomimetic

Pharmacodynamics (MOA) M3 (exocrine + smooth muscle) Ach receptor agonist (parasympathetic action)

Clinical Use Assist bladder emptying + enhance gastric motility

Pharmacokinetics Orally active Half-life 3-4 hours

Side Effects Sweating, impaired vision, nausea, bradycardia, hypotension + respiratory difficulty

Other Relevant Information: Similar in structure to Ach; added methyl group means resistant to degradation

Drug Phyostigmine (alkaloid carbamyl ester)

Class Indirectly acting cholinomimetic (reversible anticholinesterase)

Pharmacodynamics (MOA) Competitive inhibitor of cholinesterase enzyme (donates carbamyl group which blocks active site) > parasympethetic + sympathetic action (primarily acts on PNS) by prolonging Ach activity

Clinical Use Treatment of glaucoma Treat atropine poisoning (Ach antagonist)

Pharmacokinetics Half-life 30 minutes (carbamyl group removed by slow hydrolysis)

Drug Ecothipate (organophosphate compound)

Class Indirect cholinomimetic (irreversible anticholinesterase)

Pharmacodynamics (MOA) inhibitor of cholinesterase enzyme (reacts with enzyme active site; blocking it with stable group ) > parasympethetic + sympathetic action (primarily acts on PNS) by prolonging Ach activity

Clinical Use Treatment of glaucoma

Pharmacokinetics Administered as eye drops Duration of action weeks (new cholinesterase enzyme must be synthesised)

Side Effects Sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty

Cholinoceptor Antagonists

• “drugs which show affinity but no efficacy at Ach receptors, thus preventing agonists from transducing a response and activating intracellular signalling pathways”

Drug Hexamethonium

Class Nicotinic receptor antagonist

Pharmacodynamics (MOA) Competitive antagonistic action at all autonomic ganglia

Clinical Use First anti-hypertensive (inhibition of sympathetically driven kidneys + blood vessels)No longer used clinically

Side Effects Parasympethetically driven side-effects (ie what happens when you block the PNS)Loss of bladder control, pupil dilation, loss of GI motility + secretions

Drug Trimetaphan

Class Nicotinic cholinoceptor antagonist

Pharmacodynamics (MOA) Ganglion blocking drug; not technically a nicotinic receptor antagonist, but blocks ion channels (use-dependent block; more agonist > more block)

Clinical Use Controlled hypotension during surgery

Pharmacokinetics IV administrationDuration of action 2-3 minutes

Drug Atropine

Class Competitive muscarinic cholinoceptor antagonist

Pharmacodynamics (MOA) Competitively inhibits parasympethetic (+ sympathetic) action at mAChR

Clinical Use Anaesthetic premedication (dilate bronchi, dry throat + reduce lung secretion > easier to administer gas mask + reduced aspiration risk)Treatment of sinus bradycardia (normal, slow rhythm)

Pharmacokinetics Oral administrationHepatic metabolism Duration of action 2-3 hours

Side Effects Dry mouth, blurred vision, urinary retention, pupil dilation, irritability, hyperactivity

Other relevant information: NB: atropine poisoning may occur in children who eat the deadly nightshade. This is treated with phyostigmine (see earlier)

Drug Hyoscine


Pharmacodynamics (MOA) Competitively inhibits parasympethetic (+ sympathetic) action at mAChR

Clinical Use Anaesthetic premedication (dilate bronchi, dry throat + reduce lung secretion > easier to administer gas mask + reduced aspiration risk)Treatment of sinus bradycardia Motion sickness (reduces flow of information from Labyrinth to vomiting centre)Parkinsons (reduces inhibitory effect of M4 receptors on dopamine signalling)

Pharmacokinetics Administered orally or transdermallyDuration of action 2-3 hours

Side Effects Decreased sweating, reduced secretions, blurred vision, agitation, restlessness, confusion

Drug Tropicamide


Pharmacodynamics (MOA) Acts on M3 receptors within the iris of the eye to cause pupil dilation (reduces ciliary + sphincter pupillae constriction)

Clinical Use Dilation of pupil for retina examination

Pharmacokinetics Administered as eye drops

Side Effects Dry mouth, blurred vision, urinary retention

Drug Ipratropium Bromide


Pharmacodynamics (MOA) Antagonism removes PNS bronchostrictor effect in lungs

Clinical Use Used to treat asthma and COPD

Pharmacokinetics Administered as aerosol

Other Relevant Information: Quaternary amine structure localises response as positive charge prevents crossing of lipid membrane in lungs

Sympathomimetics • SNS agonists • Act on adrenoreceptors of post-ganglionic SNS

neurons • Directly acting: mimic actions of NA/A by binding and

stimulating adrenoceptors – used principally for actions in CVS, eyes + lungs

• Indirectly acting: act at the adrenergic nerve terminal as opposed to adrenoceptor

Drug Adrenaline (epinephrine)

Class Directly acting sympathomimetic

Pharmacodynamics (MOA) Non-selective (alpha + beta) agonists acting at adrenoceptors of SNS

Clinical Use Anaphylaxis:• B2 action = dilation of skeletal blood vessels > decreased

TPR, bronchodilation + reduced inflammatory mediator production

• A1 action = profound subcutaneous vasoconstriction > increased BP

• B1 action = positive chronotropic + inotropic COPD Acute heart block Anaesthesia (vasoconstriction used to localise effect)Glaucoma (a1 mediated vasoconstriction + B mediated decreased aqueous humour production)

Pharmacokinetics Administered IV, IM or locally (eye drops)Poorly absorbedDuration of action minutesMetabolised by MAO-A (uptake 1) and COMT (uptake 2)

Side Effects Dry mouth, tachycardia, arrythmias, cold extremities, hypertension, tremor, palpitations

Drug Phenylephrine

Class Directly acting Alpha-1 selective sympathomimetic

Pharmacodynamics (MOA) Selective action on alpha-1 adrenoceptors

Clinical Use Stop superficial bleeding (vasoconstrictor)Mydriasis (a1 adrenoceptors > radial muscle constriction > pupil dilation)Nasal decongestant (reduced secretions)

Pharmacokinetics Administered as eye drops, IV, intranasal Duration of action minutesBroken down by MAO

Other Relevant Information: Chemically related to adrenaline, but more resistant to COMT

Drug Clonidine

Class Directly acting Alpha-2 selective sympathomimetic

Pharmacodynamics (MOA) Agonistic action at alpha-2 adrenoceptors. A2 receptors present pre-synaptically; act to autoinhibit release of noradrenaline/adrenaline (reduce SNS action)

Clinical Uses Treatment of hypertension + migraine. Reduces sympathetic tone via central action in brainstem within the baroreceptor pathway (reduced pre-synaptic release of NA)

Pharmacokinetics Orally activeDuration of action hoursBroken down by COMT + MAO-A

Drug Isoprenaline

Class Directly acting non-selective B adrenoceptor agonist

Pharmacodynamics (MOA) Acts to potentiate action of NA/A on beta adrenoceptors

Clinical Uses Treat heart block

Pharmacokinetics IV administrationBroken down by COMTDuration of action hours

Side Effects Fatal reflex tachycardia/dysrhythmias

Other relevant information Difference in structure to adrenaline means less susceptible to metabolism by MAO-A

Drug Dobutamine

Class Directly acting beta-1 selective adrenoceptor agonist

Pharmacodynamics (MOA) Potentiates NA/A action at beta-1 receptors

Clinical Uses Acute heart block

Pharmacokinetics Administered IVHalf-life 2 minutesRapidly metabolised by COMT

Other relevant information Lacks isoprenaline’s reflex tachycardia due to lack of B2 action

Drug Salbutamol

Class Directly acting beta-2 selective sympathomimetic

Pharmacodynamics (MOA) Agonistic action at beta-2 adrenoceptors

Clinical Uses Asthma (relaxation of bronchial smooth muscle + inhibition of pro-inflammatory mediator release from mast cells)Treatment of threatened uncomplicated premature labour (relaxes uterus)

Pharmacokinetics Administration via inhalation (ventolin) or IV (for premature pregnancy)Duration of action hours

Side Effects Some reflex tachycardia, tremor

Contraindications Patients with diabetes (B2 receptors mobilise glycogen)

Other relevant information Relative resistance to metabolism by MAO and COMT

Drug Cocaine

Class Indirectly acting sympathomimetic

Pharmacodynamics (MOA) Acts to prevent uptake 1 (no MAO metabolism) so there is greater concentration of catecholamines in synaptic cleft

Pharmacokinetics Well absorbed from all sites + crosses BBBMetabolised by plasma esterases + hepatic enzymesHalf-life 30 minsExcreted in urine

Side Effects CNS: excitement + increased motor activityActivation of vomiting centres, tremors, convulsionsCVS: tachycardia, vasoconstriction and hypertension

Drug Tyramine (dietary amino acid found in cheese, red wine + soy sauce)

Class Indirectly-acting sympathomimetic

Pharmacodynamics (MOA) Some weak agonistic activity at post-synaptic adrenoceptors + competitive inhibition of uptake 1Also displaces NA from intracellular vesicles, therefore increased cytosolic [NA] > leakage into synaptic cleft

Pharmacokinetics Extensive first pass metabolism

Side Effects Under normal conditions, no effect as undergoes extensive first pass metabolismHowever when MAOs are inhibited (eg use of antidepressants), ingestion of foods containing tyramine may cause hypertensive crisis known as CHEESE REACTION

SNS Antagonists

• Act with antagonistic action at adrenoceptors• These may be:– Non-selective– Non-selective alpha– Alpha 1 selective– Non selective beta– Beta 1 selective

Drug Labetalol

Class Directly acting Non-selective b1 and a1 SNS antagonist

Pharmacodynamics (MOA) Antagonism > block of SNS activity

Clinical Uses Hypertension (decreased renin secretion + peripheral subcutaneous vasoconstriction > decreased peripheral resistance)

Pharmacokinetics Broken down by COMT + MAO-A

Other relevant information No long-term change in heart rate or cardiac output

Drug Propanolol

Class Directly acting Non-selective B-adrenoceptor antagonists

Pharmacodynamics (MOA) B-blocker > reduced SNS effects

Clinical Uses Hypertension (reduced effect of exercise or stress)Anti-arrythmic (class II)

Pharmacokinetics Orally activeBroken down by COMT + MAO-ADuration of action hours

Side Effects Bronchoconstriction, hypoglycaemia (loss of warning signs for diabetics eg palpitations), fatigue, cold extremities, bad dreams

Contraindications Asthma

Other relevant information Little cardiac effects at rest

Drug Atenolol

Class Directly acting b1-selective SNS antagonist

Pharmacodynamics (MOA) “cardioseelctive” – antagonises the effect of noradrenaline on the heart

Clinical Uses Hypertension Angina

Pharmacokinetics Broken down by COMT and MAO-A

Contraindications Asthma (despite less b2 effect)

Drug Atenolol

Class B1 selective (cardioselective) B blocker

Pharmacodynamics (MOA) Competitive antagonist at B1 adrenoceptors in heart, thus preventing action of NA (negative ionotropic + chronotropic effect)

Clinical Uses Angina, post MI, cardiac dysrythmias, chronic heart failure, hypertension

Side Effects Clinical doses > action on B2 receptors:Worsening of cardiac failureBradycardia, bronchoconstriction, hypoglycaemia, fatigue, cold extremities, CNS effects eg nightmares

Other relevant information Also use in glaucoma, migraine, benign essential tremorNot first line treatment for hypertension as does not reduce TPR

Drug Phentolamine

Class Directly acting Non-selective alpha-adrenoceptor antagonist

Pharmacodynamics (MOA) Blockade of a1 receptors > vasodilation > fall in TPR + BPBlockade of a2 receptors > loss of inhibition of pre-synaptic NA release

Clinical Uses No longer used clinically

Side Effects Postural hypotension, diarrhoea, reflex tachycardia

Drug Prazosin

Class Directly acting a1 selective adrenoceptor antagonist

Pharmacodynamics (MOA) Blockade of a1 > vasodilation > fall in TPR + BP (less reflex tachycardia)

Clinical Uses Antihypertensive (minor use in associated dislipidaemia)

Pharmacokinetics Broken down by COMT + MAO-A

Side Effects Hypotension Modest decrease in LDL, increase in HDL

Other relevant information Lack of a2 blockade > no change in synthesis and release of NA

Drug Methyldopa

Class SNS false transmitter

Pharmacodynamics (MOA) Indirectly acting adrenoceptor antagonist; in the same way that DOPA is taken up and packaged into vesicles, methyldopa is packaged and hydroxylated to form false NT alpha-methyl-noradrenalineA-m-NA is released into the synaptic cleft, but has greatest activity on alpha 2 receptors to reduce NT release.

Clinical Uses Antihypertensives (in patients with renal insufficiency) as maintains renal blood flow. Also in pregnancy-related hypertension, as no effect on foetus.

Side Effects Dry mouth, sedation, orthostatic hypotension

Other relevant information Not deaminated by MAO-A, therefore accumulates in synaptic cleft

Neuromuscular Blocking Drugs

• Drugs which act at the NMJ To prevent depolarisation of the motor end-plate – Non-depolarising: competitive antagonsts– Depolarising: agonists

Drug Tubocurarine

Class Non-depolarising NM blocking drug

Pharmacodynamics (MOA) Competitive nicotinic Ach receptor antagonist which produces a graded block of somatic NMJs

Clinical Uses Surgery (reduces amount of anaesthetic required + allows for artificial ventilation)

Pharmacokinetics Administered IVDoesn’t cross BBB or placentaOnset of action within 2-3 minsDuration of action 40-60 minsNot metabolised, excreted in bile + urine

Side Effects Flaccid paralysis (onset in order…)1. Extrinsic eye muscles > double vision2. Small muscle paralysis of face, limbs + pharynx3. Respiratory muscle paralysis Unwanted effects:Ganglion block + histamine release from mast cells > decreased TPR + bronchospasm

Contraindications Renal/hepatic impairment

Other relevant information

Naturally occurring quaternary ammonium alkaloid Reversed by anticholinesterases; recovery of movement is in reverse order to effects

Drug Atracurium

Class Non-depolarising NM blocker

Pharmacodynamics (MOA) Competitive nAChR antagonist (somatic NMJ blocked)

Pharmacokinetics Shorter duration of action than Tubocurarine

Drug Suxamethonium

Class Depolarising NM blocker

Pharmacodynamics (MOA) Post-synaptic nAChR agonist, therefore causes prolonged excitation. This prevents new action potential generation, thus inactivating ion channels (somatic NMJ blocked)

Pharmacokinetics Degraded by butyrylcholinesterases (plasma enzyme)Duration of action mins (use in short term endotracheal intubation)

Other relevant information Structure related to acetylcholine Different to HEXAmethonium = nAChR antagonist

2. Drugs and the Cardiovascular System

RAAS

• RAAS = renin angiotensin aldosterone system– Primarily responsible for fluid + BP regulation

• Drugs interfering with RAAS:– ACE inhibitors– Angiotensin II receptor antagonists (ARB)– Renin inhibitors, eg Aliskiren (no significant clinical

experience)

Drug Enalapril

Class ACE inhibitor

Pharmacodynamics (MOA) Inhibits the somatic form of ACE, thus preventing the conversion of Ang I > Ang II

Clinical Uses Used in conditions which confer increased CV risk:Hypertension, heart failure, post MI, diabetic nephropathy, progressive renal insufficiency

Side Effects Hypotension, dry cough, urticaria + angioedema, hyperkalemia, fetal injury, renal failure (in patients with renal artery stenosis)

Other relevant information Germline form of ACE is significantly different, therefore not affected

Drug Captopril

Class ACE inhibitor

Pharmacodynamics (MOA) Inhibits the somatic form of ACE, thus preventing the conversion of Ang I > Ang II

Clinical Uses Used in conditions which confer increased CV risk:Hypertension, heart failure, post MI, diabetic nephropathy, progressive renal insufficiency

Side Effects Hypotension, dry cough, urticaria + angioedema, hyperkalemia, fetal injury, renal failure (in patients with renal artery stenosis)

Other relevant information Germline form of ACE is significantly different, therefore not affected

Drug Losartan

Class Angiotensin Receptor Blocker

Pharmacodynamics (MOA) Non-competitive Antagonist of type 1 receptors for Ang II, thus preventing renal and vascular actions of Ang II

Clinical Uses Hypertension, chronic heart failure

Side Effects Hypotension, hyperkalemia, fetal injury, renal failure (in patients with renal artery stenosis)

Other relevant information Fewer side effects than ACE inhibitors

Calcium Antagonists

• Rise in intracellular calcium key step in excitation-contraction coupling in both cardiac and vascular myocytes

• Involves L-type voltage-dependent calcium channel

• 2 classes of calcium channel blockers (CCBs)– Rate limiting (bind to IC domain of receptor; exert

both cardiac and smooth muscle effects)– Non-rate slowing (bind to EC domain of receptor;

exerts only smooth muscle action), eg amlodipine

Drug Verapamil

Class Rate-limiting calcium channel blocker

Pharmacodynamics (MOA) Binds to the intracellular domain of L-type calcium channel receptor, blocking influx of calcium • Negative chronotropic + ionotropic effects on heart and

smooth muscle

Clinical Uses Angina (arising from IHD)Antidysrhythmias

Pharmacokinetics Oral administrationDuration of action 6-8 hoursHepatic metabolism

Side Effects Bradycardia, AV block, negative ionotropic effect (worsening of HF), constipation (effect on GI smooth muscle)

Drug Diltiazem



smooth muscle Clinical Uses Angina (arising from IHD)

Antidysrhythmias



Beta Blockers

• Sympathetic neurons innervating cardiac muscle release NA on depolarisation

• NA acts on B1 receptors on cardiac myocytes, to increase heart rate, contractility and excitability

• Competitive antagonists, ie beta blockers, thus tend to have a negative chronotropic and ionotropic effect

Drug Atenolol

Class B1 selective (cardioselective) B blocker

Pharmacodynamics (MOA) Competitive antagonist at B1 adrenoceptors in heart, thus preventing action of NA (negative ionotropic + chronotropic effect)

Clinical Uses Angina, post MI, cardiac dysrythmias, chronic heart failure, hypertension (not first line for hypertension as no TPR effect)

Side Effects Clinical doses > action on B2 receptors:Worsening of cardiac failureBradycardia, bronchoconstriction, hypoglycaemia, fatigue, cold extremities, CNS effects eg nightmares

Other relevant information Also use in glaucoma, migraine, benign essential tremorNot first line treatment for hypertension as does not reduce TPR

Organic Nitrates + Related Agents

• Organic nitrite is absorbed (particularly in SMC), where it undergoes degradation into nitrite free radical, then converted to nitric oxide

• Nitric oxide is an endogenous vasodilator; it acts on guanylate cyclase to increase cGMP production

• cGMP then acts to vasodilate the smooth muscle

Drug Glyceryl Trinitrate

Class Nitrate

Pharmacodynamics (MOA) Directly causes release of NO in smooth muscle cells, as well as minor release in platelets. Vasodilation reduces venous return and total peripheral resistance, thus reduces preload and afterload, and therefore the heart does not need to work as hard

Clinical Uses AnginaHeart failureBP control during anaesthesia (easy to titrate)

Pharmacokinetics Undergoes extensive first pass metabolism by the liver, therefore administered sublingually for rapid relief, or via transdermal patch for long term use Half life approx 5 mins

Side Effects Vasodilation > hypotension, headaches, flushing

Other relevant information Long term use associated with tolerance; one of the reasons GTN is used for immediate relief Often used in conjunction with beta blockers for treatment of angina

Drug Nicorandil

Class Nitrate; stimulates guanylate cyclase to cause vasodilation

Pharmacodynamics (MOA) Guanylate cyclase acts to increase cGMP production, which causes myocyte vasodilation

Clinical Uses Used to increased oxygen supply to coronary vessels, and increase venous capacitance (often post MI)

Pharmacokinetics Hepatic metabolism

Side Effects Vasodilation > hypotension, headaches, flushingReflex tachycardia

Anti-dysrhythmics

• Arrythmias/dysrhythmias = abnormalities of cardiac rhythm

• Classified according to association with heart rate (tachy = increase, brady = decrease), and site of origin:– Supraventricular: arise from atria and conduction

tissue– Ventricular: arise from ventricles – Complex: multiple sites of origin

Drug Amiodarone

Class Antidysrhythmic

Pharmacodynamics (MOA) Wide spectrum anti-dysrhythmic with complex MOA involving multiple ion channel blocks

Clinical Uses Supraventricular + ventricular arrythmias

Pharmacokinetics Half life 10-100 days

Side Effects Accumulates in the body, therefore number of adverse effects: photosensitive skin rash, hypo/hyperthyroidism, pulmonary fibrosis

Drug Diltiazem

Class Rate-limiting calcium channel blocker (class IV antiarrhythmic)


smooth muscle Clinical Uses Angina (arising from IHD)

Tachyarrythmias



Drug Verapamil



smooth muscle Clinical Uses Tachyarrythmias



Drug Digoxin

Class Cardiac glycoside

Pharmacodynamics (MOA) CVS: Inhibition of Na-K ATPase > accumulation of intracellular Ca2+ via Na/Ca exchanger = positive ionotropicCNS: increased vagal outflow > increased refractory period + reduced rate of conduction through AVN = negative chronotropic

Clinical Uses Atrial fibrillation

Pharmacokinetics T ½ 40 hours Narrow therapeutic index

Side Effects New dysrhythmia, eg AV conduction block

Other relevant information AF may cause thrombus formation in the atrium; embolus to the brain may cause a stroke High risk of digoxin toxicity; treated with immune Fab digibind, which “mops up” excess

Other Cardiac Drugs

Drug Doxazosin

Class Competitive alpha-1 adrenoceptor antagonist

Pharmacodynamics (MOA) Competes with NA for active site of alpha-1 adrenoceptors, thereby preventing vasoconstrictor action > coronary vasodilation

Clinical Uses Used in conjunction with antihypertensives in resistant hypertension

Side Effects Increased rate of chronic heart failure

Drug Sumitriptan

Class 5HT1D receptor agonist

Pharmacodynamics (MOA) Acts on seratonin receptor to inhibit trigeminal nerve transmission and constrict cerebral and coronary arteries

Clinical Uses Treatment of migraine

Contraindications Coronary disease – causes coronary vasoconstriction

Anti-Thrombotics + Anti-Coagulants

• Drugs that interfere with normal haemostasis and thrombosis pathways • Haemostasis: the essential physiological process where blood

coagulation prevents excess blood loss• Thrombosis: the pathophysiological process where blood coagulation

occurs within an INTACT blood vessel and obstructs blood flow– venous thrombosis = red thrombi (high fibrin)– Arterial thrombosis = white thrombi (high platelet)

• Virchow’s triad (addresses why thrombi may form):– Rate of blood flow – slow/stagnating– Consistency of blood – viscous [more procoagulation factors]– Blood vessel wall integrity – atherosclerotic

• Drugs that target = anti-coagulants, anti-platelets, thrombolytics

Anti-Coagulants

• Target the initial phase of the clotting cascade, which occurs following tissue factor exposure

• 4 types of drugs:– Direct thrombin inhibitors, eg Hirudin – Heparin + derivatives– Factor Xa inhibitors– Vitamin K antagonists

Drug Heparin

Class Anti-coagulant

Pharmacodynamics (MOA) Natural anti-coagulant found on mast cells in the body; exerts a conformational change which activates antithrombin III, potently inactivating thrombin

Clinical Uses Immediate anticoagulation in venous thrombosis + pulmonary embolism

Pharmacokinetics Heparin = continuous infusion, short half lifeLMW derivatives = longer half life, not orally available but only require regular administration

Side Effects Haemorrhage, hypersensitivity reactions, thrombocytopenia, osteoporosis, hypoaldosteronism

Other relevant information Derivatives also inhibit Factor X, therefore preventing formation of prothrombinase complex To reverse effects. Promatine can be given IV (forms inactive complex)

Drug Warfarin

Class Vitamin K antagonist (anti-coagulant)

Pharmacodynamics (MOA) Vitamin K is essential for clotting factor synthesis, therefore prevents normal clotting cascade

Clinical Uses Long term anticoagulation following thrombosis or MI

Pharmacokinetics Oral administrationDelayed onset of action (5 days)Narrow therapeutic window, strongly plasma protein bound

Side Effects Haemorrhage, teratogenic

Other relevant information Numerous drug interactions which make pharmacokinetics more complex – requires INR monitoring. This is because highly plasma protein bound therefore changes in pp binding affect bioavailability

Anti-Platelets

• Used in CV disease as thrombosis prevention• If AT-III does not inactivate thrombin, thrombin activates

platelets > production of clotting factors and ADP– Thrombin also releases endothelial bound vWF, which activates

factor II > IIa (thrombin)• ADP acts on active platelets via P2Y receptors, leading to

platelet aggregation and formation of a clot • Anti-platelets include:

– PAR antagonists (protease activated receptor)– ADP receptor antagonists– COX inhibitors– Glycoprotein Iib/IIIa receptor antagonists

Drug Clopidogrel

Class ADP receptor antagonist

Pharmacodynamics (MOA) Prevents platelet plug formation. ADP binding leads to the expression of GpIIb/IIIa, which act as a molecular glue for the formation of the unstable plug

Clinical Uses Anti-platelet

Pharmacokinetics Oral administration

Other relevant information Drug of choice in aspirin-sensitive patients

Drug Apirin

Class COX inhibitor

Pharmacodynamics (MOA) PAR activation liberates arachidonic acid. The action of COX on arachidonic acid in platelets generates thromboxane-A2 (pro-coagulant), therefore prevents this

Clinical Uses Anti-platelet

Pharmacokinetics Administered orally at low dose (75mg)

Side Effects Reyes syndrome, bronchospasm, GI bleeding and stomach ulcers

Contraindications Children under 16, haemophiliacs, asthmatics

Drug Abciximab

Class Glycoprotein IIb/IIIa antagonist

Pharmacodynamics (MOA) ADP receptor binding + thromboxane A2 lead to expression of GpIIb/IIIa. These act as a molecular glue in the formation of unstable platelet plug

Clinical Uses Anti-plateletTreatment of thrombotic disorders

Pharmacokinetics IV administration

Other relevant information Only single use, therefore used in high risk patients

Thrombolytics

• Large scale thrombin converts fibrinogen to fibrin.

• Fibrin strands wrap around the clot, with the eventual formation of a thrombus within the intact blood vessel

• Fibrinolytics are effective at removing pre-formed clots. They convert plasminogen to plasmin, a natural protease that digests fibrin strands

Drug Alteplase

Class Thrombolytic/fibrinolytic/clot buster

Pharmacodynamics (MOA) Recombinant tissue type plasminogen activator (tPA) > degradation of fibrin clot and release of fibrin degradation products

Clinical Uses Acute MI and ischaemic stroke

Pharmacokinetics IV short infusionDuration of action hours

Other relevant information Needs to be given within 12 hours of symptom onset

Drug Streptokinase

Class Thrombolytic/fibrinolytic/clot buster

Pharmacodynamics (MOA) Bacterial product that binds to plasminogen, causing a conformational change that exposes the active site

Clinical Uses Reduce mortality from acute MI

Pharmacokinetics IV short infusionHalf life 3-4 hours

Side Effects Bleeding, GI haemorrhage, stroke

Other relevant information Tolerance develops after first administration; develop immunity to bacterial antigens

Cholesterol Drugs

• Hypercholesteramia is a key risk factor in the development of atherosclerosis

• LDL cholesterol is the primary target to prevent atherosclerotic plaques + CHD

• Different classes of drugs include:– Statins – Bile acid sequestrants– Nicotinic acid– Fibrates

• Triglycerides are also associated with an increased risk of CHD, therefore are an important target. However this mechanism is not fully understood

Statins

• First-line drugs in treatment of dyslipidaemias • MOA: inhibition of HMG-CoA reductase (rate-

limiting enzyme in cholesterol synthesis)• In response to this…– Hepatocytes up-regulate/increase number of LDL

receptors, increasing binding and removal of LDL cholesterol from the plasma

– Increase in HDL cholesterol (mechanism not fully understood)

Drug Simvastatin

Class Statin

Pharmacodynamics (MOA) HMG-CoA reductase inhibitor – inhibits cholesterol synthesis. Effects include:• Raised HDL• Lowered LDL• Formation of plaque stabilisers

Clinical Uses Hypercholesteramia, dyslipidaemia

Pharmacokinetics Oral administration Hepatic metabolism Half life 1-2 hours

Side Effects Caused by non-selective effects on body (target organ is liver)

Other relevant information COCHRANE review has shown reservation in use of statins in primary prevention

3. Diuretics

Diuretics • Drugs that act on the renal tubule to promote an increased loss of

water in the urine = diuresis • Gross structure of renal tubule can be divided into 4 sections:

– Proximal convoluted tubule– Loop of Henle (descending and ascending limb)– Distal convoluted tubule– Collecting duct

• There are 5 main classes of diuretics, each with a different MOA:– Osmotic diuretics – act on entire kidney tubule– Carbonic anhydrase inhibitors – act principally on PCT– Loop diuretics – act on ascending limb of LOH– Thiazides – act on early DCT– Potassium sparing diuretics – act on late DCT and collecting duct

Drug Mannitol

Class Osmotic diuretic

Pharmacodynamics (MOA) Pharmacologically inert substance which is freely filtered into kidney lumen, but poorly reabsorbed. Therefore increases osmolarity of kidney filtrate, and decreases water absorption where the nephron is freely permeable to water (PCT, descending LOH, CT)

Clinical Uses Prevention of acute renal failureDecreasing intra-cranial pressure, intraocular pressure

Pharmacokinetics IV administration

Side Effects Increased ECF volume > hyponatremia. This may cause nausea, vomiting, headache + pulmonary oedema

Carbonic Anhydrase Inhibitors

Drug Acetazolamide

Class Carbonic anhydrase inhibitor

Pharmacodynamics (MOA) Inhibits action of CA, therefore increasing bicarbonate and sodium loss in the PCT. This reduces water reabsorption in the PCT as well as the CT

Clinical Uses Renal stones Metabolic alkalosis Decreasing intra-ocular pressure (glaucoma)Altitude sickness

Side Effects Hypokalemia, reduced H+ excretion > alkaline urine + metabolic acidosis

Other relevant information Relatively weak; only act on PCT and further reabsorption of sodium occurs in later nephron

Loop Diuretics

Drug Frusemide

Class Loop diuretic

Pharmacodynamics (MOA) Acts to block the Na+-2Cl--K+ co-transporter on the apical membrane of the ascending limb, thus reducing the osmolarity of the medullary interstitium > less water reabsorption in descending limb + 15-30% more filtrate loss

Clinical Uses Oedema (HF, pulmonary, renal, hepatic or cerebral)Moderate hypertensionHypercalcaemia, hyperkalemia

Pharmacokinetics Oral or IV administrationHalf life 3-6 hours Excreted unmetabolised by kidney

Side Effects Hypokalaemia, metabolic alkalosis, hypocalcaemia, and possibly hypotension, nausea and vomiting, and may induce an allergic reaction.

Thiazides

Drug Bendrofluazide

Class Thiazides

Pharmacodynamics (MOA) Blocks Na/Cl co-transporter in early DCT, thus increasing osmolarity of tubule lumen and Na+ delivery to late DCT and CT. This results in decreased water reabsorption, increased K+ loss, increased Mg2+ and Ca2+ reabsorption

Clinical Uses HypertensionCardiac failure, resistant oedema, nephrogenic diabetes insipidus (pradoxical effect here = anti-diuretic effect)

Pharmacokinetics Oral administrationHalf life 24 hours

Side Effects Hypokalemia metabolic alkalosis Diabetes mellitus

Other relevant information Mild diuretic – first line treatment of hypertension in the elderly

Potassium Sparing Diuretics

Drug Spironolactone

Class Potassium sparing diuretic

Pharmacodynamics (MOA) Aldosterone receptor antagonist, therefore acts to inhibit Na+ reabsorption in late DCT, as well as concommitant K+ excretion (basal Na/K exchanger)Results in increased tubular osmolarity + water loss, with increased H+ retention (uric acid loss)

Clinical Uses Used in primary and secondary hyperaldosteronism

Pharmacokinetics Oral administrationDuration of action days

Side Effects Hyperkalemia, metabolic acidosisGynaecomastia, menstrual disorders/testicular atrophy

Drug Amiloride

Class Potassium sparing diuretic

Pharmacodynamics (MOA) Inhibitor of aldosterone-sensitive Na+ channel, , therefore acts to inhibit Na+ reabsorption in late DCT, as well as concommitant K+ excretion (basal Na/K exchanger)Results in increased tubular osmolarity + water loss, with increased H+ retention (uric acid loss)

Clinical Uses Used in conjunction with other diuretics

Side Effects Hyperkalemia and metabolic acidosis

4. NSAIDs

NSAIDs• Inhibit COX enzyme; involved in rate limiting step of prostanoid synthesis,

thus prevents production of prostaglandin H2 from arachidonic acid • Two isoforms of COX enzyme:

– COX 1 – found in nearly all cells, actions tend to be homeostatic– COX 2 – found predominantly in pro-inflammatory cells

• Actions of NSAIDs can be predicted by actions of prostanoids, eg prostaglandin E2:– PGE2 sensitizes nociceptors, thus lowering pain threshold and causing pain. NSAIDs

raise the threshold therefore reduce perception of pain = ANALGESIC– PGE2 stimulates hypothalamic neurones to increase body temperature. Therefore

blocking its production prevents this temp rise = ANTI-PYRETIC– PGE2 enhances Th1 differentiation (>IFN-gamma) + Th17 expansion (>IL-17) – both of

these have pro-inflammatory effects therefore blocking = ANTI-INFLAMMATORY – PGE2 downregulates gastric acid secretion + stimulates mucus/bicarbonate secretion.

NSAIDs block this so remove cytoprotection + increase risk of GASTRIC ULCERATION

Drug Ibuprofen

Class Non-selective NSAID

Pharmacodynamics (MOA) Reversibly inhibits COX 1 and COX 2 with equal affinity, thus preventing prostaglandin H2 synthesis

Clinical Uses Anti-inflammatoryAnti-pyreticAnalgesic

Pharmacokinetics Orally active

Side Effects Gastric ulcers, decreased glomerular filtration rate, renal ischaemia, salt and water retention

Drug Aspirin

Class NSAID

Pharmacodynamics (MOA) Irreversible COX 1 and COX 2 inhibitor, although selective for COX 1. High affinity for COX 1 reduces thromboxane A2 synthesis in platelets, thus preventing platelet aggregation. COX 2 action prevents PGI2 synthesis, which has inhibitory actions against platelet aggregation, but this effect is much less. Also same actions as other NSAIDs

Clinical Uses Anti-plateletAnti-inflammatory, anti-pyretic, analgesic

Pharmacokinetics Orally activeIrreversible inhibitor therefore prolonged action; requires de novo COX synthesis

Side Effects Gastric irritation + ulceration, bronchospasm (in sensitive asthmatics), prolonged bleeding and nephrotoxicity

Drug Celecoxib

Class COX-2 selective NSAID

Pharmacodynamics (MOA) Selectively inhibits COX-2

Clinical Uses In patients with high risk of GI side effects


Side Effects Increase in CVS related side-effects

Other relevant information less effect on COX-1 mediate processes > fewer risks of gastric ulceration

Drug Paracetamol

Class NOT an NSAID

Pharmacodynamics (MOA) Not completely understood

Clinical Uses Analgesic + anti-pyretic

Pharmacokinetics Paracetamol is a phase I metabolite of a pro-drug (thus has free OH). Phase I metabolism of paracetamol > production of NAPQI (toxic), which then undergoes glutathione conjugation (involves glutathione transferase Other phase II metabolism pathways that can occur include methylation, sulphation or glucuronidation

Side Effects NAPQI toxicity treated with cysteine – forces NAPQI to undergo Phase II metabolism

Contraindications Hepatic impairment

5.Drugs and the GI Tract

Anti-Emetics

• These should only be administered when the cause of the nausea/vomiting is know, otherwise could mask the diagnosis of a potentially serious condition

Vomiting Pathways

Drug Promethazine

Class Anti-emetic (H1 antagonist)

Pharmacodynamics (MOA) Histaminergic antagonist: Competitive antagonist at H1, AchM and D2 receptors, therefore acting centrally (NST, vestibular nuclei, higher centres, CTZ) to block the activation of the vomiting centre

Clinical Uses Motion sickness, Meniere’s (disorder of Labyrinth), hyperemesis gravidarium, pre-/post-operatively Also relief of allergic symptoms, anaphylaxis, insomnia

Pharmacokinetics Oral administrationOnset of action 1-2 hours, peaks at 4 hoursDuration of action 24 hours

Side Effects Dizziness, tinnitus, fatigue, sedation, convulsions, anti-muscarinic side effects (dry mouth etc)

Other relevant information Potency of antagonistic action H1 > AchM > D2

Drug Metoclopramide

Class Anti-emetic (D2 antagonist)

Pharmacodynamics (MOA) Dopaminergic antagonist: competitive antagonist of D2, H1 and AchM receptors acting in the chemoreceptor trigger zone, as well as in the GIT to increase smooth muscle motility + accelerate intestinal transit

Clinical Uses Renal failure, radiation sickness, GI disorders, cancer chemotherapy

Pharmacokinetics Oral or IV administrationExtensive first pass metabolism Crosses BBB and placenta

Side Effects Drowsiness, dizziness, anxiety, extrapyramidal reactions (Parkisonian-like syndrome), hyperprolactinaemia, galactorrhea, disorders of menstration

Other relevant information Causes faster transit time through GIT, therefore may affect boavailability of co-administered drugs, and comprimise nutrient supply

Drug Hyoscine

Class Anti-emetic (AchM antagonist)

Pharmacodynamics (MOA) Muscarinic cholinoceptor antagonist; acts centrally to block the activation of the vomiting centre (AChM > D2 = H1)

Clinical Uses PREVENTION of motion sicknessPre-operative

Pharmacokinetics Oral, IV or transdermal administrationPeak of action 1-2 hours

Side Effects Drowsiness, dry mouth, mydriasis, cyclopegia (loss of vision accomodation), constipation

Other relevant information Little effect once nausea/vomiting has been established

Drug Ondasetron

Class Anti-emetic (5HT3 antagonist)

Pharmacodynamics (MOA) 5HT3 receptor antagonist; acts to block transmission via the visceral afferents to the chemoreceptor trigger zone and thus prevents activation of the vomiting centre

Clinical Uses Preventing anti-cancer drug-induced vomitingRadiotherapy-induced sicknessPost-operative nausea and vomiting

Pharmacokinetics Oral administrationExcreted in urine

Side Effects Headache, flushing, constipation

Anti-Ulcer Drugs

• Peptic ulcer disease results from the imbalance of the protective and potentially damaging factors of the mucosal barrier.

• Almost 100% of patients with peptic ulcer disease are infected with H. Pylori

• Triple Therapy is currently the best practice in treating peptic ulcer disease:– Antibiotic – eg Metronidazole, Amoxicillin or Clarithromycin – Inhibitor of Gastric Secretion – PPI (eg omeprazole), or H2

receptor antagonist (eg cimetidine, ranitidine)– Cytoprotective drug – eg Sucralfate, bismuth chelate,

misoprostal

Drug Metronidazole

Class Antibiotic

Pharmacodynamics (MOA) Active against anaerobic bacteria and protozoa

Drug Amoxicillin

Class Antibiotic

Pharmacodynamics (MOA) Broad spectrum antibiotic

Drug Clarithromycin

Class Antibiotic

Pharmacodynamics (MOA) Macrolide structured antibiotic which inhibits the translocation of bacterial tRNA

Drug Omeprazole

Class Proton Pump Inhibitor

Pharmacodynamics (MOA) Inhibitors of gastric secretion. Irreversibly inhibit the H/K ATPase responsible for H+ secretion into the canaliculi.

Clinical Uses Component of triply therapyPeptic ulcers resistant to H2 antagonists Reflux oesophagitis

Pharmacokinetics Orally activeAdministered as enteric-coated slow-release formulationDuration 2-3 days

Side Effects Uncommon; headaches, mental confusion, impotence, gynaecomastia, pain in muscles and joints

Other relevant information Inactive at neutral pH. In acid environment of the stomach, are protonated and rearranged into their active form. Inhibit secretion by >90%

Drug Cimetidine

Class Histamine Type 2 Receptor Antagonist

Pharmacodynamics (MOA) Competitive antagonists at H2 receptors on parietal cells; prevent histamine binding > less acid secretion, but also reduce effect of Ach/Gastrin binding

Clinical Uses Duodenal ulcer treatment

Pharmacokinetics Orally active Duration of action 2-3 days

Side Effects Uncommon; diarrhoea, dizziness, muscle pains, transient rashes, hypergastrinaemia

Contraindications Withdrawal often results in relapses

Other relevant information Reduces secretion by 60%

Drug Ranitidine

Class Histamine Type 2 Receptor Antagonist

Pharmacodynamics (MOA) Competitive antagonists at H2 receptors on parietal cells; prevent histamine binding > less acid secretion, but also reduce effect of Ach/Gastrin binding

Clinical Uses Duodenal ulcer treatment

Pharmacokinetics Orally active Duration of action 2-3 days

Side Effects Uncommon; diarrhoea, dizziness, muscle pains, transient rashes, hypergastrinaemia

Contraindications Withdrawal often results in relapses

Other relevant information Reduces secretion by 60%

Drug Sucralfate

Class Cytoprotective Drug

Pharmacodynamics (MOA) Polymer containing aluminium hydroxide and sucrose octasulphate; acquires strong negative charge in acidic environment, binds to positively charge compounds (eg glycoproteins) to form gel-like complexes which coat the ulcer, limiting H= diffusion and pepsin degradation

Clinical Uses Peptic ulcersComponent of triple therapy

Pharmacokinetics Orally activeDuration of action 3 hours

Side Effects Constipation, dry mouth, nausea, vomiting, headaches

Other relevant information Reduces absorption of other drugs, eg digoxin. Important to consider therapeutic window + bioavailability

Drug Bismuth chelate

Class Cytoprotective drug

Pharmacodynamics (MOA) Toxic effects on H. pylori, prevents its adherence to mucosa + inhibits its proteolytic enzymes. Enhances local prostaglandin synthesis to stimulate bicarbonate secretion

Clinical Uses Resistant cases of triple therapy


Side Effects Nausea and vomiting, blackening of tongue and faeces

Drug Misoprotol

Class Cytoprotective drug

Pharmacodynamics (MOA) Stable prostaglandin analogue; mimics action of locally produced prostaglandins to maintain the gastroduodenal mucosal barrier:Inhibits acid secretion via G-protein coupled receptor mediated inhibition of adenylate cyclaseStimulates increased secretion of protective mucusIncreased mucosal blood flow

Clinical Uses Prevention of NSAID induced gastric ulcers

Side Effects Diarrhoea, abdominal cramps, uterine contractions

Contraindications Pregnancy – induces premature labour (use in abortion)

Drugs and Inflammatory Bowel Disease Characteristic Ulcerative Colitis Crohn’s DiseaseAutoimmune disease Th2 mediated Th1 mediated

T cell expansion/apoptosis Normal Florid expansion + defective apoptosis

Gut layers affected Mucosa + submucosa All layers

Regions of the gut affected Colon Any region

Inflammation Continuous PatchyFistulae/fissures/abscesses Not present Present

Surgery Curative Not always curative

Treatment falls into 2 parts: the treatment of active disease and the maintenance of remission. These then are put into 3 categories:• Supportive therapies – acute treatment + nutrition-based therapies to

maintain remission• Treatment to reduce inflammation + relief of symptoms – glucocorticoids,

aminosalicylates, immunosuppressives • Curative therapies – anti-TNFalpha antibodies

Drug Mesalazine

Class Aminosalicylate

Pharmacodynamics (MOA) Anti-inflammatory action: reduces free radicals, upregulates endogenous anti-oxidants, reduces leukocyte infiltration

Clinical Uses Treatment of ulcerative colitis + maintenance of remission

Pharmacokinetics Oral administration (pH dependent capsules)Absorbed in small bowel and colon

Side Effects Nausea, diarrhoea, abdominal pain/cramps, urticaria

Other relevant information No immuno-supressive actionInnefective in Crohn’s

Drug Sulfasalazine

Class Aminosalicylate

Pharmacodynamics (MOA) Anti-inflammatory action: reduces free radicals, upregulates endogenous anti-oxidants, reduces leukocyte infiltration

Clinical Uses Treatment of ulcerative colitis + maintenance of remission

Pharmacokinetics Oral administration (pH dependent capsules)Absorbed in colon Metabolised by colonic flora

Side Effects Anorexia, nausea, agranulocytosis, hypospermia

Other relevant information No immuno-supressive actionInnefective in Crohn’s

Drug Prednisolone

Class Glucocorticoid

Pharmacodynamics (MOA) Cortisol-derived agonist of glucocorticoid receptors. Then act as:• Anti-inflammatories – positive transcription factors for

anti-inflammatory genes + negative transcription factors for pro-inflammatory factors

• Immunosuppressives: reduce antigen presentation, cell proliferation and clonal expansion

Clinical Uses Inducing remission in Crohn’s disease

Pharmacokinetics Administered topically (oral if severe)

Side Effects Related to effects of cortisol: osteoporosis, suppression of HPA axis, T2DM, hypertension, infection susceptibility, skin thinning, bruising, proximal myopathy, buffalo hump

Other relevant information Strategies for minimising unwanted effects include use of tapered doses, use of drugs with high therapeutic index, topical administration

Drug Fluticasone








Other relevant information Strategies for minimising unwanted effects include use of tapered doses, use of drugs with high therapeutic index, topical administrationn

Drug Budesonide








Other relevant information Strategies for minimising unwanted effects include use of tapered doses, use of drugs with high therapeutic index, topical administratiopn

Drug Azathioprine

Class Immunosuppressive

Pharmacodynamics (MOA) Pro-drug activated by gut flora to 6-mercaptopurine – this interferes with purine biosynthesis and hence dna synthesis/replication. Effects include:• Impaired acquired immune response, lymphocyte

proliferation, mononuclear cell infiltration, antibody synthesis

• Enhanced T cell apoptosis Clinical Uses Maintaining remission of UC

Inducing + maintaining remission of CDEnabling reduction of glucocorticoid dose

Pharmacokinetics Metabolised by xanthine oxidase

Side Effects Bone marrow suppression

Contraindications Co-administration with drugs that inhibit xanthine oxidase, eg allopurinol, as lead to build up of 6-mercaptopurine > blood disorders

6. Antimicrobials

Antimicrobials

• These should be toxic for the pathogenic cell but innocuous for the host. This selective toxicity depends on the existence of exploitable biochemical differences between the pathogen and host cell, which in turn depends on how far apart the cells are in terms of evolutionary development

• These include:– Anti-bacterial agents– Anti-mycobacterial agents– Anti-fungals – Anti-virals

Antibacterials

• These exploit the differences between prokaryotic bacterial cells, and eukaryotic host cells.

• Targets for antibacterial agents include:– Folate – Peptidoglycan – Ribosomes

Drug Co-trimoxazole

Class Combined folate synthesis inhibitor (sulphonamide) + folate antagonist (trimethoprim) = sequential blockade

Pharmacodynamics (MOA) Sulphonamide – structural analogue of P-aminobenzoic acid (required for folate synthesis); competes for dihydropteroate enzyme therefore interfering with DNA/RNA synthesis – BACTERIOSTATICTrimethoprim – folate antagonist that inhibits dihydrofolate enzyme action; interferes with use of folate for DNA/RNA synthesisSulphonamides potentiate the action of trimethoprim

Clinical Uses Pneumonia (AIDs patients) – infection with pneumocystis carinii

Pharmacokinetics Oral administrationHalf excreted within 34 hours

Side Effects Nausea/vomitingSkin rashesHypersensitivity reactions

Drug Penicillin

Class Beta-lactam Antibiotic

Pharmacodynamics (MOA) Beta lactam ring interferes with peptidoglycan synthesis,by inhibiting the transpeptidation enzyme that cross-links the peptide chains with the backbone of the peptidoglycan • preventing formation of bacterial cell wall > bacterial burst

= BACTERIOCIDAL Pharmacokinetics Oral administration – depends on acidity of stomach (empty

stomach)Widely bio-distributed; crosses placenta but lipid insoluble therefore doesn’t cross BBBMainly renal excretion

Side Effects Relatively free from toxic effects, but hypersensitivity reactions are common:• Skin rashes, fever• AnaphylaxisGI tract disturbances also common

Other relevant information Resistance mechanisms:• Production of B-lactamases• Reduction in permeability of outer bacterium membrane • Occurrence of modified penicillin-binding sites

Drug Cefotaxime

Class Beta-lactam antibiotic (part of cephalosporin family)

Pharmacodynamics (MOA) Interfere with peptidoglycan synthesis = BACTERIOCIDAL

Clinical Uses Crosses BBB therefore first line treatment for bacterial meningitis

Pharmacokinetics IV/IM administrationRenal excretion

Side Effects HypersensitivityNephrotoxicityDiarrhoea

Contraindications 10% of people with penicillin hypersensitivity will be cefotaxime sensitive

Other relevant information Resistance (wide-spread)• Gene encoding beta lactamase – more active in

hydrolysing cephalosporins than penicillins • Decreased penetration of drug due to mutations in outer

membrane proteins or binding site proteins

Drug Tetracycline

Class Antibiotic (inhibitor of ribosome function)

Pharmacodynamics (MOA) Binds to + actively transported into bacteria to interrupt protein synthesis via competitive binding for A binding site on 502 subunit = BACTERIOSTATIC

Clinical Uses Wide spread of bacterial infections (both gram +ve and –ve)

Pharmacokinetics Absorption is irregular + incomplete – chelation of iron + calciumWide bio-distributionExcretion by bile and glomerular filtration

Side Effects GIT disturbancesChelated calcium deposits in growing bone > deformity

Contraindications Children, pregnant women, nursing mothers

Other relevant information Resistance mechanisms:• Development of energy dependent efflux mechanisms• Mutations of ribosome structure to prevent binding

Drug Chloramphenicol

Class Antibiotic (inhibitor of ribosome function)

Pharmacodynamics (MOA) Binds to 50s subunit of ribosome, inhibiting transpeptidation and therefore protein synthesis = BACTERIOSTATIC

Clinical Uses Wide spread (gram +ve and –ve infections)

Pharmacokinetics Oral or parenteral administrationComplete absorptionHalf life 2 hours Distribution includes CSFExcretiion: 10% unchanges in urine, 90% metabolised in liver and then excreted via kidneys + bile

Side Effects Pancytopenia (decrease in all blood cells due to bone marrow suppression)Grey baby syndrome – vomiting, diarrhoea. Flaccidity, low temp, ash grey colour in newborns GI disturbances

Other relevant information Resistance mechanism: R plasmid mediated transfer of chloramphenicol acetyl-transferase. Solution: replacing terminal OH on side-chain by fluorine reduces susceptibility to acetylation

Drug Gentamicin

Class Antibiotic (aminoglycoside)

Pharmacodynamics (MOA) Binds to 30s subunit of bacteria > anticodon-codon misread > translation of defective protein = BACTERIOCIDAL Second mechanism unknown

Clinical Uses Aerobic gram –ve infectionInfection causes by streptococcus, listeria, pseudomonas aeruginosa (in conjunction with penicillin)

Pharmacokinetics Highly polar – not absorbed in GIT therefore IV/IM adminstrationNot widely distributedHalf life 2-3 hours Elimination entirely by kidney

Side Effects Ootoxicity (damage to sensory cells in cochlea and vestibular organ)Nephrotoxicity

Contraindications Renal impairementChloramphenicol (blocks oxygen-dependent active transport of gentamicin into bacterial cell)

Other relevant information Resistance mechanisms:Inactivation by microbial enzymesFailure of penetration – overcome with penicillinMutations – alter 30s binding site

Anti-mycobacterial agents

• Used to treat infections caused by mycobacterium tuberculosis and leprae– Main problem with infection is that micro-organisms can

survive inside macrophages unless they are activated by T-cell lymphokines > latent infection

• 6 month drug combination therapy is used to manage high incidence of drug resistance (6 month treatment minimum – poor compliance)– 1st phase = 2 months (isoniazid, rifampicin + pyrazinamide)– 2nd phase = 4 months (isoniazid + rifampicin)

Drug Isoniazid

Class Anti-mycobacterial

Pharmacodynamics (MOA) Bacteriostatic on resting mycobacteria Bacteriocidal on dividing mycobacteria (extracellular and intracellular)MOA not fully understood – inhibition of cell wall synthesis?

Clinical Uses TB + leprosy

Pharmacokinetics Oral administrationReadily absorbed from GIT Widely distributed (CSF)Metabolism = acetylation.

Other relevant information Therapeutic response dependent on whether patient is fast or slow acetylator (slow = better because slower metabolism)

Drug Rifampicin

Class Anti-mycobacterial agent

Pharmacodynamics (MOA) Inhibits prokaryotic DNA-dependent RNA-polymerase = BACTERIOCIDAL Effective for both extracellular and intracellular organisms

Clinical Uses TB + leprosy

Pharmacokinetics Oral administrationWidely distributedExcreted in bile + urine – undergoes enteroheptic recycling Progressive metabolism: deacetylation – metabolite less well absorbed

Side Effects Infrequent – skin rashes, fever, GIT disturbances

Drug Pyrazinamide

Class Anti-mycobacterial

Pharmacodynamics (MOA) tuberculoSTATIC at acidic pH, like that of the macrophage environment. Therefore effective against the intracellular organism in macrophage

Clinical Uses TB

Pharmacokinetics Oral administrationGood absorptionWidely distributed (inc meninges)Excretion via glomerular filtration

Side Effects Arthralgia, GIT disturbance, malaise + fever

Anti-fungals

• Fungal infections are termed mycoses; these may be systemic (rare) or superficial (more common)

• Superficial mycoses may be dermatomycoses (commonly tinea infections) or candidiasis (yeast infections of mucous membranes)

Drug Nystatin

Class Anti-fungal

Pharmacodynamics (MOA) Polyene macrolide that binds to ergosterol (within cell membrane), forming a transmembrane ion channel that disrupts permeability and transport function

Clinical Uses Fungal infections of skin + GI tract

Pharmacokinetics No absorption through mucous membranes

Side Effects Rare; nausea and vomitingVery rare; rash

Drug Miconazole

Class Anti-fungal

Pharmacodynamics (MOA) Azole group of synthetic anti-mycotic agent that blocks the synthesis of ergosterol, altering the fluidity of fungal membrane and interfering with the action of membrane-associated enzymes – results in inhibition of replication

Clinical Uses Wide spectrum of systemic and superficial infection

Pharmacokinetics IV administration for systemicOral administration for superficial Short plasma half life

Side Effects Infrequent; GIT disturbanceRare; blood dyscrasias

Anti-Virals

• Viruses: small intracellular parasites consisting of nucleic acids (RNA or DNA) enclosed by a protein coat/capsid

• Obligate intracellular parasites therefore use host cell machinery for replication; poses challenge for selective drugs– Virus-specific enzymes potential targets

• Difficulty is that clinically detectable infection is usually far advanced so treatment difficult

Drug Acyclovir

Class Anti-viral

Pharmacodynamics (MOA) Guanosine derivative that is converted to monophosphate form by thimidine kinase (viral thymidine kinase much more effective at doing this). Host cell kinases then convert monophosphate form to triphosphate form, and this then inhibits DNA viral-polymerase, terminating chain reaction and thus inhibiting nucleic acid synthesis

Clinical Uses HSV infection

Pharmacokinetics Oral (20% absorbed) or IVWidely distributed; crosses BBBRapidly broken down within host cells by cellular phosphatases (need frequent application)Excreted by kidneys

Side Effects Rare with oral administration, more common in intravenous administration:Local inflammation, renal dysfunction, nausea, headache

Other relevant information Resistance occurs due to changes in viral genes coding for thymidine kinase or DNA polymerase

Drug Zidovudine (AZT)

Class Anti-RETROviral

Pharmacodynamics (MOA) Analogue of thymidine (activated by cellular enzymes to triphosphate form) acts as competitive inhibitor of reverse transcriptase; incorporation into growing viral DNA strand results in chain termination preventing DNA synthesis

Clinical Uses AIDS – reduces opportunistic infections, thrombocytopenia, dementia + viral loadHIV+ve – prolongs life expectancyHIV+ve mothers – reduces chance of transmission to fetus

Pharmacokinetics Oral administrationUndergoes extensive first pass metabolismWidely distributed – enters cells by passive diffusionMetabolised by liver to inactive glucuronide 20% active form excreted in urine

Side Effects Common = anaemia, neutropeniaRare = GIT disturbance, skin rash, insomnia, fever, headache

Other relevant information Therapeutic response wanes with long term use – development of resistance: • Mutations in viral reverse transcriptase accumulate progressively• Decreased activation to triphosphate form

7. Cytotoxics

Cytotoxics

• Definition: “drugs that modify the growth of cells and tissues”

• Challenges with cytotoxics: It is difficult to find exploitable differences, they need to produce a near total cell kill, have no effect on resting cells (which means relapse likely)

• Cytotoxics tend to be antiproliferative, with no effect on tendency to metastasize or invade – effect on rapidly dividing normal tissues therefore result in multiple adverse effects

Drug Cyclophosphamide

Class Alkylating agent (interferes with DNA transcription/replication)

Pharmacodynamics (MOA) Ethylene immonium derivative – substrate for cytochrome P450, when oxidised becomes extremely reactive and carbonium ion binds irreversibly with cell macromolecules including RNA, proteins and DNA, causing intra/inter chain cross-linking• This interferes with transcription and replication• Most common targets N7 guanine, N1/N3 adenosine

Clinical Uses Cancer treatment Immunosuppession following allogenic tissue transplantation (at low dose)

Pharmacokinetics Rapidly metabolised, but metabolites also have cytotoxic action

Side Effects Myelotoxicity - damage bone marrow lead to reduced lekukocyte production. Impaired wound healing. Depression of growth. Sterility (because gonadal tissues are highly active). Teratogenicity - cross placenta. Loss of hair. Nausea and vomitting. GI tract epithelia, hair and nails

Drug Methotrexate

Class Antimetabolite (interferes with DNA base synthesis)

Pharmacodynamics (MOA) Interferes with thymidylate synthesis (folate synthesis), thus preventing purine (adenine + guanine) synthesis > interfering with DNA synthesis

Clinical Uses Cancer treatment Immunosuppression following allogenic tissue transplant (at low doses)


Drug Doxorubicin

Class Cytotoxic antibody (inhibits DNA/RNA chain synthesis)

Pharmacodynamics (MOA) Antibody complexes with DNA, preventing the topoisomerase from “zipping up” DNA therefore inhibiting DNA and RNA synthesis

Clinical Uses Cancer treatment


Drug Bleomycins

Class Cytotoxic antibody

Pharmacodynamics (MOA) Metal-chelating glycopeptide antibody that degrades DNA


Pharmacokinetics Administered intravenously


Other relevant information Active against non-dividing cells, therefore very toxic and high chance of pulmonary toxicity

Drug Etoposide

Class Plant alkaloid

Pharmacodynamics (MOA) Inhibition of topoisomerase II inhibits DNA synthesis > cell cycle block at G2 phase



Drug Vincristine

Class Plant alkaloid (spindle cell poison)

Pharmacodynamics (MOA) Binds to tubulin, inhibiting its polymerisation to form microtubules necessary for spindle formation. This therefore prevents cell division and thus successful replication



Drug Cisplatin

Class Miscellaneous cytotoxic

Pharmacodynamics (MOA) Interacts directly with DNA causing guanine intrastrand cross-linking > interference with transcription and replication



Drug Procarbazine

Class Miscellaneous cytotoxic

Pharmacodynamics (MOA) Alkylates DNA, interfering with DNA/RNA synthesis and mitosis at interphase



Other relevant information Activated by cytochrome P450 and MAO

8. Drugs of Abuse

Drugs of Abuse• MOA: artificially hijack the natural reward pathway; DA release

from ventral tegmental area into the nucleus accumbens > euphoria

• Classification of drugs:– Narcotics (painkillers) are opiate like drugs, eg heroin and morphine

• Opitaes bind to u opiate receptors on the GABAergic neuron cell body to suppress them, therefore suppressing GABA release > more dopamine release

– Depressants are ‘downers’, which slow down the CNS. These include alcohol, benzodiazepines (valium), and barbiturates

– Stimulants are ‘uppers’, and are probably the largest class of addictive drugs, which tend to speed everything up in the CNS, eg cocaine + nicotine

– Miscellaneous drugs have several effects and properties (e.g. stimulant as well as hallucinogenic), and these drugs include cannabis and ecstasy (MDMA).

Drug Cannabis

Class Miscellaneous drug of abuse

Origin Genus of flowering plant. > 60 Cannabinoids (active component) found in all parts of the plant, eg tetrahydrocannabinol (THC – most potent). • Marijuana = crushes dried leaves• Resin/Hashish = cannabinoid secreted from glandular trichomes• Hash oil = solvent extracted hashish (concentrated)

Pharmacodynamics (MOA)

Analogue of endogenous cannabinoid (eg anadamide – generated from arachidonic acid), which binds to endogenous CB1 receptors in brain and CB2 receptors on WBC. Binding > down-regulation of adenylyl cyclase > inhibition of GABA secretion > increased DA secretion

Clinical Uses In disease: upregulating CB receptors used to mitigate disease eg MS, as well as having an effect on fertility, obesity In pharmacology: targeting the cannabinoid system can be used to increase appetite in AIDs patients, decrease appetite in obese patients and treat neuropathic pain in MS

Pharmacokinetics Administration:• Smoking > 50% absorption but rapid onset of action• Eating > 10% absorption (first pass metabolism), delayed onset of action but prolonged effect Duration of action is dependent on adipose tissue. Cannabis is very lipid soluble, therefore sits in fat cells for long periods of time before returning to the circulation (unusual)Hepatic metabolism 25% excreted unmetabolised, 65% undergoes enterohepatic recycling. Metabolism forms 11-hydroxyTHC = active metabolite > increased intoxication

Side Effects Psychosis + schizophrenia (anterior cingulate cortex), munchies (hypothalamus), amnesia (limbic regions), effect on psychomotor performance (cerebral cortex), immunosuppressant (B2 receptors on WBC), reddening conjunctivae (vasodilation)

Drug Cocaine

Class Stimulant drug of abuse

Origin Erythroxylum coca plant. Can extract up to 0.9% of drug from plant; different forms:• Paste • Cocaine HCl (paste dissolved in acid)• Crack cocaine (Cocaine HCl precipitated in alkaline solution)• Freebase cocaine (crack dissolved in ammonia)


Binds to da transporter present on terminals of DA neurons and prevents reuptake, therefore prolonging DA effect > euphoria

Pharmacokinetics Administration• Paste + cocaine HCl – IV, oral , intranasal • Crack + freebase – inhalationOnset of action: within seconds following smoking/injectionMetabolised by liver + plasma cholinesterases Half life < 20 mins

Side Effects Local anaesthesia – blocks Na+ channels, inhibits monoamine transporters (a2 adrenoceptors)Irratibility, anxiety, hostility – CNS stimulation


Risk of sudden death: increased endothelin 1 (vasoconstriction), decreased NO production (increased platelet activation), increased SNS activation

Drug Nicotine

Class Plant-derived alkaloid


Acts on nicotinic acetylcholine receptors (especially alpha 4 and beta 2 subunits) on the cell bodies of dopaminergic neurones > DA release into nucleus accumbens > euphoria

Clinical Uses Suggestive protection against Parkinson’s and Alzheimer’s

Pharmacokinetics Administration• Intranasal spray – 20-50% absorbed• Gum – 50-70% absorbed (slow onset)• Cigarettes – 20% absorbed (rapid onset)• Transdermal patch – 70% absorbed Spray, gum + patch aim to remove spike which encourages addiction Pka of 7.9. smoke is relatively acidic therefore is ionised; spray, gum and patch aim to buffer to maximise absorptionHalf life – hours Hepatic metabolism by cytochrome P2A6 and cotidineRenal excretion

Side Effects CVS effects (due to Ach agonistic action)• Increased HR, SV, coronary vasoconstriction, skeletal vasodilation, increased

platelet activity (increased ThA2 + decreased NO)Metabolic effects: increase BMR, appetite suppressant

Drug Alcohol

See lecture 15 (too much detail for slide)

Disulfram Alcohol dehydrogenase inhibitor = Ethanol aversion drug; leads to build up of toxic metabolite acetylaldehyde which leads to horrible feeling when drinking

9. Opiates + Opioids

Pain Pathway • Ascending pathways - perception of pain • Descending inhibitory pathways – pain tolerance

– PAG = peri-aqeductal grey area (midbrain)– NRM = nucleus raphe magnus (medulla)– NRPG = nucleus reticularis paragigantocellularis– LC = locus coeruleus (brainstem)

Drug Morphine

Class Opiate

Structure Natural opiate; alkaloid derivative of papaver somniferum poppy (tertiary amine with hydoxyl groups at positions 3 and 6)


Act via endogenous opioid receptors (endogenous opioid peptides inc endorphins, enkephalins and neoendorphins). Binding to u, d or k G-protein linked receptors > decreased adenylate cyclase > decreased cAMP > increased capacity for K+ efflux + decreased Ca2+ influx > decreased action potential generation = DEPRESSANT • Analgesia: huge concentration of receptors in SC – depress afferent pathways > reduced perception + activate

descending inhibitory pathway > increased tolerance • Euphoria: Suppress GABA release from mesolimbic dopamine neurones into nucleus accumbens > increased DA • Antitussive: inhibit seratonin receptor activation in cough centre + suppress release of Ach and neurokinins in

airways

Clinical Uses AnalgesicAntitussive (usually codeine)

Pharmacokinetics

Oral administration (40-50% bioavailability) or IV administrationMetabolised in liver > morphine-6-glucuronide. Then either excreted by kidney or active metabolite secreted in bile to undergo enterohepatic recyclingComplex pharmacokinetics as largely ionized at physiological pH

Side Effects SHORT TERM: • Respiratory depression: desensitizes chemoreceptors > loss of response to arterial CO2 + medullary action to control

resp (main COD in overdose)• Nausea/vomiting: depresses natural inhibition of chemoreceptor trigger zone > activation of vomiting centre • Miosis: stimulation of occulomotor nerve > ciliary ganglion > iris > constriction (unconscious + pinprick pupils =

heroin overdose)• Constipation: depress gastric emptying and GI motility > increased water absorption• Allergy: G-protein mediated activation of mast cells > histamine release > pruritus (itching), urticaria, hypotension LONG TERM: • Tolerance: increased arrestin production > receptor internalisation > decreased response• dependence: withdrawal > upregulation of adenylate cyclase system > craving, tremor, diarhoea


Treatment for overdose is opioid receptor antagonist NALOXONE (iv administration)

Drug Codeine

Class Opiate

Structure Natural opiate (methyl-morphine) – tertiary amine with methyl group at position 3



descending inhibitory pathway > increased tolerance • Euphoria: Suppress GABA release from mesolimbic dopamine neurones into nucleus accumbens > increased DA • Antitussive: inhibit seratonin receptor activation in cough centre + suppress release of Ach and neurokinins in airways

Clinical Uses AnalgesicAntitussive

Pharmacokinetics Oral administration (5-10% bioavailability)

Side Effects SHORT TERM: • Respiratory depression: desensitizes chemoreceptors > loss of response to arterial CO2 + medullary action to control

resp (main COD in overdose)• Nausea/vomiting: depresses natural inhibition of chemoreceptor trigger zone > activation of vomiting centre • Miosis: stimulation of occulomotor nerve > ciliary ganglion > iris > constriction (unconscious + pinprick pupils = heroin

overdose)• Constipation: depress gastric emptying and GI motility > increased water absorption• Allergy: G-protein mediated activation of mast cells > histamine release > pruritus (itching), urticaria, hypotension LONG TERM: • Tolerance: increased arrestin production > receptor internalisation > decreased response• dependence: withdrawal > upregulation of adenylate cyclase system > craving, tremor, diarhoea



Drug Heroin

Class Opiate

Structure Di-acetyl-morphine – acetylated > acetyl groups at position 3 and 6 > increased potency


Act via endogenous opioid receptors (endogenous opioid peptides inc endorphins, enkephalins and neoendorphins). Binding to u, d or k G-protein linked receptors > decreased adenylate cyclase > decreased cAMP > increased capacity for K+ efflux + decreased Ca2+ influx > decreased action potential generation = DEPRESSANT • Analgesia: huge concentration of receptors in SC – depress afferent pathways > reduced perception + activate descending

inhibitory pathway > increased tolerance • Euphoria: Suppress GABA release from mesolimbic dopamine neurones into nucleus accumbens > increased DA • Antitussive: inhibit seratonin receptor activation in cough centre + suppress release of Ach and neurokinins in airways

Clinical Uses AnalgesicAntitussive (usually codeine)

Pharmacokinetics Intravenous administrationHepatic metabolism (like morphine) + plasma esterases > shorter half life > more addictive

Side Effects SHORT TERM: • Respiratory depression: desensitizes chemoreceptors > loss of response to arterial CO2 + medullary action to control resp

(main COD in overdose)• Nausea/vomiting: depresses natural inhibition of chemoreceptor trigger zone > activation of vomiting centre • Miosis: stimulation of occulomotor nerve > ciliary ganglion > iris > constriction (unconscious + pinprick pupils = heroin

overdose)• Constipation: depress gastric emptying and GI motility > increased water absorption• Allergy: G-protein mediated activation of mast cells > histamine release > pruritus (itching), urticaria, hypotension LONG TERM: • Tolerance: increased arrestin production > receptor internalisation > decreased response• dependence: withdrawal > upregulation of adenylate cyclase system > craving, tremor, diarhoea



Drug Methadone

Class Opiate



descending inhibitory pathway > increased tolerance • Euphoria: Suppress GABA release from mesolimbic dopamine neurones into nucleus accumbens > increased DA • Antitussive: inhibit seratonin receptor activation in cough centre + suppress release of Ach and neurokinins in

airways

Clinical Uses Morphine/heroin replacement to wean off addicts AnalgesicAntitussive (usually codeine)

Pharmacokinetics Lipid-soluble + efficient distributionLong half-life, therefore low dose for long time

Side Effects SHORT TERM: • Respiratory depression: desensitizes chemoreceptors > loss of response to arterial CO2 + medullary action to

control resp (main COD in overdose)• Nausea/vomiting: depresses natural inhibition of chemoreceptor trigger zone > activation of vomiting centre • Miosis: stimulation of occulomotor nerve > ciliary ganglion > iris > constriction (unconscious + pinprick pupils =

heroin overdose)• Constipation: depress gastric emptying and GI motility > increased water absorption• Allergy: G-protein mediated activation of mast cells > histamine release > pruritus (itching), urticaria, hypotension LONG TERM: • Tolerance: increased arrestin production > receptor internalisation > decreased response• dependence: withdrawal > upregulation of adenylate cyclase system > craving, tremor, diarhoea



10. Drugs and the CNS

Anxiolytics, Sedatives + Hypnotics

• These drugs all affect GABA transmission (principal inhibitory NT of the CNS), and tend to act on the GABA-A receptor complex

• GABA-A complex consists of Cl-, GABA, BDZ + BARB receptor proteins

• GABA binds to receptor, activating GABA modulin (link between GABA + BDZ protein) > opening of Cl- channel

• Anxiolytics remove anxiety WITHOUT impairing mental or physical activity

• Sedatives reduce mental and physical activity WITHOUT producing loss of consciousness

• Hypnotics induce sleep

Drug Amobarbitol

Class Barbituate

Structure Classic 6-membered ring with number of additional groups


BARBs bind to their own receptor; enhance GABA action + binding (not reciprocated by GABA) + direct effect on Cl- channel > increased DURATION of Cl- ion channel opening BARBs also appear to act as non-selective glutamate antagonists > decreased excitatory transmission (use for induction of anaesthesia)

Clinical Uses Sedative, hypnotic

Side Effects Depress respiration, “hangovers” (alter natural sleep + REM), tolerance (severe; pharmacokinetic + tissue tolerance), dependence/withdrawal (insomnia, anxiety, tremors)

Contraindications Interact with co-administered drugs, as are enzyme inducers Potentiate other CNS depressants eg alcohol

Drug Diazepam

Class Benzodiazepine

Structure 3 ring structure; lots of variations > large changes in pharmacokinetic activity


BDZ bind to their own receptor; enhance GABA action + GABA binding (reciprocrated by GABA) > increased FREQUENCY of Cl- ion channel opening

Clinical Uses Anxiolytic

Pharmacokinetics Oral administration Peak plasma within hourBind pp and highly lipid soluble – well distributedHepatic metabolism (glucuronidation)Renal excretion Duration of action = long acting (t ½ = 32 hours); metabolism via active metabolites

Side Effects Sedation, confusion, ataxiaTolerance (< than BARBs; only tissue)Dependence + withdrawalIncrease in free plasma concentrations of other drugs eg aspirin

Contraindications Potentiates other CNS depressants eg alcohol


Advantages over BARBs:• Wide margin of safety – overdose > prolonged rousable sleep treated with FLUMEZENIL• Only mild effect on Rem > less hangover• Not enzyme inducers – no interaction with other drugs

Drug Oxazepam





Clinical Uses SedativeHypnotic Anxiolytic (in hepatic impairment as alternative to diazepam)

Pharmacokinetics Oral administration (IV for status epilepticus)Peak plasma within hourBind pp and highly lipid soluble – well distributedHepatic metabolism (glucuronidation)Renal excretion Duration of action = short acting (t ½ = 8 hrs)





Drug Temazepam





Clinical Uses SedativeHypnotic

Pharmacokinetics Oral administration (IV for status epilepticus)Peak plasma within hourBind pp and highly lipid soluble – well distributedHepatic metabolism (glucuronidation)Renal excretion Duration of action = short acting (t ½ = 8 hrs)





Drug Chloral Hydrate

Pharmacodynamics (MOA) not known

Clinical Uses Sedative/hypnotic in children/elderly (wide margin of safety)

Pharmacokinetics Metabolised in liver to trichloroethanol = active component

Drug Busipirone

Class 5HT-1A agonist

Pharmacodynamics (MOA) Interacts with seratonin transmission (not fully understood)

Clinical Uses Anxiolytic

Pharmacokinetics Slow onset of action

Side Effects Few

Anti-convulsants • Epilepsy: the tendency to recurrent, unprovoked

seizures– Cause: symptomatic (structural/metabolic brain injury –

either acquired or inherited) or idiopathic (either mendelian or polygenic)

– Classification: focal or generalised (tonic-clonic or absence)

• AED act by 3 mechanisms:– Enhancing GABA mediated transmission– Inhibiting fast excitatory NT transmission – glutamate– Inhibiting neuronal AP generation – blocking NA voltage

channels

Drug Phenytoin

Class Anti-convulsant


Blockade of voltage-dated Na+ channels > reduced AP generation

Clinical Uses Partial epilepsyStatus epilepticus (prolonged seizure)

Pharmacokinetics Hepatic metabolism: oxidation, hydroxylation then conjugation (large variation)Renal excretionSaturable kinetics; dosing very important Elimination t ½ 20 hours – monitoring requires at least 5 half lives Highly pp bound

Side Effects Allergy: rash, vasculitis, fever, hepatitisToxic: ataxia, sedationChronic: folate deficiency, Vit K deficiency, peripheral neuropathy, myopathy


P450 enzyme inducer, therefore large number of drug interactions• Amiodarone + isoniazid – inhibit metabolism• Aspirin – disaplaces from PP • Valproate – displaces + inhibits • Cyp450 > reduced warfarin, estrogen containing OCP

Drug Carbazepine



Blockade of Na+ voltage-gated channels

Clinical Uses Partial seizuresSecondary generalized seizures

Pharmacokinetics Half-life 5-26 hours Hepatic metabolism: oxidation then conjugation. Active metabolite = carbazepine epoxide

Side Effects Hypersensitivity: rash, hepatitis, nephritisDose-related: ataxia, dizziness, sedationChronic: Vit K deficiency, depression


Potent hepatic enzyme inducer Complex drug interaction profile Drug monitoring useful

Drug Sodium valproate



Mechanism not known, but enhances GABA via number of mechanisms

Clinical Uses Partial seizuresGeneralised seizures

Pharmacokinetics Half life 4-12 hours Metabolism by hepatic oxidation and conjugation – no active metabolites Renal excretion

Side Effects Severe adverse drug reactions: Severe hepatic toxicity, pancreatitis, encephalopathy, tremor, blood dyscrasias

Contraindications Co-administration with penytoin, phenobarbitol + carbazemazepine


Potent inhibitor of hepatic enzymes > important drug reactions

Drug Vigabatrin


Pharmacodynamics (MOA) Irreversible inhibition of GABA transferase (involved in metabolism of GABA to SCA)

Clinical Uses Partial epilepsy

Pharmacokinetics Half life 7 hours

Side Effects Visual field constriction

Other relevant information May worsen some generalized seizures

Drug Lamotrigine

Class Anticonvulsant

Pharmacodynamics (MOA) Unknown

Clinical Uses Partial epilepsyGeneralised epilepsy

Pharmacokinetics Half life 8 hours

Side Effects Well tolerated

Anti-Parkinsonians + Neuroleptics • Parkinson’s affects the Nigrostriatal dopaminergic pathway

(projected from substantia nigra to striatum) – involved in control of movement – Neuropathology: nigrostriatal pathway degeneration,

accumulation of Lewy-Bodies (containing toxic proteins), cell loss > 85% dopaminergic neuron loss + 70% striatal DA depletion

• Schizophrenia affects the Mesolimbic dopaminergic pathway (projected from ventral tegmental area to nucleus accumbens etc) – involved in emotion – Neuropathology: excessive dopamine transmission through

mesolimbic region (DA action on D2 receptors) > positive symptoms (delusions, hallucinations, etc), and dopamine deficit in pre-frontal regions (D1 mediated) > negative symptoms (withdrawal, flattening of emotional responses)

Drug L-DOPA

Class Anti-parkinsonian

Pharmacodynamics (MOA) Dopamine replacement therapy. DOPA doesn’t cross BBB, but L-DOPA can cross BBB and be centrally converted to DOPA. This occurs if peripheral conversion of L-DOPA to DOPA does not occur (involving DOPA-decarboxylase)

Clinical Uses Hypokinesea, rigidity + tremor associated with Parkinson’s

Pharmacokinetics Start with low dose; response decreases with disease progression

Side Effects Acute:• Nausea (prevents by Domperidone)• Hypotension• Psychological (schizophrenia-like effects)Chronic:• Diskinesias• Rapid fluctuations in clinical state

Drug Domperidone

Class Anti-parkinsonian drug

Pharmacodynamics (MOA) DOPA-decarboxylase antagonist– inhibits peripheral conversion of L-DOPA > DOPA, therefore increasing quantity of L-DOPA crossing BBB

Clinical Uses Administered with L-DOPA; allowing lower dose of L-DOPA to be used, and boosting its effect

Side Effects Chronic:• Diskinesias• Rapid fluctuations in clinical state

Drug Carbidopa


Pharmacodynamics (MOA) Inhibits DOPA-decarboxylase action in periphery, so more L-DOPA reaches the CNS

Clinical Uses Treatment of bradykinesias, tremors and rigidity associated with Parkinsons

Pharmacokinetics Administered in conjunction with L-DOPA

Side Effects Chronic:• Diskinesias• Rapid fluctuations in clinical state

Drug Bromocriptine

Class Anti-parksinonian drug

Pharmacodynamics (MOA) DA (esp D2) receptor agonist

Clinical Uses Used in conjunction with L-DOPA (to treat bradykinesias etc) when L-DOPA becoming less effective

Pharmacokinetics Oral administrationCrosses BBBLonger duration of action than L-DOPA, therefore less diskinesias

Side Effects Common – confusion, dizziness, nausea/vomiting, hallucinationsRare – constipation, headache, dyskinesias

Contraindications Ergot ring structure can cause problems with heart valves

Drug Deprenyl


Pharmacodynamics (MOA) Selective MAO-B inhibitor; prevents central breakdown of DA, therefore prolonging action

Clinical Uses Preservation of naturally synthesised DA in early Parkinson’s Administration in conjunction with L-DOPA to reduce dose

Pharmacokinetics

Side Effects Rare – hypotension, nausea/vomiting, confusion, agitation

Drug Entacapone


Pharmacodynamics (MOA) COMT inhibitor; prevents peripheral conversion of L-DOPA to 3-0methylDOPA, thus increasing the bioavailability of L-DOPA

Clinical Uses To reduce L-DOPA dosageTo boost response to L-DOPA in patients starting to show tolerance

Side Effects Marked side effect profile – CVS effects

Drug Chlorpromazine

Class Neuroleptic


Dopamine receptor antagonists (particular D2 + D4) > reduce dopamine transmission through mesolimbic region > reduction in positive symptoms

Clinical Uses Treatment of schizophrenia

Pharmacokinetics Initially compensatory mechanisms to increase DA synthesis, but these decline with therefore slow onset of action

Side Effects Effects due to non-selectivity of antagonists:Blocking receptors in chemotactic trigger zone > anti-emeticBlocking of DA in tuberoinfundular pathway (endocrine) > excess prolactin > lactationBlockade of AChM receptors > blurring of vision, increased intra-ocular pressure, dry mouth, constipation (typical anti-muscarinic effects)Blockade of DA receptors in nigrostriatal pathway > Parkinsonian-like symptoms eg acute dyskinesias (at onset of treatment), or tardive dyskinesias (after prolonged therapy)

Drug Haloperidol

Class Neuroleptic






Drug Sulpride

Class Neuroleptic






Drug Clozapine

Class Neuroleptic






11. Anaesthetics

General Anaesthetics • Common property: inducing loss of consciousness at low

concentrations• Desirable effects:

– loss of consciousness (propofol) – depression of thalamocortical neurons + RAS

– analgesia (opiates)– suppression of reflex responses (enflurane) – depression of

reflex pathways in spinal cord – muscle relaxation (NM blockers)– amnesia (benzodiazepines) – decreased synaptic transmission in

hippocampus + amygdala • May be gaseous or intravenous • The more lipid-soluble, the more rapid the onset of action.

For inhaled GAs, a lower blood-gas partition co-efficient means more lipid-soluble and remains gaseous for longer.

Drug Propofoll

Class General anaesthetic

Pharmacodynamics (MOA) Binds to GABA-a receptor to facilitate opening + GABA-mediated inhibition• B3 subunit = anaesthetic effect• A5 subunit = amnesia effect

Clinical Uses Inducing loss of consciousness

Pharmacokinetics Intravenous administrationFast recovery

Drug Etomidate


Pharmacodynamics (MOA) Binds to GABA-a receptor to facilitate opening + GABA-mediated inhibition• B3 subunit = anaesthetic effect• A5 subunit = amnesia effect

Pharmacokinetics Intravenous administrationFast recovery

Drug Nitrous oxide


Pharmacodynamics (MOA) Blocks excitatory NMDA-type glutamate receptors Neuronal nicotinic Ach receptor antagonists TREK (background leak) K+ channel agonists > increase hyperpolarisation

Pharmacokinetics Gas administration Fast recovery

Drug Halothane


Pharmacodynamics (MOA) Potentiate GABA-A receptor function (no subunit specificity)Blocks excitatory NMDA-type glutamate receptors Neuronal nicotinic Ach receptor antagonists TREK (background leak) K+ channel agonists > increase hyperpolarisation

Pharmacokinetics Gas administration Medium recovery )higher blood-gas partition coefficient)

Side effects Rare liver toxicity

Drug Enflurane


Pharmacodynamics (MOA) Potentiate GABA-A receptor function (no sub-unit specificity)Blocks excitatory NMDA-type glutamate receptors Neuronal nicotinic Ach receptor antagonists TREK (background leak) K+ channel agonists > increase hyperpolarisation

Clinical Uses Suppression of reflex responses and maintenance of anaesthesia

Pharmacokinetics Gas administrationMedium recovery (higher blood-gas partition coefficient)

Local Anaesthetics

• Definition: drugs which reversible block neuronal conduction when applied locally

• Structural group areas: aromatic benzene-like ring, basic amine side chain (usually tertiary amine) + bridging group (ester linkage eg cocaine, amide linkage eg lidocaine)

• Different routes of administration:– Surface – Infiltration (subcutaneous)– Intravenous regional– Nerve block– Spinal– Epidural

Drug Cocaine

Class Local anaesthetic (ester)

Pharmacodynamics (MOA) Unionised basic structure diffuses inside sensory axon and then is ionized (to reach equilibrium). Ionized cation binds to voltage-sensitive Na+ channels, preventing rapid depolarisation by blocking the flow of ions = HYDROPHILIC PATHWAY

Pharmacokinetics Surface administrationGood mucuous membrane absorptionPka 8-990% plasma protein bound Metabolized in liver + plasma (non-specific esterases)T ½ 1 hour

Side Effects CNS stimulation: restlessness, confusion, tremor (paradoxical)CVS: myocardial depression, vasodilation, hypotension

Drug Lidocaine

Class Local anaesthetic (amide)

Pharmacodynamics (MOA) Unionised basic structure diffuses inside sensory axon and then is ionized (to reach equilibrium). Ionized cation binds to voltage-sensitive Na+ channels, preventing rapid depolarisation by blocking the flow of ions = HYDROPHILIC PATHWAY

Pharmacokinetics Various routes of administrationHydrolysed in liver, then undergoes n-dealkylation70% plasma protein bound T ½ 2 hours

Side Effects CNS: euphoria and excitationCVS: increased cardiac output, vasoconstriction, hypertension

year 2 pharmacology & therapeutics essential drug list alexandra burke-smith

Documents

degradation slide

action of acetylcholine

agonistic action

respiratory distress

parasympathetic ns

slow hydrolysis slide

autonomic nervous system

duration of action weeks