Standard Drug List 2 by ICSM SU

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

Parasympathetic Nervous System – Cholinomimetics (Cholinoceptor Agonists i.e. Nicotinic & Muscurinic) – DIRECTLY ACTING Binds to nicotinic & muscurinic receptors (parasymp)

Acetylcholine

Choline ester

Bethanechol

M3 AChR selective agonist

Eye: • Contractn of ciliary body = accommodation for near vision • Contractn of Sphincter Pupillae (circular muscle of the iris) = constricts pupil (miosis) & improves drainage of intraocular fliud (glaucoma) • Lacrimatn (tears) CVS: • Bradycardia &↓ CO (↓ed contractn) • Vasodilatn (NO producn on endothelium) Non-vascular Smooth Muscle: • Lung – Bronchoconstrictn • Gut – ↑ed peristalsis (& motility) • Bladder – ↑ed emptying Exocrine Glands: • Salivatn • ↑ed bronchial & GI secretn • SNS – sweating • Bladder emptying • Enhance GI motility

Does not differentiate b/w muscurinic & nicotinic e.g. skeletal muscle contractn & symp activity

• Resistant to degradation • Orally active (with limited access to brain) • Plasma t1/2 ≈ 3-4h

• • • • • • • • • •

Sweating Impaired vision Nausea Bradycardia & Hypotension Respiratory difficulty Sweating Blurred vision GI disturbance & pain Hypotension Respiratory distress

Glaucoma (↑ed intraocular pressure) – by t1/2 ≈ 3-4h • Selective agonist at constritn of pupil muscarinic receptor • Partial agonist for many Pilocarpine muscarinic responses – less effective on GI, smooth muscle & heart Parasympathetic Nervous System – Cholinomimetics (Cholinoceptor Agonists i.e. Nicotinic & Muscurinic) – INDIRECTLY ACTING (Anticholinesterase) Alkaloids (tertiary Reversible Effects on CNS (only non-polar • Glaucoma • Tertiary amine amine) Anticholinesterase: organophosphates i.e. these ones) • Atropine Poisoning (iv – particularly in • Can readily cross bld-brain barrier • Donates carbamyl • Low doses = excitation; convulsion children) • Primarily acts at the postNeostigmine/ group to the enzyme • High doses = unconsciousness, ganglionic parasympathetic Physostigmine • Blocks active site resp depression & death Donepezil synapse • Donepezil – Alzheimer’s disease • Carbamyl removed by • t1/2 ≈ 30min & Autonomic side-effects (see next) slow hydrolysis Alkaloids

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

Organophosphorus compunds

Irreversible Anticholinesterase – rapidly react with enzyme active site  leaving a blocking group

• Glaucoma (with prolonged action) • Insecticides

Stable & resistant to hydrolysis

THIS IS NOT AN INDIRECTLY ACTING CHOLINOMIMETIC

Can split the phosphorus-enzyme bond initially & ‘regenerate’ the enzyme

Treatment of Organophosphate Poisoning: Signs/Symptoms – Salivation, Lacrimation, Urination, Diaphoresis, GI motility, Emesis, Bronchorrhea, Bronchconstriction, Bradycardia (SLUDGE BBB)

• Cannot enter CNS – does NOT affect CNS symptoms of organophosphate poisoning • Highly lipid soluble – readily absorbed through the nasal mucosa, skin, lungs

Ecothiapate

Pralidoxime

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG • Sweating; Blurred vision; GI pain; Bradycardia; Hypotension; Respiratory difficulty Autonomic Effects: • Low Dose = ↑ muscurinic activity • Moderate Dose – further muscurinic activity & enhanced diffusion at all autonomic ganglia • High Dose – (toxic) depolarising block at ganglia

Parasympathetic Nervous System – Cholinoceptor Antagonists – NICOTINIC RECEPTOR ANTAGONISTS Trimetaphan

Hexamethonium Botulinum Toxin (BOTOX)

2 blocking ways: a) Block receptor (ligand cannot bind) – complete block b) Block ion channel once activated (ligand can bind) – incomplete block

Ganglion Blocking Drugs: • Block transmission at all autonomic ganglia – does NOT block at skeletal muscle due to different nicotinic receptors • Affects more symp than parasymp

To cause hypotension during surgery – short-acting

Toxin binds to SNARE complex – prevents exocytosis of ACh

Toxic – complete block of nicotinic receptors at autonomic ganglia

1st hypertensive medication

• CVS effects: Hypotension (dilation of blood vessels); ↓ed renin secretion; ↓ed postural reflex • Smooth Muscle: pupil dilation (impaired light reflex); bronchodilation; impaired bladder dysfunction; ↓ GI tone & motility • Exocrine: sweat, salivary, GI, bronchial & lacrimal glands all have ↓ed secretions

Parasympathetic Nervous System – Cholinoceptor Antagonists – MUSCURINIC RECEPTOR ANTAGONISTS Atropine

Hyoscine

Tropicamide Ipratropium

Block ACh action at muscarinic receptors (i.e. all parasymp & sweat glands)

CNS Effects: • Atropine  mild restlessness to agitation • Hyoscine sedation (both have similar structure, yet have opposite effects) Annaesthetic Premeditation (mimic effects of Hyoscine – sedation): • Salivary glands  copious, watery secretions • Heart = ↑ rate & contractility • Trachea & Bronchioles  dilation (remember opposite to parasymp effects) Neurological: • Motion sickness – Hyoscine patch • Parkinson’s Disease – cholin/dopaminergic balance in basal ganglia Resp – Asthma/COPD (bronchodilation) GI – Irritable Bowel Syndrome – ↓ motility & tone Examination of the retina – binds to circular muscle on the eye & ↑es pupil size Treatment of chronic obstructive lung diseases (e.g. asthma)

• ↓ secretions • ↓ sweating • Cycloplegia (paralysis of the ciliary muscle of the eye  loss of accommodation) • CNS disturbances • (N.B. Atropine Poisoning  hyperactivity then CNS depression, ↑ed body temp., dry mouth, blurred vision, urinary retention)

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

Sympathetic Nervous System – Adrenoceptor Agonists – DIRECTLY ACTING Non-selective α/β

Adrenaline

α1 selective (α1>>α2>>>β1/β2)

Phenylephrine

Related to adrenaline

• Allergic reactions & anaphylactic shock ( sev hypotension & bronchoconstrictn) • COPD & asthma emergencies • Acute management of heart block • Maintains bp during spinal anaesthesia • Prolongs duration of local anaesthesia by local vasoconstrictn • Glaucoma (↓ aq humour production) • Vasoconstrictor – stop superficial bleeding from skin & mucous membranes  hypertension & reflex ↓ in heart rate • Mydriatic (eye drops) • Nasal decongestant (nose drops; oral administration) via vasoconstrictn

• RoA (Route of Admin) – iv • DoA (Duration of Action) – few mins

• CVS effects: Tachycardia; Arrhythmias; Cold extremities; sev Hypertension (overdose)  Cerebral haemorhage & Pul oedema • ↓ed & thickened Mucous secretions (dry mouth) • Tremor (skeletal muscle)

• RoA – iv, oral or nasal drops • More resistant to COMT but not MAO

• ↓es symp tone via: • RoA – iv or oral o α2 adrenoceptor mediated pre-synaptic inhibition of NA release Clonidine o (in brainstem) baroreceptor pathway to ↓ sympathetic outflow • Treats hypertension & migraine Non-selective β • Heart block (cardiogenic shock or MI) • RoA – oral; iv; inhalation (i.e.β2/β1) • Bronchodilator – asthma but discontinued • DoA – t1/2 ≈ 30min Isoprenaline (β1=β2>>>>α1/2) due to unwanted actions (reflex • Less susceptible to Uptake 1 & tachycardia, dysrhthmias) MAO than adrenaline β1 selective • Use to treat cardiogenic shock, acute • RoA –iv (β1>>β2>>>α1/2) heart failure, MI & heart block Dobutamine • DoA – t1/2 ≈ 2min (rapid • Lacks isoprenaline’s reflex tachycardia metabolism by COMT) Β2 selective Synthetic catecholamine • Asthma – relaxatn of bronchial smooth • RoA – Asthma (oral; inhalation); (β2>>β1>>>α1/2) derivative with relative muscle & inhibitn of release of bronchoPremature Labour (i.v.) resistance to MAO & constrictor substance from mast cells Salbutamol COMT • Treatment of threatened uncomplicated premature labour Sympathetic Nervous System – Adrenoceptor Agonists – INDIRECTLY ACTING (act at adrenergic nerve terminal NOT receptor) Local anaesthetic in ophthalmology • Readily crosses bld brain barrier (unlike AD & NA) • Degraded by plasma esterases Cocaine • Plasma t1/2 ≈ 30mins • Excreted in urine Dietary a.a. – cheese, red wine & • Competes with catecholamines for Uptake 1, Tyramine • Displaces NA from intracellular storage vesicles into cytosol; NA & tyramine compete for sites soya sauce on MAO; cytoplasmic NA leaks through neuronal memb to act at postsynaptic adrenoceptors α2 selective (α2>>α1>>>β1/2)

• Reflex tachycardia • Tremor Caution with cardiac patients, hyperthyroidism & diabetes – ↑ed sensitivity to adrenoceptors • Euphoria, ↑ed motor activity (CNS effect); may  depression • Tachycar, vasoconstrictn, ↑ed bp • Tremors & convulsions ( vomit) • Resp Failure Hypertensive crisis (when MAO is inhibited)

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

Sympathetic Nervous System – Adrenoceptor Antagonists Phentolamine

Non-selective α (i.e. α2/α1)

↑ NA release from nerve terminals (α2 actions)

α1 selective

Does NOT ↑ NA release from nerve terminals

Doxazosin/Prazosin Non-selective β (i.e.β2/β1)

Propranolol β1 selective

• Angina – stabe, unsablte or variable • Hypotension & bradycardia (like propranolol

Non-selective α1/β1 (ratio 4:1 for β1: α1 )

• Hypotension by ↓ peripheral resistance • No change in heart rate

Atenolol

Labetolol

• Hypotension (vasodilatn) • Reflex tachycardia [due to fall in arterial pressure (β-receptors)] • Hypotension (vasodilatn), so ↓ CO • ↓ tachycardia (as above) – ↓ NA release • ↓in LDL & an ↑in HDL cholesterol • Class II antiarrhythmics • Glaucoma • ↓ in peripheral resistance  ↓ in bp • Bradycardia  ↓ CO

No longer clinically used

• ↑ed GIT motility • Diarrhoea

Very little change in cardiac bp & HR but very effective as antiarrhythmics

• Bronchoconstriction (asthmatics) • Cardiac Failure – pts with heart disease rely on a degree of symp drive to the heart to maintain CO • Hypoglycaemia – symp response to hypoglycaemia  useful symptoms in warning diabetic pts (sweating, palpitations, tremor) • Fatigue – ↓ed CO & muscle perfusion • Cold Extremities – loss of βreceptor mediated vasodilatation in cutaneous vessels

Rarely used due to side-effects

• • • •

Sympathetic Nervous System – False Transmitters

Methyldopa

1. Taken up by NA neurones 2. Decarboxylated & hydroxylated to form false transmitter, α-methyl-NA 3. Not deaminated by MAO, so accumulates: • Less active than NA on α1-receptors • More active on presynaptic (a2) receptors (auto-inhibitory feedback) • CNS effects, stimulates vasopressor centre in the brain stem to inhibit sympathetic outflow

• In hypertensive patients with renal insufficiency or cerebrovascular disease • Hypertensive pregnant women

Dry mouth Orthostatic hypotension Sedation Male sexual dysfunction

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

• RoA – i.v. (highly charged) • Does not cross bbb or placenta (so can be used in caesarean section) • Onset of action: 2-3min (relatively long) • Duration of paralysis: 40-60 min (long) • Not metabolised • Excretion: 70% urine; 30% bile (care if renal or hepatic function impaired)

Due to ganglion block & histamine release: • Hypotension: o Ganglion Blockade (↓ TPR) o Histamine release from mast cells via H1 receptors • Bronchospasm – due to histamine release • Tachycardia: (may  arrhythmias) • Excessive secretions (bronchial & salivary) –histamine release • Apnoea (always assist respiration)

• RoA – i.v. • Onset of action: immediate • Duration of paralysis: 5-10 min (short) • Not metabolised • Excretion: 10% urine; 80% bile

• Hyperkalaemia • Bradycardia • Raised intracranial & intraocular pressure • Muscle pain due to fasiculations

Neuromuscular Block Drugs – NON-DEPOLARISING (Competitive Nicotinic Antagonists) 4° ammonium compound (alkaloid & is powerful positive charge)

Tubocurarine/ Atracurium

• Competitive nAChR antagonist • 70 - 80% block necessary (all or nothing action) • Graded block = different proportions of fibres blocked

• Flaccid paralysis: o Extrinsic eye muscles (double vision)  o Small muscles of face, limbs, pharynx  o Respiratory muscles • Relaxation of skeletal muscles during surgical operations esp abdominal muscles (therefore require less anaesthetic so safer) • Permit artificial ventilation

Neuromuscular Block Drugs – DEPOLARISING (Nicotinic Agonists) Structure similar to ACh (2 ACh bonded together via a acetyl group)

Suxamethonium

• Normally, ACh binds to nicotine receptor  opens Na V-gated channels  degradation of ACh by acetylcholinesterase • Sux cannot be hydrolysed by acetylcholinesterase but by pseudocholinesterase  not degraded  prevents muscle cell to ‘reset’ & keeps the new restign potential below threshold  muscle fasiculations

Anaesthesia – allow intubation of the trachea or to maintain relaxation for short surgical procedures

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

Beta-blocker for 1. NEGATIVE CHRONOTOPE & IONOTROPE 2. CONTROL or CORRECT DYSRHYTHMIA

• Competitive antagonists for mainly β1 adrenoceptors •  reductn in CO, renin release & NA release by symp nerves

• • • • • • •

• No longer 1st line for hypertension in UK • Do NOT ↓peripheral resistance (PVR) (except partial agonists or vasodilatory beta blockers)

• Due to actions on beta1 (& sometimes beta2 receptors): • Bronchoconstriction • Cardiac failure & Heart block • Bradycardia • Fatigue • Cold extremities • Exacerbation of arterial disease • Hypoglycaemia in diabetics taking insulin • Hypotension • Headaches • Flushing (due to vasodilation) Excessive/prolonged use of nitrates is associated with tolerance – avoided by eccentric (asymmetric) dosing

Nicorandil

Organic nitrate for REDUCING PRELOAD

Glyceryl Trinitrate

Organic nitrate for CORONARY VASODILATORS

• Drug  release NO from endothemium  • Stimulating guanylate cyclase  • Formation of cyclic GMP  • relaxing smooth muscle in veins  • ↓ing venous return

• Venodilators (if dilatn of coronary arteries have reached max) of veins  ↓ preload • Coronary artery vasodilators – potassium channel openers used in angina (e.g. nicorandil) open KATP channels & also act as nitric oxide (NO) donors • Angina • Antiplatelet agents • Acute & chronic heart failure • BP control during anaesthesia • Negative inotropic effect (verapamil > diltiazem, not dihydropyridines) • Inhibit AV node conduction (verapamil)

• Nitrates undergo extensive ‘first pass’ metabolism by the liver • Long acting forms of nitrate (e.g. isosorbide mononitrate, or glyceryl trinitrate via a transdermal patch) are available for sustained actions

• Angina • Hypertension (mainly dihydropyridines) • Verapamil is used to treat paroxysmal SVT & atrial fibrillation Terminate superventricular tachyarrhythmias (SVT)

DIHYDROPYRIDINES

Useful for a number of superventricular and ventricular tachyarrhythmias

Drugs & the Heart

Atenolol

Isosorbide mononitrate

Verapamil Diltiazem Amlodopine

Organic nitrate

Rate-limiting Calcium channel blockers for CORONARY VASODILATORS (acting on afterload) Antidysrhythmic

Adenosine

Antidysrhythmic

Amiodarone

•  cardiac & smooth muscle actions • ↓ Ca2+ entry in cardiac & smooth muscle cells •  only smooth muscle actions • Only inhibit Ca2+ entry in smooth muscle cells • Produced by the metabolism of ATP • Acts on adenosine (A1) receptors to hyperpolarize cardiac tissue & slow conductn through AV node Momplex action –multiple ion channel block

Angina & improves survival post MI Cardiac dysrhythmias Heart failure Thyrotoxicosis Glaucoma Anxiety states Migraine

• Glyceryl trinitrate is often given sublingually for rapid relief of angina – has a short t1/2 ≈ 30mins

• • • • • • •

Bradycardia AV block Worsening of heart failure Constipation Ankle oedema Headache/Flushing Palpitations

• Iv • actions are short-lived (20-30s) & it is consequently safer than verapamil

• • • •

Chest pain Shortness of breath Dizziness Nausea

Accumulates in the body (t½ = 10 100days)

• • • • •

Photosensitive skin rashes Hypo- or hyper-thyroidism Pulmonary fibrosis Corneal deposits Neurological & GI disturbances

PHENYLALKYLAMINES BENZOTHIAZEPINES

NAME OF DRUG

TYPE

USES

Antidysrhythmic

• Inhibits Na-K-ATPase (Na/K pump)  ↑ed accumulation of intracellular Na+  ↑es intracellular Ca2+ via Na+/Ca2+ exchange • Central vagal stimulation  ↓ed rate of conduction through the AV node

• Slows ventricular rate in atrial fibrillation & relieves symptoms in chronic heart failure • Cardiac Effects: o Cardiac slowing & ↓ed rate of conductn through the AV node (due to central vagal stimulation) o ↑ed force of contraction o Disturbances of rhythm especially: block of AV conduction & ↑ed ectopic pacemaker activity

Antidysrhythmic

Blocks If channel – a Na/K channel imp in the sinoatrial node so slows heart rate

Angina in patients in normal sinus rhythm

β1 selective for POSITIVE CHRONOTROPHES

↑es the force of cardiac contraction

Acute heart failure in some situations (e.g. after cardiac surgery or in cardiogenic or septic shock)

ACE Inhibitors for REDUCING PRELOAD & AFTERLOAD

Prevent the conversion of angiotensin I to angiotensin II by ACE

• • • • •

Angiotensin Receptor Blockers for REDUCING PRELOAD & AFTERLOAD Aldosterone Antagonist for REDUCING PRELOAD & AFTERLOAD Thiazide Diuretic for REDUCING PRELOAD & AFTERLOAD α-adrenoceptor antagonist for CORONARY VASODILATOR

At AT1 receptors – preventing the renal & vascular actions of Ang II (agents act as insurmountable) Antagonist of aldosterone – inhibits the sodium retaining effects

• Hypertension • Alternative for ACEI for heart failure patients who cannot tolerate ACEI

Causes a fall in smooth muscle Na+  2° reduction in Ca2+

• Hypertension • Heart Failure

Specific for alpha1

Postural Hypotension

Non-selective alpha antagonist

Pheochromocytoma

Digoxin (Cardiac Glycosides)

Ivabradine

Dobutamine

MECHANISMS OF ACTION

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG Dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity)

Contraindications: Severe bradycardia/sick sinus syndrome/2-3rd degree heart block; Cardiogenic shock; Recent MI

• Bradycardia • First-degree heart block • Ventricular & SVA

Drugs & the Vasculature Enalapril Captopril

Losartan

Spirono-lactone

Bendrofluazide Doxazosin Phenoxybenzamine

Hypertension Heart failure Post-myocardial infarction Diabetic nephropathy Progressive renal insufficiency

• Heart failure • Resistant cases of hypotension

• • • • •

Hypotension Angioedema Hyperkalaemia Foetal injury Renal failure in pts with renal artery stenosis • Hypotension • Foetal injury • Renal failure in patients with renal artery stenosis • Hyperkalemia – aldosterone antagonism • Steroid-like effects such as gynaecomastia, menstrual disorders & testicular atrophy • Hypokalaemia • Diabetes • Gout

Tachycardia

NAME OF DRUG Clonidine/ α-methydopa

Hydralazine

TYPE

USES

PHARMACOKINETICS

α2-adrenoceptor agonists for VASODILATION

Specific for alpha2 by reducing sympathetic activity

Hypertension

K+ Channel Openers for CORONARY VASODILATION

Opening ATP-sensitive K+ channels  hyperpolarisation  closing voltage-sensitive Ca2+ channels

Severe Hypertension

Used in combination with a betablocker & diuretic

5HT1D receptor Agonist for Vasoconstriction

Vasoconstriction of large arteries & inhibits trigeminal nerve transmission

Migraine attacks

Contraindicated in pts with coronary disease as it also causes coronary vasoconstriction

Minoxidil Sumitriptan

MECHANISMS OF ACTION

SIDE -E FFECTS OF DRUG

• Reflex tachycardia  angina, headaches & fluid retention • Lupus syndrome  fever, malaise & hepatitis Severe fluid retention  oedema

Anti-coagulants, Fibrinolytics & Anti-platelet drugs Anticoagulant

Prevents the activation of vitamin K (an important co-factor in the synthesis of a number of clotting factors (II, VII, IX & X)

• Oral, absorbed quickly from GI tract • Binds strongly to plasma proteins (slow turnover of clotting factors) • Metabolised by hepatic mixed function cyt P450

Anticoagulant

Activates anti-thrombin III which inhibits factor Xa & thrombin by binding to the active serine sites

• Poorly absorbed after oral administration, therefore given either subcut. or intravenously • Short half-life so immediate effect

Anti-platelets

• Irreversibly inhibits COX-1 • Inhibits the production Of TXA2 in platelets Pro-drug which inhibits fibrinogen binding to glycoprotein IIb/IIIa receptors

• Oral • Highly plasma protein bound

Warfarin

Heparin/ LMWH

Aspirin Anti-platelets

Clopidogrel Anti-platelets

Abciximab

Antagonist of the glycoprotein IIb/IIIa receptor

In acute coronary syndromes – used in combination with heparin & aspirin to prevent ischemia in patients with unstable angina

• Oral • Peak plasma conc 4hrs after a dose but inhibitory effect on platelets not seen until after 4 days of regular dosing • IV • Binds rapidly to platelets • Cleared with platelets • Effect persists for 24-48hrs

• Haemorrhage (especially into the brain or bowel • Teratogenicity (not given to pregnant mothers) • Reversal of effects: vitamin K or prothrombin • Interactions with drugs e.g. drugs which inhibit cyt P450: (will increase plasma conc of warfarin) • Bleeding • Thrombocytopenia • Osteoporosis • Hypersensitivity • Chills, fever, urticaria, anaphylaxis • Reversal of effects: stop heparin GI sensitivity

• Bleeding (GI haemorrhage) • Diarrhoea • Rash Bleeding (may potentially be immunogenic)

NAME OF DRUG

Streptokinase

Alteplase

TYPE Thrombolytics (fibrinolytics)

Thrombolytics (fibrinolytics)

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

• Acute myocardial infarction • Acute thrombotic stroke – within 3hrs • Deep vein thrombosis; pulmonary embolus; acute arterial thromboembolism; local thromboembolism in the anterior chamber of the eye

• IV • 30-60 min infusion • Rapidly cleared; t1/212-18 mins

Bleeding (may potentially be antigenic)

• IV • 30min infusion • Rapidly cleared; t1/212-18 mins

Bleeding

• Inhibition of the enzyme leads to ↓ed hepatic cholesterol synthesis • More enzyme tending to restore cholesterol synthesis to normal • Fall in production of cholesterol also induces a compensatory ↑in hepatic LDL receptors which ↑ clearance of cholesterol from the plasma

Non-cholesterol effects of statins include: • Increased NO synthesis • Inhibition of free radical release • Reduced number and activity of inflammatory cells • Inhibition of platelet adhesion and aggregation together with reduced blood viscosity

• Do not work in patients with familial hyperchloesterolamia (who have no LDL receptors) • Doubling the dose of statins only leads to a 6% reduction in LDL • Reduce plasma LDL by 25-35%

• Myopathy can occur • Contraindication for pregnancy as cholesterol is essential for normal foetal development

Act as ligands for the nuclear transcription receptor PPAR-α (peroxisome proliferatorsactivated receptor alpha)  stimulates lipoprotein lipase activity (↑ed hydrolysis)

• Produce a moderate decrease in LDL (10%) and moderate increase in HDL (10%) and a marked fall in plasma triglycerides (30%) • First line treatment for people with very high triglyceride levels

Binds to plasminogen  conformational change exposing the active site  plasmin activity  degrades fibrin • Recombinant tPA • Activates plasmin  degrades fibrin & dissolving the clot

Statins (& Other LDL Lowering Drugs) HMG CoA Reductase Inhibitors

Simvastatin

Fibrate Benzafibrate

Ezetimibe

Inhibitors of Intestinal Cholesterol Absorption

Decreases cholesterol by 18% with little change in HDL • Reduces release of VLDL and so lowers plasma triglycerides by 30-50% • Lowers cholesterol by 10-20% and increases HDL

Nicotinic Acid Anion Exchange Resins

Colestipol

Main Uses: • Reduce LDL levels & ↓in CHD (congestive/coronary heart disease) mortality/morbidity • Support treatment in women, elderly & diabetics

• Increase the excretion of bile acids  more lipids to be converted into bile acids & so ↑ed lipid excretion • Fall in hepatocyte cholesterol concentration  ↑ in HMG CoA Reductase & LDL receptors

• Needs combination therapy with statins or fibrates Number of adverse effects

Adverse effects are confined to the gut as the resins are not absorbed: • Bloating • Diarrhoea, constipation

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

NSAIDs (Non-Steroidal Anti-inflammatory Drugs)

Aspirin

• Binds irreversibly to cyclo-oxygenase enzymes • Only be reversed by de novo synthesis of new enzyme

• Binds 200-fold more avidly to COX-1 than to COX-2 • Analgesic, antipyretic & antiinflammatory actions

Inhibits COX-1/2 REVERSIBLY

• Lowers the pain threshold • Pyrogenic – stimulates hypothalamic neurones initiating a rise in body temperature (therefore, NSAIDS reduce raised temperature) • Enhances production of a number of proinflammatory cytokines including Th2 cytokines such as IL4 & IL5 • Inhibits the production of others including Th1 cytokines such as IFNγ & IL2 • Gastric cytoprotection – downregulates HCl secretion – PGE2 stimulates mucus & bicarbonate secretion (which would otherwise  gastric ulceration) • PGE2 enhances renal blood flow and therefore GFR

Ibuprofen

• Gastric irritation, ulceration, bleeding &, in extreme cases, perforation • Reduced creatinine clearance & possible nephritis • Prolonged bleeding times, due to reduced platelet aggregation • Bronchoconstrction in susceptible individuals

Selectively inhibits COX-2

Celecoxib

It is not a NSAIDs

Paracetamol

Inhibits peroxidation (conversion of PGG2  PGH2

• Good analgesic for mild-to-moderate pain • Anti-pyretic action

Paracetamol poisoning – andidote is add a compound with –SH groups (i.v. Acetylcysteine or oral methionine)

Loss of COX-2 physiological function: • Regulation of ovulation • Regulation of parturition • Renal blood flow • Regulation of blood pressure • Therefore,  increases risk of MI Irreversible liver failure (overdose): • A reactive metabolite of paracetamol, (N-acetyl-pbenzoquinoneimine) is normally safely conjugated with glutathione • If glutathione is depleted the metabolite oxidises thiol groups of key hepatic enzymes & causes cell death  hepatotoxicity

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

Inflammatory Bowel Disease GLUCOCORTICOIDS

Prednisolone

Activate intracellular Glucocorticoid Receptors which can then act as positive or negative transcription

Fluticasone

Budesonide

Sulfasalazine

Mesalazine

Olsalazine

AMINOSALICYLATES • ↓ synthesis of eicosanoids • ↓ free radical • ↓ cytokines • ↓ leukocyte infiltration • No immunesuppressive effects

• Metabolised by colonic flora/liver • Site of Absorption: colon 5-aminosalicylic acid (5ASA) • Metabolised by…? • Site of Absorption: small bowel & colon (2 x 5-ASA molecules linked by an azo bond) • Metabolised by colonic flora • Site of Absorption: colon

Anti-inflammatory actions of GCs: • Reduce influx and activation of proinflammatory cells o Reduce adhesion molecules on endothelial cells and leukocytes o Reduce synthesis of some chemokines • Reduce production of mediators causing the signs of inflammation by reducing synthesis of: o Some cytokines and their receptors (such as IL-1 & TNFα) o Proteolytic enzymes (such as elastase) o Enzymes catalysing mediator synthesis (e.g. cyclo-oxygenase) o Eicosanoids (such as prostaglandins and leukotrienes) o Nitric oxide Immunosuppressive actions of GCs: • Reduced antigen presentation • Reduced production of mediators (e.g. IL2, IL-4, IFNg ) resulting in • Reduced cell proliferation & clonal expansion • Mainly used to maintain remission & prevent relapse • Anti-inflammatory

• • • • • • •

Osteoporosis Increased risk of Gastric ulceration Suppression of HPA axis Type II diabetes Hypertension Susceptibility to infection Skin thinning, bruising and slow wound healing • Muscle wasting & buffalo hump Minimising unwanted effects of GCs • Start with high dose & taper down • Use drug with high therapeutic index (e.g. fluticasone) • Administer topically – fluid or foam enemas or suppositories • Use an oral or topically administered drug which is degraded locally e.g. budesonide

Pharmacokinetics of 5-ASA: • Topical delivery (suppositories, enemas) • pH-dependent release capsules ( small intestine) • Slow release microspheres (small and large bowel): o Leads to gradual release of mesalazine as it travels through the bowel o 33% released in upper small intestine, remainder in distal ileum and colon

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

IMMUNOSUPPRESSIVE AGENTS

• Azathioprine is a prodrug which is activated in vivo by gut flora to 6mercaptopurine – interferes with purine biosynthesis • Interferes with DNA synthesis & cell replication It impairs: • Cell-& antibodymediated immune responses • Lymphocyte proliferation • Mononuclear cell infiltration • Synthesis of antibodies It enhances – T-cell apoptosis

CURATIVE THERAPY – Anti-TNFα

• Crohn’s is a Th1-mediated autoimmune response  TNFα plays an important role in disease pathogenesis • Anti-TNFa ↓es activation of TNFα receptors in the gut • Production of other cytokines, infiltration & activation of leukocytes is reduced • Also binds to membrane associated TNFα • Mediates complement activation & induces cytolysis of cells expressing TNFα • Promotes apoptosis of activated T cells

Azathioprine

Infliximab

USES

PHARMACOKINETICS

• More effective in Crohn’s disease • May enable reduction of glucocorticoid dose or postponement of colostomy • May induce remission in some cases of active disease

SIDE -E FFECTS OF DRUG • Bone marrow suppression • If administered with drugs which inhibit xanthine oxidase e.g. allopurinol, a drug used for the treatment of gout, 6 – Mercaptopurine levels rise & blood dyscrasias may result

• Given intravenously • Very long half-life (9.5 days) • Benefits can last for 30 weeks after a single infusion • Most patients relapse after 8 – 12 weeks • Therefore repeat infusion every 8 weeks

• 4x - 5x increase in incidence of tuberculosis & other infections • Increased risk of septicaemia, therefore can’t be used if abcess • Worsening of heart failure • Increased risk of demyelinating disease • Increased risk of malignancy • Can be immunogenic – therefore given with azathioprine

• • • •

• Water/electrolyte imbalance – Dehydration/Hypernatraemia • ECF volume – Hyponatraemia; (nausea, vomiting, pulmonary oedema)

Diuretics – drugs that act on the renal tubule to promote the excretion of Na+, Cl- & H2O Osmotic Diuretic

Mannitol

↓ H2O reabsorption / H2O excretion (Small ↑ in Na+/Cl- loss)

• Prevent acute renal failure – H2O excretion • Intra-cranial pressure  plasma osmolarity • Intra-ocular pressure  plasma osmolarity

Given iv Onset – 0.5hr DoA: 2-3hr Excretion – glomelular filtrate

NAME OF DRUG

TYPE Carbonic anhydrase inhibitors

Acetazolamide

Loop diuretics

Furosemide

Thiazides

Bendrofluazide

MECHANISMS OF ACTION • Prevent the reabsorption of HCO3and Na+ o H2O reabsorption is therefore reduced o delivery of HCO3- to distal tubule K+ loss • tubular fluid osmolarity ↓ H2O reabsorption in the collecting duct • ( Na+/ K+/ HCO3- loss) • Inhibit Na+ and Clreabsorption in ascending limb • tubular fluid osmolarity/ ↓ osmolarity of medullary interstitium = ↓ H2O reabsorption in the collecting duct • Large in urine volume and Na+, Cl- & K+ loss (& Ca2+ & Mg2+ loss) • Inhibit Na+ and Clreabsorption in early distil tubule • delivery of Na+ to collecting duct  activates N+/K+ exchange mechanism  ↓es water reabsorption  urine volume is increase [ K+ loss ( Na+/K+ exch)] • Moderate in urine volume & Na+, Cl- , K+ & Mg2+ (but reduced loss of Ca)

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

• Intra-ocular pressure (glaucoma) • Renal stones – Uric Acid • Metabolic Alkalosis – HCO3- loss

• • • •

• Acute pulmonary oedema – Heart failure, pulmonary, renal, hepatic, cerebral • Acute renal failure • Hypercalcaemia • Hyperkalaemia

• Given oral • Onset – 1hr • DoA: 4-6hr • Excretion – tubular secretion N.B. 50% unchanged, 50% metabolised

• Hypovolaemia & Hypotension • K+ loss (Ca2+/Mg2+), Metabolic Alkalosis

• Cardiac Heart failure • Hypertension – initially ↓ blood volume/long-term = vasodilation • Severe resistant oedema • Idiopathic hypercalciuria – stone formation • Nephrogenic diabetes insipidus (paradoxical)

• Given oral • Onset – 1-2hr • DoA: 8-12hr • Excretion – tubular secretion N.B. competes with uric acid

• K+ loss, Metabolic Alkalosis • Diabetes Mellitus – Inhibits insulin secretion

Given oral Onset – 0.5hr DoA: 12hr Excretion – tubular secretion

• K+ loss – Balance HCO3- in collecting duct • Metabolic acidosis

NAME OF DRUG

TYPE Potassium sparing diuretics

Spironolactone

MECHANISMS OF ACTION Block aldosterone receptors

Na channel blockade

Amiloride

Block of Na+/K+ exchange– ↑ed Na+ & ↓ed K+ loss Small ↑in urine volume

USES • Primary & secondary hyperaldosteronism

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

• Given oral • Onset – days • DoA: canrenone • Excretion – glomeular filtrate N.B. competes with uric acid • Given oral • Onset – 6hr • DoA: 24hr • Excretion – tubular secretion N.B. unchanged with urine

• Hyperkalaemia, Metabolic Acidosis • Spironolactone – Gynaecomastia, Menstrual • Disorders, Testicular Atrophy

• Motion sickness • Disorders of the labyrinth e.g Meniere’s disease • Hyperemesis gravidarium • Pre- & post-operatively (sedative & antimuscarinic action are also useful) Other uses: • Relief of allergic symptoms • Anaphylactic emergency • Night sedation; insomnia • Uraemia (severe renal failure) • Radiation sickness • Gastrointestinal disorders • Cancer chemotherapy (high doses) e.g. Cisplatin (intractable vomiting)

• • • •

• • • • • •

• Prevention of motion sickness • Has little effects once nausea/emesis is established • In operative pre-medication

Can be administered orally (peak effect in 1-2 hours), i.v., transdermally

• Main use in preventing anticancer druginduced vomiting, especially cisplatin • Radiotherapy-induced sickness • Post-operative nausea & vomiting

Administer orally; well absorbed, excreted in urine

• With K+ losing diuretics to prevent K+ loss

Anti-emetics – treatment for nausea & vomiting Phenothiazine derivative

• Competitive antagonist at histaminergic (type H1), cholinergic (muscarinic, M) & dopaminergic (type D2) receptors: H1> M > D2 • Acts centrally (labyrinth, NTS, vomiting centre) to block vomiting centre

Dopamine receptor antagonist

• Order of antagonistic potency: D2 >> H1 >>> Muscarinic receptors • Acts centrally (CTZ) • Acts in the GI tract o ↑es smooth muscle motility o ↑ed GI emptying

Anti-muscarinic

• Antagonistic: musc. >>>D2 = H1 receptors • Acts centrally (vestibular nuclei, NTS, vomiting centre) to block activation of vomiting centre Block transmission in visceral afferents & CTZ

Promethazine

Metoclopramide

Hyoscine

Ondansetron

5HT3 receptor antagonist

Administer orally Onset of action 1-2 hours Maximum effect circa 4 hours Duration of action 24 hours

• May be administered orally; rapidly absorbed; extensive first pass metabolism • May also be given i.v. • Crosses BBB • Crosses placenta

Dizziness Tinnitus Fatigue Sedation Excitation in excess Convulsions (children more susceptible) • Antimuscarininc side-effects In CNS: • Drowsiness; Dizziness; Anxiety • Extrapyramidal reactions; (parkinsonian-like syndrome: rigidity, tremor) In the endocrine system: • Hyperprolactinaemia • Galactorrhoea • Disorders of menstruation • Drowsiness • Dry mouth • Cycloplegia • Mydriasis • Constipation • Headache • Sensation of flushing and warmth • ↑ed large bowel transit time (constipation)

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

Treatment of Gastric & Duodenal Ulcers Metronidazole

Antibiotics for treatment of Helicobacter pylori

Active against anaerobic bacteria & protozoa Broad spectrum antibiotic

Amoxycillin Macrolide structure – inhibits translocation of bacterial tRNA

Clarithromycin

Used in combination with “triple therapy” • 1st Example: o Metronidazole or amoxycillin o Clarithromycin o Proton pump inhibitor, PPI (omeprazole) nd • 2 Example: o H2 receptor antagonists o Clarithromycin o Bismuth • Component of triple therapy • Peptic ulcers resistant to H2 antagonists • Reflux oesophagitis

• Compliance • Development of resistance • Adverse response to alcohol, especially with metronidazole (interferes with alcohol metabolism)

PPIs: (rare) • Orally active • Inhibit gastric acid • Administered as enteric coated secretion from the slow-release formulations parietal cell by >90% • Irreversible inhibitors Omeprazole of H+/K+ ATPase • Accumulates in cannaliculi of parietal cells & prolongs its DoA (2-3 days) HISTAMINE TYPE 2 (H2) R Healing ulcers (although less effective than Rare (relapses likely after withdrawal • Orally administered Ranitidine ANTAGONISTS – inhibit PPIs) of treatment) • Well absorbed gastric acid secretion Cimetidine CYTOPROTECTIVE • Polymer containing aluminium hydroxide & sucrose octa-sulphate • Most of orally administered drug DRUGS – enhance remains in GI • Acquires a strong negative charge in an acid environment mucosal protection • Binds to positively charged groups in large molecules • May cause constipation Sucralfate mechanisms • Reduces absorption of some other • These coat & protect the ulcer, limit H+ diffusion and pepsin and/or build a drugs (e.g. antibiotics and digoxin) degradation of mucus physical barrier • Increases PG, mucus & HCO3 secretion & ↓the number of H. pylori Like sucralfate Used in triple therapy (resistant cases) Bismuth chelate over the ulcer • Stable prostaglandin analogue – mimics the action of locally produced • Diarrhoea, abdominal cramps, PG to maintain the GI mucosal barrier uterine contractions • May be co-prescribed with oral NSAIDs when used chronically • Caution in pregnancy Misoprostol • NSAIDs block the COX enzyme for PG synthesis from arachidonic acid • Therefore, there is a reduction in the natural factors that inhibit gastric acid secretion & stimulate mucus & HCO3- production + Mainly salts of Al3 Neutralises acid, ↑ gastric • Primarlity used in non-ulcer dyspepsia “Ant-acids” & Mg2+ pH, ↓ pepsin activity • Reducing duodenal ulcer recurrence rates Treatment of Gastro-Oesophageal Reflux Disease (GORD) – treat with PPIs (drugs of choice) or H2 antagonists (less effective) &c ombine with drugs that increase gastric motility & Inhibitors of Gastric Acid secretion

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

emptying of the stomach e.g. DA2 receptor antagonists (metoclopramide)

Anxiolytics & Sedatives/Hypnotics Sodium Valporate Vigabatrin GABA Muscimol Bicuculline Picrotoxin GABA Baclofen Phaclofen Saclofen

Diazepam

Anti-compulsive; Anti-epileptic (very useful in seizures) Selective GABA-T inhibitor GABAA receptor agonists Selective GABAA receptor GABAA receptor Competitive antagonists Non-competetive) – blocks flow of Cl- ions GABAB receptor agonists Muscle relaxant in sp. cord & spasmolytic drug GABAB receptor antagonists Competitive Anxioltyics Benzodiazepines • Long-acting anxiolytic • Bind to GABAA receptor • Anti-convulsants • Cl- influx  • Anti-spastics hyperpolarisation • ↑ frequency of openings of channels • Long-acting anxiolytic – if there is hepatic impairment • Short-acting sedative/hypnotics

Oxazepam

5HT1A agonist Non-selective β-blocker

Buspirone Propranolol Temazepam/ Clonazepam Amobarbitol/ Phenobarbitol

Sedatives/ Hypnotics

Benzodiazepines (above) Barbiturates • Bind to GABAA receptor • Cl- influx  hyperpolarisation • ↑ duration of openings of channels

Anxiolytic Improves physical symptoms – tachycardia (β1) or tremor (β2) • Short-acting sedative/hypnotics • Anti-convulsants • General Anaethetics • Anti-convulsants – Phenobarbitol • Sedatives/Hypnotics – Amobarbitol

Administration: • Well absorbed P.O. • Peak [plasma] = 1hr • I.v. versus status epilepticus Distribution: • Bind to plasma proteins strongly • Highly lipid soluble  wide distribution Metabolism – extensive in the liver: • Diazepam – t1/2 = 32hr • Oxazepan – t1/2 = 8hr Excretion – urine – glucoronide conjugates Duration of Action (vary): short/long Slow onset of action (days/weeks)

• Sedation, confusion, ataxia (impaired manual skills) • Potentiate other CNS depressants (alcohol, barbs) • Tolerance (less than BARBs; ‘tissue’ only) • Dependence: withdrawal syndrome similar to BARBs (lessintense) so imp. to withdraw slowly • free [plasma] by e.g. aspirin, heparin

(see above for Benzodiazepines) • Temazepam – t1/2 = 8hr

(see above for Benzodiazepines)

• Amobarbitol – t1/2 = 20-25hr

• Low safety margins: (↓ respiration or overdosing – alkaline dieresis) • Alter natural sleep (↓ REM) • Enzyme inducers • Potentiate depressants (alcohol) • Dependence: withdrawal syndrome  insomnia, anxiety

Few side-effects

NAME OF DRUG

TYPE

Chloral Hydrate

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

Liver conversion  trichloroethanol (a BARB)

Wide margin of safety – in children & elderly

• DOPA – precursor to dopamine, converted to dopamine in brain • DOPA decarboxylase also present in peripheral tissues  cause side effects of nausea & vomiting

Parkinson’s Disease • Rigidity – stiffness, limbs feel heavy/weak • Bradykinesia – slowness of movement • Postural abnormality • Pill-rolling rest tremor • Difficulty with fine movements – macrophagia • Monotomy of speech & loss of volume of voice • Disorders of posture – flexion of the neck & trunk • Lack of arm swing • Loss of balance – lack of righting reflex, retropulsion • Short steps, shuffling gait

Acute: • Nausea – prevented by Doperidone (peripheral acting antagonist) • Hypotension • Psychological effects – schizophrenia like syndrome with delusions, hallucinations, also confusion, disorientation & nightmares Chronic: • Dyskinesias (54%) – abnormal movements, which affect the face & limbs • On-off oscilations (64%) – rapid fluctuations in clinical state, where hypokinesia & rigidity may suddenly worsen

Schizophrenia • Positive symptoms – delusions, hallucinations, thought disorders • Negative symptoms – withdrawal, flattening of emotional responses • Drugs tend to treat the positive symptoms – neuroleptics are D2 antagonists correcting the over activity of dopamine in the mesolimbic system & striatum • No effect on the forebrain where negative symptoms are produced

Anti-emetic effect: • Blocking dopamine receptors in the chemoreceptor trigger zone • Phenothiazine, effective at controlling vomiting & nausea induced by drugs • Many neuroleptics also have blocking action at histamine receptors – effective at controlling motion sickness Extrapyramidal side effects – blockade of dopamine receptors in the nigrostriatal system can induce “Parkinson” like side effects  dyskinesis Dyskinesias: Endocrine Effects: • DA is involved in Tuberoinfundibular system – regulated prolactin secretion • Neuroleptics increase serum prolactin concentrations which can lead to breast swelling (men & women) and sometimes lactation in women Blockade of cholinergic muscarinic receptors – typical peripheral antimuscarinic side effects e.g. blurring vision, ↑ed intra-ocular pressure, dry

Antiparkinsonian/Neuroleptics Ant-Parkinson’s Disease

L-DOPA

Bromocriptine Carbidopa

Tolocapone/ Entacapone Deprenyl Chlorpromazine Haloperidol Sulpiride Clozapine

Schizophrenia – neuroleptics

• D2 Receptors • Common – confusion, dizziness, nausea/vomiting • Longer DoA of L-DOPA • Rare – constipation, headache, dyskinesias, drowsiness & hallucinations Prevent DOPA decarboxylase for converting DOPA  dopamine side-effects • DOPA decarboxylase (nausea & vomiting) inhibitor • Combination of L-DOPA COMT Inhibitors • Tolocapone = CNS & peripheral • Entacapone =peripheral CNS – prevents breakdown of dopamine Peripheral – COMT inhibitors stop 3-OMD formation, ↑ing bioavailability L-DOPA MAO Inhibitors – selective In early stages of the disease or with Rare – hypotension, nausea/ for MAO-B, L-DOPA, ↓ the dose of L-DOPA vomiting, confusion & agitation All mentioned in the drugs table but NO information given

• Antagonists to D2 receptors • Clozapine shows nonselectivity with D1 or D2 • Block other receptors 5-HT

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

mouth, constipation, urinary retention

General Anaesthetics Intravenous G.A.

Propofol

Etomidate

Nitrous Oxide

Inhalation G.A.

Halothane Enflurane

Has many different subunits: • Potentiate GABAA receptor function • Β3 – suppression of reflex responses • Activation  ↑ed • α5 – amnesia inhibitory effect of GABAA receptor  ↑ed Cl- into other neurones  hyperpolarisation of nerves around  their de-activation • Poteniate GABAA receptor function (and glycine receptors) • Nitric oxide – Reduced NMDA receptor function (altered synaptic function) – least toxic but least potent (for children) • Inhibits nicotinic acetylcholine receptors (altered synaptic function) – for amnesia & relief of pain • Facilitate TREK (background leak) potassium channel opening (reduced neuronal excitability) – slow hyperpolarisation – for suppression of reflex responses

• Loss of consciousness at low concn – (e.g. isoflurane - 100μM) o Depress excitability of thalamocortical neurons o Influences reticular active neurons i.e. Reticular Formatn • Suppressn of reflexes at high concn – (e.g. isoflurane - 300μM) o Depression of reflex pathways in the sp cord • Relief of pain (analgesia) – opioid (e.g. i.v. fentanyl) o Synaptic transmission in hippocampus (new memory formation)/amygdala • Muscle relaxation – Neuro-mus blocking drugs (e.g. suxamethonm) • Amnesia – Benzodiazepines (e.g. i.v. midazolam)

INHALATION ANAESTHETIC – given for maintenance of anaesthesia • Rapidly eliminated • Rapidly control of depth of anaesthesia

INTRAVENOUS ANAESTHETIC – given for initiation of anaesthesia • Fast Induction • Less coughing/excitatory phenomena

Local Anaesthetics Lidocaine

Amide L.A.

N.B. All L.A. have aromatic region; basic amide side chain; ester or amide bond

Bock of voltage-sensitive Na+ channels in sensory neurones • Use dependant – more L.A used  more effect • May also influence: o Channel gating – bind in the inactivated state  ↑ed effect o Lowers surface tensn • Block nocioceptor – small diameter fibres & non-myelinated fibres • Are weak bases • Infected Tissue: is

Surface Anaesthesia: • Spray or powder via mucosal surface – e.g. mouth, eye, brachial tree • High concentrations needed for effect – risks systemic toxicity in high concn Infiltration Anaesthesia: • Directly into tissues and sensory nerve fibres (subcutaneous) • Used in minor surgery (e.g. removal of cysts) • Adrenaline co-injection (not in extremities) causes vasoconstriction  ↓ diffusion away from target site – ↑ DoA & ↓ systemic toxicity & ↓ chances of bleeding IV Regional Anaesthesia: • IV given distal to pressure cuff to prevent systemic toxicity (used in limb surgery) • Systemic toxicity can occur is the pressure cuff is released prematurely Nerve Block Anaesthesia: • Injected close to nerve roots – e.g. in dental surgery (slow onset, low dose) • Vasoconstriction co-injection can also be given Spinal Anaesthesia: (intra-thecal) & can be combined with glucose • Used in abdominal, pelvic and lower limb surgery (L3-L4)

Property

Absoprtion (mucus membranes)

Local Anaesthetic Lidocaine Cocaine (amide) (ester) Good Used mostly Good for surface Only used anaesthesia as a surface & used for anaesthetic all ROA’s

Protein Binding

70%

Metabolism

Hepatic Ndealkylation Amides are slowly

Plasma t1/2

2hrs

90% Liver & plasma via non specific esterases 1hr

CNS: restlessness, confusion, tremor CVS (Na blockade): v.dilation; ↓ bp

NAME OF DRUG

TYPE Ester L.A.

Cocaine

MECHANISMS OF ACTION acidic  ↑ ionisatn  less effect of L.A. (cannot cross memb)

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

• ↓ BP due to blockade of pre-ganglionic sympathetic fibres  prolonged headache Epidural Anaesthesia: No side-effects of before (i.e. no hypotension & headaches) • Injected into the fatty tissue of the epidural space to target the spinal roots • For painless childbirth, abd, pelvic & lower leg surgery; slower onset & higher dose

(symp actions) CNS: euphoria; excitation CVS: ↑ CO; v.constriction; ↑ bp

Pharmacokinetics: • Half life 12-40+ hrs with large inter-individual variation (one daily dosage) • Hepatic metabolism, hydroxylation and conjugation; excretion in the urine • Highly protein bound (70-90%), can be displaced • Start with low dose and increase with small increments until desired dose Drug Interactions: • Aspirin and valoprate displaces Phenytoin from plasma proteins • Causes initial increase in anticoagulation followed by decrease with warfarin • Oestrogen containing COCP’s (combined oral contraceptive pill) ↓Phenytoin efficacy • P450 enzyme inducer Pharmacokinetics: • Long half life of 36hrs initially decreasing to 20hrs with chronic treatment • 3x daily dosing • Hepatic oxidation and conjugation • Potent enzyme inducer – complex drug interactions Drug Interactions: • Susceptible to auto-induction with metabolism by hepatic enzymes (P450) • Macrolide antibiotics (e.g. erythromycin) inhibit metabolism • Ca channel blockers (e.g. verapamil) can double carbamezapine levels • Phenytoin induces carbamezapine induction Pharmacokinetics: • T1/2 = 9-18hrs • Hepatic oxidation and conjugation – not metabolised by P450 • Potent hepatic enzyme inhibitor A potent inhibitor of both oxidation and glucornidation

• • • • • • •

Ataxia Dizziness Sedation Hypersensitivity reactions Fever Folate deficiency Depression

• • • • •

Ataxia Dizziness Sedation Hypersensitivity reactions Depression

Anti-Convulsants

Phenytoin

Carbamzepine

Sodium Valporate

Vigabatrin Lamotrigine

• Interaction with voltagedependant sodium channels (inhibit firing) – phenytoin, carbamzepine, sodium valporate • Direct/indirect enhancement of GABA mediated transmission (inhibition) – vigabatrin • Interaction with neuronal calcium channels • Blocking receptors for excitatory neurotransmitters (glutamate mediated)

Partial epilepsy & acts via blockade of voltage gated Na channels

Partial and secondary generalised seizures by blockade of Na voltage sensitive channels

(wide-spectrum) Partial & generalised epilepsy & acts via blockade of Na voltage sensitive channels & enhances GABA mediated inhibition Enhancement of GABA mediated transmission – RARELY used (wide-spectrum) Partial & generalised epilepsy & acts via blockade of Na voltage sensitive channels

Relatively short half life (6-8h) but duration of action longer Pharmacokinetics: • 29hr t1/2, 15hrs with enzyme inducing co-medication, 60hrs with valporate coadministration • Hepatic conjugation (no phase I metabolism) – inhibited by valporate • 2% risk of hypersensitivity reaction, otherwise well tolderated Drug Interactions

• Sever hepatic toxicity –in children • Pancreatitis • Drowsiness • Encephalopathy • Tremor • Weight gain Retinopathy • • • • •

Mostly dose dependant Dizziness Sedation Diplopia Ataxia

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

• COCP can lower levels by 1/3 • Important drug interactions with valporate and other enzyme inducers (e.g. Phenytoin)

Anti-Microbial Drugs – Antibiotics

Sulphamethoxazole

Trimethoprim

Co-trimoxazole

Penicillin

Give rise to several other drugs e.g. diuretics • Sulphanilamide is a – thiazides structural analogue of P-aminobenzoic acid & competes for dihydropteroate, in the synthesis of folate • Bacteriostatic Urinary & Resp Infections • Folate is utilised in tetrahydrofolate by the enzyme dihydrofolate reductase as a co-factor in thymidylate synthesis (purines & pyramidines) • Dihydrofolate reductase is more sensitive to drug trimethoprim in bacteria ANTIBACTERIAL AGENTS WHICH INTERFERE Infections with pneumocystis carinii, which WITH THE SYNTHESIS OR ACTION OF FOLATE – causes pneumonia in patients with AIDS SEQUENTIAL BLOCKADE (combination of sulphamethoxazole &trimethoprim) ANTIBACTERIAL • Penicillin is composed of a 6-aminopenillanic acid, which consists of a AGENTS WHICH thiazolidine ring linked to a β-lactam ring INTERFERE WITH • Interfere with the synthesis of the bacterial wall peptidoglycan THE SYNTHESIS OF • Inhibis transpeptidation enzyme that cross-links peptide chains PEPTIDOGLYCAN – attached to the backbone of the peptidoglycan β-LACTAM ANTIBIOTICS RESISTANCE • Production of β-lactamases (bacteria) – solution: β-lactamase inhibitors • ↓ in permeability of the outer membrane  decreasing ability of the drug to penetrate to the target site. • Occurrence of modified penicillin-binding sites ANTIBACTERIAL AGENTS WHICH INTERFERE WITH THE SYNTHESIS OR ACTION OF FOLATE – SULPHONAMIDES ANTIBACTERIAL AGENTS WHICH INTERFERE WITH THE SYNTHESIS OR ACTION OF FOLATE – FOLATE ANTAGONISTS

Readily absorbed in the GI tract and maximum plasma concn is reached within 4-6 hours

• Oral administration – fully absorbed from the GI tract • Widely distributed throughout the tissues and body fluids – high concentrations in the lungs and kidney

• Mild/moderate: (do not warrant withdrawal) nausea & vomiting, headache, mental depression. • Severe: (warrant withdrawal) hepatitis, hypersensitivity reactions, bone marrow suppression Nausea/vomiting & skin rashes

Two-thirds of each drug is protein bound & about half of each is excreted within 24 hours

Hypersensitivity Reactions

• Orally • Drugs are widely distributed in the body fluids, passing into joints, pleural & pericardial cavities, into bile, saliva, milk & across placenta • Lipid insoluble – do not cross bbb unless meninges are inflamed • Renal excretion (tubular secretion)

• Hypersensitivity reactions – breakdown products of penicillin combine with host protein and become antigenic (skin rashes & fever  acute anaphylactic shock) • Gut bacterial flora resulting in GI tract disturbances

NAME OF DRUG

Cefotaxime

Tetracyclin

TYPE ANTIBACTERIAL AGENTS WHICH INTERFERE WITH THE SYNTHESIS OF PEPTIDOGLYCAN – CEPHALOSPORINS ANTIBACTERIAL AGENTS AFFECTING BACTERIAL PROTEIN SYNTHESIS

Chloramphenicol

ANTIMYCOBACTERIAL AGENTS for tuberculosis & leprosy

USES

(same as penicillin) RESISTANCE • All Gram -ve bacteria have the gene encoding for β-lactamase • ↓ed penetration of drug – alterations to outer membrane proteins or mutations of the binding site proteins • Active transported into • Used to prevent gram +ve & -ve bacteria bacteria and interrupt protein synthesis RESISTANCE • Competition with tRNA • Development of energy-dependent efflux for the A binding site mechanisms which transport the tetracycline’s out of the bacterium • Bacteriostatic, not bactericidal • Alterations of the target, the bacterial ribosome, can occur) Inhibition of protein • Bacteriostatic – Gram -ve and Gram +ve synthesis – binds to 50S bacteria subunit of the ribosome & inhibits transpeptidation RESISTANCE Production of chloramphenicol acetyltransferase (plasmid mediated)

Inhibition of protein synthesis by binding to the 30S subunit of the ribosome  alteration in codon:anticodon recognition  misreading of the mRNA  production of defective bacterial proteins

Gentamycin

Isoniazid

MECHANISMS OF ACTION

• Effect is bactericidal; enhanced by agents that interfere with cell wall synthesis • Effective against many aerobic Gram -ve and some Gram +ve bacteria – given with penicillin in infections by Streptococcus, Listeria or Pseudomonas aeruginosa

RESISTANCE • Inactivation by microbial enzymes, the genes for which are carried on plasmids • Failure of penetration • Lack of binding due to mutations that alter the binding-site on the 30S subunit • Limited to mycobacteria – passes freely into mammalian cells & is thus effective against intracellular organisms (evidence suggests that it inhibits the synthesis of mycolicacids, important constituents of the cell wall and peculiar to mycobacteria) • Bacteriostatic

PHARMACOKINETICS • Given parenterally, i.m. or i.v. • Widely distributed in the body as before but can cross the bbb – useful for bacterial meningitis • Excretion is via the kidney (tubular secretion) but some by bile • Orally or parenterally • Tetracycline’s chelate metal ions (e.g. iron) – non-absorbable complex • Wide distribution, entering most fluid compartments • Excretion via the bile & by glomerular filtration in the kidney • Given orally or parenterally – reaches max cocn in 2 hrs • Widely distributed in tissues & body fluids including the CSF • 30-50% plasma protein bound its half life is approximately 2 hours • 10% is excreted in the urine, and remainder is inactivated by liver • Given i.m. or i.v. – bnding to plasma proteins is minimal • The aminoglycosides are polycations & highly polar – not absorbed in the GI tract • They do not enter cells, nor cross the BBB into the CNS (plasma half life 2-3 hours) • Elimination is virtually entirely by glomerular filtration in the kidney

SIDE -E FFECTS OF DRUG • Hypersensitivity reactions (very similar to penicillin) may be seen • Nephrotoxicity & diarrhoea can occur with oral cephalosprins

• GI disturbances (direct irritation and later to modification of the gut flora) • They chelate calcium, tetracycline’s are deposited in growing bones & teeth  staining & bone deformities • Depression of the bone marrow  pancytopenia • New borns  ‘grey-baby syndrome’(vomiting, diarrhoea, flaccidity) • Hypersensititvity rxns • GI disturbances – disruptions in gut flora • Ototoxicity – progressive damage to and destruction of sensory cells in the cochlea & vestibular organ of ear • Nephrotoxicity – damage to the kidney tubules (can be reversed if the use of the drug is stopped)

• Absorbed from the GI tract or after parenteral injection (widely distributed throughout the tissues & body fluids, including the CSF) • Penetrates well into the necrotic tuberculous lesion • Metabolism, involves largely acetylation, depends on genetic factors – slow/fast

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

• Orally (widely distributed) • Excretion – Urine & bile (enterohepatic cycling) • Oral admin (wel absorbed) • Widely distributed (meninges) • Renal excretion by glomerular filtration

Infrequent – skin eruptions, fever, GI disturbances

Fungal infections of the skin and GI tract • Binds to memb & interferes with perme and transport functions • Forms a pore in memb creating transmembrane ion channel • Azoles block the synthesis of ergosterol (main sterol in the fungal cell membrane, by interacting with the enzyme necessary for the conversion of lanosterol to ergosterol) • Resulting depletion of ergosterol alters fluidity of the membrane and interferes with action of membrane associated enzymes • The overall effect is an inhibition of replication & inhibition of the transformation of candidal yeast cells into hyphae – the invasive and pathogenic form of the parasite

Drugs greater avidity for ergosterol (fungal membrane sterol) than for cholesterol, the main sterol in the plasma membrane in animal cells

Rare – nausea & vomiting

• I.v. infusion for systemic infections and orally for infections of the GI tract • Short plasma half life and needs to be given every 8 hours

GI tract disturbances & blood dyscrasias

• Acyclovir is converted to monophosphate by thymidine kinase –virus carries out phosphorylation • Converted to the triphosphate by host cellthymadine kinases • Acyclovir triphosphate inhibits viral DNApolymerase, terminating the chain • Phosphorylated to triphosphate form  competes with triphosphates (essential for formation of proviral DNA by viral

• Acyclovir triphosphate is fairly rapidly broken down within the host cells by cellular phosphatases • Given orally, i.v and topically • The drug is widely distributed, reaching concentrations in the CSF which are 50% of those in the plasma • It is excreted in the kidneys partly by glomerular filtration and partly by tubular secretion

• Local inflammation can occur during i.v. injection • Renal dysfunction has been reported when acyclovir is given i.v.; slow infusion reduces the risk

• Given orally or i.v. • Bio-availability is 60-80 % due to 1st pass metabolism & peak plasma concn occurs at 30 mins • There is little plasma protein binding no drug interactions

Anaemia & Neutropaenia

Rifampicin

Binds & inhibits DNA-dependent RNA polymerase in prokaryotic but not eukaryotic cells

Pyrazinamide

Effective against the intracellular organism in macrophages, since after phagocytosis the organism will be contained in phagolysosomes in which the pH is low

• Arthralgia • GI tract upsets; malaise & fever

Anti-Microbial Drugs – Antifungal

Nystatin

Polyene macrolide – no absorption from the mucous membranes of the body or from skin Azole group of synthetic antimycotic agents

Miconazole

Anti-Microbial Drugs – Antiviral Guanosine derivative

Acyclovir

Zidovudine (azidothymidine, AZT)

Thymadine analogue

• High specificity for herpes simplex (which cause glandular fever or shingles) • Acyclovir has reproducible effect against cytomegalovirus (CMV) which can cause glandular fever in adults or severe disease e.g. retinis, resulting in blindness in individuals with AIDS RESISTANCE due to changes in the viral genes coding for thymidine kinase or DNA ( pneumonia, encephalitis in immunocompromised pts) • In patients with AIDS: reduces the incidence of opportunistic infection; stabilises weight; reverses HIV-associated thrombocytopenia; stabilises HIV associated dementia; reduces viral load • Can prolong life If given to HIV +ve

NAME OF DRUG

TYPE

MECHANISMS OF ACTION reverse transcriptase, viral RNA-dependant DNA polymerase) • Its incorporation into the growing viral DNA strand results in chain termination

USES

PHARMACOKINETICS

individuals before the onset of AIDS • In HIV +ve mothers it ↓ risk of transmissn of the virus to the foetus by 66% • In subjects accidentally exposed to HIV e.g. hospital worker, rape victims

• Enters mammalian cells by passive diffusion (passes in to the CSF) • Metabolised to inactive glucuronide in the liver, only 20% being excreted in the urine

SIDE -E FFECTS OF DRUG

RESISTANCE(mutations reverse transriptase)

Cytotoxic Drugs Cyclophosphamide (mustard gas)

ALKYLATING AGENT

ANTIMETABOLITE

Methotrexate Doxorubicin

CYTOTOXIC ANTBIOTICS

Bleomycin Vinca alkaloids (vincristine) Podophyllotoxins (etoposide) Procarbazine Cisplatin

PLANT ALKALOIDS

• Highly reactive molecules that bind irreversibly to cell macromolecules, notably DNA, RNA and proteins • Covalently bond with nucleophiles • Reactive group is a carbonium ion • Most are bifunctional • Guanine N7 is main target, also N1 & N3 of adenine and N3 of cytosine •  intra.interchain crosslinks & interfere with transcriptn & replicatn Folate antagonist. Folate essential to synthesise purine nucleotides (interfere with thymidylate synthesis) Inhibits DNA and RNA synthesis. Mainly through inhibition of topoisomerase II action Metal-chelating glycopeptide antibiotics that causes fragmentation of DNA chains. It can act on non-dividing cells Inhibits mitosis at metaphase by binding to tubulin and inhibiting polymerisation into microtubules  prevent spindle formation Inhibits DNA synthesis by an action on topo-isomerase II/inhibits mitochondrial function & cell block at G2

MISCELLANEOUS

(monoamine oxidase inhibitor) Inhibits DNA/RNA synthesis and interferes with mitosis at interphase (similar action to alkylating agents) Interacts with DNA causing guanine intrastrand cross-links

N.B. immunopharmacology of these drugs

• Myelotoxicity - ↓ leukocyte production ∴ ↓ resistance to infection • Impaired wound healing • Depression of growth (children) • Sterility • Teratogenicity • Loss of hair • Nausea and Vomiting Fast growing cells • Inhibit cell division • Cell cycle specific drugs: Bone marrow, GI tract epithelium, Hair & nails, Spermatogonia Slow growing cells • Introduce DNA mutations • Cell cycle independent (alkylating agents) e.g. secondary tumours

NAME OF DRUG

TYPE

MECHANISMS OF ACTION

USES

PHARMACOKINETICS

SIDE -E FFECTS OF DRUG

•