Formulary

STUDENT DRUG FORMULARY

Trinity College Dublin Neshannth Shivaen Kanagsingam Shantel Thato Sima Emma Grant Michael Savio Dr. Paul Spiers

CONTENTS

Autonomic Pharmacology .............................................................. 4 Cholinergic Drugs ............................................................................................................................................. 4 Adrenergic Drugs ............................................................................................................................................. 7 Dopaminergic Drugs ...................................................................................................................................... 11

Cardiovascular Pharmacology ...................................................... 13 Anticoagulants ............................................................................................................................................... 13 Antiplatelets .................................................................................................................................................. 15 Antihaemorrhagics ........................................................................................................................................ 16 Cardiac Contraction ....................................................................................................................................... 18 Cardiac Rhythm ............................................................................................................................................. 22 Pharmacology of Vascular Tone ..................................................................................................................... 27 Volume Regulation ........................................................................................................................................ 35 Cholesterol and Lipoprotein Metabolism ....................................................................................................... 44

Neuropharmacology .................................................................... 49 General Anaesthetics: .................................................................................................................................... 49 Local Anaesthetics ......................................................................................................................................... 51 Anticonvulsant............................................................................................................................................... 52 Analgesics ...................................................................................................................................................... 56 Non-Narcotic Analgesics ................................................................................................................................ 56 Narcotic Analgesics/Opioids .......................................................................................................................... 56 Neuroleptics: See D2 Antagonists .................................................................................................................. 58 Antidepressants: See Reuptake Inhibitors, MAO Inhibitors ........................................................................... 59 Antimanic Drugs ............................................................................................................................................ 59 Sleep Modifying Drugs/Anxiety Drugs ........................................................................................................... 60 Anxiogenics/Stimulants ................................................................................................................................. 60 Anxiolytics/Sedatives .................................................................................................................................... 61

Endocrinology .............................................................................. 64 Growth Hormone Axis ................................................................................................................................... 65 Prolactin Axis ................................................................................................................................................. 68 Vasopressin Axis ............................................................................................................................................ 68 Oxytocin Axis ................................................................................................................................................. 68 Thyroid Axis ................................................................................................................................................... 68 Adrenal Axis................................................................................................................................................... 71

Gonadotropic Axis ......................................................................................................................................... 72

Other ........................................................................................... 76 5-Hydroxytryptamine .................................................................................................................................... 76 Histamine ...................................................................................................................................................... 79 Gastro-Intestinal ............................................................................................................................................ 82 Anti-Parasitic Drugs ....................................................................................................................................... 84 Other Monoaminergic Drugs ......................................................................................................................... 88 Viral Replication ............................................................................................................................................ 90 Pharmacology of Prostaglandins & Leukotrienes ........................................................................................... 93 Molecular Toxicology & Teratogenic Drug Effects ........................................................................................ 101 Insulin & Oral Hypoglycaemic Agents .......................................................................................................... 103 Calcium Homeostasis ................................................................................................................................... 107 Bone Anabolic agents .................................................................................................................................. 108 Antiresorptive Agents .................................................................................................................................. 110 Drugs Affecting The Respiratory System & The Eye ..................................................................................... 113 Drugs Used in Ophthalmic Diagnosis ........................................................................................................... 116 Drugs Used in The Treatment Of Gout & Rheumatoid Arthritis ................................................................... 116 Disease Modifying Antirheumatic Drugs (DMARD’s) .................................................................................... 119 Immunosuppressants .................................................................................................................................. 120 Anti-Inflammatory ....................................................................................................................................... 121 Cancer therapy ............................................................................................................................................ 122 Index............................................................................................................................................................ 127

AUTONOMIC PHARMACOLOGY CHOLINERGIC DRUGS MUSCARINIC AGONISTS – ACETYLCHOLINE, MUSCARINE, PILOCARPINE MECHANISM OF ACTION •

• • •

Binds to the muscarinic acetylcholine receptor (mAChR): o Various subtypes of the mAChR exist – M1, M3 & M5 are Gq-linked and M2 & M4 are Gslinked. o Gq-linked receptors activate phospholipase C, cleaving PIP2 into IP3 & DAG. This results in an increased intracellular calcium concentration and the activation of protein kinase C, which stimulates/inhibits further enzymes. o Gs-linked receptors inhibit adenylate cyclase, resulting in decreased cAMP formation and thereby reducing activation of protein kinase A. Activation of M1 receptors leads to Gq activation, resulting in a decrease in K+ conductance and increased CNS excitation & gastric secretion.

Activation of M2 receptors leads to Gs cardiac inhibition, neural inhibition, and central muscarinic effects (e.g., tremor, hypothermia).

Activation of M3 receptors leads to increased gastric & salivary secretion, GI smooth muscle contraction, ocular accommodation and vasodilation.

INDICATIONS •

Pilocarpine is used in the treatment of xerostomia (dry mouth) and glaucoma.

MUSCARINIC ANTAGONISTS – ATROPINE, IPRATROPIUM, PIRENZEPINE , TROPICAMIDE

MECHANISM OF ACTION • •

• •

Muscarinic antagonists bind to the various mAChRs, and prevent the binding of the agonists.

This results in the inhibition of muscarinic functions and unopposed sympathetic action – “parasympatholytic”. o Inhibition of secretions, e.g. salivary, lacrimal, bronchial, gastric. o Atropine increases heart rate by blocking cardiac muscarinic receptors. o Dilation of the pupil. o Decreased gastrointestinal motility. o Relaxation of smooth muscle, e.g. bronchial, biliary & urinary tract smooth muscle. o Atropine has excitatory effects on the central nervous system – caused by blocking mAChRs in the brain. o Reduces involuntary movement and rigidity of patients with Parkinson’s disease.

Non-selective examples include atropine & ipratropium.

Pirenzepine selectively blocks the M1 receptor.

INDICATIONS • • •

Atropine is used in the treatment of sinus bradycardia and to reduce secretions.

Dilation of the pupil via eye drops (tropicamide).

Pirenzepine is used in the treatment of peptic ulcer disease.

ADVERSE EFFECTS •

Atropine poisoning can lead to hyperactivity, a rise in body temperature and reduced sweating. It is treated by the use of anticholinesterases (e.g., physostigmine & neostigmine).

GANGLION-STIMULATING – NICOTINE, LOBELINE, VARENICLINE MECHANISM OF ACTION • • •

Act on either neuronal nicotinic acetylcholine receptors (nAChRs) or on motor endplate receptors.

Stimulation of autonomic ganglia leads to increased autonomic action such as tachycardia, increased blood pressure, increased secretions etc.

Stimulation of the ganglia may be followed by block by depolarisation.

INDICATIONS •

May be used to assist smoking cessation (nicotine, varenicline)

GANGLION-BLOCKING – HEXAMETHONIUM, TUBOCURARINE MECHANISM OF ACTION • •

Bind to and block autonomic and enteric ganglia.

This causes hypotension, loss of cardiovascular reflexes, inhibition of secretions, GI paralysis, and impaired micturition.

INDICATIONS •

Historically the first therapy for hypertension, but now clinically obsolete.

NEUROMUSCULAR BLOCKERS – SUXAMETHONIUM, PANCURONIUM, VECURONIUM MECHANISM OF ACTION • •

• •

Agents block neuromuscular transmission by inhibiting the synthesis, release and binding of acetylcholine at the synapse.

They can be classified as depolarising and non-depolarising: o Non-depolarising agents act as competitive antagonists at the nicotinic acetylcholine receptors at the motor endplate. o They can also block presynaptic receptors, leading in the inhibition of release of acetylcholine. o Depolarising agents (Suxamethonium) bind to and depolarise the nAChR, and provide constant stimulation due to resistance to acetylcholinesterase. o This continuous depolarisation prevents the transmission of further signals.

Suxamethonium is the only clinically used depolarising agent.

Non-depolarising agents include tubocurarine, pancuronium and vecuronium.

INDICATIONS •

Used during surgery to facilitate tracheal intubation due to complete muscle relaxation.

ADVERSE EFFECTS • • •

Tubocurarine can cause a fall in arterial blood pressure due to blockage of sympathetic ganglia.

Pancuronium can cause tachycardia due to blockage of mAChRs in the heart.

Suxamethonium can cause bradycardia, increased potassium release, increased intraocular pressure, prolonged paralysis and malignant hyperpyrexia.

ANTICHOLINESTERASES – PHYSOSTIGMINE, NEOSTIGMINE, ORGANOPHOSPHATES MECHANISM OF ACTION • • • • •

The enzyme acetylcholinesterase breaks down acetylcholine at the synapse, thereby ending the stimulation of the receptor.

Anticholinesterases act by binding to acetylcholinesterase and preventing the breakdown of acetylcholine.

Edrophonium is a short-acting anticholinesterase.

Physostigmine, neostigmine and pyridostigmine are medium-duration anticholinesterases.

Organophosphates (dysflos, ecothiophate) are irreversible.

INDICATIONS • • • •

Reversal of non-depolarising neuromuscular blockers after surgery.

Diagnosis and treatment of myasthenia gravis.

Alzheimer’s disease.

Glaucoma.

ADVERSE EFFECTS •

Poisoning may occur from exposure to insecticides or nerve gases.

ADRENERGIC DRUGS ALPHA 1 ADRENOCEPTOR AGONIST: PHENYLEPHRINE MECHANISM OF ACTION • Binds to the Alpha 1 adrenergic receptors ligand binding site acting as an agonist. Results in the activation of Gq-protein coupled receptors (GPCR), resulting in the dissociation of the alpha subunit of the G protein, which activates PLC. • PLC coverts PIP2 to IP3 and DAG, opening Calcium channels in the sarcoplasmic reticulum of the smooth muscle cells.

• Calcium entering the sarcoplasm will bind to calmodulin and the resulting complex will activate myosin light chain kinase.

• Phosphorylation of the light chain will result in the smooth muscle contraction. This primarily causes vasoconstriction and bronchoconstriction.

INDICATIONS • As a nasal decongestant SIDE EFFECTS • Rebound congestion, mucosal damage, reflex bradycardia due to increased BP

ALPHA 2 ADRENOCEPTOR AGONIST: CLONIDINE MECHANISM OF ACTION • Binds to the presynaptic Alpha 2 adrenergic receptors ligand binding site acting as an agonist.

• Results in the activation of Gi-protein coupled receptors (GPCR), with the dissociation of the beta and gamma subunits binding to and closing P/Q type calcium channels.

• Limited Ca2+ influx limits the exocytosis of synaptic vesicles containing NA. Thus reducing sympathetic effects on the heart.

• Also reduces Locus Coeruleus activity, resulting in sedative effects.

INDICATIONS • Treatment for hypertension • Sedative for anti-aggressive effects

SIDE EFFECTS • Sedation (can affect locus coeruleus arousal centre), Hypotension, Bradycardia

BETA 1 ADRENOCEPTOR AGONIST: DOBUTAMINE MECHANISM OF ACTION • Binds to the presynaptic Beta 1 adrenergic receptors, found mainly in cardiac muscle cells, ligand binding site acting as an agonist.

• Results in the activation of Gs-protein coupled receptors (GPCR), resulting in the dissociation of the alpha subunit to bind to and activate adenylate cyclase.

• cAMP produced can open IF channels for Na+ influx, for phase 4 depolarisation. cAMP also activates PKA, which can phosphorylate multiple targets, resulting in increasing force of cardiac contractile force and conduction velocity.

INDICATIONS • For acute treatment of cardiac failure SIDE EFFECTS • Can impair cardiac function in chronic use due to tachyphylaxis

BETA 2 ADRENOCEPTOR AGONIST: SALBUTAMOL MECHANISM OF ACTION • Binds to the presynaptic Beta 2 adrenergic receptors, found in vascular and bronchiolar smooth muscle, ligand binding site acting as an agonist.

• Results in the activation of Gs-protein coupled receptors (GPCR), which then activates adenylate cyclase • cAMP can activate PKA, which phosphorylates Myosin light chain kinase, which loses its affinity for Ca2+-Calmodulin, resulting in smooth muscle contraction.

• cAMP also stimulates Nitric Oxide production, which can also stimulate smooth muscle relaxation.

INDICATIONS • For those with asthma and COPD (via bronchodilation) SIDE EFFECTS • Tachycardia, Hypotension

BETA 3 ADRENOCEPTOR AGONIST: MIRABEGRON MECHANISM OF ACTION • Binds to the presynaptic Beta 3 adrenergic receptors, found detrusor smooth muscle, ligand binding site acting as an agonist.

• Results in the activation of Gs-protein coupled receptors (GPCR) • cAMP can activate PKA, which phosphorylates Myosin light chain kinase, which loses its affinity for Ca2+-Calmodulin, resulting in smooth muscle contraction.

• cAMP stimulates Nitric Oxide production, which can also stimulate smooth muscle relaxation.

INDICATIONS • Treats overactive bladder

ALPHA 1 ADRENOCEPTOR ANTAGONIST: PRAZOSIN MECHANISM OF ACTION • Reversible competitive antagonist of Alpha 1, thus inhibits NA mediated smooth muscle contraction, resulting in vasodilation.

INDICATIONS • Relaxes urethra, to decrease resistance to urinary flow SIDE EFFECTS • Hypotension, nasal congestion, etc

ALPHA 1+2 ADRENOCEPTOR ANTAGONIST: PHENOXYBENZAMINE MECHANISM OF ACTION • Irreversible antagonist by alkylating the receptors. Inhibition of the Alpha 1 receptor results in vasodilation. Inhibition of Alpha 2 results in the enhancement of NA release, thus intensifies reflex action of Alpha 1 receptor block.

INDICATIONS • Minimises haemodynamic instability post pheochromocytoma surgery.

SIDE EFFECTS • Reflex tachycardia, hypotension

BETA 1 ADRENOCEPTOR ANTAGONISTS:

1.

ATENOLOL (SPECIFIC TO BETA 1)

MECHANISM OF ACTION • Reversible block of Beta 1 receptor. Inhibition of this receptor results in reduced cardiac output by reducing contractile force and the heart rate. No cAMP being produced also means no opening of IF channels, thus reducing Phase 4 depolarisation.

INDICATIONS • Treatment for chronic heart failure, (helps to reduce O2 demand of damaged myocardium), antiarrhythmic (by reducing phase 4 depolarisation and increasing refractory period by reducing Potassium currents) SIDE EFFECTS • Withdrawal rebound tachycardia

2.

LABETALOL:

MECHANISM OF ACTION • Reversible Beta 1 and Alpha 1 blockade and partial agonist of Beta 2. Alpha 1 blockade results in vasodilation. Beta 1 blockade results in reducing heart rate, contractile force and renin release. No renin means no vasoconstriction.

INDICATIONS: • Antihypertensive, HF SIDE EFFECTS: • Withdrawal, rebound tachycardia

VISUAL SUMMARY OF ADRENERGIC DRUGS

DOPAMINERGIC DRUGS DOPAMINE D2 RECEPTOR AGONISTS: PRAMIPEXOLE, BROMOCRIPTINE MECHANISM OF ACTION • Acts on D2 receptors, which are Gi PCRs, when activated can induce inhibitory effects onto the target cell • Can act at the striatal neuronal cells of the striatum of the basal ganglia of the indirect pathway, in order inhibit the pathway, thus preventing turning down of movement by the basal ganglia.

• Also inhibits lactotroph cell growth, reducing size of adenoma and inhibit secretion of prolactin.

INDICATION: • Parkinson’s Disease, treatment of extrapyramidal side effects of traditional neuroleptics, treatment for hyperprolactinemia and prolactinoma

DOPAMINE D2 RECEPTOR ANTAGONISTS (NEUROLEPTICS): CHLORPROMAZINE, CLOZAPINE, RISPERODONE, ETC. MECHANISM OF ACTION • Acts as a blocker of D2 receptors, resulting in acute effects of increased dopamine release from dopaminergic neurons.

• Therapeutic effects come from chronic use, where excessive dopamine excitation of D1 receptors result in tachyphylaxis of the receptor, resulting in the downregulation of D1 receptors, reducing firing from neurons.

• Many of these drugs also have blockade effects on other receptors, resulting in other therapeutic effects (e.g., 5-HT2A block for treatment of drug induced psychosis) INDICATION: • Psychosis and Manic Episodes (Reduces Dopaminergic neuron firing in the long term)

SIDE EFFECTS: • Extrapyramidal effects (Parkinson like symptoms), Hyperprolactinaemia, etc.

LEVODOPA: MECHANISM OF ACTION • It is a precursor to dopamine, in order to be taken up by dopaminergic neurons in order to be converted by dopamine decarboxylase into dopamine.

• Usually given with carbidopa.

INDICATION: • Short term treatment of Parkinson’s disease (dopamine neurons degradation reduces effectiveness of drug)

DOPAMINE DECARBOXYLASE INHIBITOR: CARBIDOPA MECHANISM OF ACTION • An inhibitor of dopamine decarboxylase, but it is polar, thus is not a BBB penetrant.

• It is used along with levodopa in order to supply the CNS dopaminergic neurons with levodopa, without any levodopa being converted to dopamine in the periphery.

INDICATION: • Parkinson’s (along with Levodopa and other dopamine agonists)

VISUAL SUMMARY OF DOPAMINERGIC DRUGS

CARDIOVASCULAR PHARMACOLOGY ANTICOAGULANTS HEPARIN: LOW FRACTIONAL WEIGHT AND UNFRACTIONATED HEPARIN MECHANISM OF ACTION • Binds to antithrombin, thus potentiates its action to bind to Factor Xa (Only in unfractionated heparin) and Factor II. • Once heparin-antithrombin complex binds to the factor Xa and Factor II, the bond between enzyme and substrate is reactive, resulting in a reaction that changes the conformation of the factors protein structure, making them non-functional, thus preventing coagulation.

INDICATIONS • Treatment for Unstable Angina (to prevent thrombus formation) • Thromboembolism (to prevent further thrombus formation) CONTRAINDICATIONS • Haemophilia • Recent cerebral haemorrhage INTERACTIONS • Heparin Induced Thrombocytopenia (Heparin bind to PF4 from platelets, and then complexes with antibodies, promoting prothrombic effects)

WARFARIN: MECHANISM OF ACTION • Competitively binds to the Vitamin K Epoxide Reductase Component 1, competing with Vitamin K. • Thus, no Vitamin K is reduced for use in the production of coagulation factors II, VII, IX, X. INDICATIONS • Prophylaxis for thrombus formation in unstable angina CONTRAINDICATIONS

•

Haemophilia, Recent Haemorrhages

INTERACTIONS • Metabolised by CYP450 enzymes in the liver, note CYP450 inducer and inhibitor use

DIRECT THROMBIN INHIBITOR: DABIGATRAN, LEPIRUDIN, FACTOR XA INHIBITOR: APIXABAN, RIVAROXABAN MECHANISM OF ACTION • DTI and FXaI can directly bind to their respective serine proteases coagulation factors.

• Therefore, inhibiting their proteolytic function in activating fibrin and thrombin respectively.

INDICATIONS • Unstable angina (prophylaxis for thrombus formation) CONTRAINDICATIONS • Haemorrhage, Haemophilia INTERACTIONS • Dabigatran effect can be reversed by monoclonal antibody antidote

FIBRINOLYTIC: STREPTOKINASE, ALTEPLASE

MECHANISM OF ACTION • Cleaves and converts plasminogen into active plasmin.

• Plasmin can break down fibrin clots. Used primarily for restoring vessel patency to prevent further tissue necrosis.

INDICATIONS • ST Elevated Myocardial infarction (to break down thrombus, in order to promote reperfusion of the heart), Ischemic Stroke, Deep vein thrombosis, Pulmonary embolism CONTRAINDICATIONS • Bleeding risk, recent haemorrhage patients, haemophilia

ANTIPLATELETS SALICYLATES: ASPIRIN See Aspirin

ADP PURINERGIC 2Y12 RECEPTOR: CLOPIDOGREL (PRODRUG), PRASUGREL MECHANISM OF ACTION • Once undergoes metabolism by CYP450 enzyme in liver, pharmacologically active metabolite, irreversibly binds P2Y12 receptor.

• This receptor is usually activated by ADP, which activates a Gi GPCR, resulting in activation of platelets, resulting in platelet aggregation.

• Inhibition of this receptor, will result in no Gi protein activation, thus no adenylate cyclase inhibition.

The resulting rise in cAMP, activates Protein kinase A, which then activates VASP-P, which inhibits platelet activation.

INDICATIONS • Prophylaxis of thromboembolism, especially in angina and myocardial infarction.

PHOSPHODIESTERASE INHIBITOR: DIPYRIDAMOLE (NOTE OTHER TYPES USED IN OTHER TREATMENTS) MECHANISM OF ACTION • Inhibits Phosphodiesterase, thus cAMP is not broken down and maintained.

• The resulting rise in cAMP, activates Protein kinase A, which then activates VASP-P, which inhibits platelet activation.

INDICATIONS • Prophylaxis of thromboembolism, especially in angina and myocardial infarction.

GPIIB-IIIA ANTAGONIST: ABCIXIMAB, TIROFIBAN

MECHANISM OF ACTION • Monoclonal Ab with Arginine, Glycine and Asparagine peptide sequence, this sequence allows this antibody to bind to GPIIb-IIIa receptor, thus preventing platelet aggregation.

INDICATIONS • ST Elevated Myocardial infarction (to break down thrombus, in order to promote reperfusion of the heart) CONTRAINDICATIONS • Recent haemorrhage, those with bleeding disorders

PROSTACYCLIN ANALOGUE: EPOPROSTENOL MECHANISM OF ACTION • PGI2 analogue, resulting in activation of IP receptor, stimulating adenylate cyclase.

• The resulting rise in cAMP, activates Protein kinase A, which then activates VASP-P, which inhibits platelet activation.

ANTIHAEMORRHAGICS HAEMOSTATS: ACTIVE HAEMOSTATS (FIBRIN GLUE/PATCH), MECHANICAL HAEMOSTATS (COLLAGEN, CELLULOSE, ETC.) MECHANISM OF ACTION • Both types work by promoting clot formation, at site of injury.

• Active haemostats contain both thrombin and fibrinogen, thus contributing in the formation of the fibrin clot.

• Mechanical haemostats contain collagen, act by promoting platelet aggregation, via their binding to collagen by GPVI receptors.

• However, mechanical relies on the patient’s own production of fibrin, instead active haemostats are used.

INDICATIONS • For use in trauma and emergency surgeries

CONTRAINDICATIONS •

Mechanical haemostats are not used for those with haemophilia (where less fibrin is produced)

ANTIFIBRINOLYTIC: TRANEXAMIC ACID MECHANISM OF ACTION

• •

It competitively binds to the lysine binding site of plasminogen, thereby preventing their plasminogen maturation into plasmin.

Thus, no breakdown of fibrin, thus clot maintained for longer, reducing blood loss.

INDICATIONS

•

For use in those with haemophilia during surgery, to prevent excessive bleeding .

VWF RELEASE PROMOTER: DESMOPRESSIN SEE USE AS ANTIDIURETIC MECHANISM OF ACTION • Primarily acts on ADH receptors, in distal convoluted tubule in the renal tubule, in order to promote antidiuresis. However, it can also stimulate the release of VWF factor from endothelial cells, thus allowing for platelets aggregation via activation through their GP receptors. Results in promotion of clot formation.

INDICATEDS • Those with haemophilia, VWF disease as prophylaxis to prevent excessive bleeding during surgery.

CONTRAINDICATIONS • Those with hypertension, water retention, hyponatraemia, etc.

REPLACEMENT OF BLOOD PRODUCTS: FVIII, FIX, FVIIA, FEIBA (PROTHROMBIN AND FXA), FRESH FROZEN PLASMA MECHANISM OF ACTION • Replacement of different clotting factors, in order to promote clotting.

INDICATIONS •

Treatment for bleeding disorders such as haemophilia A and B

CONTRAINDICATIONS

•

Contraindicated with use of antifibrinolytic.

SIDE EFFECTS • Risk of thromboembolism increases VISUAL SUMMARY OF DRUGS ACTING ON COAGULATION FACTORS

VISUAL SUMMARY OF DRUGS ACTING ON PLATELET FUNCTION

CARDIAC CONTRACTION DIGOXIN (CARDIAC GLYCOSIDE) – FROM FOXGLOVE (DIGITALIS PURPUREA) MECHANSIM OF ACTION

• • • • •

Digoxin inhibits the Na+/K+ ATPase pump Increased intracellular sodium concentration Reverses/ inhibits sodium/calcium exchanger = increased intracellular Ca2+ Increased Ca2+ = increased CICR by SR More calcium for troponin C binding = increased contractility (inotropic agent)

HALF-LIFE & THERAPEUTIC INDEX: • 1.6 days • Small - 2-2.5ngram/L EFFECTS AUTONOMIC Inhibition of sodium pump in the plasma membrane of neurons -> Inhibits sympathetic outflow Sensitizes the baroreceptors Increases parasympathetic or vagal tone 1. Decrease heart rate 2. Decreased AV note velocity 3. Decreases AV refractory period ELECTROPHYSIOLOGICAL • Decreases automaticity of the AV node • Prolongs the AV node effective refractory period • Slows conduction velocity through the AV node -> negative dromotropic effect • Increases automaticity of the His-Purkinje conduction system INDICATIONS • Most widely used positive ionotropic agent • Congestive Heart Failure • Atrial Tachycardia (Atrial Flutter and AFIB) CONTRA-INDICATIONS • Beta Blockers (AV block and decreased contractility), Calcium antagonists (decreased contractility), potassium waiting diuretics (digoxin toxicity), antibiotics (digoxin toxicity).

• Coadministration with verapamil, quinidine and amiodarone can increase plasma levels of digoxin • Chronic renal failure can reduces its volume of distribution and clearance ADVERSE EFFECTS DIGOXIN TOXICITY; CARDIAC SYMPTOMS; • •

Tachyarrhythmias AV conduction block

NON-CARDIAC SYMPTOMS; • Fatigue • Nausea • Vomiting • Anorexia Treatment = digoxin antibody and reduce dose

Figure 1: Rang and Dales Flash Cards

Referenced in: Cardiac contractility, Integrated Cardiovascular Pharmacology, pharmacokinetics, Adverse Drug Reactions & Pharmacology of Cholesterol and Lipoprotein Metabolism

DOBUTAMINE MECHANISM OF ACTION • Dopamine analogue • Beta-1 non selective agonist -> ionotropic effect • Weak B2 activity and alpha 1 activity EFFECTS • Positive ionotropic agent → Increases contractility → increases cardiac output • Less effect on heart rate and there is little vasoconstriction ADMINISTRATION • Administered as a racemic mixture - both + and - isomers • The + enantiomer is a potent beta 1 agonist and alpha 1 antagonist • The - isomer is an alpha 1 agonist • Therefore there is overall beta 1 agonism INDICATIONS • Cardiogenic shock.

•

Decompensated congestive cardiac failure.

Figure 2: Rang and Dales Flashcards

Referenced in: Cardiac contractility and Adrenergic Pharmacology

MILRINONE/ ENOXIMONE (PHOSPHODIESTERASE INHIBITOR) MECHANISM OF ACTION • Phosphodiesterase’s are responsible for the intracellular degradation of cAMP or cGMP • Phosphodiesterase III = Cardiac smooth muscles specific subtype (III) • Inhibition of phosphodiesterase = Increase intracellular cAMP levels EFFECTS • Positive ionotropic effect • Enhances rate & extent of diastolic relaxation • Vasodilation (arterial and venous) INDICATIONS • Acute HF or acute exacerbations of chronic HF in patients unresponsive to other drugs CONTRA-INDICATIONS • Long term use is associated with increased mortality

Figure 3: Memorang.com

Referenced in: Cardiac contractility

LEVOSIMENDAN (CALCIUM SENSITIZING AGENT, INODILATOR) MECHANISM OF ACTION • Enhances calcium sensitivity of troponin C by binding to cardiac troponin C in a calcium-dependent manner • Opens ATP-sensitive potassium channels in vascular smooth muscle to cause smooth muscle relaxation • Causes hyperpolarization then dilation EFFECTS • Inodilator → positive ionotropic effect and dilator INDICATIONS • Improves cardiac haemodynamic in severe systolic HF and may reduce short-term mortality

Referenced in: Cardiac contractility

CARDIAC RHYTHM DISOPYRAMIDE (CLASS IA ANTIARRHYTHMIC, NA+ CHANNEL BLOCKER) MECHANISM OF ACTION • Bind to open sodium channels, • Increases the effective refractory period (K+ channel block) • Increases AV node conduction velocity (vagolytic effect)

EFFECTS • Negative inotropic effect on the ventricular myocardium → decreasing the contractility • Anti-cholinergic effects ADVERSE EFFECTS • Atropine like effects (anticholinergic) • Dry mouth • Constipation • Urinary retention – Disopyramide should not be given to patients with symptomatic prostatism.

• Blurred vision • Glaucoma • Rash • Agranulocytosis INDICATIONS • Wolff-Parkinson-White Referenced in: Pharmacology of Cardiac Rhythm

LIGNOCAINE (CLASS IB ANTIARRHYTHMIC, AMIDE LOCAL ANAESTHETIC) Also known as lidocaine MECHANISM OF ACTION • Bind to open & inactivated Na+ channels; • Shorten Action Potential Duration; • Fast dissociation – effective in depolarised or rapidly driven tissue INDICATIONS • Topical local anaesthetic • Intravenously for ventricular dysrhythmia Referenced in: Pharmacology of Cardiac Rhythm, Local Anaesthetics

FLECAINIDE (CLASS IC ANTIARRHYTHMIC) MECHANISM OF ACTION • Flecainide blocks Nav 1.5 (sodium channel in heart) • Slows the upstroke of the cardiac action potential • Blocks phase 0 more than other agents; slow association/dissociation • Greatest effect is on ventricular myocardium and His-Purkinje system EFFECTS • No change in AP duration • Marked Na+ channel block • Slowed conduction INDICATIONS • AVNRT • Wolf Parkinson’s White

ATENOLOL (BETA BLOCKER, CLASS II ANTIARRHYTHMIC) MECHANISM OF ACTION • Inhibits β1 receptors on pacemaker cells • Decreases pacemaker current through If Na+ channels • Lowers the Ca2+ and K+ current in AV node EFFECTS • Decreases conduction velocity and increases AV node refractoriness • Reduces incidence of re-entry • Little effect on ventricular conduction and repolarization INDICATIONS • Hypertension • Angina • Prevention of dysrhythmia in myocardial infarction • PSVT

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in Av node

Figure 4: Rang and Dales Flashcards

Referenced in: Pharmacology of Cardiac Rhythm, Adrenergic Pharmacology

AMIODARONE (CLASS III ANTIARRHYTHMIC) MECHANISM OF ACTION • Blocks the delayed rectifier K+ current (class III) • Blocks the Na+ current (Class I) • Blocks calcium current (Class IV) • Blocks beta-adrenoceptors (Class II) • May alter membrane elasticity leading to altered membrane and channel function HALF-LIFE • 25-110 days ADVERSE EFFECTS • EAD (Early Afterdepolarization) • Torsade de pointes • Pulmonary fibrosis

CONTRAINDICATIONS • Able to decrease the metabolism of warfarin through inhibition of cyp2c9/3a4 • Increases concentration of digoxin through P-glycoprotein inhibition

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Referenced in: Pharmacology of Cardiac Rhythm, Thyroid hormone production

ADENOSINE (ANTI-DYSRHYTHMICS) MECHANISM OF ACTION • Agonist of adenosine receptors A1 and A2 • Activates P1 purinergic receptors to open G-protein coupled K+ channels causing hyperpolarization and slow conduction • Inhibits cAMP-dependent Ca2+ influx EFFECTS • Slows AV nodal conduction • Increases ERP of AV node INDICATIONS • Supraventricular tachycardia

Referenced in: Anxiolytics, Sedatives/ Hypnotics, Pharmacology of Cardiac Rhythm

PHARMACOLOGY OF VASCULAR TONE DRUGS THAT WORK ON THE RAAS PATHWAY

CAPTOPRIL (ACE INHIBITOR)

Other drugs in this class: Enalapril, Ramipril and Lisinopril MECHANISM OF ACTION • Inhibits the angiotensin-converting enzyme in the RAAS pathway leading to inhibition of angiotensin II synthesis • Angiotensin II is a potent vasoconstrictor EFFECTS • Vascular smooth muscle relaxation • Vasodilation • Reduced blood pressure ADVERSE EFFECTS • Increased bradykinin levels = dry cough and taste disturbances • Initial hypotension • Reversible renal impairment • Teratogenic INDICATIONS • Hypertension • Heart failure • Myocardial infarction

Referenced in: Pharmacology of Volume Regulation, Pharmacology of Vascular Tone, Integrated Cardiovascular Pharmacology

LOSARTAN (ANGIOTENSIN II RECEPTOR ANTAGONIST) Other drugs in this class: Candesartan & Valsartan MECHANISM OF ACTION • Competitive antagonist of angiotensin II AT1 receptor • Angiotensin II is a potent vasoconstrictor EFFECTS • Vascular smooth muscle relaxation • Vasodilation • Reduced blood pressure ADVERSE EFFECTS • See ACE inhibitor • No dry cough INDICATIONS • Hypertension • Heart Failure • Where ACE not tolerated (bradykinin adverse effects)

Referenced in: Pharmacology of Volume Regulation, Pharmacology of Vascular Tone, Integrated Cardiovascular Pharmacology

ALISKIREN (RENIN INHIBITOR) DRUG • • •

PROPERTIES Low oral bioavailability T1/2 = 24 hours Administered once daily

MECHANISM OF ACTION • Inhibits Renin • Renin converts angiotensinogen to angiotensin I as the first step in the RAAS pathway • The inhibition of this step downregulates the RAAS pathway Referenced in: Pharmacology of Volume Regulation, Pharmacology of Vascular Tone, Integrated Cardiovascular Pharmacology

GLYCERYL TRINITRATE (NITRATES)

MECHANISM OF ACTION • Enhances release of nitric oxide by an unknown mechanism • Release of NO is enhanced by cysteine & glutathione reductants SITES OF ACTION • Acts preferentially on large vessels at therapeutic dose • Also has some effect on venous vessels leading to reduced EDP and volume-decrease preload and reduced cardiac oxygen demand PHARMACOKINETICS • Low oral bioavailability because of liver metabolism ADVERSE EFFECTS • Flushing • Headache • Syncope (fainting) INDICATIONS • Sublingual Spray - acute angina symptoms • Transdermal patch - prophylaxis of angina Referenced in: Pharmacology of Vascular Tone

SILDENAFIL (PHOSPHODIESTERASE 5 INHIBITOR) ( VIAGRA) Other drugs in this class: Tadalafil & Vardenafil MECHANISM OF ACTION • Inhibition of PDE 5 prevents the breakdown of cGMP • This prolongs the action of nitric oxide leading to vasodilation

EFFECTS • Vasodilates the smooth muscle corpus cavernosum • Increased blood flow • Penile erection ADVERSE EFFECTS • Flushing • Headaches, • Dyspepsia, • Decreased blood pressure INDICATIONS • Erectile dysfunction • Sildenafil + iloprost = primary pulmonary hypertension CONTRA-INDICATIONS • Nitrates and other vasodilatory agents

mood-t m.L.uc-Q NO

(Door-a -

PD

Cquase

5' Cit-I p

Figure 5: Rang and Dales Flashcards

Referenced in: Pharmacology of Vascular Tone

AMLODIPINE/ NIFEDIPINE (DIHYDROPYRIDINE, CALCIUM CHANNEL BLOCKER)

MECHANISM OF ACTION • Inhibits voltage-gated L-type calcium channels EFFECTS • Vasodilation of smooth muscle • Inhibition of cardiac contraction and conductance

ADVERSE EFFECTS • Nausea, • Dizziness, • Headache, • Gingival hypertrophy, • Facial flushing, • Reduced HR and AV node conduction heart block, • Reflex tachycardia ischaemia, • Peripheral ankle oedema

Referenced in: Pharmacology of Vascular Tone

VERAPAMIL (PHENYLALKYLAMINE, CALCIUM CHANNEL BLOCKER, CLASS IV ANTIARRHYTHMIC)

MECHANISM OF ACTION • Inhibits voltage-gated L-type calcium channels • Preferentially acts on pacemaker tissue as these require calcium to depolarize EFFECTS • Vasodilation of smooth muscle • Slowed rise of AP in AV node • Prolonged AP • Blockage of re-entrance arrhythmias • Inhibition of cardiac contraction and conductance ADVERSE EFFECTS • See amlodipine adverse effects • Ventricular contractility • AV block INDICATIONS • Angina, • Hypertension, • Prophylaxis of paroxysmal supraventricular tachycardia

Referenced in: Pharmacology of Vascular Tone and Antiarrhythmic pharmacology

DILTIAZEM (BENZOTHIAZEPINE, CALCIUM CHANNEL BLOCKER)

MECHANISM OF ACTION • Inhibits voltage gated L-type calcium channels EFFECTS • Vasodilation of smooth muscle • Inhibition of cardiac contraction and conductance ADVERSE EFFECTS

•

See amlodipine adverse effects

INDICATIONS • Atrial arrhythmia, • Hypertension, • Paroxysmal supraventricular tachycardia • Chronic stable angina

Referenced in: Pharmacology of Vascular Tone

NICORANDIL/ MINOXIDIL (K+ CHANNEL OPENERS)

MECHANISM OF ACTION • Opens & activates ATP-dependent K+ channels • K+ influx causes hyperpolarization which blocks the Ca2+ influx EFFECTS • Smooth muscle relaxation • Arterial vasodilation ADVERSE EFFECTS • Arterial vasodilation can lead to sympathetic reflex tachycardia INDICATIONS • Used in combination with beta blockers (Counteracts reflex tachycardia) • Nicorandil - angina • Minoxidil – hypertension

Figure 6: Rang and Dales Flashcards

Referenced in: Pharmacology of Vascular Tone

BOSENTAN (DUAL ENDOTHELIN RECEPTOR ANTAGONIST)

MECHANISM OF ACTION • Specific and competitive antagonist at both ETA & ETB receptors ADVERSE EFFECTS • Elevates serum transaminase levels • Liver function must be monitored INDICATIONS • Pulmonary hypertension

ADRENALINE (SYMPATHOMIMETIC, VASOCONSTICTOR)

MECHANISM OF ACTION • Acts on 𝛼 and β adrenergic receptors EFFECTS • Vascular smooth muscle contraction & peripheral vasoconstriction • Increased heart rate & positive ionotropic effect from activation of β1 adrenoceptors INDICATIONS • Emergency use in anaphylactic shock and cardiac arrest

Referenced in: Pharmacology of Vascular Tone

ADH/ TERLIPRESSIN (VASOCONSTRICTOR)

MECHANISM OF ACTION • Acts on Vasopressin receptor V1a, V2 • Activates adenylate cyclase to cause the release of aquaporin 2 INDICATIONS • Intravenous infusion to stop bleeding from oesophageal varices pre-surgery

Referenced in: Pharmacology of Vascular Tone

VOLUME REGULATION CARBONIC ANHYDRASE INHIBITORS: ACETAZOLAMIDE OTHER COMMONLY USED DRUGS IN THIS CLASS • •

Dichlorphenamide Methazolamide

MECHANISM OF ACTION •

•

•

• •

CAIs work in the proximal convoluted tubule of the nephron where 65-70% of sodium is reabsorbed from the filtrate and water passes freely. They inhibit carbonic anhydrase enzyme which converts carbonic acid to water and carbon dioxide.

Water and carbonic dioxide enter the intracellular space via diffusion and are converted back into carbonic acid, which dissociates into H+ and bicarbonate. Sodium and bicarbonate are reabsorbed while protons (acid) are excreted.

By inhibition of the enzyme, CAI medications result in the inhibition of the resorption of bicarbonate by the tubular cells in the basolateral membrane within the kidney, leading to retention of bicarbonate in the tubular lumen. This leads to increased delivery of sodium and bicarbonate to distal parts of the nephron.

The overall effect is the alkalization of urine and more acidic blood due to the excretion of bicarbonate.

The diuretic effect causes increased excretion of water and a decrease in blood pressure. Its initial use causes an acute decrease in plasma volume whereas there is an overall weak effect on sodium ion retention after a several day therapy because the downstream loop of Henle is able to reabsorb a large fraction of excess sodium ions that are delivered in the filtrate to these sites in the nephron.

INDICATIONS • • •

Treatment of elevated intraocular pressure, Altitude sickness prophylaxis Treatment of oedema due to congestive heart failure

CONTRAINDICATIONS • • • • •

Metabolic acidosis (important side effect- due to reduction in the reabsorption of bicarbonate) Hypersensitivity to sulfonamides e.g sulfa allergy (should not use) Hepatic disease- cirrhosis or impaired hepatic function because usage may precipitate development of hepatic encephalopathy as it decreases clearance of ammonia Marked renal impairment or decreased kidney function (avoid use) Hyperchloremic acidosis / Hypokalaemia/ Hyponatremia (should not use)

CLINICAL NOTE •

Weak diuretic, main use in glaucoma Refer to Volume Regulation lecture

LOOP DIURETICS: FUROSEMIDE OTHER COMMONLY USED DRUGS IN THIS CLASS Bumetanide (40X more potent than Furosemide) MECHANISM OF ACTION • • • • •

Inhibits Na/ K/ 2Cl co-transporter reversibly in the luminal membrane of the thick ascending loop of Henle which inhibits tubular reabsorption of sodium and chloride Results in excess excretion of water along with calcium, chloride and magnesium.

Reduces the tonicity of the medullary interstitium inhibit the reabsorption of water in the collecting duct has vasodilatory effects by increasing venous capacitance and decreasing preload

INDICATIONS • • • • •

oedema or ascites such as cirrhosis liver, nephrotic syndrome reduced acute pulmonary oedema and congestive heart failure (useful in emergency situations for intense, rapid diuresis) oedema chronic renal disease or failure hypertension complicated by renal impairment hypercalcemia.

CONTRAINDICATIONS • •

Anuria hypersensitivity to furosemide

ADVERSE EFFECTS • • • • • •

Acute hypovolemia - which can cause a rapid and severe decrease in blood volume and possibly cause hypotension, cardiac arrhythmias and/or shock Hypokalaemia and potential digoxin toxicity – because it stimulates increased exchange of tubular sodium for potassium Gout- due to block of uric acid excretion Volume depletion and body sodium depletion can cause dizziness, postural hypotension, renal impairment and decreased renal perfusion Hypomagnesemia and hypocalcaemia - which has osteoporosis effects on bone metabolism and is clinically significant for long term use Ototoxicity- (very rare) hearing damage with continued high dose treatment which is worse with aminoglycoside antibiotics

CLINICAL NOTE •

Thiazides are preferred if renal function is preserved.

Refer to Volume Regulation lecture

THIAZIDE DIURETICS: HYDROCHLOROTHIAZIDE OTHER COMMONLY USE DRUGS IN THIS CLASS • •

Bendroflumethiazide Chlorthalidone

MECHANISM OF ACTION • Inhibits Na+/Cl- transporter in the apical membrane of the distal convoluted tubule by binding to the thiazide sensitive Na+/Cl- transporter • Therefore increases the excretion of sodium in the kidney with accompanying water or fluid.

• Chloride ions are also lost in the process. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism in the collecting duct.

• Thiazide diuretics promote the reabsorption of calcium ions which contrasts loop diuretics leading to decreased calcium excretion.

• This decreased calcium excretion is beneficial to elderly people suffering from osteoporosis.

• Bendroflumethiazide action is mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium -activated potassium channel, also found in the smooth muscle.

INDICATIONS • •

Treatment of hypertension (1st line treatment) Treatment of oedema associated with congestive heart failure, nephrotic syndrome, ascites

CONTRAINDICATIONS •

Anuria

• •

hypersensitivity to sulfonamide-derived drugs.

Severe renal or hepatic insufficiency

ADVERSE EFFECTS • • • • • •

Potassium depletion which can potentiate the risk of arrhythmias if it’s a frequent problem Gout- due to blockage of urate excretion Hyperglycemia- due to impaired glucose tolerance which leads to less insulin production from the activation of potassium-ATP channels in pancreatic islet cells Hypercalcemia- because inhibition of secretion of calcium ions can increase their blood concentration Erectile dysfunction at high doses Hypersensitivity can lead to bone marrow suppression or dermatitis

CLINICAL NOTE Thiazides produce a moderate diuresis because only a maximum of 5% of the filtered sodium load is excreted Refer to Volume Regulation lecture

POTASSIUM SPARING DIURETICS – 2 GROUPS (SODIUM CHANNEL BLOCKERS & MINERALOCORTICOID RECEPTOR ANATGONISTS)

SODIUM CHANNEL BLOCKERS: AMILORIDE OTHER DRUGS USED IN THE SAME CLASS •

Triamterene

MECHANISM OF ACTION • • • •

Site of action is at the cortical collecting duct.

Directly inhibits sodium reabsorption by blocking the luminal sodium channels. This increases the excretion of sodium in the collecting duct principal cells.

Acts independently of aldosterone and so indirectly reduces the excretion of potassium which can cause hyperkalemia.

It is usually administered orally and its effects are within 2 hours and last up to 24 hours.

INDICATIONS • •

Prevent hypokalaemia Reduce hypertension and oedema (often administered in combination with a thiazide or loop diuretic)

CONTRAINDICATIONS • • • •

Decreased renal or liver function Metabolic acidosis Diabetes Contraindicated in people that are already taking potassium-sparing drugs such as spironolactone or are taking potassium supplements such as potassium chloride)

ADVERSE EFFECTS •

hyperkalaemia particularly if combined with ACE inhibitors, angiotensin receptor blockers, excess potassium in diet or taking potassium supplements

Refer to Volume Regulation lecture

MINERALOCORTICOID RECEPTOR ANTAGONISTS: SPIRONOLACTONE OTHER DRUGS USED IN THIS CLASS Eplerenone MECHANISM OF ACTION Counteracts the effects of aldosterone within the cortical collecting ducts by competing with it for intracellular receptors. This prevents the transcription of new proteins that give rise to an increased expression of sodium channels within the apical membrane.

INDICATIONS • •

Hyperaldosteronism due to the elevated levels of aldosterone Prevents potassium loss, hypertension and heart failure

CONTRAINDICATIONS • • •

Addison’s disease Hyperchloremic acidosis Decreased kidney function/ acute kidney failure

ADVERSE EFFECTS •

Hyperkalaemia particularly if combined with ACE inhibitors, angiotensin receptor blockers, excess potassium in diet or taking potassium supplements

Additional effects for Spironolactone: • • • •

Gynaecomastia (development of mammary glands in males) Erectile dysfunction Menstrual disorders Reduction in hirsutism (excessive hair growth)

CLINICAL NOTE Spironolactone binds to other steroid receptors which are minimised with eplerenone as it is more selective

Refer to Volume Regulation lecture

OSMOTIC DIURETICS: MANNITOL MECHANISM OF ACTION It is a pharmacologically inert substance that is administered intravenously. It acts indirectly by modifying the content of the filtrate by increasing the filtrate osmolarity. It works by being freely filtered in the glomerulus and poorly reabsorbed from the renal tubular fluid. This gives the diuretic its ability to carry water into the tubular fluid along with it. As a result, there is an increase in urinary output. It also increases blood plasma osmolality resulting in enhanced flow of water from tissues into interstitial fluid.

INDICATIONS • • • •

Promotes diuresis in acute renal failure Reduces intraocular pressure Prevention of intradialytic hypotension Reduces intracranial pressure in the treatment of cerebral oedema

CONTRAINDICATIONS •

Known mannitol hypersensitivity

• •

Anuria (due to renal disease) Pulmonary oedema (because it increases the plasma volume so unsuitable for treatment of most causes of oedema including cardiac failure)

EFFICACY OF DIURETICS • • •

2-3% weak potassium-sparring diuretics 10% thiazides 20-30% potent loop diuretics

Refer to Volume Regulation lecture

VASOPRESSIN (ADH) MECHANISM OF ACTION • • • • •

•

Binds to the V receptor on the kidneys’ principle cells within the distal tubules and collecting ducts This leads to an activation of adenylate cyclase (AC) which causes a subsequent increase in the second messenger cyclic amp cyclic AMP activates protein kinase A, a phosphorylating enzyme which initiates an intracellular phosphorylation cascade This causes phosphorylation of aquaporin-2 storage vesicles promoting their movement and insertion into the apical membrane.

Aquaporins are water channels that allow water to move passively into the cell via an osmotic gradient established by sodium chloride and urea thus encouraging the reabsorption of water in the kidney.

Also has a second action on vascular smooth muscle: o Binds to V receptors on vascular smooth muscle and activates G protein o G protein activates phospholipase C which results in the production of IP3 as well as DAG from the cell membrane o IP3 causes release of intracellular calcium from the endoplasmic reticulum o DAG and calcium activate protein kinase C, which just like protein kinase A, results in a signaling phosphorylation cascade o the overall effect of the signaling cascade is the contraction of vascular smooth muscle leading to an increase in the total peripheral resistance and thus an increase in blood pressure

CLINICAL NOTE • • •

Short duration of action Weak selectivity for V2 receptors Given subcutaneously or intramuscular injection or by intravenous infusion

DESMOPRESSIN

MECHANISM OF ACTION • • • • •

Selective vasopressin V2 receptor agonist present throughout the collecting ducts and DCT of the kidneys V2 receptor is Gs-protein coupled receptor that actives a signalling cascade of adenyl-cyclase (AC) when activated Causes an increase in cAMP resulting in increased water permeability This leads to decrease in urine volume and an increase in urine osmolality Signalling cascade also induces the exocytosis of von-Willebrand factor and factor VIII from the storage sites, facilitating the clotting cascade and resulting in haemostasis.

INDICATIONS • • • • •

Nocturnal polyuria Haemophilia A Diabetes insipidus Willebrand disease Uremic bleeding

CONTRAINDICTIONS •

Hyponatremia

CLINICAL NOTE • • •

Increased duration of action V2 receptor selective reduced pressor effects Can be given by several routes including nasal spray

TERLIPRESSIN MECHANISM OF ACTION •

Acts on three different receptors: o Vasopressin receptor V1a - initiates vasoconstriction, liver gluconeogenesis, platelet aggregation and release of factor VIII o Vasopressin receptor V1b - mediates corticotrophin secretion from the pituitary o Vasopressin receptor V2 - controls free water reabsorption down an osmotic gradient in the medulla of the kidney by activating adenylate cyclase which causes the release of aquaporin 2 channels into the medullar cells.

INDICATIONS • •

Treatment of bleeding oesophageal varices Maintenance of blood pressure

CONTRAINDICATIONS •

Pregnancy, renal impairment (chronic renal failure), vascular disease, arrythmias, cardiac disease, severe asthma, COPD, unstable angina, recent MI, uncontrolled hypertension

CLINICAL NOTE •

Increased duration of action

FELYPRESSIN MECHANISM OF ACTION •

Binds to vasopressin receptor V1a and causes contraction of smooth muscle

INDICATIONS •

Used as an alternative to adrenaline as a localising agent

CONTRAINDICATIONS •

Severe anaemia, cardiovascular disease, untreated hypertension, impaired respiratory function, diabetes, G6PD deficiency

CLINICAL NOTE • •

Short duration of action Usually injected with local anaesthetics such as prilocaine to prolong their action

Refer to Volume Regulation lecture

CHOLESTEROL AND LIPOPROTEIN METABOLISM

HMG CO-ENZYME A REDUCTASE INHIBITORS (STATINS) : SIMVASTATIN OTHER COMMONLY USED DRUGS IN THIS CLASS Lovastatin, Pravastatin, Atorvastatin MECHANISM OF ACTION

• •

•

Inhibits HMG Co-enzyme A reductase competitively which reduces hepatic cholesterol synthesis via the mevalonate pathway.

Activates Sterol Regulatory Element- Binding Protein (SREBP) transcription factor which binds to sterol regulatory element (SRE) DNA sequence leading to an upregulation of LDL-receptors and increased hepatic removal of LDL from circulation.

This results in reduced LDL cholesterol, triglycerides and increased HDL cholesterol.

INDICATIONS • • •

Primary hypercholesterolaemia Homozygous familial hypercholesterolaemia Cardiovascular events in atherosclerotic cardiovascular disease or diabetes prevention

CONTRAINDICATIONS • •

Avoid in pregnancy and active liver disease Caution in patients with history of liver disease and risk factors for myositis or rhabdomyolysis

INTERACTIONS • • •

Metabolized by CYP3A4, accumulates in plasma with concomitant use of drugs that inhibit CYP3A4 increasing the risk of side effects Anticoagulant effect of warfarin/ international normalised ratio is increased Greater risk of myopathy when administered with Amiodarone, calcium channel blockers, fibrates (particularly gemfibrozil), antibiotics, antifungals, antivirals.

CLINICAL NOTE

•

Simvastatin, Lovastatin, Pravastatin are short-acting (half life = 1-4hours) and administered at night to reduce peak cholesterol synthesis in the early morning.

•

Atorvastatin and Rosuvastatin are longer acting (half life = 20 hours) and more potent.

Refer to Pharmacology of Cholesterol and Lipoprotein metabolism lecture

FIBRATES: GEMFIBROZIL OTHER COMMONLY USED DRUGS IN THIS CLASS

Fenofibrate MECHANISM OF ACTION • •

Agonists of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) -nuclear TF resulting in increased transcription of genes in lipid metabolism.

Increased apoA1 results in increased HDL in plasma

•

Increase in lipoprotein lipase activity reducing VLDL, TG plasma, decreased plasma TG leads modest decrease LDL.

INDICATIONS • •

Hypertriglyceridemia (especially type IV and V hyperlipidaemia) Risk of developing coronary heart disease reduced

CONTRAINDICATIONS • • •

Septic or severe renal dysfunction including primary biliary cirrhosis Presence of cholelithiasis Gallbladder abnormalities

INTERACTIONS • •

Combination therapy of gemfibrozil with statins (Simvastatin), enhances probability of developing Rhabdomyolysis and/or myopathy by increasing statin serum levels Increases anticoagulant effect of warfarin by inhibiting CYP2C9.

Refer to Pharmacology of Cholesterol and Lipoprotein metabolism lecture

BILE ACID SEQUESTRANT: CHOLESTYRAMINE OTHER DRUGS COMMONLY USED IN THIS CLASS: Colestipol MECHANISM OF ACTION • •

Increases excretion by binding bile acids in the intestine, preventing reabsorption and enterohepatic recirculation of cholesterol.

This results in greater conversion of cholesterol in the liver via 7a-hydroxylation, which is usually controlled by negative feedback by bile acids.

INDICATIONS • • • •

Primary hypercholesterolemia Hypercholesterolemia associated with mild hypertriglyceridemia Second-line treatment for pruritus associated with cholestatic disease Incomplete biliary obstruction.

CONTRAINDICATIONS • •

Severe hypertriglyceridemia Complete biliary obstruction

CLINICAL NOTE

•

Can be used in combination with niacin and the cholesterol absorption inhibitor ezetimibe to achieve target goals in patients in both primary and secondary prevention

Refer to Pharmacology of Cholestrol and Lipoprotein metabolism lecture

CHOLESTEROL ABSORPTION INHIBITORS: EZETIMIBE MECHANISM OF ACTION

•

Inhibits absorption of dietary cholesterol by selectively blocking a transport protein Niemann-Pick C1- like 1 (NCPC1L1) in the brush border of enterocytes without affecting the absorption of fat soluble vitamins, triglycerides or bile acids.

INDICATIONS

• • •

Primary Hypercholesterolaemia (co-administered with a statin or in monotherapy) prevention of cardiovascular events homozygous familial hypercholesterolemia

CONTRAINDICATIONS

• • • •

Hypersensitivity pregnancy and lactation when co-administered with statins active liver disease persistent or unexplained elevations in serum transaminases.

Refer to Pharmacology of Cholestrol and Lipoprotein metabolism lecture

NIACIN

•

a vitamin used in the synthesis of NAD, NADP cofactors in metabolic processes

MECHANISM OF ACTION

•

•

Undergoes biochemical reactions in the mitochondria with nicotinamide and tryptophan to form NAD and NADP, which are active forms of niacin that participate in catabolic redox reactions and are cofactors in anabolic redox reactions in their reduced forms (NADH and NADPH respectively).

It affects the lipolysis in the adipose tissue and increases HDL through apoA1 augments reverse cholesterol transport.

INDICATIONS

• • • • • • •

Diabetic encephalopathy Schizophrenia malignant glioma neurodegenerative diseases hyperphosphatemia in chronic kidney disease arthritis Decreases incidence of cardiovascular events and age associated neurological disorders such as Alzheimer's disease.

CONTRAINDICATIONS

• • • • •

Active peptic ulcer disease active liver disease Unexplained and persistent elevations and hepatic transaminases hypersensitivity to niacin arterial bleeding

ADVERSE EFFECTS • • •

flushing, GI disturbance, palpitations high does can precipitate gout high doses can disturb liver function and impair glucose tolerance in diabetic patients

CLINICAL NOTE

• •

most potent agent used to increase HDL cholesterol Not authorized in Ireland at present Refer to Pharmacology of Cholestrol and Lipoprotein metabolism lecture

FISH OIL DERIVATIVES: EICOSAPENTAENOIC ACID & DOCOSAHEXAENOIC ACID MECHANISM OF ACTION •

Reduce plasma triglycerides by inhibition of VLDL TG biosynthesis

• • • •

reduce platelet function prolong bleeding anti-inflammatory reduce plasma fibrinogen

CLINICAL NOTE •

There is evidence to show an improvement in survival in patients who have recently had a myocardial infarction

Refer to Pharmacology of Cholestrol and Lipoprotein metabolism lecture

NEUROPHARMACOLOGY

GENERAL ANAESTHETICS: Note Guedel’s Classifications on Anaesthesia depth and contraindicated use on patient who has consumed alcohol INDICATIONS:

•

Loss of consciousness, memory, muscle reflexes and tonicity during surgery

INHALED ANAESTHETICS: NITRIC OXIDE, HALOGENATED ETHERS (E.G. ISOFLURANE) MECHANISM OF ACTION

• •

•

Positive allosteric modulator of GABA A receptor and Negative allosteric modulator of NMDA receptor.

Prolonged GABA A receptor inhibitory action and decreased NMDA receptor action, can result in therapeutic effects such as analgesia, amnesia (during surgery), anaesthesia, and unconsciousness.

Fast onset and offset of action, due to lipophilicity.

SIDE EFFECTS:

• •

Possible anoxia (for NO) malignant hyperthermia (for halogenated ethers)

INTRAVENOUS ANAESTHETICS:

KETAMINE: MECHANISM OF ACTION

•

Negative allosteric modulator and blocker of NMDA receptor. Decreased NMDA receptor pathway results in the inhibition of pain, memory, sensory consciousness.

SIDE EFFECTS:

•

Hallucinations, psychosis (not used as often for anaesthetics)

BARBITURATES (THIOPENTONE SODIUM), PROPOFOL, ALPHAXALONE MECHANISM OF ACTION

• •

Positive allosteric modulator of GABA A receptor, prolonging opening of ion channel, thus more Cl- ion influx into the neuron.

Results in hyperpolarization of neurons, resulting in inhibition of action potential firing.

SIDE EFFECTS:

•

Respiratory depression

INTERACTIONS:

•

With alcohol, which has a similar depressive action of these drugs, result in further depression of CNS and respiratory system, which can be fatal

LOCAL ANAESTHETICS SODIUM CHANNEL BLOCKERS: BENZOCAINE, LIGNOCAINE

MECHANISM OF ACTION

• •

Binds to the S6 subunit of the sodium channel, reducing its permeability for sodium influx into the neuron, thus no depolarisation and propagation of action potentials.

Usually affects pain fibres first due to lower myelination as well as smaller diameter making them more susceptible to drug effects.

INDICATIONS:

•

Reduce sensation, especially pain of peripheral area before simple surgical procedures

SIDE EFFECTS:

• • •

Further CNS depression, drowsiness which can progress into a coma.

Respiratory depression, which can lead to asphyxiation Drugs such as lignocaine, which have a longer duration of action (due to slower metabolism by microsomal enzymes), can further contribute to side effects

VISUAL SUMMARY OF ANAESTHETICS

ANTICONVULSANT INDICATIONS

•

In conditions that induce seizures, by reducing brain activity, thus reducing opportunity for hypersynchronisation of neuron firing, characteristic to seizures

GABA A RECEPTOR POSITIVE ALLOSTERIC MODULATOR: BENZODIAZEPINES, BARBITURATES MECHANISM OF ACTION

• • •

Benzodiazepines (diazepam) can bind to the site between alpha and gamma subunits of the GABA A receptors.

Barbiturates bind to the alpha subunit of the GABA A receptor, which prolongs its opening thus more Cl- ion influx into the neuron.

Results in hyperpolarization of neurons, resulting in inhibition of action potential firing. This results in reduced activity of the neurons, thus less opportunity for the neuronal firing to synchronise, which would result in seizures.

GABA TRANSAMINASE INHIBITOR: TIAGABINE MECHANISM OF ACTION

•

Inhibits GABA Transaminase, preventing GABA metabolism into succinate semialdehyde. Thus, more GABA can be recycled for use, thus stores of GABA not depleted, further potentiating their inhibitory function in reducing neuronal firing.

Thus, reduces neuronal activity to prevent them from synchronising.

GAT INHIBITOR: VIGABATRIN MECHANISM OF ACTION

• •

Inhibits GAT-1 reuptake of GABA, thus more remains in the synaptic cleft Therefore, further potentiates their inhibitory function.

SODIUM CHANNEL BLOCKERS: CARBAMAZEPINE, PHENYTOIN MECHANISM OF ACTION

• •

Blockade of sodium channel results in sodium influx into the neuron, thus no depolarisation and propagation of action potentials.

Reduction of firing rate results in reduced chance to for neuronal firing to hyper synchronise.

SODIUM CHANNEL ALLOSTERIC MODULATOR: LACOSAMIDE MECHANISM OF ACTION

• •

Change of conformation of the sodium channel results in sodium influx into the neuron, thus no depolarisation and propagation of action potentials.

Reduction of firing rate results in reduced chance to hypersynchronise.

P/Q-TYPE CALCIUM CHANNEL BLOCKER: PREGABALIN MECHANISM OF ACTION

• •

Blockade of this channel in the axon terminal, prevents calcium influx, resulting in no interactions between calcium and synaptotagmins and other synaptic docking proteins.

Thus, no exocytosis of neurotransmitter, thus reduced stimulation of the postsynaptic neuron. Thus, reduced neuronal firing.

T-TYPE CALCIUM CHANNEL BLOCKER: ETHOSUXIMIDE

MECHANISM OF ACTION

• •

Found in areas in the brain that regulate synchronisation and sleep, such as thalamocortical neurons.

Blockade here, prevents thalamocortical firing, thus further reducing opportunity for hypersynchronisation.

POTASSIUM CHANNEL OPENERS: EZOGABINE MECHANISM OF ACTION

• •

Positive allosteric modulator of potassium channel, thus prolongs their opening and increases efflux of potassium ions out of the cell, resulting in hyperpolarisation.

Thus, no action potential firing, reducing their activity and opportunity for hypersynchronisation of firing.

SODIUM VALPROATE MECHANISM OF ACTION

•

Can block both sodium and T-type calcium channels, reducing firing of neurons.

CONTRAINDICATIONS

•

In pregnant women, due to teratogenic effects, which can affect development of the foetus

SIDE EFFECTS

•

Teratogenic effect, nausea, drowsiness, etc.

SYNAPTIC VESICLE PROTEIN 2A MODULATOR: LEVETIRACETAM MECHANISM OF ACTION

• •

Negative modulator of this protein, prevents its function of docking glutamatergic vesicles at the axon terminal.

Thus, no exocytosis of glutamate, thus no stimulation of post-synaptic neuron.

VISUAL SUMMARY OF ANTICONVULSANTS

ANALGESICS NON-NARCOTIC ANALGESICS TRADITIONAL NSAIDS: ASPIRIN See Aspirin

COXIBS: MECHANISM OF ACTION

• •

Binds to a side pocket within the active site of the enzyme COX 2, present only in COX 2.

Thus, has more selective effects compared to NSAIDS, giving them a better side effect profile.

PARACETAMOL: MECHANISM OF ACTION

• • •

Binds to the active site of the COX 3 enzyme (a COX 1 variant found in the brain).

This results in more selective analgesic effects in the central nervous system but does not produce analgesic effects at the periphery.

Thus, also has better side effect profile than NSAID.

NARCOTIC ANALGESICS/OPIOIDS OPIOID RECEPTOR AGONISTS: MORPHINE, METHADONE, HEROIN (3X MORE POTENT THAN MORPHINE), ETC MECHANISM OF ACTION

• •

•

Binds selectively to mu opioid receptors to act as an agonist.

This receptor is a Gi PCR, that when opened, results in its beta and gamma subunits of the G protein to open K+ and close P/Q Ca2+ channels, resulting in hyperpolarisation of the neuron as well as preventing Ca2+ dependant exocytosis of neurotransmitters.

These drugs can act spinally to inhibit the ascending pathways, supraspinally to elicit release of other endogenous opioids from the nucleus raphe magnus for further analgesic effect and can act peripherally on receptors of inflamed tissue.

INDICATIONS

•

Analgesia, especially the more central effects

SIDE EFFECTS:

•

Mood changes, possible dependence development and addiction, sedative, constipation (by reducing gut motility by acting on receptors here).

OPIOID RECEPTOR ANTAGONIST: NALOXONE MECHANISM OF ACTION

•

Inhibits action of all subtypes of opioid receptors, in order to reverse effects of the opioids.

INDICATIONS

•

Opioid overdose, Opioid detoxification

VISUAL SUMMARY OF ANALGESICS

NEUROLEPTICS: SEE D2 ANTAGONISTS

VISUAL SUMMARY OF NEUROLEPTIC

ANTIDEPRESSANTS: SEE REUPTAKE INHIBITORS, MAO INHIBITORS ANTIMANIC DRUGS INDICATIONS

•

In treatment of manic episodes during bipolar disorder and other psychoses. Usually used alongside antidepressants to treat for both depressive and manic phases.

LITHIUM: MECHANISM OF ACTION

• • •

While the main method of action is not well known, it is believed that its therapeutic effects stems from upregulation of complex 2 and 3 of the electron transport chain (which is usually affected during bipolar disorders).

Known to raise 5-HT levels (treats for depressive phases) Lowers NA levels (reduces locus coeruleus activity, resulting in sedative effect to reduce mania).

SIDE EFFECTS:

•

Due to lithium being taken up into neurons via Na+ channels but is not exported, results in ion imbalances, which can lead to damage and dysfunction of neurons, kidney, thyroid, etc.

VILAZODONE: MECHANISM OF ACTION

•

Has SSRI effect, thus inhibits reuptake of 5-HT, thus treating depression. Has partial agonist effect at 5HT-1A, resulting reduced release of serotonin, thus can provide sedative effects, thus providing anti-aggressive effects.

AGOMELATINE MECHANISM OF ACTION

• •

Melatonin receptor agonist, resulting in the anti-aggressive effects by achieving sedative effect.

Also has 5-HT2C receptor antagonist activity, in order to reduce 5-HT side effects of antidepressant drugs (e.g., nausea, sexual dysfunction, etc.)

OTHER ANTIMANIC DRUGS: ANTICONVULSANTS AND NEUROLEPTICS (DUE TO REDUCTION OF ACTIVITY OF NEURONS FOR ANTI -AGGRESSIVE EFFECTS)

SLEEP MODIFYING DRUGS/ANXIETY DRUGS ANXIOGENICS/STIMULANTS GABA A RECEPTOR ANTAGONIST: BICUCULLINE MECHANISM OF ACTION

• •

Competitive Antagonist of the receptor, blocking its interaction with GABA Leads to the inhibition of GABAergic inhibition of neurons involved in arousal, resulting in stimulating arousal.

SIDE EFFECTS

•

Can induce seizures, due to reducing GABA-Anergic inhibition of neuronal firing, leading to increased opportunity for hypersynchronisation.

ALPHA 2 ADRENERGIC RECEPTOR ANTAGONIST: YOHIMBINE MECHANISM OF ACTION

• •

Inhibition of the receptor, results in the enhancement of NA release form axon terminal.

This enhances subcortical activity of the Locus Coeruleus, thus enhancing their action in stimulating arousal.

GABA B AGONISTS: GHB

MECHANISM OF ACTION

•

Acts paradoxically on Gi PCR GABA B receptor, resulting in stimulatory effects in the brain.

SIDE EFFECTS:

•

Loss of consciousness (drug of abuse)

H3 RECEPTOR INVERSE AGONIST: SEE PITOLISANT MECHANISM OF ACTION

• •

Reverses function of the H3 Gi PCR, resulting in enhancement of histamine release.

This increases activity of the Tuberomammillary Nuclei involved in arousal.

INDICATION:

•

Narcolepsy

ANXIOLYTICS/SEDATIVES GABA A RECEPTOR ALLOSTERIC MODULATORS: B ARBITURATES, BENZODIAZEPINES, ZALEPON MECHANISM OF ACTION

• • •

Binds to the allosteric site of the receptor, and prolonging the opening of the Clchannel, enhancing hyperpolarisation and GABA-mediated inhibition.

Enhances the GABAergic action of the Ventrolateral Preoptic Nucleus of the Hypothalamus in inhibiting brain activity during sleep.

Benzodiazepines have a weaker anaesthetic effect, compared to barbiturates, thus not used alone for anaesthesia.

INTERACTIONS

•

Upon chronic use of benzodiazepines, the GABA-A Receptor fold into itself, thus reducing its activity, which can result in increased activity of neurons, leading to multiple side effects.

SIDE EFFECTS:

• • •

Chronic use can lead to reduced efficacy, leading to dependence Seizures Respiratory depression, etc.

OREXIN RECEPTOR ANTAGONIST: SUVOREXANT MECHANISM OF ACTION

• •

Antagonises orexin receptors, thus prevents orexin action on receptors from orexin neurons from hypothalamus Thus, no stimulation of other brain centres involved in arousal.

ALPHA 1 ADRENORECEPTOR ANTAGONIST: CHLORPROMAZINE, CLOZAPINE (THEIR SECONDARY EFFECT ON THE RECEPTOR BLOCK) MECHANISM OF ACTION

•

Receptor block here, reduces Locus Coeruleus activity, reducing their arousal stimulating activity. Thus, leading to sedative effects.

INDICATION:

•

Secondary effect of some neuroleptics for anti-aggressive effects

5HT-1A RECEPTOR PARTIAL AGONIST: ARIPIPRAZOLE, VILAZODONE (SECONDARY EFFECTS) MECHANISM OF ACTION

• •

Partial agonism of the receptor, result in the activation of Gi PCR mechanism resulting in the limiting the release of 5HT from axon.

This reduces the activity of the Raphe Nuclei, leading to sedative effects.

INDICATIONS:

•

Secondary effect for anti-aggressive effects

VISUAL SUMMARY OF DRUGS CONTROLLING SLEEP/AWAKE STATES

ENDOCRINOLOGY

GROWTH HORMONE AXIS SYNTHETIC GHRH: SERMORELIN MECHANISM OF ACTION

•

GHRH is given to bind to the GHRH receptor in order to stimulate GH from Somatotrophs of the anterior pituitary gland.

INDICATIONS:

•

In GH deficiency

RECOMBINANT HUMAN GH: SOMATROPIN MECHANISM OF ACTION

• •

Analogue of GH, which can bind to the GH receptor, which results in activation of JAK. JAK phosphorylates and activates STAT and MAPK, for the activation of transcription of genes involved in growth, metabolism, IGF-1 production, etc.

INDICATIONS:

•

In GH deficiency

RECOMBINANT IGF-1: MECASERMIN MECHANISM OF ACTION

•

Analogue of the IGF-1, which binds to the IGF-1 receptors, which activate tyrosine kinase for the activation of down streaming effects resulting in cell proliferation.

INDICATIONS:

•

In GH deficiency (for GH insensitive patients)

SOMATOSTATIN ANALOGUES: LANREOTIDE (PRODRUG TO OCTREOTIDE) MECHANISM OF ACTION

•

Inhibit somatotrophs of the anterior pituitary gland, so that no GH is secreted.

INDICATIONS

•

Treatment for GH excess disorders (e.g., Gigantism, Acromegaly)

GH RECEPTOR ANTAGONIST: PEGVISOMANT MECHANISM OF ACTION

•

Antagonistic effect to the receptor results in the reduced secretion of IGF-1 secretion and GH actions.

INDICATIONS:

•

Treatment of GH excess disorders (when there is inadequate responses to other treatment)

VISUAL OF GROWTH DRUGS

SUMMARY

PROLACTIN AXIS SEE D2 RECEPTOR AGONIST

VASOPRESSIN AXIS SEE DESMOPRESSIN FOR TREATMENT OF NEUROGENIC DIABETES INSIPIDUS

OXYTOCIN AXIS OXYTOCIN: MECHANISM OF ACTION

• •

Binds to Gq metabotropic Oxytocin Receptor, resulting in PLC metabolising of PIP2 to DAG and IP3.

IP3 can open Ca2+ channels on reticular stores for the release of Ca2+ into cytoplasm for triggering uterine smooth muscle contractions.

INDICATIONS:

•

Induction of labour, reduce postpartum haemorrhage, promote lactation during breast-feeding

THYROID AXIS TRH ANALOGUE: PROTIRELIN MECHANISM OF ACTION

•

Stimulates TSH release from Thyrotroph.

INDICATION:

• • •

Used primarily for the diagnosis of thyroid disorders.

Hyperthyroidism shows low TSH due to the negative feedback effect of thyroid hormones on thyrotrophs.

Hypothyroidism shows high TSH, due to reduced feedback effect.

THIOUREYLENES:

MECHANISM OF ACTION

•

Inhibits thyroperoxidase, thus preventing linking of iodine with thyroglobulin precursor, thus synthesis of thyroid hormone inhibited.

INDICATION:

•

Treatment of hyperthyroidism

RADIOACTIVE IODINE (131 I): MECHANISM OF ACTION

• •

Taken up by thyroid and incorporated with thyroglobulin.

Emits cytotoxic gamma and beta radiation, killing thyroid hormone producing cell.

INDICATION:

•

Treatment for hyperthyroidism, diagnostic for hyperthyroidism

SIDE EFFECTS

•

Cytotoxic effects can later progress to cause hypothyroidism.

POTASSIUM IODIDE: MECHANISM OF ACTION

•

High levels of iodine can inhibit Thyroid Hormone synthesis, as well as decreasing size of the gland.

INDICATION

•

used in preparation for surgical resection of gland, treatment of hyperthyroidism

T4 AND T3 HORMONE: MECHANISM OF ACTION

• • •

T4 hormone can be converted to T3, thus has a longer duration of action. T3 and T4 can bind to the nuclear receptor thyroid hormone receptor.

Then the receptor-hormone complex can bind dimerise with Retinoid X Receptor (RXR). The dimerised complex can then bind to the Thyroid Hormone Response Elements of the DNA. Results in the transcription of genes involved in thyroid hormone effects such as increased metabolic rate.

INDICATION:

•

Hypothyroidism

VISUAL SUMMARY OF THYROID DRUGS

ADRENAL AXIS SYNTHETIC ACTH: TETRACOSACTIDE MECHANISM OF ACTION

•

Stimulates glucocorticoid production at the adrenal gland cortex.

INDICATIONS:

•

Not used for treatment for adrenal insufficiency due to negative feedback of glucocorticoids produced, instead used as a diagnostic test for adrenal insufficiency

GLUCOCORTICOIDS ANALOGUES: CORTISOL, PREDNISONE MECHANISM OF ACTION

• • •

Glucocorticoid (GC) analogues can bind to the same nuclear receptor as GC, resulting in the formation of a GC-Receptor complex, which then enters the nucleus to dimerise with RXR. This dimer then attaches to a glucocorticoid response element section of the DNA. This results in the transcription of genes involved in immunosuppression, metabolism, etc.

INDICATIONS:

•

Replacement therapy for Addison’s syndrome

DEXAMETHASONE: MECHANISM OF ACTION

• •

Another glucocorticoid analogue, used as a diagnostic test for its negative feedback effect on the ACTH, resulting in reduced adrenal gland production and secretion of cortisol.

Cortisol can still be measured, but dexamethasone is not measured in serum readings, so can see the extent of negative feedback effect.

INDICATIONS:

•

Diagnostic for Cushing’s syndrome

MINERALOCORTICOID ANALOGUES: FLUDROCORTISONE MECHANISM OF ACTION

•

It is an analogue of cortisone, but is more specific to the mineralocorticoid (MC) receptor.

• • •

Binding to the same nuclear receptor as MC, resulting in the formation of a MCReceptor complex, which then enters the nucleus to homodimerize with another of the same complex.

This dimer then attaches to a mineralocorticoid response element section of the DNA. This results in the transcription of genes expressing Na+ channels and Na+/K+ pumps, for Na+ reabsorption and water retention.

INDICATIONS:

•

Replacement therapy for Addison’s disease

MINERALOCORTICOID RECEPTOR ANTAGONISTS: SEE SPIRONOLACTONE AND EPLERENONE VISUAL SUMMARY OF ADRENAL DRUGS

GONADOTROPIC AXIS GNRH ANALOGUES: GONADORELIN, BUSERELIN, GOSERELIN, LEUPRORELIN MECHANISM OF ACTION

• • •

Stimulates gonadotrophs in order to release FSH and LH. FSH is important for the maturation of ovarian follicles.

LH is important for when it peaks for ovulation.

Leuprorelin (Long Half-life for the desensitisation of GNRH receptor on gonadotrophs, thus inhibiting gonadotroph release), which can treat for hormonedependent diseases.

INDICATIONS:

• • •

Gonadorelin (Short Half-life for evaluating functional capacity of gonadotrophs) Buserelin (for treating infertility) Leuprorelin (treatment for hormone-dependant prostatic cancer and endometriosis)

DANAZOL MECHANISM OF ACTION

•

A synthetic steroid that inhibits the release of GNRH, thus inhibits FSH and LH release.

CLOMIPHENE MECHANISM OF ACTION

•

Oestrogen Antagonist, which stimulates gonadotropin release by inhibiting negative feedback effect of oestrogen.

INDICATIONS:

•

For treating infertility

OESTROGENS MECHANISM OF ACTION

•

Acts on nuclear receptors, which then the oestrogen-complex then binds to the response element of the DNA for the transcription of genes involved in growth of uterus lining, breast growth, blood clotting factors, inhibit bone resorption, etc.

INDICATIONS

• • • •

Contraceptive (along with progesterone via their negative feedback effect on FSH and LH secretion) Treatment for osteoporosis Excessive menstruation Replacement therapy for menopause.

SIDE EFFECTS

•

Increased risk of venous thrombosis and risk of breast and ovarian cancer

SELECTIVE ESTROGEN RECEPTOR MODULATOR (SERM): SEE RALOXIFENE FOR TREATMENT FOR OSTEOPOROSIS

TESTOSTERONE MECHANISM OF ACTION

• • •

Initially converted into an active metabolite by 5alpha-reductase into dihydrotestosterone.

Both testosterone and its active metabolite can bind to its respective nuclear receptor, which forms a hormone-receptor complex.

Complex then binds to the response element on the DNA for the gene transcription of genes involved in growth and other body changes seen in puberty.

INDICATIONS:

•

Hormone replacement therapy for testicular failure and as anabolic agents

•

Decrease of gonadotropin release (infertility), Na+ and water retention

SE:

VISUAL SUMMARY OF GONADOTROPIC DRUGS (ABOVE TESTOSTERONE) (BELOW OVARIAN ASSOCIATED DRUGS)

OTHER

5-HYDROXYTRYPTAMINE BUSPIRONE MECHANISM OF ACTION • • •

Agonist of the 5-HT1A receptor which is present in the CNS and some blood vessels.

5-HT1 receptors are Gi-linked receptors, leading to inhibition of adenylate cyclase, decreased cAMP and decreased activation of protein kinase A. This results in neural inhibition and vasoconstriction.

INDICATIONS •

Buspirone is used for the treatment of generalised anxiety disorder due to its neural inhibitory effects.

ADVERSE EFFECTS • • •

Headaches, dizziness, nervousness, nausea and light-headedness.

Minimal sedation and cognitive dysfunction.

Dependence is unlikely.

SUMATRIPTAN MECHANISM OF ACTION • • •

Agonist of the 5-HT1B and 5-HT1D receptor which are present in the CNS and some blood vessels.

5-HT1 receptors are Gi-linked receptors, leading to inhibition of adenylate cyclase, decreased cAMP and decreased activation of protein kinase A. Reduces the severity of migraine headaches by constricting intracranial vasculature.

INDICATIONS •

Sumatriptan is used for the treatment of migraines.

ADVERSE EFFECTS •

Increased blood pressure has been reported with triptan use due to presence of the 5-HT1B receptor in the vasculature of the heart and elsewhere.

LASMIDITAN MECHANISM OF ACTION •

Agonist of the 5-HT1F receptor, which is present in the CNS and some blood vessels.

•

5-HT1 receptors are Gi-linked receptors, leading to inhibition of adenylate cyclase, decreased cAMP and decreased activation of protein kinase A.

INDICATIONS • •

Lasmiditan is a drug approved in late 2019 for the treatment of migraine.

The targeting of 5-HT1F receptors rather than 5-HT1B and 5-HT1D receptors allows the drug to avoid the hypertensive effects of the triptans (Sumatriptan).

ADVERSE EFFECTS •

Dizziness and sleepiness leading to a possible risk of driving impairment.

LSD (LYSERGIC ACID DIETHYLAMIDE) MECHANISM OF ACTION • • •

Agonist of the 5-HT2 receptor which is present in the CNS and peripheral sites such as blood vessels, platelets and autonomic neurons.

5-HT2A-C are Gq-linked receptors, leading to increased intracellular calcium and protein kinase C activation.

LSD is non-selective for the 5-HT2 receptors and acts as a potent hallucinogen.

ADVERSE EFFECTS • •

Potent hallucinations Mood alterations, sleep disturbances, anxiety

LORCASERIN MECHANISM OF ACTION • • •

Selective agonist of the 5-HT2C receptor which is present in the CNS and peripheral sites such as blood vessels, platelets and autonomic neurons.

5-HT2C receptors are linked to Gq, leading to increased intracellular calcium and protein kinase C activation.

Activation of 5-HT2C receptors in the CNS stimulates pro-opiomelanocortin neurons, resulting in a decrease in appetite.

INDICATIONS •

Lorcaserin was used as a weight-loss drug, but was discontinued in the USA in 2020 due to an increased risk of cancer.

ADVERSE EFFECTS •

Nausea, headache, dry mouth, dizziness, constipation and lethargy.

PRUCALOPRIDE

MECHANISM OF ACTION • • •

Selective agonist of the 5-HT4 receptor which is present primarily in the enteric nervous system.

5-HT4 receptors are linked to Gs, leading to the stimulation of adenylate cyclase and an increase in cAMP levels in the cell.

This results in increased gastrointestinal motility.

INDICATIONS •

Treatment of impaired motility associated with chronic constipation.

ADVERSE EFFECTS • •

Headache Abdominal pain, nausea & diarrhoea

ERGOTAMINE MECHANISM OF ACTION • •

Ergot alkaloids can bind to 5-HT1 receptors, alpha adrenoceptors and dopamine receptors, leading to complexity in function.

It also acts as a partial agonist of the 5-HT2 receptor.

INDICATIONS •

Treatment of migraine

ADVERSE EFFECTS •

Nausea

PIZOTIFEN MECHANISM OF ACTION •

Antagonist of the 5-HT2C receptor.

INDICATIONS •

Prevention of migraine and cluster headache.

ADVERSE EFFECTS •

Sedation, dry mouth, drowsiness.

ONDANSETRON MECHANISM OF ACTION •

Antagonist of the 5-HT3 receptor which is present in the peripheral nervous system and the CNS.

•

The 5-HT3 receptor is coupled to an ion channel, and binding of an agonist increases neuromuscular excitability.

INDICATIONS •

Anti-emetic drug (controlling nausea and vomiting)

ADVERSE EFFECTS • •

QT prolongation Severe allergic reaction

HISTAMINE H1 ANTAGONISTS – DIPHENHYDRAMINE, LORATADINE, CETIRIZINE MECHANISM OF ACTION •

• •

•

Binds to H1 receptors and acts as an inverse agonist. o The H1 histamine receptor is a GPCR linked to Gq, which activates phospholipase C (PLC). o PLC then acts on PIP2 to form inositol triphosphate (IP3) and diacyl glycerol (DAG). o This results in increased intracellular calcium and the activation of protein kinase C, which phosphorylates various proteins and has downstream effects. o Cardiovascular effects include increased contractility and heart rate, bronchial vasoconstriction, dilation of post-capillary venules, and terminal arteriole dilation. o On skin, it can lead to reddening and the development of a wheal and flare – known as the triple response.

Binding of the antihistamines results in lowered allergic inflammation, neurotransmission in CNS, increased sedation, lowered cognition and increased appetite.

First generation antihistamines: o Chlorpheniramine, diphenhydramine etc. o Bind to other receptors, e.g. cholinergic, adrenergic and serotonergic – therefore, they have low specificity. o Neutral compounds at physiological pH, and readily cross the blood-brain barrier.

Second generation antihistamines: o Loratadine, cetirizine, fexofenadine etc. o Decreased CNS penetration compared to 1st generation antihistamines due to ionisation at physiological pH.

INDICATIONS •

Used to treat allergic reactions.

ADVERSE EFFECTS •

•

First generation antihistamines: o Binding to cholinergic receptors can cause dry mouth, urinary retention and sinus tachycardia. o Binding to alpha-adrenergic receptors can cause hypotension, dizziness and reflex tachycardia. o Binding to serotonergic receptors can cause increased appetite. o Binding to H1 receptors can cause sedation, decreased neurotransmission in the CNS and increased appetite.

Second generation antihistamines: o Cardiotoxic effects at high concentrations. o Terfenadine was known to cause ventricular arrhythmias (now withdrawn). o Metabolised by cytochrome P450, which can impact other medications also metabolised via P450.

H2 ANTAGONIST – CIMETIDINE, RANITIDINE MECHANISM OF ACTION • •

Structurally similar to histamine.

Competitively bind to H2 receptors on parietal cells. o H2 receptors are GPCRs linked to Gs, which activates adenylate cyclase. o This enzyme converts ATP to cAMP. o This results in the activation of protein kinase A, which phosphorylates other proteins leading to downstream effects.

o

• •

Protein kinase A phosphorylates the H-K pump present in parietal cells, resulting in decreased efflux of protons into the lumen.

By blocking H2 receptors, there is decreased cAMP production, and a reduction in gastric acid secretion in parietal cells.

It is ionised at physiological pH, resulting in low CNS penetration.

INDICATIONS • • •

Heart burn Peptic ulcer disease Zollinger-Ellison syndrome

ADVERSE EFFECTS • • • •

Inhibition of CYP450 drug metabolism – increased duration of action of drugs metabolised by this pathway.

Headache Diarrhoea Rash

H3 ANTAGONIST - PITOLISANT MECHANISM OF ACTION •

•

Inverse agonist of the H3 histamine receptor o H3 receptors are present as autoreceptors in histaminergic presynaptic neurons and as heteroreceptors in non-histaminergic neurons. o The receptors act to presynaptically reduce the release of histamine from the neurons. o Binding of pitolisant increases activity of histaminergic neurons Binding of pitolisant increases the activity of histaminergic neurons.

INDICATIONS •

Narcolepsy (sleep disorder with excessive daytime sleepiness)

ADVERSE EFFECTS • • •

Difficulty sleeping Nausea Feeling worried

GASTRO-INTESTINAL H2 ANTAGONISTS – CIMETIDINE, RANITIDINE • •

See H2 Antagonists Blockage of H2 receptor by cimetidine & ranitidine leads to decreased gastric secretion.

ANTICHOLINERGICS - PIRENZIPINE • •

See Muscarinic Antagonists Blockage of M1 receptor by pirenzepine leads to decreased gastric secretion.

PROTON PUMP INHIBITORS - OMEPRAZOLE MECHANISM OF ACTION

• • • •

Acid labile prodrug.

The active metabolite irreversibly inhibits the H+-K+-ATPase (proton pump) by forming a covalent disulphide link with a cysteinyl residue in the pump.

This results in irreversible inhibition of gastric acid secretion.

The most common PPI used is omeprazole.

INDICATIONS • • • • • •

Treatment of NSAID-induced ulcers.

Maintenance of clot integrity in haemorrhagic ulcers.

Short-term treatment of gastric ulcers.

Treatment of active duodenal / peptic ulcers (H. pylori).

Gastroesophageal reflux disease (GERD).

Hypersecretory states (Zollinger-Ellison syndrome).

ADVERSE EFFECTS • • •

Abdominal pain Diarrhoea Nausea & vomiting

ANTACIDS – MAGNESIUM & ALUMINIUM HYDROXIDES, SODIUM BICARBONATE MECHANISM OF ACTION • •

Chemically neutralises stomach acid.

Aluminium and magnesium bind to and neutralise pepsin.

INDICATIONS • •

Pain relief and healing in peptic ulcer disease.

Relieve symptoms of acid indigestion, heart-burn, dyspepsia or GERD.

ADVERSE EFFECTS • •

All antacids can interfere with absorption of oral drugs given at the same time.

Can alter solubility and absorption of drugs due to effects on pH.

SUCRALFATE MECHANISM OF ACTION • • •

Viscous polymer of sucrose octasulphate and aluminium hydroxide.

Adheres to necrotic ulcer tissue – forming a protective barrier to acid, pepsin and bile.

May stimulate prostaglandin synthesis, and increased mucous and bicarbonate secretion.

INDICATIONS •

Peptic ulcer disease.

ADVERSE EFFECTS •

Constipation.

COLLOIDAL BISMUTH MECHANISM OF ACTION • • •

Selective binding to ulcer crater which protects it from acid and pepsin.

May also inhibit activity of pepsin and stimulate mucous production.

Toxic to H. pylori.

INDICATIONS •

Peptic ulcer disease.

MISOPROSTOL MECHANISM OF ACTION • • •

Stable analogue of prostaglandin E1.

Prostaglandins E and I generally protect the GI tract, and deficiency can contribute to ulcer formation.

Exerts a direct action on the ECL cell, inhibiting basal secretion of gastric acid.

INDICATIONS •

Approved for prevention of NSAID-induced ulcers.

ADVERSE EFFECTS • •

Diarrhoea Uterine contraction

ANTI-PARASITIC DRUGS ANTI-MALARIALS MECHANISM OF ACTION •

Anti-malarial agents target 4 physiological pathways: o Haem metabolism: ▪ Chloroquine is effective against the erythrocytic forms of P. ovale, malariae and knowlesi. Resistance has developed in P. vivax and falciparum.

▪ Chloroquine is uncharged at neutral pH and can freely diffuse into the parasite.

▪ It inhibits haem polymerase, and prevents the parasite from using amino acids from haemoglobin proteolysis.

▪ Mefloquine is another compound to acts in the same way as chloroquine.

▪

o

o

o

Artemisinin and artesunate contain an unusual peroxide bridge, which is activated by the haem iron present in parasites. This causes alkylation of parasitic proteins, and also give rise to highly reactive oxygen containing compounds.

Electron transport: ▪ The mechanism of primaquine is unclear. It is active against liver hypnozoites of all human malarial parasites, and leads to the destruction of gametocytes – preventing transmission of al 4 species.

▪ It has 14 metabolites that exist, and interfere with ubiquinone function.

▪ Atovaquone is a structural analogue of ubiquinone. It inhibits interaction between reduced ubiquinone and cytochrome BC1, disrupting the electron transport chain.

This results in disrupted pyrimidine synthesis and plasmodial DNA replication.

Protein translation: ▪ Doxycycline is a structural isomer of tetracycline. It is an antibiotic, and is frequently used in combination therapy with other anti-parasitic drugs.

Folate metabolism: ▪ Proguanil is a biguanide derivative. Its antimalarial action is due to a metabolitecycloguanil.

▪ It inhibits the plasmodial dihydrofolate reductase-thymidylate synthase complex.

This prevents the formation of tetrahydrofolate, and therefore inhibits further DNA and protein synthesis in the parasite.

INDICATIONS • • • •

Treatment of plasmodium infection (malaria).

Artemisinin and artesunate are the first line of treatment for chloroquine-resistant P. falciparum.

Primaquine is used as a radical cure for P. vivax and ovale.

Proguanil is used in the treatment of hepatic and pre-erythrocytic forms of P. falciparum and vivax. It is used in combination therapy with atovaquone for chemoprophylaxis.

ADVERSE EFFECTS • •

Chloroquine in large doses can cause nausea, vomiting, dizziness, blurring of vision, headache and urticarial symptoms. It can also result in retinopathies and hearing loss.

Primaquine can cause oxidative stress-induced haemolysis, and may be fatal in patients with a G6PD deficiency. It should never be administered to pregnant women.

METRONIDAZOLE MECHANISM OF ACTION • • •

Prodrug containing a nitro group which is reduced to become active.

The reduced form binds to proteins, membranes and DNA in target cells, causing severe damage.

Active against trophozoites in tissue but not in the lumen.

INDICATIONS • •

Treatment of patients with invasive amoebiasis.

Administered with an agent with greater luminal activity (iodoquinol or paromomycin).

ADVERSE EFFECTS

• •

Nausea, vomiting, epigastric distress and abdominal cramps.

Metallic taste in mouth.

PENTAMIDINE MECHANISM OF ACTION • • •

High affinity for DNA in kinetoplasts.

Suppresses replication and function.

Inhibits dihydrofolate reductase.

INDICATIONS •

Used in the treatment of early stage trypanosomiasis (sleeping sickness).

SURAMIN MECHANISM OF ACTION • •

Inhibits many enzymes involved in energy metabolism (e.g. glycerol phosphate dehydrogenase).

Inhibits RNA polymerase and therefore interferes with parasite replication.

INDICATIONS •

Used in the treatment of early stage trypanosomiasis (sleeping sickness).

MELARSOPROL MECHANISM OF ACTION • •

Inhibits pyruvate kinase, inhibiting glycolysis and ATP formation.

Inhibits uptake of adenine and adenosine by transport proteins.

INDICATIONS •

Used in the treatment of late stage trypanosomiasis (sleeping sickness).

ADVERSE EFFECTS •

Reactive encephalopathy occurs in 5-10% of patients – 50% mortality rate.

IVERMECTIN MECHANISM OF ACTION • • • •

Semisynthetic macrocytic lactone that is active against a range of helminths and arthropods.

Low affinity and does not affect GABA receptors in humans.

Ivermectin opens glutamate-gated chloride channels, leading to hyperpolarisation of neuromuscular cells and pharyngeal paralysis.

It also activates GABA receptors to cause hyperpolarisation.

• •

It binds to allosteric sites on nicotinic acetylcholine receptors, increasing neurotransmission and motor paralysis.

Inhibits nutrient uptake by O. volvulus and kills developing larvae (microfilariae). It also kills larvae in utero.

INDICATIONS •

Treatment of helminth-related diseases e.g. strongyloidiasis and onchocerciasis.

ADVERSE EFFECTS • • • • • •

Inflammatory / allergic responses to dying microfilariae.

Headache Rash Oedema Abdominal pain Hypotension

ALBENDAZOLE MECHANISM OF ACTION • • • • •

Binds to beta-tubulin and inhibits polymerisation.

Selective for the nematodal isoform of beta-tubulin (250-400 fold).

Disrupts nematode motility and DNA replication leading to degenerative changes in integument and intestinal cells of helminths.

Results in immobilisation, starvation and death of nematodes.

Mebendazole is a similar drug.

INDICATIONS • •

Treatment of cestodal infestations (cysticercosis, hydatid disease).

Effective against most known nematodes.

PRAZIQUANTEL MECHANISM OF ACTION •

Binds to protein kinase C binding site in the beta-subunit of voltage-gated calcium channels in schistosomes – leads to contraction of musculature and paralysis.

INDICATIONS •

Drug of choice in the treatment of adult cestode (tapeworm) and trematode (fluke) infections.

DIETHYLCARBAMAZINE (DEC) MECHANISM OF ACTION • •

Derivative of piperazine.

Exact MOA is unknown:

o o o

Stimulates innate immune mechanisms.

Inhibits microtubule polymerisation.

Inhibition of arachidonic acid metabolism

INDICATIONS •

Drug of choice for certain filarial infections including lymphatic filariasis.

ADVERSE EFFECTS •

Mazzotti reaction.

OTHER MONOAMINERGIC DRUGS VMAT INHIBITOR: RESERPINE MECHANISM OF ACTION • An irreversible inhibitor of VMAT, which is a protein that transport monoamine neurotransmitters (e.g., NA, DA, 5-HT) into synaptic vesicles. This inhibition results in the vesicle being empty, thus no release of neurotransmitter into synaptic cleft.

INDICATION • Antihypertensive (as it reduced NA and DA release)

MONOAMINE OXIDASE INHIBITORS: E.G. SELEGILINE MECHANISM OF ACTION • Inhibits MAO mediated metabolism of neurotransmitters DA, NA, 5-HT. Thus, stores of neurotransmitters are not depleted.

• Thus, further potentiates neurotransmitter effects.

INDICATION: • Treats for depression, Parkinson’s disease SIDE EFFECTS: • Must note Wine-Cheese Tyramine effect, resulting in hypertensive crisis.

INTERACTIONS: • Tyramine, which is also metabolised by MAO enzyme, is instead converted to octopamine by dopamine hydroxylase.

• Octopamine can disrupt storage of neurotransmitters within synaptic vesicles, resulting in their leak into the synaptic cleft, resulting in sympathomimetic effects.

REUPTAKE INHIBITORS: TRICYCLIC INHIBITORS (NON -SELECTIVE), SELECTIVE 5-HT AND/OR NA REUPTAKE INHIBITORS (SSNRIS), E.G. AMITRIPTYLINE & ESCITALOPRAM MECHANISM OF ACTION

• •

Many different mechanisms of actions, but their main therapeutic effect derives from the inhibit reuptake of multiple different monoamine neurotransmitters.

Thus, more remains in the synaptic cleft, thus maintaining stimulation of post-synaptic neuron receptors.

INDICATIONS: • Treatment of depression, ADHD, etc.

VISUAL SUMMARY OF OTHER MONOAMINERGIC DRUGS

VIRAL REPLICATION FUSION INHIBITORS

MARAVIROC (ANTIVIRAL, FUSION INHIBITOR) MECHANISM OF ACTION • Negative allosteric modulator of CCR5 receptor (antagonist) • CCR5 = Chemokine receptor found on human cells • Blocks this coreceptor that HIV would normally bind to INDICATIONS • HIV ADVERSE EFFECTS • Liver problems (hepatotoxicity) • Skin reactions • Allergic reactions NOTES • Maraviroc not effective in HIV strains which use CXCR4 co-receptor for fusion

ENFUVIRTIDE (ANTI-VIRAL, FUSION INHIBITOR) MECHANISM OF ACTION • Mimics a region of HR2 & prevents the formation of HR1-HR2 complex • Binds to GP41 causing steric hindrance

• •

Through steric hindrance, it inhibits refolding & viral fusion with host cell membrane Virus trapped in binding stage

INDICATIONS • HIV ION CHANNEL BLOCKERS

AMANTADINE/ RIMANTADINE (VIRAL UNCOATING INHIBITOR, ION CHANNEL BLOCKER) MECHANISM OF ACTION • M2 Channel found in Influenza A opens at a low pH • Allows influx of protons into the viral core which causes dissociation between M1 protein and viral RNP • There is also pH induced conformational change in haemagglutinin permits fusion with endosomal membrane • Membrane fusion allows the viral RNPS to be released into the cytoplasm of the host cell which is then transported to the nucleus and allows for viral replication • Amantadine blocks the M2 ion channel so that proton translocation is blocked INDICATIONS • Influenza A • Parkinsonism • Drug-induced extra-pyramidal reactions INHIBITION OF DNA INTEGRATION

RALTEGRAVIR (HIV INTEGRASE INHIBITOR) MECHANISM OF ACTION • HIV integration serves to insert the viral DNA into the host chromosomal DNA which is essential for HIV replication • Binds to active site of HIV integrase to block strand transfer (2nd step of integration) INDICATIONS • HIV INHIBITION OF VIRAL POLYMERASE

ZIDOVUDINE (NRTI – NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR) MECHANISM OF ACTION • Zidovudine = structural analogue of thymidine • Phosphorylated to its active 5’-triphosphate metabolite -> zidovudine triphosphate • Inhibits the activity of HIV-1 reverse transcriptase via DNA chain termination • Competes with natural substrate GTP and incorporates itself into viral DNA • Weak inhibitor of cellular DNA polymerase alpha and gamma INDICATIONS • HIV

Proviral

Hoşt Chromoso mal HIV

HIV

Ihtqrase

PROTEASE INHIBITORS

RITONAVIR (HIV PROTEASE INHIBITOR) MECHANISM OF ACTION • Inhibits the cleavage of Gag/Pol HIV polyprotein • Potent inhibitor of cytochrome p450 EFFECTS • Viral particles which bud from infected cells are immature and non-infectious ADVERSE EFFECTS • Lipodystrophy syndrome • Metabolic abnormalities NEURAMINIDASE INHIBITORS

ZANAMIVIR/OSELTAMIVIR (NEURAMINIDASE INHIBITOR) MECHANISM OF ACTION • • •

Homologue of sialic acid which HA of influenza binds to Neuraminidase would normally cleave SA from cells so virus can be release Zanamivir binds to the active site of neuraminidase so as to prevent this action

INDICATIONS •

Influenza A & B

Aida Se New VironS

I zQ Ose(+amivir

PHARMACOLOGY OF PROSTAGLANDINS & LEUKOTRIENES

Ara chidon(c COW-IIQ(.-.-..

tnhibi±ors

ASPIRIN (NSAID, ANTIPLATELET AGENT) MECHANISM OF ACTION • Blocks prostaglandin synthesis • COX-1 & COX-2 inhibitor • Acetylates serine 529 in COX-1 and serine 516 in COX-2 • Stops the conversion of arachidonic acid into thromboxane A2 EFFECTS • Inhibition of platelet aggregation • Analgesia

• •

Anti-inflammatory Anti-pyretic

INDICATIONS • Prophylaxis management of MI & stroke • Anti-thrombogenic agent • Acute pain • Osteoarthritis • Rheumatoid arthritis • Acute gout • Postoperative • Muscle skeletal injuries • Fever bacterial infection CONTRA-INDICATIONS SHORT • • •

TERM Dyspepsia Nausea Bleeding

LONG TERM • GI issues (bleeding and peptic ulcers) • Renal function (increases sodium and water reabsorption, increased blood pressure, chronic renal toxicity through reduced GFR) OTHERS • Reye’s syndrome rare; swelling of liver and brain. Therefore, not administered to children <16 with fever syndromes • Allergy • Intolerance seen in patients with asthma, nasal polyps, rhinitis can lead to bronchoconstriction hyperactivity due to more AA available LOX pathway (increases leukotriene synthesis)

Referenced in: Non-Narcotic Analgesics, Pharmacology of Volume Regulation, Integrated Cardiovascular pharmacology, Gout and Rheumatoid Arthritis, Antiplatelet Agents, Pharmacology of Leukotrienes and Prostaglandins, Overdose & Poisoning and Pharmacogenetics NSAIDS

PROPIONIC ACID DERIVATES IBUPROFEN (NSAID)

HALF-LIFE • 2 hours

MECHANISM OF ACTION • COX inhibitor (More COX-2 then COX-1 isoform) • Forms hydrogen bond with arginine 120 to inhibit arachidonic acid entering hydrophobic catalytic site

EFFECTS • COX-2 inhibition = decreases synthesis of prostaglandins involved in mediating inflammation, pain, fever and swelling • COX-1 inhibition = adverse effects of Ibuprofen like gastric ulceration INDICATIONS

•

Moderate to severe inflammatory pain (Rheumatoid Arthritis/ Osteoarthritis)

Referenced in: Non-narcotic analgesics, Pharmacology of leukotrienes and prostaglandins

NAPROXEN (NSAID)

HALF-LIFE

•

15 hours

MECHANISM OF ACTION

•

See Ibuprofen

EFFECTS

•

See Ibuprofen

INDICATIONS

•

See Ibuprofen

Referenced in: Pharmacology of leukotrienes and prostaglandins

INDOLE/ ACETIC ACID DERIVATES DICLOFENAC (DIFENE) (NSAID)

HALF-LIFE

•

Short – 2hr

MECHANISM OF ACTION

•

COX inhibitor – More COX-2 inhibition then COX-1

EFFECTS

•

See Ibuprofen

INDICATIONS

•

Rheumatoid arthritis

• • • •

Osteoarthritis Back pain Post-operative pain Inflammation in orthopaedic and dental surgeries

Referenced in: Pharmacology of leukotrienes and prostaglandins INDOMETHACIN (NSAID)

HALF-LIFE

•

4 hour

MECHANISM OF ACTION

•

Potent very selective COX-1 inhibitor

EFFECTS

•

See Ibuprofen

INDICATIONS

•

Highly toxic potential only used in RA and OA patients where other NSAIDs are not tolerated

Referenced in: Pharmacology of leukotrienes and prostaglandins FENAMATES PONSTAN/ MEFENAMIC ACID

HALF-LIFE

•

2 hours

MECHANISM OF ACTION

•

Potent more selective COX-2 inhibitor

EFFECTS

•

See Ibuprofen

INDICATIONS

• • • •

RA OA Trauma Headache

• •

Dental pain Post-op

OXICAM DERIVATIVES PIROXICAM

HALF-LIFE

•

Very long – 30 hours

MECHANISM OF ACTION

•

Potent slightly more selective for COX-2

EFFECTS

•

See Ibuprofen

INDICATIONS

• • •

RA OA Not a first line NSAID

Referenced in: Pharmacology of leukotrienes and prostaglandins ACETAMINOPHEN (NON-OPIOID ANALGESIC, ANTIPYRETIC) ( PARACETAMOL)

HALF-LIFE

•

3-4 hours

EFFECTS

• •

Weak anti-inflammatory effects No platelet inhibition

ADVERSE EFFECTS

•

Renal and liver damage associated with long term use

INDICATIONS

• • • • •

When aspirin and other NSAIDs are contraindicated Headache Cold/ Flu Menstrual pain Toothache

Referenced in: Pharmacology of leukotrienes and prostaglandins, Toxigenic and teratogenic drugs, Non-narcotic analgesics, overdose and poisoning CELECOXIB (NSAID) PRIMARILY DEVELOPED TO INHIBIT INFLAMMATION WHILE MAINTAINING CYTOPROTECTIVE EFFECTS

MECHANISM OF ACTION

•

Selective non-competitive COX-2 inhibitor

EFFECTS

• •

See Ibuprofen NO antiplatelet action

INDICATIONS

• • •

OA RA acute pain Risk

Referenced in: Pharmacology of leukotrienes and prostaglandins, Non-Narcotic Analgesics ZILEUTON (LOX INHIBITOR)

MECHANISM OF ACTION

•

Oral 5-LOX inhibitor

EFFECTS

• •

Inhibition of leukotriene prevents inflammation, bronchoconstriction, oedema and mucous secretion Zileuton induces bronchodilation and improves symptoms and pulmonary function tests

INDICATIONS

• •

Asthma Not indicated for use of reversal of bronchospasm in acute asthma attacks

NOTES

•

Not widely used: Low bioavailability, low potency, adverse liver toxicity

Lea kot-n•en e

Referenced in: Pharmacology of leukotrienes and prostaglandins MONTELUKAST & ZAFIRLUKAST (LEUKOTRIENE RECEPTOR ANTAGONISTS)

MECHANISM OF ACTION

•

Cysteinyl LT receptor antagonists

INDICATIONS

• • •

Prophylactic treatment of asthma symptoms Seasonal allergic rhinitis Generally, not used as monotherapy or in acute asthma attacks

ADMINISTRATION

• • •

Oral administration Chewable tablet Therapeutic effect occurs within one day

Cha don (C

Acid 6- Lox

LTD Cqs LTI J CHS rs) CLQ-c-e.et-o

Cece pto vs)

Referenced in: Pharmacology of leukotrienes and prostaglandins PROSTANOID RECEPTOR MIMETICS

MISOPROSTOL

MECHANISM OF ACTION

•

PGE analogue

INDICATIONS

• • •

Termination of pregnancy Induction of labour Prevention of peptic ulcer

Referenced in: Non-Narcotic Analgesics, Pharmacology of leukotrienes and prostaglandins, Peptic Ulcer Disease ILOPROST Other drugs in this class: Epoprostenol & Cicaprost

MECHANISM OF ACTION

•

Prostaglandin I2 (PGI2) analogue

EFFECTS

•

Prevents platelet aggregation

INDICATIONS

•

Primary pulmonary hypertension (with sildenafil)

Referenced in: Pharmacology of leukotrienes and prostaglandins, pharmacology of vascular tone LATANOPROST & TRAVOPROST

MECHANISM OF ACTION

•

Prostaglandin F2 alpha (PGF2𝜶) analogue

INDICATIONS

• • •

Open angle glaucoma Ocular hypertension Reduce intraocular pressure

Referenced in: Pharmacology of leukotrienes and prostaglandins

MOLECULAR TOXICOLOGY & TERATOGENIC DRUG EFFECTS VARENICLINE

MECHANISM OF ACTION

•

Partial agonist at nicotinic ACh receptor (𝛼4β2 subtype)

ADVERSE EFFECTS

• • • • •

Behaviour changes Anxiety Psychosis Suicidal ideation Mood swings

Referenced in: Molecular Toxicology and Teratogenic Drugs, Non-Drug Poisoning, Cholinergic Pharmacology BUPROPION (PSYCHOTROPIC)

MECHANISM OF ACTION

•

Norepinephrine and dopamine reuptake inhibitor

ADVERSE EFFECTS

•

Reduces desire to smoke

Referenced in: Non-Drug Poisoning, Anti-depressants, Pharmacology of Leukotrienes and Prostaglandins, Molecular Toxicology and Teratogenic Drugs THALIDOMIDE

MECHANISM OF ACTION

Teratogenic • • •

Teratogenic ability to bypass embryonic defence system for prevention of toxic substances entering the embryonic cells Evades the efflux transportation system Capable of inducing oxidative stress to ROS dependent signalling pathways in apical ectodermal ridge responsible for limb bud growth and zone of polarizing activity

Anti-myeloma effects • •

Inhibits production of IL-6 (growth factor for proliferation of myeloma cells) Activates apoptotic pathways through capase-8 mediated cell death

ADVERSE EFFECTS

• •

In 1950s administered for morning sickness Caused major limb deformities

INDICATIONS

• •

Multiple myeloma Erythema nodosum leprosum

Referenced in: Principles of Pharmacology I, Molecular Toxicology and Teratogenic Drugs ORGANOPHOSPHATES (NERVE GASES, SARIN, PESTICIDES, MALATHION)

MECHANISM OF ACTION

•

Causes irreversible binding of phosphate to AChE leading to increase in Ach levels

EFFECTS

• • •

Muscle paralysis Lacrimation Diarrhoea

TREATMENT OF TOXIC EFFECTS

•

Pralidoxime prevents hydroxylation of the phosphate and instead acetylates

Referenced in: Molecular Toxicology and Teratogenic Drugs, Cholinergic Pharmacology, Non-Drug Poisoning

INSULIN & ORAL HYPOGLYCAEMIC AGENTS INSULIN

STRUCTURE OF INSULIN

• • • •

Proinsulin transported to Golgi apparatus and converted to C–peptide and insulin Cleaved at di-peptide cleavage site Insulin (51 AA) and C peptide packaged in storage granules until release Stored in a crystallized form of two atoms of Zinc and six molecules of insulin

INSULIN RECEPTOR • Tetramer • 2𝛼 & 2β subunits • Tetrameric form higher affinity for insulin then 𝛼β dimer form

MECHANISM OF ACTION

• • • • • • • •

ATP-sensitive K+ channels determine the RMP in β cells of the pancreas Glucose enters β cells through GLUT2 transporter Rise in ATP within β cells blocks ATP-K+ channels causing membrane depolarization Depolarization opens voltage-dependent Ca2+ channels leading to Ca2+ influx Triggers insulin secretion Insulin binds to Beta subunit of insulin receptor The β-subunit has tyrosine kinase activity (can alter gene expression) Binding of insulin to the receptor causes GLUT4 channels to be inserted into plasma membrane allowing transport of glucose into cell

Referenced in: Insulin and Oral hypoglycaemic Agents, Adrenergic Pharmacology METFORMIN (BIGUANIDE ANTIHYPERGLYCAEMIC)

EFFECTS

• •

DOA: 10-12 hours Increases sensitivity to insulin

MECHANISM OF ACTION

• • • •

Decreases blood glucose level by decreasing gluconeogenesis (hepatic glucose production) Decreases intestinal absorption of glucose Increases insulin sensitivity by increasing peripheral glucose uptake and utilization (smooth muscle/ adipose tissue) Inhibits mitochondrial 1 activity preventing production of mitochondrial ATP which activates AMPK

INDICATIONS

•

Type 2 diabetes mellitis – especially in obese patients

Referenced in: Insulin and Oral hypoglycaemic Agents GLICLAZIDE (SULPHONYLUREA)

EFFECTS

• •

DOA: 6-12 hours Stimulates insulin release

MECHANISM OF ACTION

• • • • •

Binds to β cell Sulphyl ureal receptor (SUR1) Blocks ATP sensitive K+ channels Results in decrease in K+ efflux and overall depolarization of β cells Opens voltage-dependent Ca2+ channels in β cell leading to calmodulin activation Exoctyosis of insulin

ADVERSE EFFECTS

•

Hypoglycaemia due to over secretion of insulin

INDICATIONS

•

Non-insulin-dependent diabetes mellitus (NIDDM)

Referenced in: Insulin and Oral hypoglycaemic Agents THIAZOLIDINEDIONES (GLITAZONES)

MECHANISM OF ACTION

• • • •

Agonist for the nuclear hormone receptor peroxisome proliferator-activity receptor 𝛾 (PPAR 𝛾) – mainly found in adipose tissue PPAR 𝛾 alters the transcription of several genes involved in glucose, lipid metabolism and energy balance Forms a heterodimer complex with the retinoid receptor to promote transcription of lipoprotein lipase, GLUT4 and fatty acid transport protein This reduces insulin resistance in adipose tissue

Referenced in: Insulin and Oral hypoglycaemic Agents EXENATIDE (GLP-1 ANALOGUE/ AGONIST)

MECHANISM OF ACTION

• • • • •

GLP is a protein isolated from the salivary gland of Glia monsters Activates GLP-1 receptor This increases insulin secretion from β-cells in a glucose-dependent manner Supresses the secretion of glucagon by α-cells Slows gastric emptying and decreases food intake (appetite suppression)

ADMINISTRATION

• • •

Administered by injection Used in conjunction with metformin, sulphonyl urea or glitazone NOT associated with hypoglycaemia unless used with sulphonylurea

Referenced in: Insulin and Oral hypoglycaemic Agents SITAGLIPTIN (GLIPTIN, DPP-4 INHIBITOR) MECHANISM OF ACTION

•

Inhibits dipeptidyl peptidase-4 in a glucose dependent manner

EFFECTS

• •

Increased insulin synthesis Decreased glucagon release in a glucose-dependent manner

Letea s e

Pancreas Su

Qup

«ested

LL.u-ase

bP?-lF

Figure 7: diabetescontrol.com

Referenced in: Insulin and Oral hypoglycaemic Agents DAPAGLIFLOZIN (SODIUM GLUCOSE CO -TRANSPORTER-2 INHIBITOR) MECHANISM OF ACTION

•

Inhibits SGLT2 to decrease glucose reabsorption in the proximal tubule

EFFECTS

• •

SGLT2 is responsible for reabsorption of around 90% of glucose filtered out at the glomerulus Results in lower blood glucose levels and higher levels in urine

Referenced in: Insulin and Oral hypoglycaemic Agents GLUCAGON (NATURAL COUNTER-REGULATORY HORMONE) METABOLISM

• •

Short half life Extensively degraded in the liver kidney and plasma

INDICATIONS

•

Short term correction of hypoglycaemia

Referenced in: Insulin and Oral hypoglycaemic Agents DIABETES TYPE 2 TREATMENT ALGORITHIM

CALCIUM HOMEOSTASIS BACKGROUND INFORMATION •

Antiresorptive agents (slow rate of bone loss): o Bisphosphates o Hormone replacement therapy o Selective Estrogen Receptor Modulators (SERM) o RANKL anatoginists

•

Bone anabolic agents (increase bone formation): o Parathyroid hormone analogues o Vitamin D replacement o Calcium salts Management of hypo/hypercalcemia: o Targets correction of the cause - If due to dysfunction of endocrine system, endocrinologist is involved; if due to certain treatments or medications, they are altered or removed if possible.

•

BONE ANABOLIC AGENTS CALCIUM SALT AGENTS CALCIUM GLUCONATE AND CALCIUM LACTATE •

oral calcium replacements

CALCIUM CARBONATE •

chewable tablets

MECHANISM OF ACTION • •

•

• •

•

•

•

• •

Calcium Gluconate is the gluconate salt of calcium and is essential for normal nerve, muscle, and cardiac function as well as to prevent bone loss and maintain calcium balance.

Bone calcium is in constant exchange with plasma calcium so disturbances in the calcium balance may deplete body stores. Therefore, calcium salt agents such as these promote restoration of calcium balance.

Administration of calcium gluconate is the first step in the emergency management of hyperkalaemia: o The resting membrane potential (RMP) becomes less negative in hyperkalaemia, bringing it closer to the threshold potential (TP). o This means that the cardiac myocyte requires less of a stimulus to create an action potential. o Calcium gluconate prevents this by increasing the threshold potential. o As a result, the gap between RMP and TP is restored. This stabilises and protects the cardiac membrane, preventing the development of potentially fatal arrhythmias.

Calcium lactate salt consists of two lactate anions for each calcium cation and is commercially prepared by neutralising lactic acid with calcium carbonate or calcium hydroxide.

In aqueous environments such as in the gastrointestinal (GI) tract, calcium lactate dissociates into calcium cation and lactic acid anions which are the conjugate base of lactic acid that is a ubiquitous intermediate in metabolic pathways such as gluconeogenesis.

Calcium must be in its freely soluble form in order to be absorbed or bound to a soluble organic molecule and absorption mainly occurs at the duodenum and proximal jejunum due to the more acidic pH and abundance of the calcium binding proteins.

Mean calcium absorption in the small intestine is about 25% of calcium intake and is mediated by both passive diffusion and active transport.

Calcium carbonate is an inorganic salt that is basic and acts by neutralizing hydrochloric acid in gastric secretions. This neutralization results in the formation of calcium chloride, carbon dioxide and water.

Around 90% of calcium chloride is converted to insoluble calcium salts such as calcium phosphate and calcium carbonate.

The calcium is quickly taken up by skeletal tissues following absorption and distribution into extracellular fluids and can also act as a co-factor to several enzymes.

Due to their poor absorption, they can act as antacids within the stomach to minimize gastric reflux disorders.

INDICATIONS

• • • •

Calcium deficiency Hypoparathyroidism Supplement osteoporosis Calcium recommended daily intake > 1200mg daily

CONTRAINDICATIONS • •

Conditions associated with hypercalcaemia or elevated vitamin D levels for example sarcoidosis History or active renal calculi

Refer to Calcium Homeostasis lecture for more information

VITAMIN D SUPPLEMENTS: ERGOCALCIFEROL D2 MECHANISM OF ACTIION • • • • • • •

Fat soluble vitamin that is considered a hormone Cholecalciferol (vitamin D3) is synthesized in the skin from precursor 7-dehydrocholesterol and is stimulated by UV light Ergocalciferol (vitamin D2) is derived from plants and is added to food preparations commercially vitamin D is metabolized in the liver via a hydroxylation reaction into a hydroxycholecalciferol A second hydroxylation reaction occurs in the proximal renal tubular cells to activate the metabolite Calcitriol Calcitriol, (active vitamin D) signals through nuclear receptors and increases calcium absorption by increasing receptor expression in the intestinal mucosa vitamin D is stored in fat tissue therefore a single large dose may be effective for several weeks

INDICATIONS • • • • •

Hyperparathyroidism Renal and liver disease Dietary deficiency lack of sunlight osteoporosis

Refer to Calcium Homeostasis lecture for more information

PARATHYROID HORMONE PEPTIDE: TERIPEPTIDE MECHANISM OF ACTION •

stimulate bone formation by increasing the number and action of osteoblasts

• •

Increase bone mass, structural integrity and bone strength Parathyroid hormone effects: o Increases the reabsorption of calcium and promotes phosphate excretion thereby increasing calcium levels and decreasing phosphate levels o increased conversion of vitamin D to biologically active vitamin D (calcitriol) promoting calcium reabsorption

•

Pathological over secretion of PTH results in bone loss while intermittent low dose exposure of PTH leads to bone formation and mass

INDICATIONS •

Severe osteoporosis

CLINICAL NOTE • •

administered subcutaneously daily for a maximum of 24 months important to start an anti-resorptive agent following discontinuation because bone mineral content is lost quickly when stopped

Refer to Calcium Homeostasis lecture for more information

ANTIRESORPTIVE AGENTS HORMONE REPLACEMENT THERAPY • • • •

Oestrogen decreases bone resorption which by inhibiting osteoclasts and thus decreasing the transcription of genes such as RANK ligand and cytokines.

It does not increase bone mass but slows down bone loss.

The risk includes venous thromboembolism because it has clotting factors, breast and cervical cancer.

The risks outweigh the benefits for use for osteoporosis so not recommended.

Refer to Calcium Homeostasis lecture for more information

BISPHOSPHONATES • •

Three classes: non-nitrogen, linear nitrogen and ringed nitrogen compounds Examples: Etidronate (non-nitrogen), Alendronate (linear nitrogen), Risedronate (ringed nitrogen), Zoledronate (ringed nitrogen)

MECHANISM OF ACTION

• •

•

Agents are incorporated into the bone matrix during remodeling and can remain there for months to years because they form tight complexes with calcium.

The osteoclast cells then slowly release bisphosphonates which inhibit osteoclast activity that is responsible for bone resorption at high concentrations. This is because the bisphosphate is toxic to the osteoclasts as they can cause apoptosis of the cells.

Some of the nitrogen agents can particularly inhibit prenylation reactions, which are reactions that are required for attachment or anchoring of specific cell surface proteins to the surface of the osteoclast cells. When these surface proteins are not expressed, the cells are not able to attach onto bone tissue efficiently for the resorptive processes to occur.

INDICATIONS • • •

Treatment and prophylaxis of osteoporosis decreased risk of fractures Bone malignancy IV zoledronate- prevent bone fractures pain hyperkalemia and reduce liberation of growth factors from bone

CONTRAINDICATIONS • • •

History of hypersensitivity to the best phosphonate Hypercalcemia Chronic kidney disease

ADVERSE EFFECTS • •

Gastro-intestinal disturbances (peptic ulcers, oesophagitis) Osteonecrosis of the Jaw (ONJ) with IV administration so a dental checkup is needed before commencing therapy

DENTAL EFFECTS: • • •

ONJ is generally linked to delayed healing and infection and usually follows a tooth extraction due to the imbalance of bone homeostasis or remodeling Signs include pain swelling, infection of gums/jaw, numbness and loosening of the tooth Risk is higher with more potent agents and prolonged use and IV administration

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERM): RALOXIFENE

MECHANISM OF ACTION •

•

Modifies gene expression by binding to nuclear oestrogen receptors (both alpha and beta receptors) and therefore selectively turns transcription on or off in tissues, it acts as an agonist in bone tissue therefore stimulating osteoblasts and inhibiting osteoclasts. This promotes bone formation.

It acts as an antagonist in the endometrium and breast and therefore contributes to reduced breast cancer and no increase in risk of endometrial or ovarian cancer.

INDICATIONS •

Treatment and prevention of osteoporosis in postmenopausal women with increased risk of breast cancer.

CONTRAINDICATIONS •

In stroke patients due to increased risk of venous thromboembolism

Refer to Calcium Homeostasis lecture for more information

RANKL ANTAGONISTS: DENOSUMAB MECHANISM OF ACTION • • • •

• •

Osteoblasts express a ligand termed Receptor activator of nuclear factor kappa-B ligand (RANK ligand).

Denosumab is a monoclonal antibody that acts as a RANKL inhibitor and acts similarly to the endogenous osteoprotegerin (OPG) molecule which limits the effects of the RANK ligand.

The RANK ligand is expressed on osteoblasts precursor cells and its expression is mainly driven by a parathyroid hormone.

The RANK ligand can interact with its receptor which is present on the surface of osteoclast precursor cells, leading to the maturation of osteoclast cells that are involved in bone reabsorption during the bone remodeling processes.

Denosumab therefore inhibits the Rank ligand by combining with it leading to reduced osteoclast formation, differentiation and survival.

It can be given subcutaneously every 6 months.

INDICATIONS •

Patients who have contraindications to bisphosphonate or are unable to adhere to them

CONTRAINDICATIONS •

Patients with rare hereditary problems of fructose intolerance

CLINICAL NOTE Primary prevention of osteoporosis: • •

1st line: Bisphosphonates (evaluated after 5 years) 2nd line: o Denosumab o SERMS o Parathyroid hormone peptides o Strontium ranelate Refer to Calcium Homeostasis lecture for more information

DRUGS AFFECTING THE RESPIRATORY SYSTEM & THE EYE BRONCHODILATOR AGENTS ATROPINE •

See Atropine

XANTHINES (THEOPHYLLINE ) MECHANISM OF ACTION • Acts as a phosphodiesterase inhibitor • Increase cAMP levels causing bronchodilation • Causes inhibition of type IV PDE in T lymphocytes and eosinophils • This gives them their immunomodulatory and anti-inflammatory effect INDICATIONS •

Treatment of symptoms associated with chronic asthma, emphysema and chronic bronchitis

CONTRAINDICATIONS • • • • •

Overactive thyroid gland Diabetes Cystic fibrosis Alcoholism High blood pressure

SIDE EFFECTS • Cardiac arrhythmias (at high concentrations) • Insomnia • Nausea

CLINICAL NOTE • Narrow therapeutic index • Long acting bronchodilator given orally in slow release form

BETA AGONISTS (ADRENALINE, ISOPRENALINE, SALBUTAMOL) •

See Beta Agonists

ANTI INFLAMMATORY AGENTS SODIUM CROMOGLYCATE MECHANISM OF ACTION • Mast cell stabilizer that prevents the subsequent release of inflammatory mediators by activating a natural “turn-off switch” in mast cells via phosphorylation of cell membrane proteins inhibiting mediator release • Inflammatory mediators include histamine and leukotrienes and are responsible for allergic symptoms and bronchoconstriction • Inhibits mast cell degranulation, normally implicated in anaphylaxis following exposure to reactive allergens • More effective in young than elderly INDICATIONS • Prophylaxis of mild to moderate bronchial asthma • Adjunctive treatment of allergic rhinitis and systemic mast cell disease (mastocytosis) in pediatric patients and adults • Available as an ophthalmic solution for the symptomatic treatment of certain allergic eye conditions such as keratitis • Improves symptoms of diarrhoea, flushing, headaches, vomiting, urticaria, abdominal pain, nausea and itching in some patients CONTRAINDICATIONS • • • •

Hypersensitivity Acute bronchospasm, status asthmaticus Hepatic disease, renal failure, renal impairment Pregnancy, breastfeeding

GLUCOCORTICOIDS MECHANISM OF ACTION • Potent inhibitors of inflammatory processes by either:

o

• •

Directly binding to the glucocorticoid/glucocorticoid receptor complex to glucocorticoid responsive elements in the gene promoter regions o Or by an interaction of this complex with other transcription factors particularly activating protein-1 or nuclear factor-kappa Beta This leads to decreased generation of PAF, leukotriene C4/D4 due to increased synthesis of lipocortin which inhibits phospholipase A2 This leads to reduced formation of cytokines and therefore decreases activation of inflammatory cells

INDICATIONS •

Treat conditions caused by inflammation such as asthma, COPD, allergies, rheumatoid arthritis, osteoarthritis, Crohn’s disease, eczema and Multiple sclerosis.

CONTRAINDICATIONS • • • • • • •

Hypersensitivity Concurrent administration of liver or live-attenuated vaccines Systemic fungal infection Osteoporosis Uncontrolled hyperglycaemia Diabetes mellitus Glaucoma

ADVERSE EFFECTS • •

Cataracts Immunosuppression (can be reduced if administered by inhalation – beclomethasone)

LEUKOTRIENE PATHWAY MODULATORS: ZILEUTON, ZAFIRLUKAST, MONTELUKAST MECHANISM OF ACTION • •

•

The key enzyme in the leukotriene pathway is 5-lipoxygenase, a dioxygenase.

In asthma, there are two main approaches: o Inhibition of 5-lipoxygenase (zileuton) o cycLT1 antagonists (zafirlukast, montelukast) both agents effective as oral preparations

INDICATIONS • • •

Asthma Allergic rhinitis COPD

CONTRAINDICATIONS •

Hepatic impairment

BIOLOGICS MECHANISM OF ACTION • • • • •

Biologic therapies target specific inflammatory pathways involved in the pathogenesis of asthma Airway inflammation in severe asthma is divided into T2 high and T2 low T2 high is characterised by generation of key cytokines, interleukin-4, -5 and -13 which generate and regulate airway inflammation.

Biomarkers to mark the presence of T2 high inflammation include eosinophils and IgE There is: o Anti-IgE therapy that has improved outcomes in allergic asthma o Anti-IL-5 biologics and anti-IL-4R biologics shown to reduce asthma exacerbations, improve lung function, reduce oral corticosteroid

DRUGS USED IN OPHTHALMIC DIAGNOSIS MUSCARINIC ANTAGONISTS – TOPICAMIDE •

See Muscarinic Antagonists

BETA-BLOCKERS – TIMOLOL •

See Beta Blockers

CARBONIC ANHYDRASE INHIBITOR – DORZOLAMIDE •

See Carbonic Anhydrase Inhibitors

ALPHA 2 AGONISTS – BRIMONIDINE MECHANISM OF ACTION •

See Alpha-2 Agonists

CLINICAL NOTE • •

Treats open angle glaucoma when other agents are ineffective Used alone or in conjunction with beta blockers

DRUGS USED IN THE TREATMENT OF GOUT & RHEUMATOID ARTHRITIS MANAGEMENT OF ACUTE GOUT

NSAIDS: IBUPROPHEN OR INDOMETHACIN

MECHANISM OF ACTION • Inhibits the cyclooxygenase enzyme (more COX-2 than COX-1 isoform) by forming a hydrogen bond with arginine 120 to inhibit arachidonic acid (precursor for cyclooxygenase and leukotriene pathways) entering hydrophobic catalytic site and thereby inhibits prostaglandin and thromboxane synthesis:

o

•

Anti-inflammatory – reduces Prostaglandin E2 leading to less vasodilation and vascular permeability and therefore less oedema o Analgesic – reduces prostaglandins leading to less sensitisation of nociceptive nerve endings to inflammatory mediators such as bradykinin and 5-HT. o Antipyretic – reduces prostaglandin in hypothalamus which resets the thermostat To be more specific: o COX-2 inhibition = decreases synthesis of prostaglandins involved in mediating inflammation, pain, fever and swelling o COX-1 inhibition = adverse effects of Ibuprofen like gastric ulceration

INDICATIONS • • •

Moderate to severe inflammatory pain Rheumatoid Arthritis/ Osteoarthritis Management of acute gout

CONTRAINDICTIONS • Avoid low dose aspirin because it may precipitate attack by reducing renal clearance of uric acid CIINICAL NOTE • •

Half life = 2 hours Side effects include gastrointestinal bleeding

COLCHICINE MECHANISM OF ACTION • Binds to tubulin to form a colchicine-tubulin complex that inhibits polymerisation of neutrophil microtubules by preventing addition of dimers.

• This leads to impaired cell motility and cell division by inhibiting neutrophil activation in the acutely inflamed joint by attenuating inflammatory response • Overall effect: o Decrease the release of the chemotactic factor o Decreased mobility and adhesion of neutrophils o Decreased trafficking of phagocytosed particles to lysosomes o Decreased tyrosine phosphorylation of neutrophil proteins leading to decreased Leukotriene 4 synthesis INDICATIONS • Acute gout • Short term use during initiation of allopurinol therapy ( which is used for chronic gout ) CONTRAINDICATIONS • gastrointestinal intolerance • dosing restrictions in patients with renal and hepatic dysfunction INTERACTIONS • Undergoes extensive enterohepatic circulation mediated by liver MDR protein • Cyclosporine & Tacrolimus are nephrotoxic acting to reduce glomerular filtration rate compromising renal excretion of colchicine CLINICAL NOTE

• •

Side effects include diarrhoea, myelosuppression Initially co-administered with drugs that alter urate homeostasis to avoid precipitating an acute attack

MANAGEMENT OF CHRONIC GOUT

ALLOPURINOL MECHANISM OF ACTION • Competitively binds xanthine oxidase enzyme which convert guanine and adenine to uric acid via hypoxanthine which is moderately soluble • Active metabolite oxypurinol prevents molybdenum from interconverting between +4 and +6 oxidation state – it freezes the enzyme • Therefore the inhibition of oxidation of xanthine to uric acid has an overall effect of reduced concentration of insoluble uric acid and urate in tissues

INDICATIONS • Prophylaxis of gout (NOT appropriate in treatment of acute gout because it disrupts urate homeostasis which can precipitate an attack) • Prophylaxis of uric acid renal stone CONTRAINDICATIONS • Caution in hepatic and renal impairment • Contraindicated in pregnancy ADVERSE EFFECTS • Rash – discontinue use • Hypersensitivity reactions including exfoliation, vasculitis, hepatitis and renal impairment • Hepatotoxicity

•

Blood disorders including haemolytic anaemia and leukopenia

INTERACTIONS • 6-Mercaptopurine (increased risk of toxicity)

CLINICAL NOTE • A prophylactic NSAID (which is not aspirin) or colchicine is usually co-administered • Check if patient who presents with gout is prescribed a thiazide diuretic before prescribing

URICOSURIC AGENTS: PROBENECID MECHANISM OF ACTION • •

Increase uric acid secretion by inhibiting reabsorption in the proximal tubule Mechanism of action is unclear but it lowers plasma urate, dissolves urate crystals and reverses crystal deposition in synovial joints

INDICATIONS •

Tumour lysis syndrome (chemotherapy) to prevent kidney damage

DISEASE MODIFYING ANTIRHEUMATIC DRUGS (DMARD’S) HYDROXYCHLOROQUINE & SULPHASALAZINE MECHANISM OF ACTION • MOA unclear but has a long term depressive effect on inflammation by improving symptoms and reducing disease activity.

• Hydroxychloroquine interferes with leukocyte function inhibiting IL-1.

• Also has inhibitory effect on the DNA synthesis at high doses.

• Sulphasalazine is the most commonly used DMARD in the U.K.

INDICATIONS • Suppressive treatment and treatment of acute attacks of malaria.

• Treatment of discoid and systemic lupus erythematosus, and rheumatoid arthritis.

CLINICAL NOTE • Hydroxychloroquine is reserved for cases where other treatments have failed.

• Low toxicity.

• Acute haemolysis may be caused in those with G6PDH deficiency.

GOLD AND PENICILLAMINE

MECHANISM OF ACTION • • • •

Gold salts accumulate in bone marrow, liver & spleen.

Impairs macrophage function and cytokine activity which supresses phagocytosis and lysosomal enzyme activity.

Inhibits PG synthesis and complement activation.

Potentially acts by suppressing IgM antibody responses and formation of immune complexes as well as IL-1 generation.

CLINICAL NOTE •

Absorption decreased by food. Metabolised in the liver, excreted in urine and faeces

IMMUNOSUPPRESSANTS

METHOTREXATE MECHANISM OF ACTION • Folic acid antagonist that decreases inflammatory cells in the synovium • Reversibly inhibits dihydrofolate reductase • Leading to reduced intracellular levels of THF and therefore preventing the synthesis of purines and thymidine INDICATIONS • Reducing joint erosions in established and early rheumatoid arthritis CONTRAINDICATIONS • Renal dysfunction • Liver disease • Active infectious disease • Excessive alcohol consumption.

LEFLUNOMIDE MECHANISM OF ACTION • Pyrimidine synthesis inhibitor that works by inhibiting dihydroorotate dehydrogenase.

• It undergoes biotransformation to active metabolite to inhibit the dihydroorotate dehydrogenase.

• Prevents pyrimidine synthesis by specifically targeting lymphocyte proliferation.

• Also inhibits osteoclast production and therefore slows progression.

INDICATIONS • Active rheumatoid arthritis as a disease-modifying antirheumatic drug (DMARD).

• Active psoriatic arthritis.

CONTRAINDICATIONS • Severe hepatic impairment due to hepatotoxicity.

• Hypersensitivity • Previous or current skin reactions • Immunosuppression • Impaired bone marrow function

AZATHIOPRINE ANTIMETABOLITE (PRODRUG) MECHANISM OF ACTION • Inhibits DNA and RNA synthesis, energy storage and cell signaling by targeting the proliferating lymphoid cells • NB: Azathioprine is converted to 6-mercaptopurine nonenzymatically. o 6-mercaptopurine is then metabolized to 6-methylmercaptopurine by thiopurine methyltransferase, 6-thiouric acid by xanthine oxidase, or 6-thiosine-5'-monophosphate by hypoxanthine phosphoribosyl transferase.

INDICATIONS • Treatment of rheumatoid arthritis • Prevention of renal transplant rejection SIDE EFFECTS • Bone marrow suppression • Leukopenia

CYCLOSPORINE MECHANISM OF ACTION • Binds to cyclophilin inhibiting calcineurin which results in reduced transcription of IL-2 and IL-2 receptors.

• This causes reduced proliferation of cytotoxic T cells INDICATIONS • Refractory rheumatoid arthritis SIDE EFFECTS • Nephron or Hepatic toxicity due to TGF-beta increasing the synthesis of extracellular matrix (interstitial fibrosis)

ANTI-INFLAMMATORY TUMOUR NECROSIS FACTOR ALPHA INHIBITORS: INFLIXIMAB MECHANISM OF ACTION • •

Partially humanised monoclonal antibody against TNF alpha (Recombinant DNA technology) Sequences derived from mouse antihuman sequences and from human sequences

•

Reduces development of neutralising Ab to infliximab

INDICATIONS • • • •

Rheumatoid Arthritis Ankylosing spondylitis Psoriasis and psoriatic arthritis Inflammatory bowel disease

CONTRAINDICATIONS • • • •

Acute and chronic infections Demyelinating disorders Class III or IV heart failure Recent Malignancies

CANCER THERAPY

METHOTREXATE •

See Methotrexate

AZATHIOPRINE •

See Azathioprine

5-FLUOROURACIL MECHANISM OF ACTION • • • • • •

An irreversible inhibitor FU is converted to fluorodeoxyuridine monophosphate (FdUMP) by pathway that converts uracil to dUMP It forms a stable complex with thymidylate synthase (TS), and thus inhibits deoxythymidine monophosphate (dTMP) production FdUMP also inhibits thymidylate synthase by forming a stable enzyme-substrate-cofactor complex with MTHF as well dTMP is essential for DNA replication and repair Reduced levels of dTMP cause cytotoxicity and therefore inhibit DNA synthesis – “thymine less death”

INDICATIONS •

Palliative management of certain types of cancer including renal cell, pancreas, colon, oesophageal, gastric, rectum, breast.

CONTRAINDICATIONS •

Suppressed bone marrow function

•

Hypersensitivity

THIOGUANINE MECHANISM OF ACTION • • • • • • •

A guanine analogue converted by HGPRT to 6-thioGMP 6-thioGMP is converted by guanylyl kinase to 6-thioGTP for incorporation into DNA Interferes with RNA transcription and DNA replication leading to cell death 6-thioGMP inhibits inosine monophosphate dehydrogenase depleting cellular pools of GMP TGMP interferes with the synthesis of guanine nucleotides by its inhibition of purine biosynthesis by feedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase.

Thioguanine nucleotides are incorporated into both the DNA and the RNA by phosphodiester linkages

INDICATIONS • •

Treatment of acute nonlymphocytic leukaemia Treatment of chronic phase of chronic myelogenous leukaemia

CONTRAINDICATIONS • • •

Anaemia Decreased function of bone marrow Hepatic veno-occlusive disease (type of liver disease)

CYTARABINE MECHANISM OF ACTION • • • •

A cytidine analogue that is metabolised into araCTP and competes with CTP for DNA polymerase.

Incorporation into DNA results in chain termination and cell death by hindering the rotation of the molecule within the DNA. DNA replication stops, specifically during the S phase of the cell cycle DNA replication and repair also stops due to the inhibition of DNA polymerase by cytarabine.

INDICATIONS • • • •

Treatment of acute lymphoblastic leukaemia Remission induction therapy in acute myeloid leukaemia in adult and pediatric patients The treatment of chronic myeloid leukaemia (blast phase) Prophylaxis and treatment of meningeal leukaemia.

CONTRAINDICATIONS • •

Hypersensitivity Active meningeal infections

ADVERSE EFFECTS •

Myelosuppression

CLINICAL NOTE •

Has a time equivalent to one cell cycle to effectively inhibit the replication of tumour cells therefore the bolus dose of cytarabine is given every 8 to 12 hours to maintain optimum intracellular levels.

ALKYLATING AGENTS: CYCLOPHOSPHAMIDE, C ARMUSTINE MECHANISM OF ACTION • • •

Directly modify DNA structure by preventing strand separation inhibiting DNA replication and transcription It also causes strand breakages and alkylation of proteins and enzymes producing cellular dysfunction The DNA damage is greater than the DNA repair so this results in cell death

INDICATIONS • • • •

Non-Hodgkin's lymphoma Leukaemia Multiple myeloma Breast & ovarian cancer.

CONTRAINDICATIONS •

Pregnancy and lactation -severe effects to both foetus and neonate

•

Hypersensitivity

•

Bone marrow suppression

•

Suppressed renal or hepatic function

PLATINUM AGENTS: CISPLATIN, CARBOPLATIN MECHANISM OF ACTION • • •

Targets nucleophilic centres in guanine, cytosine and guanine It is responsible for crosslinking adjacent residues on the same DNA strand This inhibits DNA synthesis

INDICATIONS •

Treatment of cancer

ADVERSE EFFECTS • • •

Their use is limited by their severe, dose-limiting effects In total, a cancer patient can experience any combination of around 40 specific side effects The dose-limiting side effect for cisplatin is nephrotoxicity, for carboplatin it is myelosuppression

•

Other common side effects include diarrhoea, anaphylaxis, cardiotoxicity, cytopenia, hepatotoxicity, ototoxicity, mucositis, stomatitis, pain, alopecia, anorexia, cachexia, asthenia, nausea and vomiting.

BLEOMYCIN MECHANISM OF ACTION • • • • •

Binds to guanosine-cytosine-rich portions of DNA via association of the "S" tripeptide, combining with Fe2+ to form a haem like ring complex Bleomycin/Fe complex reacts with oxygen to produce free radicals These free radicals cause single and double stranded DNA breaks between 3’-4’ bonds in deoxyribose and therefore are cytotoxic These strand breaks produce free base propenals - particularly thymine and result in cell cycle arrest at the G2 phase This halts the progression of cell replication and thus prevents tissue growth and repair

INDICATIONS •

Primarily as an antineoplastic agent in the treatment of cancer - squamous cell carcinomas, malignant lymphomas, testicular cancers, germinal cell tumours, gestational trophoblastic disease, Hodgkin lymphoma, and non-Hodgkin lymphoma.

ADVERSE EFFECTS •

Pulmonary toxicity referred to as bleomycin pulmonary toxicity which can lead to pulmonary fibrosis

TOPOISOMERASE INHIBITORS: DOXORUBICIN MECHANISM OF ACTION • • • • •

Type of chemotherapy drug that is classified an antitumour antibiotic It slows the growth of cancer cells by blocking an enzyme called topoisomerase II It does this by intercalating into the DNA structure preventing strand passage and relegation steo of the catalytic cycle of type II topoisomerase It causes the formation of free radicals that contain quinone/hydroquinone moieties that enable compounds to accept/donate electrons These free radicals cause strand scission and cell death

INDICATIONS •

Treatment of cancers of the stomach, ovary, prostate, squamous cell cancer thyroid; small cell cancer of lung, liver, lymphomas, multiple myeloma, Hodgkin's disease, acute lymphocytic leukaemia and acute myeloid leukaemia

ADVERSE EFFECTS • •

Dose limiting toxicity – cardiotoxicity (free radical mediated damage of cell membrane) Bone marrow suppression (side effect)

MICROTUBULE INHIBITORS: PLANT ALKALOIDS – VINBLASTIN/VINCRISTINE AND TAXANES (PACLITAXEL) MECHANISM OF ACTION • • •

Bind to tubulin preventing polymerisation and spindle formation by inhibiting the formation of microtubules This inhibition arrests the cell cycle at the metaphase as it disrupts mitotic spindle formation Taxanes bind specifically to the inside of the microtubule preventing depolymerisation

INDICATIONS • • •

Acute lymphocytic leukaemia Lymphoid blast crisis of chronic myeloid leukaemia Hodgkin and Non-Hodgkin lymphoma

CONTRAINDICATIONS •

Demyelinating Charcot-Marie-Tooth syndrome (for Vincristine)

SIDE EFFECTS • •

Peripheral neuropathy (for Vinicristine) Myelosuppression (for Viniblastin)

HORMONES USED IN CHEMOTHERAPY • • •

OESTROGEN: used in cancers which are partially hormone dependent such as Prostatic carcinoma ANTI-OESTROGENS: compete with oestradiol for cytoplasmic oestrogen receptor and used for breast cancer. An example includes Tamoxifen ANTI ANDROGENS: inhibit translocation of the androgen receptor to the nucleus and used in the treatment of prostate cancer

INDEX # 131 Iodine A Abciximab Acetaminophen Acetazolamide Acetylcholine ADH Adenosine Adrenaline Agomelatine Albendazole Alendronate Aliskiren Allopurinol Alphaxalone Alteplase Amantadine (& Rimantadine) Amiloride Amiodarone Amlodipine (& nifedipine) Apixaban Aripiprazole Artemisinin Artesunate Aspirin Atenolol Atorvastatin Atovaquone Atropine Azathioprine B Barbiturates Bendroflumethiazide Benzocaine Benzodiazepines Bicuculline Bleomycin Blood Products Bosentan Brimonidine Bromocriptine Bumetanide Bupropion Buserelin Buspirone C Calcium carbonate Calcium gluconate Calcium lactate Captopril Carbamazepine Carbidopa

Carboplatin Carmustine Celecoxib Cetirizine Chloroquine Chlorthalidone Chlorpromazine Cholestyramine Cimetidine Cisplatin Clomiphene Clonidine Clopidogrel Clozapine Colchicine Colestipol Colloidal Bismuth Cortisol Coxibs Cyclophosphamide Cyclosporine Cytarabine D Dabigatran Danazol Dapagliflozin Denosumab Desmopressin Dexamethasone Dichlorphenamide Diclofenac Diethylcarbamazine Digoxin Diltiazem Diphenhydramine Dipyridamole Disopyramide Dobutamine Dorzolamide Doxorubicin Doxycycline E Enfuvirtide Eplerenone Epoprostenol Ergocalciferol Ergotamine Ethosuximide Etidronate Exenatide Ezetimibe Ezogabine F FEIBA Fenofibrate Flecainide Fludrocortisone

Fluorouracil Furosemide G Gemfibrozil GHB Gliclazide Glucagon Glyceryl Trinitrate Gold Gonadorelin Goserelin H Haemostats Heparin Heroin Hydrochlorothiazide Hydroxychloroquine I Ibuprofen Iloprost Indomethacin Infliximab Insulin Ipratropium Isoflurane Isoprenaline Ivermectin K Ketamine L Labetalol Lacosamide Lanreotide Lasmiditan Latanoprost (& Travoprost) Leflunomide Lepirudin Leuprorelin Levetiracetam Levodopa Levosimendan Lignocaine Lithium Lobeline Loratadine Lorcaserin Losartan Lovastatin LSD M Mannitol

Maraviroc Mecasermin Mefloquine Melarsoprol Metformin Methadone Methazolamide Methotrexate Metronidazole Milrinone (& Enoximone) Mirabegron Misoprostol Montelukast (& Zafirlukast) Morphine Muscarine N Naloxone Naproxen Neostigmine Niacin Nicorandil Nicotine Nitric Oxide O Octreotide Oestrogens Omeprazole Ondansetron Organophosphates Oxytocin P Paclitaxel Pancuronium Paracetamol Pegvisomant Penicillamine Pentamidine Phenoxybenzamine Phenylephrine Phenytoin Physostigmine Pilocarpine Pirenzepine Piroxicam Pitolisant Pizotifen Ponstan (& Mefenamic Acid) Potassium Iodide Pramipexole Prasugrel Pravastatin Praziquantel Prazosin Prednisone Pregabalin Primaquine Probenecid

Proguanil Propofol Protirelin Prucalopride R Raloxifene Raltegravir Reserpine Risedronate Risperodone Ritonavir Rivaroxaban S Salbutamol Selegiline Sermorelin Sildenafil Simvastatin Sitagliptin Sodium Valproate Somatropin Spironolactone Streptokinase Sucralfate Sulphasalazine Sumatriptan Suramin Suxamethonium T T3 hormone T4 hormone Taxane Teripeptide Testosterone hormone Tetracosactide Thalidomide Theophylline Thiazolidinediones Thioguanine Thiopentone Sodium Thioureylenes Tiagabine Timolol Tirofiban Tranexamic Acid Triamterene Tropicamide V Varenicline Vecuronium Verapamil Vigabatrin Vilazodone Vinblastine Vincristine

W Warfarin Y Yohimbine Z Zaleplon Zanamivir (& Oseltamivir) Zidovudine Zileuton Zoledronate