Pharmacology+And+Therapeutics+(Spring+Term)+ … · TROPICAMIDE& Peripherally+Acting+Muscarinic+Antagonist+–+EYE+ (Antimuscarinic&Drug)& + GLAUCOMA+ DILATIONOF+THE+PUPILS+ Tropicamide

Drugs / Medication List

Pharmacology And Therapeutics (Spring Term)

Drug Name Action Use Reference

ATROPINE Peripherally Acting Muscarinic Antagonist – HEART RATE

(Antimuscarinic Drug)

After myocardial infarction (where there is typically a lot of reflex vagus activity which depresses the heart activity/HR, and is therefore reversed by atropine)

P&T Spring Lecture 1

IPRATROPIUM (bd, td)

TIOTROPIUM (od)

Peripherally Acting Muscarinic Antagonist – BRONCHI


The drugs used to modify bronchial function in clinical practice.

Ideally administered via inhalation because:

1. Drug directed to the target tissue 2. By directly targeting bronchial tissue, a lower dose is

required so fewer systemic effects.

Clinically useful in conditions such as ASTHMA and COPD.

OXYBUTYNIN

TOLTERODINE

Peripherally Acting Muscarinic Antagonist – BLADDER


Useful to modify bladder function.

Tolterodine is relatively specific to bladder β2 receptors than other drugs (like atropine).

Clinically useful in:

• OVERACTIVE BLADDERS • URINARY FREQUENCY • INCONTINENCE

The drug tightens the sphincter (increased sympathetic, decreased parasympathetic control), so decreased leakage.

However, these drugs do not work on stress incontinence (i.e. increased intra-‐abdominal pressure).

TROPICAMIDE Peripherally Acting Muscarinic Antagonist – EYE


GLAUCOMA

DILATION OF THE PUPILS

Tropicamide is a diagnostic drug which is designed for use only in the eye.


ADVERSE EFFECTS OF ALL ANTIMUSCARINIC DRUGS GIVEN SYSTEMICALLY:

• Dry mouth (most commonest symptom) • Erectile dysfunction • Bronchodilation (perhaps good side effect?) • Constipation • ‘Too Good’ Sphincter – Decreased detrussor activity so increased urinary bladder retention • Dry Eyes • Blurred vision • Increased intraocular pressure

HYOSCINE Centrally Acting Muscarinic Antagonist


Acts in the BRAIN.

Hyoscine is similar to atropine, but more sedating. Widely used in travel/sea-‐sickness (labyrinthine sedative).


BENZHEXOL Centrally Acting Muscarinic Antagonist


Used as to treat Parkinson’s Disease

Angiotensin Converting Enzyme Inhibitors

(e.g. ENALAPRIL, LISINOPRIL)

Angiotensin Converting Enzyme Inhibitors

(ACE-‐Inhibitors / ACEI)

These inhibit the somatic form of the ACE enzyme, so prevent the conversion of angiotensin I into angiotensin II.

Uses:

• Hypertension • Heart failure • Post-‐myocardial infarction • Diabetic neuropathy • Progressive renal insufficiency • Patients at high risk of cardiovascular disease.

Side Effects:

• Cough • Hypotension • Urticaria / Angioedema • Hyperkalaemia (Contraindications – take care if the

patient is, or may be prescribed, K+ supplements or K+ sparing diuretics which may further increase blood K+ levels)

• Foetal Injury • Renal failure in patients with renal artery stenosis

(secondary to fall in bp)


Angiotensin Receptor Blockers

(e.g. LOSARTAN, IRBESARTAN)

Angiotensin Receptor Blockers

(ARB/AIIA)

Acts as antagonists of the Type I Receptors (AT1) receptor for angiotensin II.

This prevents the renal and vascular actions of angiontensin II.

They are widely used in hypertension as an alternative to ACEI (fewer side effects), and are used in chronic heart failure patients who cannot tolerate ACEI.

Uses:

• Similar to ACEI • Alternative therapeutic intervention

Side Effects:

• Hypotension • Hyperkalaemia (Contraindications – take care if the

patient is, or may be prescribed, K+ supplements or K+ sparing diuretics which may further increase blood K+ levels)

• Foetal Injury • Renal Failure in patients with renal artery stenosis

(secondary to a fall in bp, meaning a reduced renal perfusion)

Direct Renin Antagonist

(e.g. ALISKIREN)

Direct Renin Antagonist • Inhibits the enzyme activity of renin, so prevents the conversion of angiotensinogen into angiotensin I

• Ultimately prevents the formation of angiotensin II • New class of agents


PHENYLALKYLAMINES (e.g. Verapamil)

Calcium Channel Blockers (CCB)

Rate Slowing Calcium Antagonists

Cardiac and Smooth Muscle Actions

• Reduce Ca2+ entry into cardiac and smooth muscle cells

• Negative inotropy effects (decrease contractility) • Inhibits AV Node Conduction

Uses:

• HYPERTENSION • ANGINA • Treating Paroxysmal SVT (Tachycardia originating

above the ventricular tissue) • Atrial Fibrillation

Unwanted Actions:

• Bradycardia and AV Block • Worsening of Heart Failure • Constipation

Negative Ionotropic Effect: Verapamil > Ditiazem


BENZOTHIAZEPINES (e.g. Diltiazem)


Rate Slowing Calcium Antagonist

Cardiac and Smooth Muscle Actions

• Reduce Ca2+ entry into cardiac and smooth muscle cells

Uses:

• HYPERTENSION • ANGINA

Unwanted Actions:

• Bradycardia and AV Block • Worsening of Heart Failure • Constipation

Negative Ionotropic Effect: Verapamil > Ditiazem

DIHYDROPYRIDINES (e.g. Amlodipine)


Non-‐Rate Slowing Calcium Antagonist

Smooth Muscle Actions Only

• Inhibits Ca2+ entry into vascular smooth muscle cells

Uses:

• HYPERTENSION • ANGINA (Dihydropyridines are preferred here)

Unwanted Actions:

• Ankle Oedema • Headache/Flushing • Palpitations (Reflex tachycardia)

Beta Blockers

(β-‐Adrenoceptor Antagonists)

e.g. ATENOLOL, BISOPROLOL, PROPRANOLOL

Competitive Antagonists of Beta-‐Adrenoceptors

Atenolol – Selective β1 Blocker

Bisoprolol – Selective β1 blocker

Propranolol – Non-‐Selective β-‐Blocker

Uses:

• Angina • Post Myocardial-‐Infarction • Cardiac Dysrhythmias • Chronic Heart Failure • Hypertension • Also in:

o Thyrotoxicosis o Glaucoma o Anxiety States o Migraine o Prophylaxis o Benign Essential Tumour

Mechanism of Action:

• Competitive antagonist of Beta Adrenoceptors • Many clinically used agents show selectivity (e.g.

atenolol for B1)

Use in Hypertension:

• No longer 1st line treatment • Mechanism not fully understood, but B1 antagonists


preferred • They do not reduce PVR

Effects:

• Reduce cardiac output • Reduce renin release by the kidney • May diminish NA release by sympathetic nerves • Lipophilic agents (e.g. propranolol) exert central

sympatho-‐inhibitory actions.

Unwanted Actions:

Can be due to either the actions on β1 and sometimes due to β2 in partial selectivity.

• Worsening of cardiac failure • Bradycardia (heart block) • Bronchoconstriction • Hypoglycaemia (in diabetics on insulin) • Increased risk of new onset of diabetes • Fatigue • Cold extremities and worsened peripheral artery

disease • Impotence • CNS effects (lipophilic agents) e.g. nightmares

ORGANIC NITRATES

(e.g. glyceryl trinitrate (GTN) and nicorandil)


• Stimulate the release of NO in smooth muscle cells (nitrate based drugs)

• Stimulate guanylate cyclase (NICORANDIL) • Causes VASODILATION

Uses:

• Angina • Acute and chronic heart failure • BP control during anaesthesia


Effects:

• Reduces PRELOAD (venous return) • Reduces AFTERLOAD (peripheral resistance) • Minor Effects: Antiplatelet agents, coronary artery

vasodilators

Pharmacokinetics:

• Nitrates undergo extensive first pass metabolism by the liver.

• GTN is often given sublingually for rapid angina relief. • Longer acting transdermal patches available (e.g. GTN

and isosorbide mononitrate)

Unwanted Effects: Hypotension, headaches and flushing associated with vasodilation.

Excess Use: associated with tolerance.

Anti-‐Arrhythmic Drugs Treat: SUPRAVENTRICULAR ARRHYTHMIAS e.g. adenosine, amidoarone, dronedarone

Verapamil (CCB)

ADENOSINE:

• Used i.v. to terminate supraventricular tachyarrhythmias (SVT)

• Short-‐lived action (20-‐30s) • Safer to use than verapamil.

Mechanism of Action

• Adenosine is an endogenous mediator produced by the metabolism of ATP.

• Acts on adenosine receptor (A1) to hyperpolarise cardiac tissue and slow conduction through AV node.

Adverse Effects:

• Chest pain • Dyspnoea (shortness of breath) • Dizziness • Nausea

AMIODARONE & DRONEDARONE:

• Used in supraventricular and ventricular tachyarrhythmias

• Complex mechanism of action – probably involves multiple ion channel block.

Adverse Effects:

• Amiodarone accumulates in the body (t1/2 10-‐100d) • Has a number of important adverse effects:

o Photosensitive skin rashes o Hypo-‐ and Hyper-‐ thyroidism

• Pulmonary fibrosis • Corneal deposits • Neurological and gastrointestinal disturbances

• Dronedarone is non-‐iodinated and less toxic than

amidarone, but less effective.


Treat: VENTRICULAR ARRHYTHMIAS e.g. flecainide, lidocaine,

(Amidarone, Dronedarone)

Treat: COMPLEX (e.g. supraventricular arrhythmias and ventricular arrhythmias) disopyramide

DIGOXIN and CARDIAC GLYCOSIDES

Cardiac Glycosides • Digoxin slows ventricular rate in ATRIAL FIBRILLATION and relieves the symptoms of CHRONIC HEART FAILURE.

• Long t1/2 of ~40hours • Narrow therapeutic window • An immune Fab (Digibind) is available for digoxin

toxicity.


• Inhibits Na-‐K-‐ATPase (Na/K Pump) • This results in the increased accumulation of

intracellular Na+, so increases intracellular Ca2+ (as more Na+ can be exchanged out of the cell for Ca2+ via the Na+/Ca2+ exchanger)


• So POSITIVE INOTROPIC EFFECT. • Central vagal stimulation causes reduced rate of

conduction through AV node

Adverse Effects: (Common and severe)

• Dysrhythmias (e.g. AV Conduction block, ectopic pacemaker activity)

• N.B. hypokalaemia and hypomagnaesia (usually a consequence of diuretic use), lower the threshold for digoxin toxicity.

IVABRADINE Use:

• Treating angina in patients with normal sinus rhythm.


• Blocks If Channel (f-‐funny) (an Na-‐K channel important in the SA node)

• Slows heart rate.

Contraindications:

• Severe bradycardia • Sick Sinus Syndrome • 2-‐3rd degree heart block • Cardiogenic Shock • Recent MI

Adverse Effects:

• Bradycardia • First-‐degree heart block • Ventricular and supraventricular arrhythmias


CARDIAC INOTROPES (e.g. Dobutamine and Milrinone)

Dobutamine – β1 adrenoceptor AGONIST (with little effect on heart rate)

Milrinone – Phosphodiesterase inhibitors. Have inotropic effects by inhibiting breakdown of cAMP in cardiac myocytes.

Agents that INCREASE THE FORCE OF CARDIAC CONTRACTION

Used to treat acute heart failure in some situations (e.g. after cardiac surgery or in cardiogenic/septic shock).

Despite increasing cardiac contractile function, so far all inotropes have reduced survival in chronic heart failure.

ALPHA BLOCKERS (e.g. doxazosin and phenoxybenzamine)

and SYMPATHOLYTICS (clonidine, moxonidine)

Alpha Blockers – antagonists of α1-‐adrenoceptors

Alpha blockers can be:

• COMPETITIVE e.g. dozazosin • IRREVERSIBLE e.g. phenoxybenzamine

Used occasionally in combination with anti-‐hypertensives in resistant hypertension, but routine use has declined since shown to be associated with increased rates of chronic heart failure.

Phenoxybenzamine – combined with a beta-‐blocker, provides long-‐lasting alpha blockade in catecholamine-‐secreting tumours (e.g. phaeochromacytoma)

Sympatholytics

Centrally acting anti-‐hypertensive agents e.g. clonidine (α2* adrenoceptor agonist) and moxonidine (imadazoline agonist) inhibit sympathetic outflow from the brain, and occasionally used as antihypertensive agents.

(*α2 is an inhibitory alpha adrenergic receptor)


VASOCONSTRICTORS

e.g. Sumitriptan

Sumitriptan used in migrane treatment SUMITRIPTAN

• Agonst at 5HT1D Receptor (Serotonin Receptor) • Constricts some large arteries and inhibits trigeminal

nerve transmission • Used to treat migraine attacks. • Contraindication in patients with coronary disease.

Other ergot alkaloids are also used in migraine (usually act as partial agonist of 5HT1 receptors)


ADRENALINE Endogenous catecholamine Produced by the adrenal gland, used in cardiac arrest and anaphylactic shock.


PROMETHAZONE

-‐ ANTI-‐EMETIC

Anti-‐emetic

• Acts as a competitive antagonist at Histaminergic (H1), Muscarinic Cholinergic (M) and Dopaminergic (D2) Receptors

• Potency: H1 > M > D2

Acts centrally (labyrinth, NTS and vomiting centres) to block activation of the vomiting centre.

Use an anti-‐emetic in:

• Motion Sickness (Prophylaxis, and during onset) • Disorders of Labyrinth (e.g. Meniere’s) • Hyperemesis Gravidarium • Pre & Post-‐Operatively (sedative and anti-‐muscarinic

effects are also useful)

Other Uses:

• Relief of allergic symptoms • Anaphylactic emergency • Night sedation and insomnia


Unwanted Effects:

• Dizziness • Tinnitus • Fatigue • Sedation • Excitation in excess • Convulsions (children more susceptible) • Antimuscarinic side-‐effects

Pharmacokinetics:

• Oral administration • Onset of action 1-‐2h • Maximum effect at around 4h • Duration of action – 24h

METACLOPRAMIDE

-‐ ANTI-‐EMETIC

Primarily Dopamine Receptor Antagonist

Potency: D2 >> H1 >> Muscarinic Receptors

• Order of antagonistic potency: D2 >> H1 >> Muscarinic Receptors

• Acts centrally, especially at the Chemoreceptor Trigger Zone (CTZ)

• Acts in the Gastrointestinal Tract:

o INCREASES SMOOTH MUSCLE MOTILITY (from oesophagus to small intestine)

o ACCELERATED GASTRIC EMPTYING o ACCELERATED TRANSIT OF INTESTINAL

CONTENTS (from duodenum to ileo-‐coecal valve)

NOTE – Care must be taken with bioavailability of co-‐administered drugs e.g. adsorption and hence effectiveness of digoxin may be reduced. Nutrient supply may be compromised – especially important in conditions such as diabetes mellitus.


Use: Used to treat nausea and vomiting associated with:

• Uraemia – Severe renal failure • Radiation Sickness • Gastrointestinal Disorders • Cancer Chemotherapy (high doses) e.g. cisplatin

(intractable vomiting)

Unwanted Effects: • Drowsiness • Dizziness • Anxiety • Extrapyramidal reactions:

o Children more susceptible than adults (Parkinsonian-‐like syndrome: rigidity, tremor and motor restlessness)

• Note: No Anti-‐Psychotic Actions • In the endocrine system:

o Hyperprolactinaemia o Galatorrhoea o Disorders of menstruation

Pharmacokinetic Considerations: • May be administered orally – rapidly absorbed • Extensive first pass metabolism • May also be given intravenously • Crosses BBB • Crosses Placenta

HYOSCINE

-‐ (ANTI-‐EMETIC)

Muscarinic Receptor Antagonist (Anti-‐Muscarinic) Mode of action

• Order of antagonistic potency: Muscarinic >>> D2 = H1 Receptors

• Acts centrally, especially in the VESTIBULAR NUCLEI, NTS, VOMITING CENTRES to block activation of vomiting centres.

Use as an Anti-‐Emetic • Prevention of motion sickness • Has little effects once nausea/emesis is established • In operative pre-‐medication

N.B Atropine is less effective Unwanted Effects:

• Typical Anti-‐Muscarinic Side-‐Effects: o Drowsiness, Dry Mouth o Cyclopegia (Paralysis of cilliary muscles of the

eye) o Mydriasis o Constipation (not usually at anti-‐emetic

doses)

Pharmacokinetic Considerations • Can be administered orally (peak effect in 1-‐2 hours) • Intravenous • Transdermally


ONDANSETRON 5HT3 RECEPTOR ANTAGONIST Mode of action:

• Acts to BLOCK TRANSMISSION IN VISCERAL AFFERENTS and CTZ

Use as an anti-‐emetic:

• Main use in preventing anti-‐cancer drug-‐induced vomiting, especially cisplatin

• Radiotherapy-‐induced sickness • Post-‐Operative nausea and vomiting

Unwanted Effects: • Headache • Sensation of flushing and warmth • Increased large bowel transit time (constipation)

Pharmacokinetic considerations: • Administer Orally • Well absorbed, excreted in the urine.

DIURETIC:

OSMOTIC DIURETIC e.g. Mannitol

Osmotic Diuretics are:

• Pharmacologically inert • Filtered by the glomerulus, but not

reabsorbed. • Increase the osmolarity of tubular fluid (and

plasma) so reduce the osmotic gradient.

Therefore, they DECREASE water reabsorption where the nephron is freely permeable to water: • Proximal Tubule • Descending Limb of Loop of Henle • Collecting Duct

This causes a DECREASED H2O REABSORPTION and INCREASED H2O EXCRETION (There is also a small increase in Na+/Cl-‐ loss)

• Clinical uses:

o Prevent ACUTE renal failure (by increase H2O excretion) (urine production ceases)

o Reduce INTRA-‐CRANIAL PRESSURE o Reduce INTRA-‐OCULAR PRESSURE o Increase Plasma Osmolarity

• Unwanted Effects:

o Increased EXTRACELLULAR FLUID volume which can lead to:

§ Hyponatraemia (associated with nausea, vomiting and pulmonary oedema)

DIURETIC

CARBONIC ANHYDRASE INHIBITORS

e.g. Acetazolamine

Carbonic anhydrase inhibitors are weak diuretics. They act mainly on the PROXIMAL TUBULE, to: • Prevent the reabsorption of HCO3

-‐ and Na+ • H2O reabsorption is therefore reduced.

Increased delivery of HCO3-‐ and Na+ to the distal tubule, so an increased K+ loss. INCREASED TUBULAR FLUID OSMOLARITY and DECREASED H2O REABSORPTION IN THE COLLECTING DUCT. Therefore, they INCREASE URINE VOLUME (increased H2O excretion – alkaline urine due to HCO3

-‐) and K+, Na+ and HCO3-‐

Excretion

• Clinical Uses: o Renal Stones – Uric Acid o Metabolic Alkalosis – Increased HCO3

-‐ loss o Decreased intraocular pressure

• Unwanted Effects: o K+ Loss o Metabolic Acidosis

DIURETIC

LOOP DIURETICS

e.g. Frusemide (Furosemide)

Loop Diuretics are POWERFUL Diuretics that act on the ascending limb of the loop of Henle. INHIBIT Na+ and Cl-‐ Reabsorption in the ascending limb by 30% Ca2+ and Mg2+ Loss -‐ Loss of K+ Recycling Therefore, they DECREASE THE OSMOLARITY of the medullary interstitium.

Increase the delivery of Na+ to the distal tubule, so increased K+ loss (due to increased Na+/K+ Exchange) Increased tubular fluid osmolarity (and so decrease the osmolarity of the medullary interstitium), which leads to decreased H2O reabsorption at the collecting duct.

Effects of Loop Diuretics (e.g. Frusemide) Large increase in urine volume and Na+, Cl-‐ and K+ loss (+Ca2+ and Mg2+ Loss) CLINICAL USES:

• OEDEMA – Heart failure, pulmonary, renal, hepatic and cerebral

• MODERATE HYPERTENSION – Piretanide • HYPERCALCAEMIA • HYPERKALAEMIA

UNWANTED EFFECTS:

• HYPERVOLAEMIA • HYPERTENSION • K+ Loss (Ca2+/Mg2+), Metabolic Alkalosis

DIURETIC

THIAZIDES

e.g. Bendrofluazide (Bendroflymethiazide

These are moderately powerful diuretics, which act on the early distal tubule. Inhibit Na+ and Cl-‐ reabsorption in the early distal tubule (by about 5-‐10%) So there is an increased delivery of Na+ to the distal tubules, so an increased K+ Loss (as there is an increased Na+/K+ exchange) There is an increased Mg2+ loss and increased Ca2+ reabsorption (REDUCED LOSS OF CALCIUM) Increased tubular fluid osmolarity, so decreased water reabsorption in the collecting duct. Thiazide diuretics lead to moderate increase in urine volume and Na+, Cl-‐ and K+ loss (Mg2+ loss)

Clinical Uses

• Cardiac Failure • Hypertension (Initially a decreased blood volume

decreases – in the long term, thiazides cause vasodilation)

• Severe Resistant Oedema • Idiopathic Hypercalciuria (Stone Formation) • Nephrogenic Diabetes Insipidus (Paradoxical)

bhj Unwanted Effects

• K+ loss • Metabolic Alkalosis • Diabetes Mellitus (Inhibits insulin secretion)

DIURETIC

POTASSIUM SPARING DIURETICS

e.g. Amiloride, Spironolactone

Classes of K+ Sparing Drugs • ALDOSTERONE RECEPTOR ANTAGONISTS

o e.g. SPIRONOLACTONE

• INHIBITORS of ALDOSTERONE-‐SENSITIVE Na+ CHANNELS

o e.g. amiloride

Potassium Sparing Diuretics e.g. Amiloride, Spironolactone • INHIBIT Na+ REABSORPTION – (and therefore the

secretion of K+) in the early distal tubule (by 5%)

• INCREASED TUBULAR FLUID OSMOLARITY – so decreased H2O reabsorption in the collecting duct

• DECREASED REABSORPTION OF Na+ TO DISTAL TUBULE – so increased H+ retention (Na+ / H+ exchanger)

• INCREASED URIC ACID LOSS

SMALL INCREASE IN URINE VOLUME and Na+ Loss Clinical Uses:

• For use with K+ losing diuretics – use Amiloride • Primary and Secondary Hyperaldosteronism – use

spironolactone

Unwanted Effects: • Hyperkalaemia • Metabolic Acidosis • Spironolactone – Gynaecomastia, Menstrual

Disorders, Testicular Atrophy

TRIPLE THERAPY:

ANTIBIOTICS + PPI

(FOR PEPTIC ULCERS – AGAINST H. PYLORI)

ANTI-‐ULCER DRUGS – ANTIBIOTICS Triple Therapy -‐ Example 1

• METRONIDAZOLE (active against anaerobic bacteria and protozoa) or AMOXYCILLIN (broad spectrum antibiotic) – depending on pattern of local resistance.

• CLARITHROMYCIN antibiotics with a macrolide structure – inhibits translocation of bacterial tRNA.

‘Triple Therapy’ is currently the best practice in treating peptic ulcer disease

• A single antibiotic is not sufficiently effective – partly due to the development of resistance.

• THREE PROBLEMS WITH TRIPLE THERAPY:

• COMPLIANCE • DEVELOPMENT OF RESISTANCE (Vaccinations may

soon be available) • ADVERSE RESPONSE TO ALCOHOL – especially with

metronidazole (interferes with alcohol metabolism)

• PROTON PUMP INHIBITOR (PPI) improves antibiotic efficiency possibly by increasing gastric pH which improves stability and absorption.

Triple Therapy – Example 2 • H2 Receptor Antagonist • Clarithromycin • Bismuth

PROTEIN PUMP INHIBITORS

e.g. OMEPRAZOLE

ANTI-‐ULCER DRUGS – INHIBITORS OF GASTRIC ACID SECRETION TREATMENT OF GASTRIC ULCERS Inhibit basal and stimulated gastric acid secretion from the parietal cell by >90%

Mechanism of Action: • PPIs are irreversible inhibitors of the H+/K+ ATPase • Inactive at neutral pH • As it is a weak base, it accumulates in the cannaliculi

of parietal cells: this concentrates its action there and prolongs its duration of action (2-‐3 days) and minimises its effects on ion pumps elsewhere in the body.

Uses • Component of Triple Therapy • Peptic Ulcers resistant to H2 Antagonists • Reflux Oesophagitis

Pharmacokinetics

• Orally active • Administered as enteric-‐coated slow-‐release

formulations

Unwanted Effects – Rare

HISTAMINE TYPE 2 (H2) RECEPTOR ANTAGONISTS

e.g. CIMETIDINE, RANITIDINE

ANTI-‐ULCER DRUGS – INHIBITORS OF GASTRIC ACID SECRETION Inhibit gastric acid secretion by approximately 60% and are less effective at healing ulcers than PPIs

• Orally administered • Well absorbed • Unwanted effects are rare

Relapses likely after withdrawal of treatment

CYTOPROTECTIVE DRUGS

e.g. SULCRAFATE

ANTI-‐ULCER DRUGS – CYTOPROTECTIVE DRUGS These drugs ENHANCE MUCOSAL PROTECTION MECHANISMS and/or BUILD A PHYSICAL BARRIER over the ulcer.

This is a polymer containing aluminium hydroxide and sucrose octa-‐sulphate.

Mechanism of Action: • Acquires a strong negative charge in an acid

environment • Binds to positively charged groups in large molecules

(proteins, glycoproteins) resulting in gel-‐like complexes.

• These coat and protect the ulcer, limit H+ diffusion and pepsin degradation of mucus.

• Increases PG, mucus and HCO3-‐ secretion and reduces

the number of H. Pylori

Side Effects: • Most of orally administered drug remains in the

gastrointestinal tract • May cause constipation • Reduces absorption of some other drugs (e.g.

antibiotics and digoxin)


e.g. BISMUTH CHELATE

ANTI-‐ULCER DRUGS – CYTOPROTECTIVE DRUGS These drugs ENHANCE MUCOSAL PROTECTION MECHANISMS and/or BUILD A PHYSICAL BARRIER over the ulcer.

Acts like sulcrafate Used in triple therapy (resistant cases


e.g. MISOPROSTAL

ANTI-‐ULCER DRUGS – CYTOPROTECTIVE DRUGS (A stable prostaglandin analogue) Mimics the action of locally produced prostaglandins to maintain the gastroduodenal mucosal barrier.

Misoprostal may be co-‐prescribed with oral NSAIDs (non-‐steroidal anti-‐inflammatory drugs), when used chronically:

• NSAIDs block the COX enzyme required for PG synthesis from arachidonic acid

• Therefore, there is a REDUCTION in the natural factors that inhibit gastric secretion, and stimulate mucus and HCO3

-‐ production

Unwanted Effects: • Diarrhoea, Abdominal Cramps, Uterine Contractions • DO NOT USE IN PREGNANCY

ANTACIDS ANTI-‐ULCER DRUGS – ANTACIDS

• Mainly salts of Al3+ and Mg2+ • Neutralises acid, raises gastric pH, reduces

pepsin activity

• Primarily used for NON-‐ULCER DYSPEPSIA • May be effective in reducing duodenal ulcer

recurrence rates

LIPID LOWERING DRUGS -‐

Bile Acid Sequestrants

Bile Acid Sequestrants: • Decrease LDL to some extent • However, they increase hepatic synthesis of LDL • Therefore, they are not very effective


STATINS

(e.g. Rosuvastatin, Atorvastatin, Simvastatin, Pravastatin, Fluvastatin)

Mechanism of Action: Statins block the HMG-‐CoA Reductase Enzyme

Cholesterol Synthesis Pathway:

• Geranyl pyrophosphate and Farnesyl Pyrophosphate – these are lipids involved in the modification of proteins (e.g. rho and ras)

• These lipids can only by synthesised within the cell. • Statins inhibit the production of these lipids.

Mechanism by which Statins reduce elevated LDL:

• Inhibition of HMG-‐CoA Reductase and hence, decrease cholesterol synthesis within hepatocytes.

• Increase the expression of LDL Receptors on hepatocytes:

o This means more LDL Receptors bind to, and internalise more circulating LDLs

Summary of Statin Effects:

• All statins are similar: they bring about the same reduction in risk.

• There is a strong correlation between LDL level and risk.

• Relatively safe. • Improves survival ad reduces risk in everyone. • Anti-‐inflammatory actions (same molecule

mechanism of action, but acts on different cell types) • Focus on patients with high LDL and high CRP (these

are potentially the highest risk patients)


FIBRATES

Mechanism of Action: Activate PPAR Alpha receptors à Decrease in fatty acids and triglycerides

• PPAR – Perioxisome Proliferator Activated Receptors • Thiazolidinediones (glitazones) are PPAR gamma

activators (and are used in diabetes) • Anti-‐inflammatory action • Shown to reduce mortality (by 1 trial) • 2nd choice to statins.

LIPID LOWERING DRUGS –

NICOTINIC ACID

Decreases cholesterol, LDL and triglyceride levels and increases HDL levels

• Other effects:

o Anti-‐Coagulant o Anti-‐Platelet o Anti-‐Inflammatory

• Shown to reduce risk in trials • Side effects include:

o Flushing and Hepatic Effects

LIPID LOWERING DRUGS –

EZETIMIBE

Mechanism of action: inhibits cholesterol absorption

• Must be activated by the liver, secreted into the bile

and reabsorbed. • Reduces cholesterol levels by 15-‐20% • May be used in combination with statins

e.g. Atorvastatin + Ezetimibe à Extra 12% reduction in cholesterol levels

• But – o No effect on carotid-‐intima media thickness o Unknown effects on events/survival

Not shown to work very well in practice

LIPID LOWERING DRUGS – Cholesterol Ester Transfer Protein (CETP) and reverse cholesterol transport

• CETP inhibitors increase HDL levels (since

they cannot be broken down) • However – they increase blood pressure

(therefore increase mortality, and hence are no longer used)

ANTICOAGULANTS: Warfarin

Mechanism of Action: PREVENTS activation of VITAMIN K Vitamin K required as a cofactor in synthesis/post-‐translational modification of Factors VII, IX, X and II (Thrombin) Administration: Oral, absorbed quickly from the GI tract. Peak blood concentration within 1 hour Pharmacological effects are delayed 12-‐16h, peak after 48h and lasts 4-‐5 days. This is because of the slow turnover of clotting factors.

Pharmacokinetics: Binds strongly to plasma proteins (99% bound to albumin) Results in a small volume of distribution. Metabolised by HEPATIC MIXED FUNTION CYTOCHROME P450 Anticoagulant activity is monitored by the International Normalised Ratio (a measure of prothrombin time) Adverse Effects: Haemorrhage (especially into the brain or bowel) Teratogenicity (NOT GIVEN in pregnant mothers) Reversal of Effects: • Low doses of Vitamin K • Fresh Frozen Plasma (FFP) or prothrombin complex

concentrate can be infused if a rapid reversal of warfarin effect is needed.

Drug Interactions: With drugs that inhibit cytochrome p450

Antibacterial agents e.g. Erythromycin Antifungal agents e.g. Fluconazole

With drugs that induce cytochrome p450 Anticonvulsants e.g. Phenobarbital

With drugs that inhibit platelet function E.g. Aspirin

With drugs that displace warfarin from plasma proteins (binding globulins)

E.g. Aspirin

ANTICOAGULANTS: Heparin and Low Molecular Weight Heparin

Mechanism of Action: Activates Anti-‐Thrombin III Anti-‐Thrombin III then INHIBITS FACTOR Xa and THROMBIN (FIIa) by binding to the active serine sites.

LMWH has a similar effect on Xa, but less of an effect on thrombin.

Administration • Poorly absorbed after oral administration • Therefore, given either:

o SUBCUTANEOUSLY o INTRAVENOUSLY

Pharmacokinetics

• Immediate onset when given Intravenously (I.V.) Delayed by about 1 hour if given subcutaneously (LMWH)

• Short Half-‐Life • Heparin exhibits saturation kinetics (apparent 1/2

life increases with increasing dose). • Anticoagulant activity is measured.

• LMWH has a longer half-‐life, exhibits 1st Order

kinetics. Its activity does not require monitoring.

Adverse Effects • Bleeding • Thrombocytopenia • Osteoporosis (associated with long term therapy

over 3 months) • Hypersensitivity

o Chills, fever, urticaria, possibly anaphylaxis

Reversal of Effects • Stop I.V. Heparin and LMWH. • Give IV PROTAMINE

o Protamine binds to heparin to produce an inactive complex.

ANTIPLATELET DRUGS: Aspirin

Mechanism of Action: Irreversibly inhibits COX-‐1 Enzyme Inhibits the production of TXA2 (Thromboxane A2) in platelets However, production of PGI2 by endothelium is not severely affected

Administration: • Oral

Pharmacokinetics:

• Highly plasma protein bound

Adverse Effects: • GI Sensitivity

ANTIPLATELET DRUGS: Clopidogrel

Mechanism of Action: A pro-‐drug which inhibits fibrinogen binding to glycoprotein IIb/IIIa Receptors.

Administration: • Oral

Pharmacokinetics:

• Peak plasma concentration 4hours after a single dose

• Inhibitory effect on platelet not seen until 4 days of regular dosing.

Adverse Effects: • Bleeding – GI Haemorrhage, Diarrhoea, Rash • In some patients, neutropenia

ANTIPLATELET DRUGS: Abciximab

Mechanism of Action: Antagonist of the Glycoprotein IIb/IIIa Receptor. This is a hybrid murine/human MONOCLONAL ANTIBODY which is licensed for use in ACUTE CORONARY SYNDROMES. Used in combination with heparin and aspirin to prevent ischaemia is patients with unstable angina.

Administration: • Intravenously (I.V.)

Pharmacokinetics: • Binds rapidly to platelets. • Cleared with platelets. • Antiplatelet effect persists for 24-‐48 hours.

Adverse Effects: • Bleeding • May potentially be IMMUNOGENIC

FIBRINOLYTIC (THROMBOLYTIC) DRUGS Streptokinase

Mechanism of Action: Non-‐Enzyme Protein Derived from culture of β-‐Haemolytic Streptococci Binds to plasminogen, causing a conformational change – this exposes the active site and causes plasmin activity. Activated plasmin degrades fibrin.

Administration: • Intravenous (I.V.) • 30-‐60 minutes infusion.

Pharmacokinetics:

• Rapidly cleared • t1/2 12-‐18 minutes

Adverse Effects:

• Bleeding • May potentially be antigenic

FIBRINOLYTIC (THROMBOLYTIC) DRUGS Alteplase

Mechanism of Action: Is recombinant tPA (Tissue Plasminogen Activator) It works better on plasminogen bound to fibrin than on soluble plasminogen in the plasma – and is therefore said to be CLOT SENSITIVE. It activates plasmin that then degrades fibrin and dissolves the clot.

Administration: • Intravenous (I.V.) 30 minute infusion

Pharmacokinetics:

• Rapidly cleared • t1/2 12-‐18 minutes

Adverse Effects:

• Bleeding

Ibuprofen Indomethacin (NSAID)

Non-‐Steroidal Anti-‐Inflammatory Drugs • Typical non-‐selective NSAIDs • Inhibit cyclo-‐oxygenase REVERSIBLY • Inhibit both COX-‐1 and COX2 • Have anti-‐inflammatory, analgesic and

antipyretic actions

Aspirin (NSAID)

Non-‐Steroidal Anti-‐Inflammatory Drugs

• Binds more avidly to COX-‐1 than COX-‐2 • Binds irreversibly to COX enzymes -‐ A

unique property among the NSAIDs o It acetylates an amino acid in the

active site of COX (making its actions long lasting)

o Its actions can only be reversed by the synthesis of new COX (as part of a continuous production)

• Serious side-‐effects at therapeutic doses • As well as usual NSAID actions, they also reduce

platelet aggregation

Aspirin – Mechanism of Action • Aspirin inhibits TXA2 Production by platelets and

prostacyclin production by endothelial cells (NOTE – Prsostacyclin is DIFFERENT to Prostaglandin)

• However, as platelets have no nucleus, COX1 is not re-‐synthesised and therefore TXA2 synthesis stops until a new batch of platelets are produced.

• As endothelial cells have nuclei, they can therefore replenish COX1 and prostacyclin synthesis continues.

Covalent binding of aspirin confers its anti-‐platelet property which is unique among NSAIDs.

Anti-‐Platelet Actions of Aspirin is due to: • Very high degree of COX-‐1 inhibition which

effectively suppresses TXA2 production by platelets

• Covalent binding which permanently inhibits platelet COX-‐1

• Relatively low capacity to inhibit COX-‐2 Major Side-‐Effects of Aspirin seen at therapeutic doses are:

• Gastric irritation and ulceration • Bronchospasm in sensitive asthmatics • Prolonged bleeding times • Nephrotoxicity

Side effects are more likely with aspirin than other NSAIDs because it inhibits COX covalently.

Celecoxib (NSAID)

Non-‐Steroidal Anti-‐Inflammatory Drugs

• Selectively inhibits COX-‐2 • Less effective on COX-‐1 mediated processes than

conventional NSAIDs such as ibuprofen and indomethacin

• Fewer ulcers (c.f. non-‐selective NSAIDS) • But not all COX2 activity is pathological • COX2 regulates – ovulation, parturition, renal

blood flow, blood pressure (therefore COX2 inhibition is not always desirable)

COX-‐2 Inhibitors: • Have a good GIT safety profile • Are well tolerated (but not recommended) for

patients with asthma • BUT have unwanted CVS effects

o Increased risk of myocardial infarction in 5 out of 8 trials when compared with non-‐selective NSAID

Cardiovascular Effects of COX-‐2 Inhibitors:

• May selectively inhibit PGI2 production and spare TXA2 production leading to more aggregation

• It is not the only mechanism – since MIs still occur even in patients taking aspirin.

• Non-‐selective NSAIDS also inhibit COX-‐2

• There is increasing evidence that COX-‐2 inhibitors pose higher risk of cardiovascular disease than conventional NSAIDS even though mechanism is unclear.

• Debate over the safety of the COX-‐2 inhibitors is continuing.

Paracetamol Analgesic, Antipyretic

• Is a good analgesic for mild-‐to-‐moderate pain

• Has ANTI-‐PYRETIC ACTION • However, it does NOT HAVE ANY ANTI-‐

INFLAMMATORY EFFECT • Therefore, it is not an NSAID

Mechanism of Action • The mechanism of action of paracetamol is

unclear – several mechanisms have been postulated.

• The most likely mechanism in man is: Paracetamol acts to inhibit the peroxidation of PGG2 into PGH2 (also catalysed by COX)

Side Effects of Paracetamol • Paracetamol is generally a very safe drug • However, in overdose it may cause IRREVERSIBLE

LIVER FAILURE o A reactive, but minor metabolite (NAPQI) is

normally safely conjugated with glutathione o If glutathione is depleted, the metabolite

oxidises thiol groups of key hepatic enzymes and causes cell death

Antidote for Paracetamol Poisoning

• Add compound with –SH Groups • Usually intravenous acetylcysteine • Occasionally oral methionine • Far fewer successful suicides with paracetamol

since purchase has been limited

Morphine (OPIATE) Opiate, as it is a direct derivative of the Poppy resin. Administration: Oral – 40-‐50% absorbed into the bloodstream Slow acting – may take up to 30 minutes to have an effect Can be administered i.v. Distribution: Limited access to the brain Largely ionised at physiological pH (so becomes polar), and diffuses across the lipid membranes slowly A large proportion of the administered dose does not access the brain. Metabolism: Rapid hepatic metabolism (GLUCORONIDATION at the 6’ position) Morphine is converted to morphine-‐6-‐glucuronide, but this compound ‘gives a handle’ for the kidney to easily clear/filter. Morphine-‐6-‐glucuronide, however, is more potent (so increased effect) and is subject to ENTEROHEPATIC CIRCULATION. Therefore morphine-‐6-‐glucuronidde may be secreted into the bile, and morphine may be regenerated in the GI Tract and reabsorbed. Excretion: Urine

Codeine (Opiate) Codeine Pharmacokinetics • Structurally similar to morphine (except for the

methyl group in the 3’ position) • Far less potent than morphine • Oral codeine is about 5-‐10% the strength of i.v.

morphine

Heroin (Semi-‐Synthetic Opioid)

Heroin Administration

• Oral

Distribution • Very LIPID SOLUBLE • Enters the brain quicker than morphine • Converted to morphine in cells

Metabolism

• Metabolised by plasma esterases • Heroin is broken down more rapidly than morphine

Short-‐acting (high abuse potential because the euphoric effect wears off quickly)

Fentanyl (Opioid) Opioid – Synthetic compound that does not generally resemble morphine in structure.

Administration Buccal (lollipop) or Intradermal (patch) Absorption -‐ 50-‐100% Absorption Distribution Very LIPID SOLUBLE and is more potent orally (a lot is reabsorbed the mouth and intranasally, so more gets into the system). Enters the bloodstream via the mucus membranes/skin Metabolism -‐ Hepatic metabolism (oxidation) Excretion -‐ Excreted in the Urine

Methadone (Opioid) Opioid – Synthetic compound that does not generally resemble morphine in structure.

• Administration o Oral

• Distribution

o The most lipid soluble opioid, therefore dissipates into fat very quickly.

o Methadone is commonly used as a morphine/heroin substitute (e.g. in weaning off addicts) because of the fact that it distributes into the fat very quickly.

o So the half-‐life of methadone is MUCH LONGER (150h), and can be given to morphine addicts as it is released slowly (hence a low constant background level of opiates)

o Therefore long acting, with a prolonged euphoric effect.

Naloxone (Opioid Receptor Antagonist)

Opioid Receptor Antagonist • Naloxone (Opioid Antagonist) • i.v. administration • Short acting • Used in opioid overdose

Prednisolone, Fluticasone, Budesonide (Glucocorticoids)

Glucocorticoids – used in the TREATMENT OF INFLAMMATORY BOWEL DISEASE (CD & IBD) Derived from cortisol Unwanted Effects of Glucocorticoids:

• Osteoporosis • Increased risk of gastric ulceration • Suppression of the HPA (Hypothalamo-‐

Pituitary-‐Adrenal) Axis • Type II Diabetes • Hypertension • Susceptibility to infection • Skin thinning, bruising and slow wound

healing • Muscle wasting and buffalo hump (c.f.

Cushing’s)

The activation of glucocorticoid receptors can lead to: • Increase the expression of anti-‐inflammatory genes

(GCR acting as a positive transcription factor) • Decrease the expression of pro-‐inflammatory genes

(GCR acting as a negative transcription factor) Glucocorticoids as anti-‐inflammatory Reduce influx and activation of pro-‐inflammatory cells

• Reduce expression of adhesion molecules on endothelial cells and leukocytes

• Reduce synthesis of some chemokines

Reduced production of inflammatory mediators (e.g. IL-‐2, IL-‐4, IFN-‐γ) that normally cause vasodilation, fluid exudation (swelling), further inflammatory cell recruitment and tissue degradation. This essentially is a reduced synthesis of the following mediators:

• Some cytokines and cytokine receptors (e.g. IL-‐1 and TNF-‐α)

• Proteolytic enzymes (e.g. elastase) • Enzymes that catalyse mediator synthesis (e.g.

cyclooxygenase) • Eicosanoids (e.g. prostaglandins and leukotrienes) • Nitric Oxide

Glucocorticoids as immunosuppressives Glucocorticoids are potent immunosuppressives which cause :

• Reduction in antigen presentation • Reduction in production of certain mediators (e.g. IL-‐

2, IL-‐4 and IFN-‐γ) • Reduction in cell proliferation and clonal expansion

Glucocorticoids virtually suppress all types of inflammation.

Mesealazine (5-‐ASA) Olsalazine (2x 5-‐ASA) (Sulfalazine) (Aminosalicylates)

These are all types of aminosalicylates – ONLY EFFECTIVE IN ULCERATIVE COLITIS. Anti-‐inflammatory, but NOT IMMUNOSUPPRESSIVE They are useful in the treatment of active ulcerative colitis and for maintenance of remission However, they are ineffective in Crohn’s Disease

Mechanisms of Anti-‐Inflammatory Actions: • Reduce synthesis of eicosanoids • Reduce free radical levels • Reduce inflammatory cytokine production • Reduce leukocyte infiltration

Metabolised by: Site of

Absorption:

Mesalazine (Not absorbed as it is in the most basic form – c.f. sulfasalazine)

Small bowel and colon

Olsalazine Colonic flora Colon

(Sulfasalazine) Colonic Flora, Liver

Colon

Azothioprine Immunosuppressive Agent Effective in BOTH CROHN’s DISEASE and ULCERATIVE COLITIS Can be used to induce remission in Crohn’s Disease (Treatment >17 Weeks) May enable reduction of glucocorticoid dose or postponement of colostomy. Useful for maintaining remission in Crohn’s Disease and some patients with Ulcerative Colitis.

Mechanism of Immunosuppression

• Azothioprine is a PRODRUG activated in vivo by gut flora to 6-‐MERCAPTOPURINE

• This interferes with purine biosynthesis • Interferes with DNA SYNTHESIS and CELL

REPLICATION

• It impairs: o Cell-‐ and Antibody-‐ mediated immune

responses o Lymphocyte proliferation o Mononuclear cell infiltration o Synthesis of antibodies

• It enhances:

o T-‐Cell Apoptosis

Unwanted Effects • Bone marrow suppression • Metabolised by xanthine oxidase

• Care must be taken to check whether there is a co-‐

administration of drugs which INHIBIT XANTHINE OXIDASE e.g. allopurinol which can cause a build-‐up of 6-‐Mercaptopurine leading to blood disorders.

Anti-‐TNFα INFLIXMAB (i.v.)

Used successfully in the treatment of Crohn’s Disease Some evidence of effectiveness in Ulcerative Colitis Potentially curative, rather than just simply palliative Successful in some patients with refractory disease and fistulae

Mechanism of Action of Infliximab (Anti-‐TNFα) • Indicates that TNFα plays an important role in the

pathogenesis of IBD • Anti-‐TNFα reduces activation of TNDα receptors in the

gut. • Production of other cytokines, infiltration and

activation of leukocytes is also reduced.

• Anti-‐TNFα also binds to membrane associated TNFα • Mediates complement activation and induces

cytolysis of cells expressing TNFα • This promotes apoptosis of activated T-‐Cells

Pharmacokinetics of Infliximab (Anti-‐TNFα)

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

weeks.

Adverse Effects of Infliximab (Anti-‐TNFα) • 4x to 5x increase in incidence of Tuberculosis and

other infections • Also risk of reactivating dormant TB • Increased risk of SEPTICAEMIA – therefore,

contraindications if abscesses are present • Worsening of heart failure • Increased risk of demyelinating disease • Increased risk of malignancy

• Can be immunogenic (monoclonal antibody) – therefore given with azathioprine

• Should only be used by specialists where adequate resuscitation facilities are available – due to a RISK OF ANAPHYLAXIS

• 2-‐4% risk of serious side-‐effect

Infliximab Summary • In steroid-‐dependent patients infliximab + AZA

doubles the number of patients in steroid-‐free remission after 1 year of treatment, but still only by 40%.

• This combination delays relapse • It is most beneficial in patients who:

o Have not taken thiopurines before o Are young (~26 years) o Have colonic CD

Adalimumab (sc.) TNF Inhibitor Binds to TNFα and prevents activation

Natalizumab Antibody against alpha-‐4-‐integrin • Antibody against alpha-‐4-‐integrin • Cell adhesion molecule • Evidence that it induces remission in some patients

with Crohn’s Disease • Generally well tolerated • Rarely (1:1000) encephalopathy if taken in

combination with other drugs.

Muscimol GABAA Agonist (I.e. Post-‐Synaptic GABA Receptor)

• This is a selective GABAA Receptor agonist (i.e. does not stimulate GABAB receptors etc.)

Cellular Mechanism of Action:

• Binding of GABA (or GABAR Agonist) to GABAA Receptors causes an activation of the Cl-‐ channel on the same post-‐synaptic knob

• This leads to hyperpolarisation and an INHIBITORY POST-‐SYNAPTIC POTENTIAL

• Therefore, this causes an inhibition of firing by the post-‐synaptic knob

Principles of GABA-‐ergic Transmission

Bicuculline GABAA Antagonist • Competitive Antagonsist Principles of GABA-‐ergic Transmission

Picrotoxin GABAA Antagonist • Non-‐competitive • Binds to chloride channel itself and blocks the action

of GABA receptors non-‐competitively • Inhibits hyperpolarisation


Convulsants GABAA Antagonists • Not used clinically Principles of GABA-‐ergic Transmission

Benzodiazepines and Barbiturates

GABAA Antagonists • Clinically used drugs (see other lecture) Principles of GABA-‐ergic Transmission

Baclofen GABAB Agonist

(I.e. Pre-‐Synaptic GABA Receptor) Selective GABAB Agonist Inhibit neurotransmitter release and function in two ways:

• AUTORECEPTORS – (Negative Feedback on the presynaptic knob)

• HETERORECEPTORS – (Sit on neurones of other terminals e.g. Dopaminergic Neurones, and regulate other neurones, such as by decreasing dopamine release)


Cellular Mechanism of Action: • G-‐Protein linked • Decreased Calcium Conductance (i.e. Influx of Ca2+

decreased) so decreased neurotransmitter release (reduce vesicular transport)

• Increased K+ conductance, (so efflux of K+ increased) and therefore more hyperpolarisation

• Used as a muscle relaxant (effects in the spinal cord) • Used also as a spasmolytic drug (Anti-‐Spastic Drug)

Phaclofen GABAB Antagonist Antagonises GABAB Receptor Principles of GABA-‐ergic Transmission

Saclofen GABAB Antagonist Competitive Antagonist (most commonly used) Principles of GABA-‐ergic Transmission

Flumazenil Competitive Benzodiazepine Antagonist Acts on BDZ Receptor on GABAA Receptor Protein

• Benzodiazepine binding to the BDZ receptor leads to enhanced GABA Action

• Enhanced GABA Binding to the GABA receptor protein (reciprocated)

Anxiolytics, Sedatives and Hypnotics

Anaesthetics Barbiturates e.g. THIOPENTONE

These are all barbiturates producing such effects. • Unwanted Side Effects of Barbiturates o They are not the 1st drug of choice due to

their unwanted effects o Low Safety Margins:

§ Depress Respiration § Overdosing is lethal (Treated with

forced alkaline diuresis to promote excretion)

o Alters natural sleep (Decreased REM Sleep) à hangovers/irritability

o Enzyme inducers o Potentiate the effect of other CNS

depressants e.g. Alcohol


Anticonvulsants Barbiturates e.g. Phenobarbital


Anti-‐spastic Barbiturates e.g. Diazepam


o Development of Tolerance (both pharmacokinetics and tissue tolerance)

o Dependence: Withdrawal Syndrome Causes: § Insomnia § Anxiety § Tremor § Convulsions § Death

Sedatives / Hypnotics e.g. Amobarbital

Used for severe intractable insomnia Half-‐Life 20-‐25 Hours Side effects – see above.


Benzodiazepines All benzodiazepines act at GABAA Receptors Pharmacokinetics: Administration:

• Well absorbed P.O. (Orally) • Plasma concentration peaks at around 1 hour

(oxazepam is slower) • I.v. administration for status epilepticus (prolonged

tonic clonic seizure activity >30minutes)

Absorption: • Well absorbed following oral administration

Distribution:

• Binds to plasma proteins strongly • Highly lipid soluble – wide distribution

Metabolism:

• Extensive hepatic metabolism (glucoronidation)

Excretion: • Excreted in the urine as glucoronide conjugates

Duration of action:

• Varies greatly • Short Acting • Long Acting (due to slow metabolism and/or active

metabolites)


Anxiolytics e.g. Diazepam, Chloridazepoxide (Librium), Nitrazepam, Oxazepam

Advantages of Benzodiazepines: • Wide margin of safety:

o Overdose leads to prolonged sleep which is rousable

o No respiratory depression o Flumazenil

• Mild effect on REM Sleep • Do not induce liver enzymes

Unwanted Effects of Benzodiazepines

• Sedation, Confusion, Ataxia (Impaired manual skills) • Potentiate the effects of other CNS Depressants

(Alcohols, BARBs) • Tolerance (Less than BARBs, ‘tissue’ tolerance only, so

no pharmacokinetic tolerance) • Dependence:

o Withdrawal Syndrome (similar to barbiturates, but less intense)

o Withdraw slowly • Free plasma concentrations are increased by certain

drugs e.g. aspirin and heparin


Sedatives/Hypnotics e.g. Temazepam, Oxazepam, Lorazepam, Nitrazepam


Other Sedatives / Hypnotics Chloral Hydrate

• Liver à Trichloroethanol • Mechanism of action – unknown • Wide margin of safety (safe for use in children and the

elderly)


Other Anxiolytics: Propranolol

• Improves physical symptoms Tachycardia – β1

Tremor – β2

• Commonly used to ‘cure’ stage fright


Other Anxiolytics: Buspirone

• 5HT1A Agonist • Slow Onset of Action (Days/Weeks) • Few Side-‐Effects


L-‐DOPA (SINAMET, MADOPAR – with peripheral inhibitors)

Dopamine Replacement Therapy DOPA is the precursor to dopamine, and is converted to dopamine in the brain. However, the enzyme DOPA Decarboxylase is also present in peripheral tissues Therefore, 95% of administered L-‐DOPA would be metabolised to dopamine in the periphery with major side effects of nausea and vomiting. Therefore L-‐DOPA is commonly prescribed with a peripheral DOPA decarboxylase inhibitor Preparations include:

• SINAMET (Carbidopa + L-‐DOPA) • MADOPAR (Benserazide + L-‐DOPA)

L-‐DOPA Clinical Uses: • Hypokinesia, rigidity & tremor • Start with low doses of the drug, and increase dose

until the maximum benefit is achieved without side-‐effects

• Effectiveness of L-‐DOPA declines with time, however Side Effects:

• Acute o Nausea – prevented by doperidone

(peripheral acting antagonist) o Hypotension o Psychological effects – Schizophrenia-‐like

syndrome with delusions, hallucinations, also confusion, disorientation and nightmares

• Chronic o Dyskinesias – abnormal movements of the

limbs and face. Can occur within 2 years of treatment. Disappear if the doses are reduced, but clinical symptoms then reappear.

o “On-‐Off” Effects – Rapid fluctuation in clinical states. Off periods may last from minutes to hours. Occurs more with L-‐DOPA.

Dopaminergic Pathways and Anti-‐Parkinson and Schziophrenic Drugs

Bromocriptine Pergolide Ropinerol

Dopamine Agonists Actions:

• Act on D2 Receptors

Dopamine Agonists: Actions • Act on D2 Receptors • Longer duration of action than L-‐DOPA • Smoother and more sustained response • Actions independent of dopaminergic neurons • Incidence of dyskinesias is less • Can be used in conjunction with L-‐DOPA

Adverse Effects:

• Common – Confusion, Dizziness, Nausea/Vomiting, Hallucinations

• Rare – Constipation, Headache, Dyskinesias


Deprenyl (Selegiline)

MAO Inhibitors

Deprenyl (Selegiline) • Selectively inhibits MAO-‐B (and hence inhibits

dopamine breakdown) • Predominantly acts in dopaminergic areas of the CNS. • Actions are without peripheral side effects of non-‐

selective MAO-‐I’s

• Clinical Uses o It can be given alone in the early stages of

Parkinson’s Disease o Alternatively, it can be given in combination

with L-‐DOPA (reduce the dose of L-‐DOPA by 30-‐50%)

• Side Effects (Rare) o Hypotension o Nausea/Vomiting o Confusion o Agitation


Resagiline

MAO Inhibitors

• Shown to have neuroprotective properties by inhibiting apoptosis

• Promotes anti-‐apoptosis genes leading to increased cell survival

• Early clinical trials suggest that Resagiline may slow the progression of Parkinson’s disease


Tolocapone (CNS & Peripheral) Entacapone (Peripheral only)

COMT Inhibitors

CNS Effects Prevents the breakdown of dopamine in the brain

Peripheral Effects COMT in the periphery converts L-‐DOPA to 3-‐0-‐methyl-‐DOPA (3-‐0MD). 3-‐0MD and L-‐DOPA compete for the same transport system into the brain. COMT inhibitors stop 3-‐0MD formation, thus increasing the bioavailability of L-‐DOPA, thus more L-‐DOPA crosses into the brain and is converted to dopamine in the CNS. Therefore, this reduces L-‐DOPA dosage.


Neuroleptics • Mechanism of action – dopamine antagonists • Site of action – ‘D2-‐like’ receptors • Most neuroleptics block other receptors e.g.

5-‐HT, thus accounting for some of their side effects

• Clozapine is relatively non-‐selective between D1 and D2 receptors, but does have a high affinity for D4 receptors that have been shown to be increased in schizophrenia.

• Drugs treat positive symptoms, but not negative ones.

• Delayed effects – takes weeks to work. • Initially neuroleptics induce an increase in DA

synthesis and neuronal activity. This declines with time.

Other Actions/Side Effects: • Anti-‐emetic effect • Blocking dopamine receptors in the chemoreceptor

trigger zone. • Neuroleptic Phenothiazine – effective at controlling

vomiting and nausea induced by drugs (e.g. chemotherapy), renal failure

• Many neuroleptics also have a blocking action at histamine receptors.

• Effective at controlling motion sickness.

• Extrapyramidal side effects – Blockade of dopamine receptors in the nigrostriatal system can induce ‘Parkinson’ like side-‐effects

Acute dyskinesias – Related to blockade of dopamine receptors in the striatum which leads to an increase in cholinergic function. Develop at onset of treatment, reversible on drug withdrawal or anti-‐cholinergic drugs. Tardive dyskinesias – Involuntary movements, often involving the face and tongue. Occur in about 20% of patients after several months or years of therapy.

• Made worse by drug withdrawal or anti-‐cholinergics. • May be related to proliferation in presynaptic DA

receptors or drug toxicity. • Incidence is less with atypical drugs.

Endocrine Effects:

• DA is involved in the tuberoinfundibular system that regulates prolactin secretion.

• Neuroleptics increase serum prolactin levels – this can lead to gynaecomastia (men and women) and lactation (women)

Blockade of Muscarinic Cholinergic Receptors • Leads to typical peripheral anti-‐muscarinic side-‐

effects e.g. blurred vision, increased intraocular pressure, dry mouth, constipation, urinary retention


General Anaesthetics

Clinical setting:

Desired effect Drug

Loss of consciousness Induction: propofol (i.v.)

Maintenance: enflurane (inhalation) Suppression of reflex responses

Analgesia Opioid (e.g. i.v. fentanyl)

Muscle relaxation Neuromuscular blocking drugs (e.g. suxamethonium)

Amnesia Benzodiazepines (e.g. i.v. midazolam)

Principles of General Anaesthesia

Local Anaesthetics Ester: Cocaine / Amide: Lidocaine Routes/Methods of Administration

1. Surface Anaesthesia Mucosal surface (mouth, bronchial tree), Spray (powder), High concentrations – can lead to systemic toxicity

2. Infiltration Anaesthesia Directly into tissues à sensory nerve terminals, Used in minor surgery Adrenaline Co-‐Injection (NOT in EXTREMITIES i.e. fingers or toes, as it can cause ischaemic damage due to its potent vasoconstrictor effects in extremities)

3. Intravenous Regional Anaesthesia Intravenous, distal to a pressure cuff (which is also administered) e.g. during limb surgery System toxicity can be caused by premature cuff release (so the local anaesthetic reaches systemic circulation)

4. Nerve Block Anaesthesia Close to nerve trunks (e.g. dental nerves), Widely used in low doses, with slow onset, Co-‐injected with a vasoconstrictor

5. Spinal Anaesthesia Administered in the sub-‐arachnoid space (spinal roots), Used in abdominal, pelvic, lower limb surgery Causes a decrease in blood pressure; prolonged headache

6. Epidural Anaesthesia Fatty tissue of epidural space – spinal roots, Uses similar to spinal anaesthesia (abdominal, pelvic, lower limb surgery) and painless childbirth, Slower onset – higher doses

Lidocaine and cocaine: pharmacokinetics

Lidocaine (amide) Cocaine (ester)

Absorption (across mucous membranes) Good Good

Plasma protein binding 70% 90%

Metabolism Hepatic

N-‐dealkylation

Hepatic and plasma

Non-‐specific esterases

Plasma half-‐life 2 hours 1 hour

Principles of Local Anaesthesia

Administration: • Cocaine: Now only used as a surface anaesthetic (in ophthalmology) • Lidocaine: may be administered by any route

Metabolism: • Cocaine: Metabolised rapidly • Lidocaine: Relatively resistant to metabolism

Unwanted Effects: • Lidocaine: A classic local anaesthetic; therefore most of its side effects apply to other local anaesthetics • Cocaine: exception to the rule (unwanted effects affect the CNS and CVS)

Lidocaine Unwanted Effects: • CNS – Paradoxical Effect (you would expect it to damp down CNS activity, but it stimulates CNS activity) • CVS – Predictable Effects (due to Na+ Channel Blockade)

Cocaine Unwanted Effects: • CNS & CVS – Unwanted effects occur due to the sympathetic actions of cocaine (it blocks NA reuptake)

Lidocaine and cocaine: unwanted effects

Lidocaine Cocaine

CNS

CNS stimulation

Restlessness & confusion

Tremor

Euphoria and excitation

CVS

Myocardial depression

Vasodilatation

Reduced BP

Increased CO

Vasoconstriction

Increased BP

Methotrexate Cytotoxic Drugs – ALKYLATING AGENTS

Alkylating Agent (Cytotoxic Drugs) Interfere with thymidylate synthesis (generation of pyrimidines)

Folic Acid: • An essential nutrient • Important for nucleotide synthesis

Methotrexate:

• Structurally similar to folic acid • Can substitute for folate

Fluorouracil:

• Characteristic of pyrimidines: structurally similar to both uracil and thymidine except for the fluorine group

• Fluorine makes the molecule unreactive at that point – therefore it can interfere with nucleic acid synthesis

Methotrexate and Fluorouracil: • DHFR (Dihydrofolate Reductase) generates

tetrahydrofolate derivatives • Folate metabolites donate and accept electrons

and protons as part of the synthetic pathway • Uridine derivatives à Thymidine derivatives (by

the passage of electrons) • Thymidylate synthetase is a key target for

chemotherapy Methotrexate: Blocks DHFR Activity

• It is a folate mimic – DHFR binds to methotrexate as if it were folate, but as methotrexate cannot participate in the reaction, it essentially BLOCKS DHFR

Fluorouracil: Uridine and Thymidine Analogue • Thymidylate synthetase binds to fluorouracil

(thinking it is a uridine)

Cytotoxic Drugs

Fluorouracil Cytotoxic Drugs – ALKYLATING AGENTS

Alkylating Agent (Cytotoxic Drugs) Inhibit enzymes in DNA synthesis (e.g. thymidylate synthetase)

Cytotoxic Drugs

Azothioprine Cytotoxic Drugs – ALKYLATING AGENTS

Alkylating Agent (Cytotoxic Drugs) Inhibit purine synthesis

Cytotoxic Drugs

Actinomycin D Cytotoxic Drugs –CYTOTOXIC ANTIBODIES

Intercalates with DNA and interferes with topoisomerase II • Topoisomerase II cuts the DNA, allows it to unwind, and re-‐joins it – this allows proliferation to occur.

• Actinomycin D inhibits topoisomerase II by binding DNA in this way

Cytotoxic Drugs

DOXORUBICIN Cytotoxic Drugs –CYTOTOXIC ANTIBODIES

Inhibits DNA and RNA synthesis

• It has the ability to intercalate DNA and inhibit topoisomerase II

Cytotoxic Drugs

BLEOMYCINS Cytotoxic Drugs –CYTOTOXIC ANTIBODIES

Metal-‐Chelating-‐Glycopeptide antibiotics that degrade DNA

• Chelate metals and generate free radicals (oxygen derived)

• Free radicals cause DNA strand breaks • Bleomycins are active against non-‐dividing cells,

since they do not rely on cell proliferation • Problems associated with high damage to LUNG

TISSUE • Intravenous administration

Cytotoxic Drugs

PODOPHYLLOTOXINS e.g. etoposide Cytotoxic Drugs – PLANT ALKALOIDS

Podophyllotoxins: e.g. etoposide

• Inhibit DNA synthesis and cause a cell cycle block at G2

Cytotoxic Drugs

VINCA ALKALOIDS e.g. Vincristine Cytotoxic Drugs – PLANT ALKALOIDS

Vinca Alkaloids: e.g. vincristine

• Bind to tubulin and inhibit its polymerisation into microtubules – this prevents spindle fibre formation

Cytotoxic Drugs

HYDROXYUREA Cytotoxic Drugs – MISC.

• Inhibits ribonucleotide reductase (involved in nucleic acid synthesis)

Cytotoxic Drugs

CISPLATIN Cytotoxic Drugs – MISC.

• Interacts with DNA and causes guanine intra-‐strand cross-‐links

Cytotoxic Drugs

PROCARBAZINE Cytotoxic Drugs – MISC.

• Inhibits DNA and RNA Synthesis and interferes with mitosis at interphase

• Metabolically activated by cytochrome P450 and MAO à alkylate DNA (at N7 and O6 of guanine)

• Prodrug – a substrate for Cytochrome P450 and MAO

• N-‐N à N=N (this activates it and produces multiple metabolites, including alkylating agents)

• Alkylating agents covalently bind to DNA to produce bulky DNA adducts

Cytotoxic Drugs

Hormones As Cytotoxic Drugs

• Used for chemotherapy but are not technically cytotoxic

• Can inhibit tumours in hormone-‐sensitive tissues (e.g. prostate, breast)

• Gonadotrophin-‐releasing hormone analogues e.g. Goserelin

Hormones: Prednisolone Fosfestrol Tamoxifen

Mechanism Glucocorticoid Androgen SERM

Use Leukaemias & lymphomas

Prostate cancer

Breast cancer

General Toxic Effects

• Myelotoxicity • Impaired wound healing • Depression of growth (children) • Sterility • Teratogenicity • Loss of hair • Nausea and Vomiting

Cytotoxic Drugs

Side Effects: On fast growing cells:

• Inhibit cell division • Cell-‐cycle specific drugs affect: bone marrow, GI

Tract, Epithelium, hair & nails, spermatogonia On slow growing cells:

• Introduce DNA mutations • Cell-‐cycle independent drugs (alkylating agents)

cause secondary tumours

Phenytoin (PHT) Anticonvulsant (Anti-‐Epileptic)

• Blocks voltage-‐gated Na+ channels Indications: • Partial Epilepsy • Status Epilepticus


• Blocks voltage-‐gated Na+ Channels Drug Level Monitoring

• Useful Elimination Half-‐Life

• 20 Hours Metabolism

• Hepatic metabolism • Oxidation & hydroxylation, then conjugation • Potent hepatic enzyme inducer

Active Metabolites

• None Drug Interactions

• Complex Adverse Drug Reactions

• Ataxia • Sedation

• Hypersensitivity • Rash • Fever • Gingival hypertrophy • Folate deficiency • Megaloblastic anaemia • Vitamin K deficiency • Depression • Hirsutism • Peripheral neuropathy • Osteomalacia • Reduced bone density • Hypocalcaemia • Hepatitis • Vasculitis • Myopathy • Coagulation defects • Bone marrow hypoplasia

Carbamazepine Anticonvulsant (Anti-‐Epileptic)

• Blockade of voltage-‐gated Na+ Channels Indications: • Partial and Secondary Generalised Seizures


• Blocks voltage-‐gated Na+ Channels Drug Level Monitoring

• Useful Elimination Half-‐Life

• 5-‐26 hours (x3 daily dosing, unless SR preparations)

Metabolism • Hepatic oxidation then conjugation • CBZ is a potent hepatic enzyme inducer

Active Metabolites

• Carbamezepine epoxide

Drug Interactions • Complex drug interaction profile

Adverse Drug Reactions

• Hypersensitivity (rash, hepatitis, nephritis) • Dose-‐Related (Ataxia, dizziness, sedation,

diplopia) • Chronic (Vitamin K Deficiency, depression,

impotence, osteomalacia, hyponatraemia)

Lamotrigine Anticonvulsant (Anti-‐Epileptic)

• Blocks voltage-‐gated Na+ channels Indications: • Partial and generalised epilepsy (wide

spectrum)

Mechanism of Action: • Blocks voltage-‐gated Na+ Channels

Drug Level Monitoring

• N/A Elimination Half-‐Life

• 29 hours (monotherapy) • 15 hours (enzyme inducing co-‐medication) • 60 hours (valproate co-‐medication)

Metabolism

• Hepatic metabolism • Glucuronidation (no phase I metabolism) • Does not induce hepatic enzymes

Active Metabolites

• None

Drug Interactions • Valproate • Enzyme inducing AEDs

Adverse Drug Reactions • Usually well tolerated • Rash (high incidence; may be severe) • Headache • Blood dyscrasias • Ataxia • Diplopia • Dizziness • Sedation • Insomnia • Mood disturbance

(Sodium) Valproate Anticonvulsant (Anti-‐Epileptic)

• Enhances GABA transmission by several mechanisms

Indications: • Partial or generalised epilepsy (wide spectrum)


• Enhances GABA transmission by several mechanisms

Drug Level Monitoring • N/A

Elimination Half-‐Life

• 4-‐12 hours

Metabolism • Hepatic metabolism • Oxidation, then conjugation • Potent hepatic enzyme inhibitor

Active Metabolites

• None

Drug Interactions • Many

Adverse Drug Reactions • Severe hepatic toxicity (especially in young

patients) • Pancreatitis • Encephalopathy (ammonia driven) • Drowsiness • Tremor • Blood dyscrasias • Hair thinning and hair loss • Weight gain • Endocrine (PCO)

Sulphanilamide (P-‐Aminobenzoic Acid Analogue) (ANTI-‐MICROBIAL DRUG)

Folate is required for DNA/RNA Synthesis in both man and bacteria Man has evolved specific uptake processes for transporting folate into the cells. Bacteria have to synthesise folate. P-‐aminobenzoic acid is essential for the synthesis of folic acid in bacteria. Sulphanilamide is a structural analogue of P-‐aminobenzoic acid that COMPETES for the enzyme dihydropteroate which is involved in the synthesis of folate. They interfere with bacterial DNA/RNA synthesis and are bacteriostatic i.e. they arrest the growth of the bacteria, but do not kill them – it is then up to the host defence system.

Pharmacokinetics: • Readily absorbed in the GI tract. • Maximum plasma concentration is reached

within 4-‐6 hours

Side Effects: Mild/moderate (do not warrant withdrawal)

• Nausea and vomiting • Headache • Mental depression

Severe (warrants withdrawal)

• Hepatitis-‐type reaction • Hypersensitivity reactions • Bone marrow suppression

Note – WIDESPREAD RESISTANCE

Anti-‐Microbial Drugs

Trimethoprim (Folate Antagonists) (ANTI-‐MICROBIAL DRUG)

The utilisation of folate, in the form of tetrahydrofolate as a co-‐factor in thymidylate synthesis is an example of a pathway in which there is a differential sensitivity of human and bacterial enzymes to drugs. This pathway is virtually identical in micro-‐organisms and man, but one of the key enzymes dihydrofolate reductase is many times more sensitive to particular analogues in either man or bacteria.

Pharmacokinetics • Oral administration • Trimethoprim is fully absorbed from the GI tract • Widely distributed throughout the tissues and

body fluids • Reaches high concentrations in the lungs and

kidneys.


Trimethoprim is a folate antagonist that is more sensitive to the dihydrofolate reductase enzyme in BACTERIA than in man (IC50 [mmol/l] 0.005 bacteria, 260 man)

Unwanted Effects

• Nausea/vomiting • Skin rashes • Hypersensitivity – even the small dose of

sulphonamide which is used in co-‐trimoxazole can still cause serious hypersensitivity reactions, which are not dose related.

Clinical uses • Urinary tract and Respiratory tract infections

Co-‐Trimoxazole (Sequential Blockade) (ANTI-‐MICROBIAL DRUG)

Sulphamethazole and trimethoprim.

• Since sulphonamides affect the earlier stage in the same metabolic pathway i.e. folate synthesis, they potentiate the actions of trimethoprim.

• When given in combination, the drugs are effective at one tenth or less of what would be needed if each drug was given on its own.

Pharmacokinetics • When given as co-‐trimoxazole, about two-‐thirds

of each drug is protein bound and about half of each is excreted within 24 hours.

Clinical Uses • For infections with pneumocystis carinii which

causes pneumonia in patients with AIDS, co-‐trimoxazole is used in high doses.


Penicillin (β-‐Lactam Antibiotics) (ANTI-‐MICROBIAL DRUG)

β-‐Lactam antibiotics e.g. penicillin inhibit the formation of peptidoglycan and are subsequently bacteriocidal Method of Action:

• Interfere with the synthesis of the bacterial wall peptidoglycan

• Inhibit the transpeptidation enzyme that cross links the peptide chains attached to the backbone of the peptidoglycan.

Pharmacokinetics When administered orally -‐ Different penicillins are absorbed to differing degrees depending on their stability in acid and their adsorption on to food. The drugs are widely distributed by the bodily fluids, passing into joints, pleural and pericardial cavities, into the bile, the saliva and the milk, and across the placenta. Being lipid insoluble they do not enter mammalian cells. They therefore do not readily cross the blood brain barrier, UNLESS the meninges are inflamed, in which case they may reach effective therapeutic concentrations.


Elimination Elimination of most penicllins is mainly renal and occurs rapidly -‐ 90% tubular secretion

Unwanted Effects Relatively free from direct toxic effects Hypersensitivity reactions – breakdown products of penicillins combine with host protein and become antigenic. Most common reactions are skin rashes and fever, acute anaphylactic shock. A side effect of broad spectrum penicillins is effect on the gut bacterial flora -‐ in GI tract disturbances. Resistance to β-‐Lactam Antibiotics

1. Production of β-‐Lactamases by bacteria Genetically controlled and can be transferred from one bacterium to another. Staphylococcal resistance via β-‐lactamase production has spread progressively. In developed countries, at least 80% of staphylococci now produce β-‐Lactamase. Solution: Use β-‐lactamase inhibitors e.g. CLAVULANIC ACID which functions by covalently binding to the enzyme at, or close to, its active site.

2. Reduction in the Permeability of the outer membrane Therefore, there is a decreased ability of the drug to penetrate to the target site.

3. The occurrence of modified penicillin-‐binding sites

CLAVULANIC ACID (β-‐lactamase inhibitors)

Functions by covalently binding to the β-‐Lactamase enzyme at, or close to, its active site.

Reduces resistance to penicillin Anti-‐Microbial Drugs

CEPHALOSPORINS (β-‐Lactam Antibiotics) (ANTI-‐MICROBIAL DRUG)

e.g. Cephalexin (oral), Cefuroxime and Cefotaxime (parenteral) e.g. cefoperazone, cefotaxime (can cross BBB) Mechanism of Action

• Same as penicillins, interfere with peptidoglycan synthesis

• Resistance to this group of drugs has increased. • Nearly all Gram –ve bacteria have the gene

encoding for β-‐lactamase, which is more active in hydrolysing cephalosporins than penicillin.

• Resistance also occurs if there is decreased penetration of the drug – due to alterations of the membrane proteins or mutations of the binding site proteins.

• They are bactericidal.

Pharmacokinetics Some cephalosporins may be given orally, but most are given parenterally – intramuscular (i.m.) or intravenous (i.v.) Widely distributed in the body, passing into the pleural, pericardial and joint fluids, and across the placenta. Some cephalosporins cross the blood brain barrier e.g. cefoperazone, cefotaxime (Drug of choice for bacterial meningitis) Excretion (Most Cephalosporins)

• Excretion is mostly via the kidney – largely by tubular secretion

• But 40% of ceftriaxone and 75% of cefoperazone is eliminated in the bile.

• Since different β-‐Lactam antibiotics may bind to different binding proteins, it may be feasible to combine two or more of these agents and achieve a synergistic action between them.

Unwanted Effects:

• Hypersensitivity reactions (similar to those with penicillin) may be seen.

• Some cross-‐reaction occur (about 10% of penicillin sensitive individuals will be allergic to cephalosporins)

• Nephrotoxicity has been reported (especially with cephradine)

• Diarrhoea can occur with oral cephalosporins.


TETRACYCLINES (Drugs that inhibit bacterial protein synthesis) (ANTI-‐MICROBIAL DRUG)

Tetracyclines are broad-‐spectrum antibiotics that have a polycyclic structure. Method of Action

• Actively transported into bacteria and interrupt protein synthesis.

• Competition with tRNA for the A-‐binding site. • Bacteriostatic, not bactericidal.

Spectrum

• Very wide and include Gram +ve and Gram –ve bacteria, mycoplasma, Rickettsia, Chlamydia, some spirochaetes and some protozoa (e.g. amoebae)

• However, many strains have become resistant to these agents.

• The basis of resistance is the development of energy-‐dependent efflux-‐mechanisms which transport the tetracyclines OUT OF THE BACTERIUM, but alterations of the target (the bacterial ribosome) also occur.

Pharmacokinetics • Usually given orally • Can also be given parenterally • The absorption of most preparations from the

gut is irregular and incomplete, and is improved by the absence of food

• Since tetracycline’s chelate metal ions (e.g. iron), forming a non-‐absorbable complex, absorption is decreased by the presence of MILK, certain antacids and iron preparations

• The drugs have wide distribution • The enter most fluid compartments

Excretion

• Excretion is both via the bile and by glomerular filtration in the kidney

• Most tetracyclines will accumulate if renal function is impaired.

Exception – DOXYCYCLINE (largely excreted into the gastrointestinal tract via the bile). Unwanted Effects

• Most common is gastrointestinal disturbances, due initially to direct irritation and later by the modification of gut flora

• Because they chelate calcium, tetracyclines are deposited in GROWING BONES and TEETH, causing staining and sometimes bone deformities. They should therefore not be given to children, pregnant women or nursing mothers.

• Phototoxicity (sensitisation to sunlight) has been seen – more particularly with demeclocycline.

• Minocycline can produce vestibular disturbances (dizziness and nausea) – the frequency of which is dose related.

• High doses of tetracyclines can decrease protein synthesis in host cells – an anti-‐anabolic effect.


Chloramphenicol (Drugs that inhibit bacterial protein synthesis) (ANTI-‐MICROBIAL DRUG)

Mechanism of Action • Inhibition of protein synthesis. • Chloramphenicol binds to the 50s Subunit of the

ribosome and inhibits transpeptidation.

Spectrum • Wide spectrum of activity, including Gram –ve and

Gram +ve bacteria. • They are bacteriostatic for most organisms.

Resistance

• Resistance is due to the production of chloramphenicol acetyl-‐transferase and is plasmid-‐mediated.

• R-‐plasmids containing determinants for multiple drug resistance for chloramphenicol, streptomycin and tetracyclines etc. may be transferred from one bacterial specie to another by promiscuous plasmids.

• Derivatives of chloramphenicol with the terminal –OH on the side-‐chain replaced by fluorine are not as susceptible to acetylation, and thus retain antibacterial activity.

Pharmacokinetics • Oral chloramphenicol is rapidly and completely

absorbed • Reaches maximum concentration in the plasma

within 2 hours. • Can be given parenterally

• Widely distributed throughout the tissues and

body fluids (including CSF) • In the plasma, 30-‐50% plasma protein bound • Half-‐life is approximately 2 hours

• About 10% is excreted unchanged in the urine • The remainder is inactivated in the liver. • Metabolites are excreted via the kidney and the

bile.

Unwanted Effects • The most important unwanted effect is

depression of the bone marrow resulting in pancytopenia

• Decrease in all blood cell elements – an effect which (although rare) can occur even with very low doses in some individuals.

• Chloramphenicol should be used with great care in new-‐borns because inadequate inactivation and excretion of the drug can result in ‘grey baby syndrome’ – vomiting, diarrhoea, flaccidity, low temperature and an ash grey colour.

• This carries a 40% mortality rate

• Hypersensitivity reactions can occur • GI disturbances • Other alteration of the intestinal microbial flora.


AMINOGLYCOSIDES e.g. GENTAMICIN (Drugs that inhibit bacterial protein synthesis) (ANTI-‐MICROBIAL DRUG)

Method of action • The aminoglycosides inhibit bacterial protein

synthesis by binding to the 30s Subunit of the ribosome

• This causes an alteration in the codon:anticodon recognition and results in a misreading of mRNA, and the production of defective bacterial proteins

• However, this action does not entirely explain their rapid lethality – so it is possible there may be a second target.

• Their penetration through the cell membrane of the bacterium depends on an oxygen-‐dependent active transport system, which chloramphenicol can block.

• Their effect is bactericidal and is enhanced by agents that interfere with cell wall synthesis.

Resistance • Resistance to aminoglycosides is becoming a

problem, and may be due to a number of factors – the most important is inactivation by microbial enzymes.

• Other mechanisms of resistance include: o Failure of penetration (overcome

concomitant use of penicillin and/or vanocomycin which synergies with aminoglycosides)

o Lack of binding of the drug due to mutations that alter the binding-‐site on the 30S subunit.

Spectrum • The aminoglycosides are effective against many

aerobic Gram –ve and some Gram +ve bacteria • They may be given together with penicillin in

infections caused by Streptococcus, Listeria or Pseudomonas aeruginosa

Pharmacokinetics • The aminoglycosides are polycations and highly

polar – hence are not absorbed in the GI tract • Given intramuscularly (i.m.) or intravenously

(i.v.). • Binding to plasma proteins is minimal.

• They do not enter cells and do not cross the

blood brain barrier into the CNS. • Plasma half-‐life is 2-‐3 hours. • Elimination is virtually entirely by glomerular

filtration in the kidney. • Tissue concentrations increase during

treatment, and can reach toxic levels after about a week of unmodified dosage.

Unwanted Effects: • Ototoxicity – progressive damage to and

destruction of the sensory cells in the cochlea and vestibular organs of the ear.

• Nephrotoxicity – damage to the kidney tubules. o Can be reversed if the use of the drug is

stopped. o Since elimination of these drugs is

almost entirely renal, their nephrotoxic action can impair their own excretion and a vicious cycle can be set up.

o Plasma concentrations must be monitored regularly.


ISONIAZID (Antimycobacterial agent) (ANTI-‐MICROBIAL DRUG)

Mechanism of Action: • The antibacterial activity of isoniazid is limited to

mycobacteria. • It is bacteriostatic on resting organisms, and can kill

dividing bacteria (bactericidal effect).

• It passes freely into mammalian cells and therefore effective against intracellular organisms

• The mechanism of action is not fully understood – some evidence suggests inhibition of the synthesis of mycolicacids (important constituents of the cell wall and peculiar to mycobacterium)

Pharmacokinetics • Readily absorbed from the GI tract, or after

parenteral injection • Widely distributed throughout the tissues and

body fluids, and CSF.

• Importantly – penetrates well into NECROTIC TUBERCULOUS LESION

• Metabolism, involves largely acetylation, depends on genetic factors that determine whether a person is a slow (t½=3hours) or rapid (t½=1.5hours) acetylator of the drug.

• Slow acetylators have a better therapeutic response.


RIFAMPICIN (Antimycobacterial agent) (ANTI-‐MICROBIAL DRUG)

Mechanism of Action: • Binds to and inhibits DNA-‐dependent RNA

polymerase in prokaryotic, but not eukaryotic cells. • It is one of the most active anti-‐tuberculosis agents

known. • It is also active against most other Gram +ve

bacteria as well as many Gram -‐ve species. • It enters phagocytic cells and can kill intracellular

micro-‐organisms.

Pharmacokinetics • Rifampicin is given orally. • Widely distributed in the tissues and body

fluids

• Excreted partly in the urine and partly in the bile-‐ some of it undergoing enterohepatic cycling.

• There is progressive metabolism of the drug by

deacetylation during its repeated passage through the liver.

• The metabolite retains antibacterial activity but

is less well absorbed from the GI tract. Unwanted effects

• Infrequent, occurring in fewer than 4% of individuals

• E.g. skin eruptions, fever, GI tract disturbances


PYRAZINAMIDE (Antimycobacterial agent) (ANTI-‐MICROBIAL DRUG)

Mechanism of Action • Pyrazinamide is inactive at neutral pH, but

tuberculostatic at acidic pH. • It is effective against the intracellular organism in

macrophages, since after phagocytosis the organism with be contained in phagolysosomes, in which the pH is low.

Pharmacokinetics • Oral administration -‐ the drug is well absorbed

after oral administration • Widely distributed, penetrating well into the

meninges • Excreted through the kidneys (mainly

glomerular filtration)

Unwanted Effects • Arthralgia (associated with high concentrations

of plasma urates) • GI tract upsets • Malaise • Fever


NYSTATIN (Anti-‐Fungal Agent) (ANTI-‐MICROBIAL DRUG)

Nystatin is a polyene macrolide. Mechanism of Action

• Binds to cell membrane and interferes with permeability and transport functions.

• It forms a pore in the membrane – the hydrophilic core of the molecule creating a transmembrane ion channel

• Nystatin has a selective action, binding avidly to the

membranes of fungi and some protozoa, and less avidly to mammalian cells, and not at all to bacteria.

• The relative specificity for fungi may be due to the drug’s greater avidity for ergosterol (fungal membrane sterol) than for cholesterol (the main sterol in the plasma membrane in animal cells).

• It is effective against most fungi and yeast

There is virtually no absorption from the mucous membranes of the body, or from the skin, and its use is limited to fungal infections of the SKIN and GI TRACT. Unwanted Effects

• Rare -‐ Limited to nausea and vomiting when high doses are taken by mouth

• Very rare -‐ Rash


MICONAZOLE (Anti-‐Fungal Agent) (ANTI-‐MICROBIAL DRUG)

Miconazole belongs to the azole group of synthetic antimycotic agents, with a broad spectrum of activity. Mechanism of Action

• Azoles block the synthesis of ergosterol (the main sterol in the fungal cell membrane) by:

o Interacting with the enxyme necessary for conversion of lanosterol to ergosterol.

• The resulting depletion of ergosterol alters the fluidity of the membrane and this interferes with the action of the membrane associated enzymes.

• The overall effect is an inhibition of replication. • A further repercussion is the inhibition of the

transformation of candida yeast cells into hyphae (the invasive and pathogenic form of the parasite)

Pharmacokinetics • Miconazole is given by intravenous infusion for

systemic infections • Given orally for infections of the GI tract. • Short plasma half-‐life.

Unwanted Effects

• Relatively infrequent (most commonly being GI Tract disturbances, blood dyscrasias)


ACYCLOVIR (Anti-‐Viral Agent) (ANTI-‐MICROBIAL DRUG)

• Acyclovir is a guanosine derivative with a high specificity for herpes simplex.

• Mechanism of Action

• Acyclovir is converted to the monophosphate by thymidine kinase – the virus specific form of this enzyme is much more effective at carrying out the phosphorylation than the host cell’s thymidine kinase.

• The monophosphate-‐form is subsequently converted to triphosphate by the host cell kinases.

It is therefore only adequately activated in infected cells.

• Acyclovir triphosphate inhibits viral DNA-‐polymerase, terminating the chain reaction.

• It is 30 times more potent against the herpes virus enzyme than the host enzyme.

• Acyclovir triphosphate is fairly rapidly broken down

within the host cells by cellular phosphatases.

Herpes simplex is more sensitive to acyclovir than other herpes viruses which cause glandular fever or shingles. Acyclovir has a small, but reproducible effect against cytomegalovirus (CMV) which can cause glandular fever in adults, or severe disease e.g. retinis, resulting in blindness in individuals with AIDS. Resistance

• Resistance due to changes in the viral genes coding for thymidine kinase or DNA polymerase has been reported

• Acyclovir-‐resistant herpes simplex virus has been the cause of pneumonia and encephalitis in immunocompromised patients.

Pharmacokinetics

• Acyclovir can be given orally, i.v. or topically • When given orally, only about 20% of the dose is

absorbed • Peak plasma concentrations reached in 1-‐2

hours


• i.v. infusion results in plasma concentration 10-‐ to 20-‐ fold higher

• The drug is widely distributed, reaching concentrations in the CSF which are 50% of those in the plasma

Excretion

• Excretion is in the kidneys, partly by glomerular filtration and partly by tubular secretion

Side Effects

• Local inflammation can occur during intravenous injection if there is extravasation of the solution (as it is very alkaline)

• Renal dysfunction has been reported when acyclovir is given intravenously – slow infusion reduces the risk.

• Nausea • Headache

ZIDOVUDINE (AZIDOTHYMIDINE, AZT) (Anti-‐Viral Agent) (ANTI-‐MICROBIAL DRUG)

Mechanism of Action • Zidovudine is an analogue of thymidine • In retroviruses, such as the HIV Virus, it is an active

inhibitor of reverse transcriptase enzyme.

• It is phosphorylated by cellular enzymes to the triphosphate form, which competes with the equivalent cellular triphosphates which are essential substrates for the formation of proviral DNA by viral reverse transcriptase (viral RNA-‐dependant DNA polymerase)

• Its incorporation into the growing viral DNA strand results in chain termination

• Mammalian alpha DNA polymerase is relatively resistant to the effect. However, gamma DNA polymerase in the host cell mitochondrion is fairly sensitive to the compound, and this may be the basis of unwanted effects.

Pharmacokinetics • Given Orally • Bioavailability of zidovudine is 60-‐80% due to

first pass metabolism • Peak plasma concentration occurs at 30 minutes • It can also be given intravenously

• There is little plasma protein binding so there

are no drug interactions due to the displacement by other drugs.

• Zidovudine enters mammalian cells by passive diffusion – unlike most other nucleotides which require active uptake.

• The drug passes into the CSF and the brain • Most of the drug is metabolised to inactive

glucoronide in the liver – only 20% of the active form being excreted in the urine.


Resistance • In most patients the therapeutic response to

zidovudine wanes with long-‐term use, particularly in late-‐stage disease.

• It is known that the virus develops resistance to the drug due to mutations resulting in amino acid substitutions in the viral reverse transcriptase and that these genetic changes accumulate progressively.

• Thus, the virus is a constantly moving target. • Resistant strains can be transferred between

individuals. • Other factors which could underlie the loss of

efficacy of the drug are: o Decreased activation of zidovudine to the

triphosphate o Increased virus load due to reduction in

immune mechanisms Increased virulence of the pathogen

Uses: In patients with AIDS

• It reduces the incidence of opportunistic infection (such as Pneumocystis Carnii Pneumonia)

• Stabilises weight • Reverses HIV-‐Associated thrombocytopenia • Stabilises HIV-‐associated dementia • Reduces viral load

If given to HIV +ve individuals before the onset of AIDS

• In combination with other drugs, can dramatically prolong the life expectancy

In HIV +ve mothers • Reduces the risk of transmission of the virus to

the foetus by 66%

In subjects who have been accidentally exposed to HIV • E.g. hospital worker, rape victim, condom

problems etc. Unwanted Effects

• Common unwanted effects: o Anaemia o Neutropenia

• Uncommon Effects: o GI tract disturbances o Skin rash o Insomnia o Fever o Headache o Abnormalities of liver function o Myopathy (particularly)

• Confusion, anxiety, depression, and a flu-‐like

syndrome also reported.

Documents

Pharmacology+And+Therapeutics+(Spring+Term)+ … · TROPICAMIDE& Peripherally+Acting+Muscarinic+Antagonist+–+EYE+ (Antimuscarinic&Drug)& + GLAUCOMA+ DILATIONOF+THE+PUPILS+ Tropicamide