Piri Pharm Tables Pharmacology Therapeutics Spring

Drugs
/ Medication List
Pharmacology And Therapeutics (Spring Term)
Drug Name Action Use Reference
ATROPINE Peripherally Acting Muscarinic Antagonist – HEART After myocardial infarction (where there is typically a lot of P&T Spring
RATE reflex vagus activity which depresses the heart activity/HR, Lecture 1
and is therefore reversed by atropine)
(Antimuscarinic Drug)
IPRATROPIUM (bd, td) Peripherally Acting Muscarinic Antagonist – The drugs used to modify bronchial function in clinical
BRONCHI practice.
TIOTROPIUM (od)
(Antimuscarinic Drug) 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 Peripherally Acting Muscarinic Antagonist – Useful to modify bladder function.
BLADDER
TOLTERODINE Tolterodine is relatively specific to bladder β2 receptors than
(Antimuscarinic Drug) 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 P&T Spring
Lecture 1
(Antimuscarinic Drug) 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. P&T Spring
Lecture 1
(Antimuscarinic Drug) 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

(Antimuscarinic Drug)

Angiotensin Angiotensin Converting Enzyme Inhibitors These inhibit the somatic form of the ACE enzyme, so prevent P&T Spring
Converting Enzyme the conversion of angiotensin I into angiotensin II. Lecture 2
Inhibitors (ACE-‐Inhibitors / ACEI)
Uses:
(e.g. ENALAPRIL,
LISINOPRIL) • 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 Angiotensin Receptor Blockers Acts as antagonists of the Type I Receptors (AT1) receptor for
Blockers angiotensin II.
(ARB/AIIA)
(e.g. LOSARTAN, This prevents the renal and vascular actions of angiontensin
IRBESARTAN) 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 Direct Renin Antagonist • Inhibits the enzyme activity of renin, so prevents the P&T Spring
Antagonist conversion of angiotensinogen into angiotensin I Lecture 2
• Ultimately prevents the formation of angiotensin II
(e.g. ALISKIREN) • New class of agents

PHENYLALKYLAMINES Calcium Channel Blockers (CCB) • Reduce Ca2+ entry into cardiac and smooth muscle P&T Spring
(e.g. Verapamil) cells Lecture 2
Rate Slowing Calcium Antagonists • Negative inotropy effects (decrease contractility)
• Inhibits AV Node Conduction
Cardiac and Smooth Muscle Actions
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 Calcium Channel Blockers (CCB) • Reduce Ca2+ entry into cardiac and smooth muscle
(e.g. Diltiazem) cells
Rate Slowing Calcium Antagonist
Uses:
Cardiac and Smooth Muscle Actions
• HYPERTENSION
• ANGINA
Unwanted Actions:
• Bradycardia and AV Block

• Worsening of Heart Failure
• Constipation
Negative Ionotropic Effect: Verapamil > Ditiazem

DIHYDROPYRIDINES Calcium Channel Blockers (CCB) • Inhibits Ca2+ entry into vascular smooth muscle cells
(e.g. Amlodipine)
Non-‐Rate Slowing Calcium Antagonist Uses:
Smooth Muscle Actions Only • HYPERTENSION

• ANGINA (Dihydropyridines are preferred here)
Unwanted Actions:
• Ankle Oedema
• Headache/Flushing
• Palpitations (Reflex tachycardia)

Beta Blockers Competitive Antagonists of Beta-‐Adrenoceptors Uses: P&T Spring

Lecture 2
(β-‐Adrenoceptor Atenolol – Selective β1 Blocker • Angina
Antagonists) • Post Myocardial-‐Infarction
Bisoprolol – Selective β1 blocker • Cardiac Dysrhythmias
e.g. ATENOLOL, • Chronic Heart Failure
BISOPROLOL, Propranolol – Non-‐Selective β-‐Blocker
• Hypertension
PROPRANOLOL • 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 Mechanism of Action: P&T Spring

Lecture 2
(e.g. glyceryl trinitrate • Stimulate the release of NO in smooth muscle cells
(GTN) and nicorandil) (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 ADENOSINE: P&T Spring
e.g. adenosine, amidoarone, dronedarone Lecture 3
• Used i.v. to terminate supraventricular
Verapamil (CCB) 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 Cardiac Glycosides • Digoxin slows ventricular rate in ATRIAL P&T Spring
GLYCOSIDES FIBRILLATION and relieves the symptoms of CHRONIC Lecture 3
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: P&T Spring

Lecture 3
• 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 Dobutamine – β1 adrenoceptor AGONIST (with little Agents that INCREASE THE FORCE OF CARDIAC
(e.g. Dobutamine and effect on heart rate) CONTRACTION
Milrinone)
Used to treat acute heart failure in some situations (e.g. after
cardiac surgery or in cardiogenic/septic shock).
Milrinone – Phosphodiesterase inhibitors.
Have inotropic effects by inhibiting breakdown of Despite increasing cardiac contractile function, so far all
cAMP in cardiac myocytes. inotropes have reduced survival in chronic heart failure.
ALPHA BLOCKERS (e.g. Alpha Blockers – antagonists of α1-‐adrenoceptors Alpha blockers can be: P&T Spring
doxazosin and Lecture 3
phenoxybenzamine) • COMPETITIVE e.g. dozazosin
• IRREVERSIBLE e.g. phenoxybenzamine
and SYMPATHOLYTICS
(clonidine, Used occasionally in combination with anti-‐hypertensives in
moxonidine) 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 Sumitriptan used in migrane treatment SUMITRIPTAN P&T Spring
Lecture 3
e.g. 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 P&T Spring
anaphylactic shock. Lecture 3
PROMETHAZONE Anti-‐emetic Acts centrally (labyrinth, NTS and vomiting centres) to block P&T Spring
activation of the vomiting centre. Lecture 10
-‐ ANTI-‐EMETIC • Acts as a competitive antagonist at
Histaminergic (H1), Muscarinic Cholinergic Use an anti-‐emetic in:
(M) and Dopaminergic (D2) Receptors
• Potency: H1 > M > D2 • 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

• Order of antagonistic potency: D2 >> H1 >> Muscarinic
METACLOPRAMIDE Primarily Dopamine Receptor Antagonist Receptors P&T Spring
Lecture 10
-‐ ANTI-‐EMETIC 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

Mode of action
HYOSCINE Muscarinic Receptor Antagonist (Anti-‐Muscarinic) • Order of antagonistic potency: Muscarinic >>> D2 = H1 P&T Spring
Receptors Lecture 10
-‐ (ANTI-‐EMETIC) • 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 Use as an anti-‐emetic:
• Main use in preventing anti-‐cancer drug-‐induced
Mode of action: vomiting, especially cisplatin
• Acts to BLOCK TRANSMISSION IN VISCERAL • Radiotherapy-‐induced sickness
AFFERENTS and CTZ • 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 Diuretics are: • Clinical uses:
o Prevent ACUTE renal failure (by increase H2O
OSMOTIC DIURETIC • Pharmacologically inert excretion)
e.g. Mannitol • Filtered by the glomerulus, but not (urine production ceases)
reabsorbed.
• Increase the osmolarity of tubular fluid (and o Reduce INTRA-‐CRANIAL PRESSURE
plasma) so reduce the osmotic gradient. o Reduce INTRA-‐OCULAR PRESSURE
o Increase Plasma Osmolarity
Therefore, they DECREASE water reabsorption where
the nephron is freely permeable to water: • Unwanted Effects:
o Increased EXTRACELLULAR FLUID volume
• Proximal Tubule which can lead to:
• Descending Limb of Loop of Henle § Hyponatraemia (associated with
• Collecting Duct nausea, vomiting and pulmonary
oedema)
This causes a DECREASED H2O REABSORPTION and
INCREASED H2O EXCRETION
(There is also a small increase in Na+/Cl-‐ loss)

Increased delivery of HCO3-‐ and Na+ to the distal tubule, so
DIURETIC Carbonic anhydrase inhibitors are weak diuretics. an increased K+ loss.
They act mainly on the PROXIMAL TUBULE, to:
CARBONIC INCREASED TUBULAR FLUID OSMOLARITY and DECREASED
ANHYDRASE • Prevent the reabsorption of HCO3-‐ and Na+ H2O REABSORPTION IN THE COLLECTING DUCT.
INHIBITORS • H2O reabsorption is therefore reduced.
Therefore, they INCREASE URINE VOLUME (increased H2O
excretion – alkaline urine due to HCO3-‐) and K+, Na+ and HCO3-‐
Excretion
e.g. Acetazolamine

• 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 are POWERFUL Diuretics that act on Effects of Loop Diuretics (e.g. Frusemide)
the ascending limb of the loop of Henle.
LOOP DIURETICS Large increase in urine volume and Na+, Cl-‐ and K+ loss (+Ca2+
INHIBIT Na+ and Cl-‐ Reabsorption in the ascending and Mg2+ Loss)
limb by 30%
CLINICAL USES:
e.g. Frusemide
Ca2+ and Mg2+ Loss -‐ Loss of K+ Recycling • OEDEMA – Heart failure, pulmonary, renal, hepatic
(Furosemide)
and cerebral
Therefore, they DECREASE THE OSMOLARITY of the • MODERATE HYPERTENSION – Piretanide
medullary interstitium. • HYPERCALCAEMIA
• HYPERKALAEMIA
Increase the delivery of Na+ to the distal tubule, so
increased K+ loss (due to increased Na+/K+ Exchange) UNWANTED EFFECTS:
• HYPERVOLAEMIA
Increased tubular fluid osmolarity (and so decrease • HYPERTENSION
the osmolarity of the medullary interstitium), which • K+ Loss (Ca2+/Mg2+), Metabolic Alkalosis
leads to decreased H2O reabsorption at the
collecting duct.

DIURETIC These are moderately powerful diuretics, which act Clinical Uses
on the early distal tubule. • Cardiac Failure
THIAZIDES • Hypertension (Initially a decreased blood volume
Inhibit Na+ and Cl-‐ reabsorption in the early distal decreases – in the long term, thiazides cause
tubule (by about 5-‐10%) vasodilation)
• Severe Resistant Oedema
e.g. Bendrofluazide
So there is an increased delivery of Na+ to the distal • Idiopathic Hypercalciuria (Stone Formation)
(Bendroflymethiazide
tubules, so an increased K+ Loss (as there is an • Nephrogenic Diabetes Insipidus (Paradoxical)
increased Na+/K+ exchange) bhj
Unwanted Effects
There is an increased Mg2+ loss and increased Ca2+ • K+ loss
reabsorption (REDUCED LOSS OF CALCIUM) • Metabolic Alkalosis
Increased tubular fluid osmolarity, so decreased • Diabetes Mellitus (Inhibits insulin secretion)
water reabsorption in the collecting duct.

Thiazide diuretics lead to moderate increase in urine
volume and Na+, Cl-‐ and K+ loss (Mg2+ loss)

Classes of K+ Sparing Drugs Potassium Sparing Diuretics e.g. Amiloride, Spironolactone
DIURETIC • ALDOSTERONE RECEPTOR ANTAGONISTS • INHIBIT Na+ REABSORPTION – (and therefore the
o e.g. SPIRONOLACTONE secretion of K+) in the early distal tubule (by 5%)
POTASSIUM SPARING
DIURETICS • INHIBITORS of ALDOSTERONE-‐SENSITIVE Na+ • INCREASED TUBULAR FLUID OSMOLARITY – so
CHANNELS decreased H2O reabsorption in the collecting duct
e.g. Amiloride, o e.g. amiloride
Spironolactone • 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:
ANTI-‐ULCER DRUGS – ANTIBIOTICS ‘Triple Therapy’ is currently the best practice in treating

peptic ulcer disease
• A single antibiotic is not sufficiently effective – partly
ANTIBIOTICS + PPI Triple Therapy -‐ Example 1 due to the development of resistance.
•
(FOR PEPTIC ULCERS – • METRONIDAZOLE (active against anaerobic THREE PROBLEMS WITH TRIPLE THERAPY:
AGAINST H. PYLORI) bacteria and protozoa) or AMOXYCILLIN • COMPLIANCE
(broad spectrum antibiotic) – depending on • DEVELOPMENT OF RESISTANCE (Vaccinations may
pattern of local resistance. soon be available)
• ADVERSE RESPONSE TO ALCOHOL – especially with
• CLARITHROMYCIN antibiotics with a metronidazole (interferes with alcohol metabolism)
macrolide structure – inhibits translocation
of bacterial tRNA.

• 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
ANTI-‐ULCER DRUGS – INHIBITORS Mechanism of Action:

• PPIs are irreversible inhibitors of the H+/K+ ATPase
INHIBITORS OF GASTRIC ACID SECRETION • Inactive at neutral pH
• As it is a weak base, it accumulates in the cannaliculi
e.g. OMEPRAZOLE TREATMENT OF GASTRIC ULCERS of parietal cells: this concentrates its action there and
prolongs its duration of action (2-‐3 days) and
Inhibit basal and stimulated gastric acid secretion minimises its effects on ion pumps elsewhere in the
from the parietal cell by >90% 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
ANTI-‐ULCER DRUGS – INHIBITORS

• Orally administered
(H2) RECEPTOR OF GASTRIC ACID SECRETION • Well absorbed
ANTAGONISTS • Unwanted effects are rare
Inhibit gastric acid secretion by approximately 60%
e.g. CIMETIDINE, and are less effective at healing ulcers than PPIs Relapses likely after withdrawal of treatment
RANITIDINE
CYTOPROTECTIVE
ANTI-‐ULCER DRUGS – Mechanism of Action:

• Acquires a strong negative charge in an acid
DRUGS CYTOPROTECTIVE DRUGS environment
e.g. SULCRAFATE
• Binds to positively charged groups in large molecules
These drugs ENHANCE MUCOSAL PROTECTION (proteins, glycoproteins) resulting in gel-‐like
MECHANISMS and/or BUILD A PHYSICAL BARRIER complexes.
over the ulcer. • These coat and protect the ulcer, limit H+ diffusion
and pepsin degradation of mucus.
• Increases PG, mucus and HCO3-‐ secretion and reduces
This is a polymer containing aluminium hydroxide the number of H. Pylori
and sucrose octa-‐sulphate.
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)

CYTOPROTECTIVE
ANTI-‐ULCER DRUGS –

Acts like sulcrafate
DRUGS CYTOPROTECTIVE DRUGS
e.g. BISMUTH
Used in triple therapy (resistant cases
These drugs ENHANCE MUCOSAL PROTECTION
CHELATE
MECHANISMS and/or BUILD A PHYSICAL BARRIER
over the ulcer.
CYTOPROTECTIVE
ANTI-‐ULCER DRUGS – Misoprostal may be co-‐prescribed with oral NSAIDs (non-‐

steroidal anti-‐inflammatory drugs), when used chronically:
DRUGS CYTOPROTECTIVE DRUGS
e.g. MISOPROSTAL
• NSAIDs block the COX enzyme required for PG
(A stable prostaglandin analogue) synthesis from arachidonic acid
• Therefore, there is a REDUCTION in the natural
Mimics the action of locally produced prostaglandins factors that inhibit gastric secretion, and stimulate
to maintain the gastroduodenal mucosal barrier. mucus and HCO3-‐ production

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

ANTACIDS
ANTI-‐ULCER DRUGS – ANTACIDS

• Primarily used for NON-‐ULCER DYSPEPSIA
• May be effective in reducing duodenal ulcer
• Mainly salts of Al3+ and Mg2+ recurrence rates
• Neutralises acid, raises gastric pH, reduces
pepsin activity

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

LIPID LOWERING Mechanism of Action: Cholesterol Synthesis Pathway:
DRUGS -‐ • Geranyl pyrophosphate and Farnesyl Pyrophosphate –
Statins block the HMG-‐CoA Reductase Enzyme these are lipids involved in the modification of
STATINS proteins (e.g. rho and ras)
• These lipids can only by synthesised within the cell.
(e.g. Rosuvastatin,
• Statins inhibit the production of these lipids.
Atorvastatin,

Simvastatin,
Mechanism by which Statins reduce elevated LDL:
Pravastatin,
• Inhibition of HMG-‐CoA Reductase and hence,
Fluvastatin)
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)

LIPID LOWERING Mechanism of Action: • PPAR – Perioxisome Proliferator Activated Receptors
DRUGS -‐ • Thiazolidinediones (glitazones) are PPAR gamma
Activate PPAR Alpha receptors à Decrease in fatty activators (and are used in diabetes)
FIBRATES acids and triglycerides • Anti-‐inflammatory action
• Shown to reduce mortality (by 1 trial)
• 2nd choice to statins.

LIPID LOWERING Decreases cholesterol, LDL and triglyceride levels and • Other effects:
DRUGS – increases HDL levels o Anti-‐Coagulant
o Anti-‐Platelet
NICOTINIC ACID o Anti-‐Inflammatory
• Shown to reduce risk in trials
• Side effects include:
o Flushing and Hepatic Effects

LIPID LOWERING Mechanism of action: inhibits cholesterol absorption • Must be activated by the liver, secreted into the bile
DRUGS – and reabsorbed.
• Reduces cholesterol levels by 15-‐20%
EZETIMIBE • 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 • CETP inhibitors increase HDL levels (since
DRUGS – they cannot be broken down)
• However – they increase blood pressure
Cholesterol Ester (therefore increase mortality, and hence are
Transfer Protein no longer used)
(CETP) and reverse
cholesterol transport

ANTICOAGULANTS: Mechanism of Action: Pharmacokinetics:
PREVENTS activation of VITAMIN K Binds strongly to plasma proteins (99% bound to albumin)
Warfarin Results in a small volume of distribution.
Vitamin K required as a cofactor in synthesis/post-‐
translational modification of Factors VII, IX, X and II Metabolised by HEPATIC MIXED FUNTION CYTOCHROME
(Thrombin) P450

Administration: Anticoagulant activity is monitored by the International
Oral, absorbed quickly from the GI tract. Normalised Ratio (a measure of prothrombin time)
Peak blood concentration within 1 hour
Adverse Effects:
Pharmacological effects are delayed 12-‐16h, peak Haemorrhage (especially into the brain or bowel)
after 48h and lasts 4-‐5 days. Teratogenicity (NOT GIVEN in pregnant mothers)
This is because of the slow turnover of clotting
factors. 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: Mechanism of Action: Administration
• Poorly absorbed after oral administration
Heparin and Low Activates Anti-‐Thrombin III • Therefore, given either:
Molecular Weight Anti-‐Thrombin III then INHIBITS FACTOR Xa and o SUBCUTANEOUSLY
Heparin THROMBIN (FIIa) by binding to the active serine o INTRAVENOUSLY
sites.
Pharmacokinetics
LMWH has a similar effect on Xa, but less of an effect • Immediate onset when given Intravenously (I.V.)
on thrombin. 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: Mechanism of Action: Administration:
Irreversibly inhibits COX-‐1 Enzyme • Oral
Aspirin
Inhibits the production of TXA2 (Thromboxane A2) in Pharmacokinetics:
platelets • Highly plasma protein bound

However, production of PGI2 by endothelium is not Adverse Effects:
severely affected • GI Sensitivity

• Oral
Clopidogrel A pro-‐drug which inhibits fibrinogen binding to
glycoprotein IIb/IIIa Receptors. 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

• Intravenously (I.V.)
Abciximab Antagonist of the Glycoprotein IIb/IIIa Receptor. Pharmacokinetics:
• Binds rapidly to platelets.
This is a hybrid murine/human MONOCLONAL • Cleared with platelets.
ANTIBODY which is licensed for use in ACUTE • Antiplatelet effect persists for 24-‐48 hours.
CORONARY SYNDROMES. Adverse Effects:
• Bleeding
Used in combination with heparin and aspirin to • May potentially be IMMUNOGENIC
prevent ischaemia is patients with unstable angina.

FIBRINOLYTIC Mechanism of Action: Administration:
(THROMBOLYTIC) • Intravenous (I.V.)
DRUGS Non-‐Enzyme Protein • 30-‐60 minutes infusion.

Streptokinase Derived from culture of β-‐Haemolytic Streptococci Pharmacokinetics:
• Rapidly cleared
Binds to plasminogen, causing a conformational • t1/2 12-‐18 minutes
change – this exposes the active site and causes
plasmin activity. Adverse Effects:
• Bleeding
Activated plasmin degrades fibrin. • May potentially be antigenic

FIBRINOLYTIC Mechanism of Action: Administration:
(THROMBOLYTIC) Is recombinant tPA (Tissue Plasminogen Activator) • Intravenous (I.V.) 30 minute infusion
DRUGS It works better on plasminogen bound to fibrin than
on soluble plasminogen in the plasma – and is Pharmacokinetics:
Alteplase therefore said to be CLOT SENSITIVE. • Rapidly cleared
• t1/2 12-‐18 minutes
It activates plasmin that then degrades fibrin and
dissolves the clot. Adverse Effects:
• Bleeding

Ibuprofen Non-‐Steroidal Anti-‐Inflammatory Drugs • Typical non-‐selective NSAIDs
Indomethacin • Inhibit cyclo-‐oxygenase REVERSIBLY
• Inhibit both COX-‐1 and COX2
(NSAID) • Have anti-‐inflammatory, analgesic and
antipyretic actions
Aspirin Non-‐Steroidal Anti-‐Inflammatory Drugs

• Serious side-‐effects at therapeutic doses
(NSAID) • Binds more avidly to COX-‐1 than COX-‐2 • As well as usual NSAID actions, they also reduce
• Binds irreversibly to COX enzymes -‐ A platelet aggregation
unique property among the NSAIDs
o It acetylates an amino acid in the Aspirin – Mechanism of Action
active site of COX (making its actions • Aspirin inhibits TXA2 Production by platelets and
long lasting) prostacyclin production by endothelial cells
o Its actions can only be reversed by (NOTE – Prsostacyclin is DIFFERENT to
the synthesis of new COX (as part of Prostaglandin)
a continuous production)
• 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 Non-‐Steroidal Anti-‐Inflammatory Drugs • Selectively inhibits COX-‐2
• Less effective on COX-‐1 mediated processes than
(NSAID) 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 • Is a good analgesic for mild-‐to-‐moderate Mechanism of Action
pain • The mechanism of action of paracetamol is
Analgesic, Antipyretic • Has ANTI-‐PYRETIC ACTION unclear – several mechanisms have been
• However, it does NOT HAVE ANY ANTI-‐ postulated.
INFLAMMATORY EFFECT
• Therefore, it is not an NSAID • 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-‐ Heroin

Synthetic Opioid) 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 Administration
resemble morphine in structure. 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 • Administration
resemble morphine in structure. 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 • Naloxone (Opioid Antagonist)
• i.v. administration
(Opioid Receptor • Short acting
Antagonist) • Used in opioid overdose

Prednisolone, Glucocorticoids – used in the TREATMENT OF The activation of glucocorticoid receptors can lead to:
Fluticasone, INFLAMMATORY BOWEL DISEASE (CD & IBD) • Increase the expression of anti-‐inflammatory genes
Budesonide (GCR acting as a positive transcription factor)
Derived from cortisol • Decrease the expression of pro-‐inflammatory genes
(Glucocorticoids) (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)
Unwanted Effects of Glucocorticoids: • Eicosanoids (e.g. prostaglandins and leukotrienes)
• Osteoporosis • Nitric Oxide
• Increased risk of gastric ulceration
• Suppression of the HPA (Hypothalamo-‐ Glucocorticoids as immunosuppressives
Pituitary-‐Adrenal) Axis Glucocorticoids are potent immunosuppressives which cause :
• Type II Diabetes • Reduction in antigen presentation
• Hypertension • Reduction in production of certain mediators (e.g. IL-‐
• Susceptibility to infection 2, IL-‐4 and IFN-‐γ)
• Skin thinning, bruising and slow wound • Reduction in cell proliferation and clonal expansion
healing
• Muscle wasting and buffalo hump (c.f. Glucocorticoids virtually suppress all types of inflammation.
Cushing’s)

Mesealazine (5-‐ASA) These are all types of aminosalicylates – ONLY Mechanisms of Anti-‐Inflammatory Actions:
Olsalazine (2x 5-‐ASA) EFFECTIVE IN ULCERATIVE COLITIS. • Reduce synthesis of eicosanoids
• Reduce free radical levels
(Sulfalazine) Anti-‐inflammatory, but NOT IMMUNOSUPPRESSIVE • Reduce inflammatory cytokine production
• Reduce leukocyte infiltration
(Aminosalicylates) They are useful in the treatment of active ulcerative
colitis and for maintenance of remission Metabolised by: Site of
Absorption:
However, they are ineffective in Crohn’s Disease
Mesalazine (Not absorbed as Small bowel and
it is in the most colon
basic form – c.f.
sulfasalazine)
Olsalazine Colonic flora Colon
(Sulfasalazine) Colonic Flora, Colon

Liver

Azothioprine
Immunosuppressive Agent Mechanism of Immunosuppression
• Azothioprine is a PRODRUG activated in vivo by gut
Effective in BOTH CROHN’s DISEASE and flora to 6-‐MERCAPTOPURINE
ULCERATIVE COLITIS
• This interferes with purine biosynthesis
Can be used to induce remission in Crohn’s Disease • Interferes with DNA SYNTHESIS and CELL
(Treatment >17 Weeks) REPLICATION

May enable reduction of glucocorticoid dose or • It impairs:
postponement of colostomy. o Cell-‐ and Antibody-‐ mediated immune
responses
Useful for maintaining remission in Crohn’s Disease o Lymphocyte proliferation
and some patients with Ulcerative Colitis. 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 Used successfully in the treatment of Crohn’s Disease Mechanism of Action of Infliximab (Anti-‐TNFα)
Some evidence of effectiveness in Ulcerative Colitis • Indicates that TNFα plays an important role in the
INFLIXMAB (i.v.) pathogenesis of IBD
Potentially curative, rather than just simply palliative • Anti-‐TNFα reduces activation of TNDα receptors in the
gut.
Successful in some patients with refractory disease • Production of other cytokines, infiltration and
and fistulae 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 • This is a selective GABAA Receptor agonist (i.e. does
not stimulate GABAB receptors etc.) Principles of
(I.e. Post-‐Synaptic GABA Receptor) GABA-‐ergic
Cellular Mechanism of Action: Transmission
• 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

Bicuculline GABAA Antagonist • Competitive Antagonsist
Principles of
GABA-‐ergic
Transmission
Picrotoxin GABAA Antagonist • Non-‐competitive
• Binds to chloride channel itself and blocks the action Principles of
of GABA receptors non-‐competitively GABA-‐ergic
• Inhibits hyperpolarisation Transmission

Convulsants GABAA Antagonists • Not used clinically
Principles of
GABA-‐ergic
Transmission
Benzodiazepines and GABAA Antagonists • Clinically used drugs (see other lecture)
Barbiturates Principles of
GABA-‐ergic
Transmission

Baclofen GABAB Agonist Selective GABAB Agonist
(I.e. Pre-‐Synaptic GABA Receptor) Principles of
Inhibit neurotransmitter release and function in two ways: GABA-‐ergic
• AUTORECEPTORS – (Negative Feedback on the Transmission
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 Anxiolytics,
enhanced GABA Action Sedatives and
• Enhanced GABA Binding to the GABA receptor protein Hypnotics
(reciprocated)

Anaesthetics These are all barbiturates producing such effects. • Unwanted Side Effects of Barbiturates
Barbiturates o They are not the 1st drug of choice due to Anxiolytics,
e.g. THIOPENTONE their unwanted effects Sedatives and
o Low Safety Margins: Hypnotics
Anticonvulsants § Depress Respiration
Barbiturates § Overdosing is lethal (Treated with Anxiolytics,
e.g. Phenobarbital forced alkaline diuresis to promote Sedatives and
excretion) Hypnotics
Anti-‐spastic o Alters natural sleep (Decreased REM Sleep) à
Barbiturates hangovers/irritability Anxiolytics,
e.g. Diazepam o Enzyme inducers Sedatives and
o Potentiate the effect of other CNS Hypnotics
depressants e.g. Alcohol
o Development of Tolerance (both
pharmacokinetics and tissue tolerance)

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

Sedatives / Hypnotics Used for severe intractable insomnia
e.g. Amobarbital Half-‐Life 20-‐25 Hours Anxiolytics,
Sedatives and
Side effects – see above. Hypnotics
Benzodiazepines All benzodiazepines act at GABAA Receptors Pharmacokinetics:
Administration: Anxiolytics,
• Well absorbed P.O. (Orally) Sedatives and
• Plasma concentration peaks at around 1 hour Hypnotics
(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 Advantages of Benzodiazepines:
• Wide margin of safety: Anxiolytics,
e.g. Diazepam, o Overdose leads to prolonged sleep which is Sedatives and
Chloridazepoxide rousable Hypnotics
(Librium), Nitrazepam, o No respiratory depression
Oxazepam o Flumazenil
• Mild effect on REM Sleep
Sedatives/Hypnotics • Do not induce liver enzymes
e.g. Temazepam, Anxiolytics,
Oxazepam, Unwanted Effects of Benzodiazepines Sedatives and
Lorazepam, • Sedation, Confusion, Ataxia (Impaired manual skills) Hypnotics
Nitrazepam • 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

Other Sedatives / • Liver à Trichloroethanol
Hypnotics • Mechanism of action – unknown Anxiolytics,
• Wide margin of safety (safe for use in children and the Sedatives and
Chloral Hydrate elderly) Hypnotics

Other Anxiolytics: • Improves physical symptoms
Propranolol Tachycardia – β1 Anxiolytics,
Tremor – β2 Sedatives and
Hypnotics
• Commonly used to ‘cure’ stage fright

Other Anxiolytics: • 5HT1A Agonist
Buspirone • Slow Onset of Action (Days/Weeks) Anxiolytics,
• Few Side-‐Effects Sedatives and
Hypnotics

L-‐DOPA Dopamine Replacement Therapy L-‐DOPA Clinical Uses:
• Hypokinesia, rigidity & tremor Dopaminergic
(SINAMET, MADOPAR DOPA is the precursor to dopamine, and is converted • Start with low doses of the drug, and increase dose Pathways and
– with peripheral to dopamine in the brain. until the maximum benefit is achieved without side-‐ Anti-‐Parkinson
inhibitors) effects and Schziophrenic
However, the enzyme DOPA Decarboxylase is also • Effectiveness of L-‐DOPA declines with time, however Drugs
present in peripheral tissues Side Effects:
Therefore, 95% of administered L-‐DOPA would be • Acute
metabolised to dopamine in the periphery with o Nausea – prevented by doperidone
major side effects of nausea and vomiting. (peripheral acting antagonist)
o Hypotension
Therefore L-‐DOPA is commonly prescribed with a o Psychological effects – Schizophrenia-‐like
peripheral DOPA decarboxylase inhibitor syndrome with delusions, hallucinations, also
confusion, disorientation and nightmares
Preparations include:
• SINAMET (Carbidopa + L-‐DOPA)
• MADOPAR (Benserazide + L-‐DOPA) • 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.

Bromocriptine Dopamine Agonists Dopamine Agonists: Actions
Pergolide • Act on D2 Receptors Dopaminergic
Ropinerol Actions: • Longer duration of action than L-‐DOPA Pathways and
• Act on D2 Receptors • Smoother and more sustained response Anti-‐Parkinson
• Actions independent of dopaminergic neurons and Schziophrenic
• Incidence of dyskinesias is less Drugs
• 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 Dopaminergic
dopamine breakdown) Pathways and
• Predominantly acts in dopaminergic areas of the CNS. Anti-‐Parkinson
• Actions are without peripheral side effects of non-‐ and Schziophrenic
selective MAO-‐I’s Drugs

• 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 Dopaminergic
• Promotes anti-‐apoptosis genes leading to increased Pathways and
cell survival Anti-‐Parkinson
• Early clinical trials suggest that Resagiline may slow and Schziophrenic
the progression of Parkinson’s disease Drugs

Tolocapone (CNS & COMT Inhibitors CNS Effects
Peripheral) Prevents the breakdown of dopamine in the brain Dopaminergic
Pathways and
Entacapone Peripheral Effects Anti-‐Parkinson
(Peripheral only) COMT in the periphery converts L-‐DOPA to 3-‐0-‐methyl-‐DOPA and Schziophrenic
(3-‐0MD). 3-‐0MD and L-‐DOPA compete for the same transport Drugs
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 Other Actions/Side Effects:
• Site of action – ‘D2-‐like’ receptors • Anti-‐emetic effect Dopaminergic
• Most neuroleptics block other receptors e.g. • Blocking dopamine receptors in the chemoreceptor Pathways and
5-‐HT, thus accounting for some of their side trigger zone. Anti-‐Parkinson
effects • Neuroleptic Phenothiazine – effective at controlling and Schziophrenic
vomiting and nausea induced by drugs (e.g. Drugs
• Clozapine is relatively non-‐selective between chemotherapy), renal failure
D1 and D2 receptors, but does have a high • Many neuroleptics also have a blocking action at
affinity for D4 receptors that have been histamine receptors.
shown to be increased in schizophrenia. • Effective at controlling motion sickness.

• Drugs treat positive symptoms, but not • Extrapyramidal side effects – Blockade of dopamine
negative ones. receptors in the nigrostriatal system can induce
• Delayed effects – takes weeks to work. ‘Parkinson’ like side-‐effects
• Initially neuroleptics induce an increase in DA
synthesis and neuronal activity. This declines Acute dyskinesias – Related to blockade of dopamine
with time. 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
Principles of
Clinical setting:
General
Anaesthesia
Desired effect Drug

Loss of consciousness Induction: propofol (i.v.)
Suppression of reflex responses Maintenance: enflurane (inhalation)

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

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

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

Local Anaesthetics Ester: Cocaine /
Amide: Lidocaine Principles of Local
Anaesthesia
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%

Hepatic Hepatic and plasma
Metabolism
N-‐dealkylation Non-‐specific esterases
Plasma half-‐life 2 hours 1 hour

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 stimulation
CNS Restlessness & confusion Euphoria and excitation
Tremor
Myocardial depression Increased CO

CVS Vasodilatation Vasoconstriction
Reduced BP Increased BP

Methotrexate Alkylating Agent (Cytotoxic Drugs) Folic Acid:
• An essential nutrient Cytotoxic Drugs
Cytotoxic Drugs – Interfere with thymidylate synthesis (generation of • Important for nucleotide synthesis
ALKYLATING AGENTS pyrimidines)
Methotrexate:
Fluorouracil Alkylating Agent (Cytotoxic Drugs) • Structurally similar to folic acid
• Can substitute for folate Cytotoxic Drugs
Cytotoxic Drugs – Inhibit enzymes in DNA synthesis
ALKYLATING AGENTS (e.g. thymidylate synthetase) 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)

Azothioprine Alkylating Agent (Cytotoxic Drugs)
Cytotoxic Drugs
Cytotoxic Drugs – Inhibit purine synthesis
ALKYLATING AGENTS

Actinomycin D Intercalates with DNA and interferes with topoisomerase II • Topoisomerase II cuts the DNA, allows it to
unwind, and re-‐joins it – this allows proliferation Cytotoxic Drugs
Cytotoxic Drugs – to occur.
CYTOTOXIC • Actinomycin D inhibits topoisomerase II by
ANTIBODIES binding DNA in this way

DOXORUBICIN Inhibits DNA and RNA synthesis • It has the ability to intercalate DNA and inhibit
topoisomerase II Cytotoxic Drugs
Cytotoxic Drugs –
CYTOTOXIC
ANTIBODIES

BLEOMYCINS Metal-‐Chelating-‐Glycopeptide antibiotics that degrade DNA • Chelate m etals and generate free radicals
(oxygen derived) Cytotoxic Drugs
Cytotoxic Drugs – • Free radicals cause DNA strand breaks
CYTOTOXIC • Bleomycins are active against non-‐dividing cells,
ANTIBODIES since they do not rely on cell proliferation
• Problems associated with high damage to LUNG
TISSUE
• Intravenous administration

PODOPHYLLOTOXINS Podophyllotoxins: e.g. etoposide • Inhibit DNA synthesis and cause a cell cycle block
e.g. etoposide at G2 Cytotoxic Drugs

Cytotoxic Drugs –
PLANT ALKALOIDS

VINCA ALKALOIDS e.g. Vinca Alkaloids: e.g. vincristine • Bind to tubulin and inhibit its polymerisation
Vincristine into microtubules – this prevents spindle fibre Cytotoxic Drugs
formation
Cytotoxic Drugs –
PLANT ALKALOIDS

HYDROXYUREA • Inhibits ribonucleotide reductase (involved in
nucleic acid synthesis) Cytotoxic Drugs
Cytotoxic Drugs –
MISC.

CISPLATIN • Interacts with DNA and causes guanine intra-‐
strand cross-‐links Cytotoxic Drugs
Cytotoxic Drugs –
MISC.

PROCARBAZINE • Inhibits DNA and RNA Synthesis and interferes
with mitosis at interphase Cytotoxic Drugs
Cytotoxic Drugs – • Metabolically activated by cytochrome P450 and
MISC. 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

Hormones • Used for chemotherapy but are not technically
As Cytotoxic Drugs cytotoxic Cytotoxic Drugs
Hormones: Prednisolone Fosfestrol Tamoxifen
• Can inhibit tumours in hormone-‐sensitive tissues
(e.g. prostate, breast) Mechanism Glucocorticoid Androgen SERM
• Gonadotrophin-‐releasing hormone analogues e.g.
Goserelin Leukaemias & Prostate Breast
Use
lymphomas cancer cancer

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

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) • Blocks voltage-‐gated Na+ channels Indications:
• Partial Epilepsy
Anticonvulsant • Status Epilepticus
(Anti-‐Epileptic)
• 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 • Blockade of voltage-‐gated Na+ Channels Indications:
• Partial and Secondary Generalised Seizures
Anticonvulsant
(Anti-‐Epileptic) Mechanism of Action:

• Useful

• 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

• Hypersensitivity (rash, hepatitis, nephritis)
• Dose-‐Related (Ataxia, dizziness, sedation,
diplopia)
• Chronic (Vitamin K Deficiency, depression,
impotence, osteomalacia, hyponatraemia)

Lamotrigine • Blocks voltage-‐gated Na+ channels Indications:
• Partial and generalised epilepsy (wide
Anticonvulsant spectrum)
(Anti-‐Epileptic)

• N/A

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

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

Active Metabolites
• None

Drug Interactions
• Valproate
• Enzyme inducing AEDs

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

(Sodium) Valproate • Enhances GABA transmission by several Indications:
mechanisms • Partial or generalised epilepsy (wide spectrum)
Anticonvulsant
(Anti-‐Epileptic) Mechanism of Action:
• Enhances GABA transmission by several
mechanisms

• N/A

• 4-‐12 hours

Metabolism
• Oxidation, then conjugation
• Potent hepatic enzyme inhibitor

Active Metabolites
• None

Drug Interactions
• Many

• 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 Folate is required for DNA/RNA Synthesis in both man and Pharmacokinetics:
(P-‐Aminobenzoic Acid bacteria • Readily absorbed in the GI tract. Anti-‐Microbial
Analogue) Man has evolved specific uptake processes for transporting • Maximum plasma concentration is reached Drugs
folate into the cells. within 4-‐6 hours
(ANTI-‐MICROBIAL
DRUG) Bacteria have to synthesise folate. P-‐aminobenzoic acid is Side Effects:
essential for the synthesis of folic acid in bacteria. Mild/moderate (do not warrant withdrawal)
• Nausea and vomiting
Sulphanilamide is a structural analogue of P-‐aminobenzoic • Headache
acid that COMPETES for the enzyme dihydropteroate which • Mental depression
is involved in the synthesis of folate.
Severe (warrants withdrawal)
They interfere with bacterial DNA/RNA synthesis and are • Hepatitis-‐type reaction
bacteriostatic i.e. they arrest the growth of the bacteria, but • Hypersensitivity reactions
do not kill them – it is then up to the host defence system. • Bone marrow suppression

Note – WIDESPREAD RESISTANCE

Trimethoprim The utilisation of folate, in the form of tetrahydrofolate as a Pharmacokinetics
(Folate Antagonists) co-‐factor in thymidylate synthesis is an example of a • Oral administration Anti-‐Microbial
pathway in which there is a differential sensitivity of human • Trimethoprim is fully absorbed from the GI tract Drugs
(ANTI-‐MICROBIAL and bacterial enzymes to drugs. • Widely distributed throughout the tissues and
DRUG) body fluids
This pathway is virtually identical in micro-‐organisms and • Reaches high concentrations in the lungs and
man, but one of the key enzymes dihydrofolate reductase is kidneys.
many times more sensitive to particular analogues in either
man or bacteria.

Trimethoprim is a folate antagonist that is more sensitive to Unwanted Effects
the dihydrofolate reductase enzyme in BACTERIA than in • Nausea/vomiting
man (IC50 [mmol/l] 0.005 bacteria, 260 man) • 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 Sulphamethazole and trimethoprim. Pharmacokinetics
(Sequential Blockade) • When given as co-‐trimoxazole, about two-‐thirds Anti-‐Microbial
• Since sulphonamides affect the earlier stage in the of each drug is protein bound and about half of Drugs
(ANTI-‐MICROBIAL same metabolic pathway i.e. folate synthesis, they each is excreted within 24 hours.
DRUG) potentiate the actions of trimethoprim.
Clinical Uses
• When given in combination, the drugs are effective • For infections with pneumocystis carinii which
at one tenth or less of what would be needed if causes pneumonia in patients with AIDS, co-‐
each drug was given on its own. trimoxazole is used in high doses.

Penicillin β-‐Lactam antibiotics e.g. penicillin inhibit the formation of Pharmacokinetics
(β-‐Lactam Antibiotics) peptidoglycan and are subsequently bacteriocidal When administered orally -‐ Different penicillins are Anti-‐Microbial
absorbed to differing degrees depending on their Drugs
(ANTI-‐MICROBIAL Method of Action: stability in acid and their adsorption on to food.
DRUG) • Interfere with the synthesis of the bacterial wall
peptidoglycan The drugs are widely distributed by the bodily fluids,
• Inhibit the transpeptidation enzyme that cross links passing into joints, pleural and pericardial cavities, into
the peptide chains attached to the backbone of the the bile, the saliva and the milk, and across the placenta.
peptidoglycan.
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 Functions by covalently binding to the β-‐Lactamase enzyme Reduces resistance to penicillin
at, or close to, its active site. Anti-‐Microbial
(β-‐lactamase Drugs
inhibitors)

CEPHALOSPORINS e.g. Cephalexin (oral), Cefuroxime and Cefotaxime
(β-‐Lactam Antibiotics) (parenteral) Pharmacokinetics Anti-‐Microbial
Some cephalosporins may be given orally, but most are Drugs
e.g. cefoperazone, cefotaxime (can cross BBB) given parenterally – intramuscular (i.m.) or intravenous
(ANTI-‐MICROBIAL (i.v.)
DRUG)
Mechanism of Action Widely distributed in the body, passing into the pleural,
• Same as penicillins, interfere with peptidoglycan pericardial and joint fluids, and across the placenta.
synthesis
• Resistance to this group of drugs has increased. Some cephalosporins cross the blood brain barrier
• Nearly all Gram –ve bacteria have the gene e.g. cefoperazone, cefotaxime (Drug of choice for
encoding for β-‐lactamase, which is more active in bacterial meningitis)
hydrolysing cephalosporins than penicillin.
Excretion (Most Cephalosporins)
• Resistance also occurs if there is decreased • Excretion is mostly via the kidney – largely by
penetration of the drug – due to alterations of the tubular secretion
membrane proteins or mutations of the binding • But 40% of ceftriaxone and 75% of
site proteins. cefoperazone is eliminated in the bile.
• Since different β-‐Lactam antibiotics may bind to
• They are bactericidal. 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 Tetracyclines are broad-‐spectrum antibiotics that have a Pharmacokinetics
(Drugs that inhibit polycyclic structure. • Usually given orally Anti-‐Microbial
bacterial protein • Can also be given parenterally Drugs
synthesis) Method of Action • The absorption of most preparations from the
• Actively transported into bacteria and interrupt gut is irregular and incomplete, and is improved
(ANTI-‐MICROBIAL protein synthesis. by the absence of food
DRUG) • Competition with tRNA for the A-‐binding site. • Since tetracycline’s chelate metal ions (e.g.
• Bacteriostatic, not bactericidal. iron), forming a non-‐absorbable complex,
absorption is decreased by the presence of
Spectrum MILK, certain antacids and iron preparations
• Very wide and include Gram +ve and Gram –ve • The drugs have wide distribution
bacteria, mycoplasma, Rickettsia, Chlamydia, some • The enter most fluid compartments
spirochaetes and some protozoa (e.g. amoebae)
Excretion
• However, many strains have become resistant to • Excretion is both via the bile and by glomerular
these agents. filtration in the kidney
• The basis of resistance is the development of • Most tetracyclines will accumulate if renal
energy-‐dependent efflux-‐mechanisms which function is impaired.
transport the tetracyclines OUT OF THE Exception – DOXYCYCLINE (largely excreted into the
BACTERIUM, but alterations of the target (the gastrointestinal tract via the bile).
bacterial ribosome) also occur.
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 Mechanism of Action Pharmacokinetics
(Drugs that inhibit • Inhibition of protein synthesis. • Oral chloramphenicol is rapidly and completely Anti-‐Microbial
bacterial protein • Chloramphenicol binds to the 50s Subunit of the absorbed Drugs
synthesis) ribosome and inhibits transpeptidation. • Reaches maximum concentration in the plasma
within 2 hours.
(ANTI-‐MICROBIAL Spectrum • Can be given parenterally
DRUG) • Wide spectrum of activity, including Gram –ve and
Gram +ve bacteria. • Widely distributed throughout the tissues and
• They are bacteriostatic for most organisms. body fluids (including CSF)
• In the plasma, 30-‐50% plasma protein bound
Resistance • Half-‐life is approximately 2 hours
• Resistance is due to the production of
chloramphenicol acetyl-‐transferase and is plasmid-‐ • About 10% is excreted unchanged in the urine
mediated. • The remainder is inactivated in the liver.
• Metabolites are excreted via the kidney and the
• R-‐plasmids containing determinants for multiple bile.
drug resistance for chloramphenicol, streptomycin
and tetracyclines etc. may be transferred from one Unwanted Effects
bacterial specie to another by promiscuous • The most important unwanted effect is
plasmids. depression of the bone marrow resulting in
pancytopenia
• Derivatives of chloramphenicol with the terminal –
OH on the side-‐chain replaced by fluorine are not as • Decrease in all blood cell elements – an effect
susceptible to acetylation, and thus retain which (although rare) can occur even with very
antibacterial activity. 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 Method of action Pharmacokinetics
e.g. GENTAMICIN • The aminoglycosides inhibit bacterial protein • The aminoglycosides are polycations and highly Anti-‐Microbial
synthesis by binding to the 30s Subunit of the polar – hence are not absorbed in the GI tract Drugs
(Drugs that inhibit ribosome • Given intramuscularly (i.m.) or intravenously
bacterial protein • This causes an alteration in the codon:anticodon (i.v.).
synthesis) recognition and results in a misreading of mRNA, • Binding to plasma proteins is minimal.
and the production of defective bacterial proteins
(ANTI-‐MICROBIAL • They do not enter cells and do not cross the
DRUG) • However, this action does not entirely explain their blood brain barrier into the CNS.
rapid lethality – so it is possible there may be a • Plasma half-‐life is 2-‐3 hours.
second target. • Elimination is virtually entirely by glomerular
filtration in the kidney.
• Their penetration through the cell membrane of the • Tissue concentrations increase during
bacterium depends on an oxygen-‐dependent active treatment, and can reach toxic levels after about
transport system, which chloramphenicol can a week of unmodified dosage.
block.
• Their effect is bactericidal and is enhanced by Unwanted Effects:
agents that interfere with cell wall synthesis. • Ototoxicity – progressive damage to and
destruction of the sensory cells in the cochlea
Resistance and vestibular organs of the ear.
• Resistance to aminoglycosides is becoming a
problem, and may be due to a number of factors – • Nephrotoxicity – damage to the kidney tubules.
the most important is inactivation by microbial o Can be reversed if the use of the drug is
enzymes. stopped.
• Other mechanisms of resistance include: o Since elimination of these drugs is
o Failure of penetration (overcome almost entirely renal, their nephrotoxic
concomitant use of penicillin and/or action can impair their own excretion
vanocomycin which synergies with and a vicious cycle can be set up.
aminoglycosides) o Plasma concentrations must be
o Lack of binding of the drug due to monitored regularly.
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

ISONIAZID Mechanism of Action: Pharmacokinetics
• The antibacterial activity of isoniazid is limited to • Readily absorbed from the GI tract, or after Anti-‐Microbial
(Antimycobacterial mycobacteria. parenteral injection Drugs
agent) • It is bacteriostatic on resting organisms, and can kill • Widely distributed throughout the tissues and
dividing bacteria (bactericidal effect). body fluids, and CSF.
(ANTI-‐MICROBIAL
DRUG) • It passes freely into mammalian cells and therefore • Importantly – penetrates well into NECROTIC
effective against intracellular organisms TUBERCULOUS LESION
• The mechanism of action is not fully understood – • Metabolism, involves largely acetylation,
some evidence suggests inhibition of the synthesis depends on genetic factors that determine
of mycolicacids (important constituents of the cell whether a person is a slow (t½=3hours) or rapid
wall and peculiar to mycobacterium) (t½=1.5hours) acetylator of the drug.
• Slow acetylators have a better therapeutic
response.

RIFAMPICIN Mechanism of Action: Pharmacokinetics
• Binds to and inhibits DNA-‐dependent RNA • Rifampicin is given orally. Anti-‐Microbial
(Antimycobacterial polymerase in prokaryotic, but not eukaryotic cells. • Widely distributed in the tissues and body Drugs
agent) • It is one of the most active anti-‐tuberculosis agents fluids
known.
(ANTI-‐MICROBIAL • It is also active against most other Gram +ve • Excreted partly in the urine and partly in the
DRUG) bacteria as well as many Gram -‐ve species. bile-‐ some of it undergoing enterohepatic
• It enters phagocytic cells and can kill intracellular cycling.
micro-‐organisms.
• 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 Mechanism of Action Pharmacokinetics
• Pyrazinamide is inactive at neutral pH, but • Oral administration -‐ the drug is well absorbed Anti-‐Microbial
(Antimycobacterial tuberculostatic at acidic pH. after oral administration Drugs
agent) • It is effective against the intracellular organism in • Widely distributed, penetrating well into the
macrophages, since after phagocytosis the meninges
(ANTI-‐MICROBIAL organism with be contained in phagolysosomes, in • Excreted through the kidneys (mainly
DRUG) which the pH is low. glomerular filtration)

Unwanted Effects
• Arthralgia (associated with high concentrations
of plasma urates)
• GI tract upsets
• Malaise
• Fever

NYSTATIN Nystatin is a polyene macrolide.
There is virtually no absorption from the mucous Anti-‐Microbial
(Anti-‐Fungal Agent) Mechanism of Action membranes of the body, or from the skin, and its use is Drugs
• Binds to cell membrane and interferes with limited to fungal infections of the SKIN and GI TRACT.
(ANTI-‐MICROBIAL permeability and transport functions.
DRUG) Unwanted Effects
• It forms a pore in the membrane – the hydrophilic • Rare -‐ Limited to nausea and vomiting when high
core of the molecule creating a transmembrane ion doses are taken by mouth
channel • Very rare -‐ Rash

• 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

MICONAZOLE Miconazole belongs to the azole group of synthetic Pharmacokinetics
antimycotic agents, with a broad spectrum of activity. • Miconazole is given by intravenous infusion for Anti-‐Microbial
(Anti-‐Fungal Agent) systemic infections Drugs
Mechanism of Action • Given orally for infections of the GI tract.
(ANTI-‐MICROBIAL • Azoles block the synthesis of ergosterol (the main • Short plasma half-‐life.
DRUG) sterol in the fungal cell membrane) by:
o Interacting with the enxyme necessary for Unwanted Effects
conversion of lanosterol to ergosterol. • Relatively infrequent (most commonly being GI
Tract disturbances, blood dyscrasias)
• 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)

ACYCLOVIR • Acyclovir is a guanosine derivative with a high Herpes simplex is more sensitive to acyclovir than other
specificity for herpes simplex. herpes viruses which cause glandular fever or shingles. Anti-‐Microbial
(Anti-‐Viral Agent) • Drugs
Mechanism of Action Acyclovir has a small, but reproducible effect against
(ANTI-‐MICROBIAL • Acyclovir is converted to the monophosphate by cytomegalovirus (CMV) which can cause glandular fever
DRUG) thymidine kinase – the virus specific form of this in adults, or severe disease e.g. retinis, resulting in
enzyme is much more effective at carrying out the blindness in individuals with AIDS.
phosphorylation than the host cell’s thymidine
kinase. Resistance
• The monophosphate-‐form is subsequently • Resistance due to changes in the viral genes
converted to triphosphate by the host cell kinases. coding for thymidine kinase or DNA polymerase
has been reported
It is therefore only adequately activated in infected cells. • Acyclovir-‐resistant herpes simplex virus has been
the cause of pneumonia and encephalitis in
• Acyclovir triphosphate inhibits viral DNA-‐ immunocompromised patients.
polymerase, terminating the chain reaction.
• It is 30 times more potent against the herpes virus Pharmacokinetics
enzyme than the host enzyme. • Acyclovir can be given orally, i.v. or topically
• When given orally, only about 20% of the dose is
• Acyclovir triphosphate is fairly rapidly broken down absorbed
within the host cells by cellular phosphatases. • 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 Mechanism of Action Pharmacokinetics
(AZIDOTHYMIDINE, • Zidovudine is an analogue of thymidine • Given Orally Anti-‐Microbial
AZT) • In retroviruses, such as the HIV Virus, it is an active • Bioavailability of zidovudine is 60-‐80% due to Drugs
inhibitor of reverse transcriptase enzyme. first pass metabolism
(Anti-‐Viral Agent) • Peak plasma concentration occurs at 30 minutes
• It is phosphorylated by cellular enzymes to the • It can also be given intravenously
(ANTI-‐MICROBIAL triphosphate form, which competes with the
DRUG) equivalent cellular triphosphates which are • There is little plasma protein binding so there
essential substrates for the formation of proviral are no drug interactions due to the displacement
DNA by viral reverse transcriptase (viral RNA-‐ by other drugs.
dependant DNA polymerase) • Zidovudine enters mammalian cells by passive
• Its incorporation into the growing viral DNA strand diffusion – unlike most other nucleotides which
results in chain termination require active uptake.

• Mammalian alpha DNA polymerase is relatively • The drug passes into the CSF and the brain
resistant to the effect. However, gamma DNA • Most of the drug is metabolised to inactive
polymerase in the host cell mitochondrion is fairly glucoronide in the liver – only 20% of the active
sensitive to the compound, and this may be the form being excreted in the urine.
basis of unwanted effects.

Resistance Uses:
• In most patients the therapeutic response to In patients with AIDS
zidovudine wanes with long-‐term use, particularly • It reduces the incidence of opportunistic
in late-‐stage disease. infection (such as Pneumocystis Carnii
• It is known that the virus develops resistance to the Pneumonia)
drug due to mutations resulting in amino acid • Stabilises weight
substitutions in the viral reverse transcriptase and • Reverses HIV-‐Associated thrombocytopenia
that these genetic changes accumulate • Stabilises HIV-‐associated dementia
progressively. • Reduces viral load

• Thus, the virus is a constantly moving target. If given to HIV +ve individuals before the onset of AIDS
• Resistant strains can be transferred between • In combination with other drugs, can
individuals. dramatically prolong the life expectancy
• Other factors which could underlie the loss of
efficacy of the drug are: In HIV +ve mothers
o Decreased activation of zidovudine to the • Reduces the risk of transmission of the virus to
triphosphate the foetus by 66%
o Increased virus load due to reduction in
immune mechanisms In subjects who have been accidentally exposed to HIV
Increased virulence of the pathogen • 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.

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Drugs

Pharmacology And Therapeutics (Spring Term)

Drug Name Action Use Reference

1. Drug directed to the target tissue

Clinically useful in conditions such as ASTHMA and COPD.

Clinically useful in:

The drug tightens the sphincter (increased sympathetic,

ADVERSE EFFECTS OF ALL ANTIMUSCARINIC DRUGS GIVEN SYSTEMICALLY:

• Dry mouth (most commonest symptom)

• Similar to ACEI

• Bradycardia and AV Block

Negative Ionotropic Effect: Verapamil > Ditiazem

• Bradycardia and AV Block

Negative Ionotropic Effect: Verapamil > Ditiazem

Smooth Muscle Actions Only • HYPERTENSION

Beta Blockers Competitive Antagonists of Beta-­‐Adrenoceptors Uses: P&T Spring

Mechanism of Action:

• Competitive antagonist of Beta Adrenoceptors

Use in Hypertension:

• No longer 1st line treatment

• Reduce cardiac output

• Worsening of cardiac failure

ORGANIC NITRATES Mechanism of Action: P&T Spring

• Reduces PRELOAD (venous return)

• Nitrates undergo extensive first pass metabolism by

Unwanted Effects: Hypotension, headaches and flushing

Excess Use: associated with tolerance.

Mechanism of Action

• Adenosine is an endogenous mediator produced by

AMIODARONE & DRONEDARONE:

• Used in supraventricular and ventricular

• Amiodarone accumulates in the body (t1/2 10-­‐100d)

Treat: VENTRICULAR ARRHYTHMIAS

Treat: COMPLEX (e.g. supraventricular arrhythmias

Mechanism of Action:

• Inhibits Na-­‐K-­‐ATPase (Na/K Pump)

Adverse Effects: (Common and severe)

• Dysrhythmias (e.g. AV Conduction block, ectopic

IVABRADINE Use: P&T Spring

Mechanism of Action:

• Blocks If Channel (f-­‐funny) (an Na-­‐K channel important

Phenoxybenzamine – combined with a beta-­‐blocker, provides

Centrally acting anti-­‐hypertensive agents e.g. clonidine (α2*

(*α2 is an inhibitory alpha adrenergic receptor)

• Relief of allergic symptoms

Aspirin Non-­‐Steroidal Anti-­‐Inflammatory Drugs

Heroin (Semi-­‐ Heroin

Olsalazine Colonic flora Colon

(Sulfasalazine) Colonic Flora, Colon

Natalizumab Antibody against alpha-­‐4-­‐integrin • Antibody against alpha-­‐4-­‐integrin

Lidocaine (amide) Cocaine (ester)

Absorption (across mucous membranes) Good Good

Plasma protein binding 70% 90%

Myocardial depression Increased CO

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Beta Blockers Competitive Antagonists of Beta-‐Adrenoceptors Uses: P&T Spring

• Amiodarone accumulates in the body (t1/2 10-‐100d)

• Inhibits Na-‐K-‐ATPase (Na/K Pump)

• Blocks If Channel (f-‐funny) (an Na-‐K channel important

Phenoxybenzamine – combined with a beta-‐blocker, provides

Centrally acting anti-‐hypertensive agents e.g. clonidine (α2*

Aspirin Non-‐Steroidal Anti-‐Inflammatory Drugs

Heroin (Semi-‐ Heroin

Natalizumab Antibody against alpha-‐4-‐integrin • Antibody against alpha-‐4-‐integrin