DRUG EXAMPLES USES MECHANISM SIDE EFFECTSACE inhibitors Ramipril,

Lisinopril• Hypertension• Heart Failure• Post MI

Block ATIATII by binding to the site on the enzyme that normally accommodates the terminal leucine of ATI. Inhibits vasoconstriction.

• Hypotension• Dry cough

(increased bradykinin)

• Renal failure in pts with bilateral renal stenosis

Beta-Blockers Atenolol, Propanolol

• Hypertension• Angina• Arrhythmias• Stable heart failure

block β -adrenergic receptors inhibiting the effects of adrenaline and nonadrenaline. β 1 (heart) blockage decreases HR and contractility, β 2 (bronchial and vascular smooth muscle) blockage causes vasodilation.

• Provocation of asthma, heart failure.

• Cold hands• Bradycardia -

fatigue

Calcium Channel Blockers

Dihydropines – Amlodipine, Phenyalkylamines - Verapamil, Benzthiazepines - Diltiazem

• Hypertension• Angina• Supraventricular

arrhythmia – (Phenylalkylamines only)

Vasodilationblock cellular entry of Ca+ by preventing opening of voltage-gated L-type and T-type calcium channels

• Flushing, headache,• P.oedema• Phenyalkylamines –

can worsen heart failure

• Gynaecomastia• Impotence

Thiazide Diuretics

Bendrofluazide, hydrochlorothiazide

• Hypertension• Combined with loop

for Heart Failure

increase water excretion by decreasing reabsorption of Na+ and Cl- in the distal tubule by binding to the Cl-

site of the electroneutral Na+/Cl- co-transport system and inhibiting its action causing a decrease in blood volume, venous return and CO

• Hypokalaemia• Hyponatraemia• Hypotension• Gout• Type II DM

Loop Diuretics Frusemide, Bumetanide

• Hypertension (but less effective than thiazides – used when renal impairment or resistant to multiple drug Tx)

• Heart Failure

Block Na+ resorption in ascending loop of Henle – diuretic effect.

• Hypokalaemia• Hyponatraemia• Hypotension• Gout

Potassium-sparing diuretics

Spironolactone, Amiloride

• Secondary Hypertension

• Severe heart Failure

Blocks action of aldosterone in distal convoluted tubule – diuretic effect

• Hypokalaemia• Hyponatraemia• Abdominal

discomfort

Angiotensin II receptor antagonists

Losarten, Valsarten

• Hypertension• Alternative to ACE

inhibitor in heart failure

Vasodilation – by inhibition at the angiotensin II receptor

• Usually mild• No cough like in

ACE inhibitors

Alpha-adrenoreceptor antagonists

Doxazosin, Prazosin

• Hypertension (in addition to other hypertensives)

Reduces peripheral resistance by inhibiting α 1-adrenoreceptor-mediated vasoconstriction.

• Postural Hypotension

• Dizziness

Fibrinolytics Streptokinase • Thrombolysis – Acute MI, stroke, PE

Forms a complex with, and activates, plasminogen into plasmin.

• Nausea/vomiting• Bleeding

Antiplatelet agentsAsprin • Prevention and

treatment of MI and stroke.

Irreversibly inhibits COX and so stops synthesis of Thromboxane A2 from Arachidonic Acid which leads to ↓ platelet aggregation.

• Haemorrhage

Clopidogrel • Prevention and treatment of MI and stroke.

Inhibits activation of the glycoprotein IIb/IIIa receptor on the surface of platelets which is required for aggregation to occur.

• Haemorrhage

AnticoagulantsWarfarin • Prophylaxis+treatme

nt DVT, PEProphylaxis of embolization in AF, Rheumatic disease + prosthetic valves.

Blocks reduction of Vit. K epoxide → necessary for synthesis of factors II, VII, IX and X.

• Haemorrhage

Heparin • Treatment of DVT, PE. Prophylaxis of DVT/PE post op.

• MI.

Activates antithrombin III, which limits blood clotting by inactivating thrombin and factor X.

• Haemorrhage

Statins Atorvastatin, Simvastatin, Pravastatin

• Prevention of cardiovascular disease

Reversibly inhibit enzyme HMG CoA reductase which catalyses the rate-limiting step in the synthesis of cholesterol:HMG CoA→mevalonic acid→cholesterol.This ↓ in synthesis ↑ LDL receptors so ↓ LDL levels.

• Myopathy (muscle ache)

• Disturbed LFTs• Abdominal pain

Nitrates Glyceral trinitrate (GTN), Isosorbide mononitrate

• Prophylaxis and Treatment of angina.

• LVF

Prodrugs – they decompose to form NO which activates guanylyl cyclase, thereby ↑ cyclic guanosine monophosphate (cGMP). Protein kinase G is activated and contractile proteins are phosphorylated. This all leads to Dilation of vessels.

• Postural hypotension

• Tachycardia• Headache• Flushing• Dizziness

Potassium channel activators

Nicorandil (only licensed one)

• Prophylaxis of angina

Relaxation of smooth muscle and vasodilation.Activates K+ channels of vascular smooth muscle

• Headache

causing K+ to flow out of cells causing hyperpolarization. This therefore inhibits influx of Ca2+ and so inhibits contraction.

AntiarrythmicsClass Ia Quinidine,

Disopyramide, Procainamide

• VT• WPW

Block Na2+ channels which increases refractory period and in addition there is a blockade of K+ channels which delays repolarisation.

• GI disturbances• Hypotension

Class Ib Lignocaine, Mexiletine, Phenytoin

• Ventricular arrythmi, especially VT

Block Na2+ channels but little effect on refractory period as K+ channels not blocked. ↓ duration of the action potential.

• Nausea and Vomiting

• CNS toxicity• Hypotension• Bradycardia

Class Ic Flecainide • Pre-excitation AF• cardioversion of

paroxsms,AVNRT ,AVRT, WPW, AF , AT , NSVT (non-sustained VT)

Marked Na2+ channel blockage ↑refractory period, no effect on the duration of the action potential.

• CNS toxicity• Hypotension• Proarrythmogenic

after recent MI – may increase mortality

Class II Beta blockers (see above also)

• Junctional tachyarrhythmias, Paroxysmal events,AF, Flutter, NSVT, SVT’s.

↓ rate of spontaneous depolarisation of SA and AV nodal tissue↓ conduction through AV node

• Provocation of asthma, heart failure.

• Cold hands

Class III Amiodarone, Bretylium, Sotalol (Beta blocker with class III properties)

• AF, AT, AVRT, AVNRT, WPW, NSVT

Block K+ channels so prolong the duration of the action potential.

• Amiodarone : GI disturbances. Corneal microdeposits, throtoxicosis, photosensitivity

Class IV Calcium channel

blockers (see above also)

• AVRT, AVNRT, Paroxysms

Block Ca2+ channels – acts predominantly on the AVN and affect the plateau phase of the action potential.

• Flushing, headache• P.oedema• Phenyalkylamines –

can worsen heart failure

• Gynaecomastia• Impotence

Digoxin • AF• Atrial Flutter

Not strictly antiarrythmic – indirect actions on the Action potential through stimulation of the vagus nerve:

• Intracellular Ca2+

overload – junctional escape beats, junctional

↓ automaticity of the SA node which slows sinus rate ↑ refractory period of the AVN which ↓ AV conduction

tachycardia, ventricular ectopic beats, VT.

• Increased vagal activity can cause AT with 2:1 AVN block

• GI disturbances• Neurological

disturbances• Gynaecomastia

Adenosine • Supraventricular arrythmias

Potent effect on SA node producing sinus bradycardia. Slows impulse conduction through the AVN but has no effect on conduction in the ventricles.

• Bradycardia and AV block

• Malaise, flushing, headache chest pain, bronchospasm

Atropine • Sinus bradycardia• AV block• Cardiopulmonary

resuscitation

Inhibits effect of the vagus nerve on the heart which↑ rate of firing of SA node↑ conduction through the AVN via blockade of muscarinic M2 receptors.

• Rhythm disturbances

• Constipation• Reduced Bronchial

secretions

Endocrinology-DiabetesInsulin: Is a polypeptide containing 51 amino acids arranged in two chains (A and B) linked by Disulphide bridges. A precursor called proinsulin, is hyrdolysed inside storage granules to form insulin and a residual C-peptide. The granules store insulin as crystals containing zinc and insulin.Insulin Release: Glucose is the most potent stimulus for insulin with surges at meal times. The B cells possess K+ channels that are regulated by intra cellular adenosine triphosphate (ATP) (Katp channels). When the blood glucose increases, more glucose enters the B-cells and its metabolism results in an increase in intracellular ATP, which closes the Katp channels. The resulting depolorization of the B-cell initiates an influx of Ca2+ ions through you voltage sensitive Ca+ channels and this triggers insulin release.Insulin is destroyed the GI tract so must be given subcutaneously and IV or IM in some circumstances. Injections should be rotated within the same region to avoid lipid hypertrophy. Absorption is fastest from the abdomen and slower from the thigh.

Insulin Regimes1) Short acting insulin mixed with intermediate acting insulin injected subcutaneous twice daily, before breakfast and

before the evening meal/2) Injection of intermediate acting insulin to provide background level of insulin and soluble insulin three times a day.

Short Acting InsulinSoluble Insulin Actrapid • IV for

hyperglycaemic emergencies.

• Subcutaneous injection

Simple solution of insulin (onset 30 mins, peak activities 2-4hrs, subsides by 8hrs)If IV effects only last 30 minutes.

Insulin lispro and Insulin

Humalog and Novorapid

• Blood glucose control

Insulin analogues have a faster onset and shorter

• Hypoglycaemia

aspart (Rapid Acting)

action than soluble insulin. This is because they do not self associate to form dimmers.Onset 20-30 minutes Peak action 1-2 hrs Duration 3-4 hrs

• Insulin auto antibodies

• Lipohypertrophy

Intermediate and Long Acting Insulin(duration of action between 16-35 hours)

Semilente (amorphous insulin zinc)

• Blood glucose control

Suspension of amorphous insulin zinc.

• Hypoglycaemia

Lente Humulin L or Monotard

• Blood glucose conrol Mixture of amorphous insulin zinc (30%) and insulin zinc crystals (70%), the latter prolonging the duration of the preparation Onset of action (2-4 hours). Peak action (6-12hrs) (Duration 20 hrs)

• Hypoglycaemia

Isophane Insulin (NPH)

Insulatard • A complex of protamine and insulin. The mixture is such that no free binding sites remain on the proatmine. After injection, proteolytic enzymes degrade the protamine and the insulin is absorbed. The duration of NPH is similar to that of LenteOnset of action (30-90 mins) Peak action (4-6 hrs) Duration action (8-16 hrs)

• Hypoglycaemia

Biphasic fixed mixtures

Human mixed (short- and intermediate-acting) insulins: These include Humulin 20/80, Humulin 30/70, Humulin 50/50, Mixtard 20/80, Mixtard 30/70, and Mixtard 50/50.

Human mixed insulin analogues (with ultra-

• Contain various proportions of soluble isophane insulin (e.g. 30% soluble and 70% isophane) The soluble component gives rapid onset and the isophane insulin prolongs the action. A pre-mixed short and intermediate-acting insulin will start to work half an hour after being injected, peak at 1-12 hours and last for 16-24 hours.The ultra-short acting insulins lispro and aspart are also available in a biphasic

• Hypglycaemia

short and intermediate-acting properties): These include Humalog Mix25 (insulin lispro) and NovoMix 30 (insulin aspart).

form which retains the rapid onset of action (about 15 minutes) but has a duration of action similar to that of intermediate-acting isophane insulins.

Ultralente Humulin ULUltratard

A suspension of poorly soluble insulin zinc crystals that has a duration of up to 35 hours. The long duration of ultra lente can lead to insulin accumulation and dangerous hypoglycaemia. Onset of action (2-4 hrs) Peak (6-23 hours)

• Hypoglycaemia

Insulin glargine

Lantus Is soluble at acid pH. It has a long peakless activity (11-12 hrs) and is given once a day.

• Hyoglycaemia

Oral Anti Diabetic DrugsTablets are introduced when metabolic control cannot be obtained by diet and lifestyle changes alone. Choice depends on individuals characteristics. Patients with baseline Hb1A1c 9% are les likely to achieve target HbA1c with monotherapy. Drug of choice started at low dose, dose is increased, additional drugs are introduces in combination therapy to maximum of 2-3 drugs. Insulin is usually introduced in combination with metformin.Bigunides Metformin

Only diabetic drug that reduces cardiovascular risks.It reduces weight.

• Type 2 diabetes• PCOS• Non Alcoholic fatty

liver disease

The exact mechanism of action of metformin is uncertain. It appears to act mainly by reducing hepatic gluconeogenesis, it also decreases absorption of glucose from the gastrointestinal tract and increases insulin sensitivity by increasing peripheral utilization of glucose.]

Evidence suggests that increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors since metformin is not effective in patients who no longer have any residual insulin production.The

• Lactic acidosis rare and limited to those with impaired liver of kidney function.

• GI upset diarrhoea, vomiting cramps.

'average' person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third. Metformin stimulates the hepatic enzyme AMP-activated protein kinase (AMPK), which plays an important role in the metabolism of fats and glucose. Causing weight loss. The molecular targets with which metformin directly interacts remain elusive.Metformin is not metabolized, rather it is primarily excreted in the urine with an elimination half-life of 6.2 hours

Sulphonyreas Glipizide (short half life)Glicazide (short half life)Glibenclamide (longer duration of action)Tolbutamide.

• Type II diabetes (people with ideal weight)

These drugs are indicated in patients (especially those near their ideal weight) in whom diet fails to control the hyperglycaemia. In about 30% control is not achieved by these drugs. They stimulate insulin release from the pancreatic islets and so patient must have partially functional B-cells for these drugs to be of use.

• GI disturbance• Rashes• Hypoglycaemia• Hypoglycaemic

coma• Contraindicated in

severe hyperglycaemia, surgery and major illness

Glitazones Rosiglitazone and Pioglitazone

• Type II diabetes given alone or in combination with metofrmin or sulphonyreas in patients who cannot tolerate metformin or sulphonyreas combinations.

Slow onset maximum effect 1-2 months of treatment. Reduce hepatic glucose output and increase absorption into the peripheral tissues. Triglycerides decline and LDL is also reduced. Drugs increase sensitivity to insulin by binding to the nuclear peroxisome proliferator activated receptor gamma (PPAR-y) and by derepression, increase transcription of

• Weight gain• Fluid retention• Contraindicated in

pregnancy

insulin sensitive genes.

a- Glucosidase inhibitors

Acarbose • Type II diabetes Inhibits intestinal a-glycosidases, delaying the digestion of starch and sucrose. It is taken with meals and lowers the post prandial increase of blood gluocose.

• Flautlence• Diarrhoea • Abdominal Pain

Prolactinomas- oligomenorrhoea, amenoffhoea, galactorrhea, infertility, loss of libido, erectile dysfunction, osteoporosis. TRH stimulates prolactin, Dopamine inhibits it.Dopamine agonist drugs

Bromocriptine (ergot derivative)Cabergoline

• Prolactinoma• Acromegaly• Hypogandism• Galactorrhea

Stimulates dopamine receptors in the brain.

• Nausea• Psyhchiatric

Symptoms• Postural

Hypotension• Fibrotic changes

which can lead to valvular heart disease.

Acromegaly Over secretion of GH =gigantism before puberty, acromegaly after puberty. (growth of hands feet, tightening of rings) Somatostatin analogues

Somatuline AutogelSandostatin LAROcreotide

• Acromegaly Somatostatin analogue. Inhibits the production of GH.

• Gallstones• Conratindicated in

liver and kidney failure, diabetes mellitus, Insulinoma.

Diabetes Insipidus (no ADH produced so leads to excretion of large volumes of isotonic water)ADH analogue Desmopressin

(nasal spray, tablets, or subcutaneous injection)

• Diabetes Insipidus Desmopressin is preferred to vasopressin because it is a longer acting analogue. Make sure to reduce fluid intake.

• Water retention• Hyponatremia• Contraindicated in

heart failure, people using diuretics for other conditions. Alcoholics

Hypothyroidism tiredness and lethargy are the most common symptoms. Depression of basal metabolic rate, appetite and cardiac output. Low output heart failure might occur. Skin is dry. Thyroid deprivation in early life leads to dwarfism and cretinism.Thyroxine Levothyroxine • Hypothyroidism Administered orally is the

treatment of choice. Synthetic T4 is the sodium salt of levothyroxine (L-thryoxine). Its effects are delayed until the plasma protein and tissue binding sites are occupied. Treatment is assessed by

• Concomitant conditions worsened by thyroxine therapy. Heart disease, heart failure, infarction, angina, chronic lung disease, breathlessness,

monitoring TSH levels, which fall to normal when optimum dose is achieved. Daily dose 100 and 150ug best take on waking.

adrenal disease. Due to increase in oxygen demand of most tissues as well as myocardium

Liothyronine • Hypothyrioidism Is the sodium salt of T3 and because it is less protein bound, it acts more quickly than T4. The main use of T3 is in hypothyroid coma, when it is given with hydrocortisone by IV injection.

• See above

Hyperthyroidism basal metabolic rate is increased, causing heat intolerance, arrthymias and increased appetite with weight loss. Skin is warm and moist. Tachycardia sweating and tremor. Angina and high output failure may occure. Upper eyelids are retracted. Treatment also includeds beta blockers discussed above (Propranalol or atenolol)Antithyroids Carbimazole • Hyperthyroidism Rapidly converted to

methimazole in vivoOnce daily doses, 40mg for 1 month, then 30mg for 1 month, 20mg for 1 month and then 10 mg daily until reassessed.. Onset of action 3-4 weeks

• Rashes • Agranulocytosis• Patients should

report a sore throat!

Thionamides • Hyperthyroidism Possess a thiocarbamide group that is essential for their activity. They prevent the synthesis of thyroid hormones by competitively inhibiting the peroxidise catalysed reactions necessary for iodine organification. They also block the coupling of iodotyrosine especially diiodothyronine formation. Onset of action 3-4 weeks

• ? immunosuppressive

Propylthiouracil • Hyperthyroidism Reserved for patients intolerant of carbimazole. Also inhibits the peripheral deiodination of t4

• ?immunosupressive

Iodides • Hyperthyroidism Have poorly understood actions on the thyroid. They inhibit organification and and hormone release. In addition iodide decreases the size and vascularity of the hyperplastic gland, effects which are useful in

• Skin rashes• Nausea• Vomiting• Allergic reaction.

preparation of patients for thyroidectomy. They inhibit hormone release quickly (2-7 days) is a valuabe treatment for thyrotoxic crisis. Cannot be used in long term because its antithyroid action tends to diminish.

Primary Hypoadrenalism: Addisons disease Normally! Glucocorticoids mainly cortisol are produced in the cells of the zona fasiculata and zona reticularis. The release of cortisol is controlled by negative feedback mechanism involving the hypothalamus and anterior pituitary. Low plasma cortisol levels results in the release of ACTH. Which stimulates coritsol synthesis and release by activiating adenlyl cyclise. Cyclic adenosine monophosphate (cAMP) then activates protein kinase A, which phoshoporylates and increases the activity of cholesterylester hydrolase, the rate limiting step in steroid synthesis. Alodosterone release is effected by ACTH, but Renin release is more important influence. The steroids are examples of gene active hormones. The steroid diffuses into the cells. In the absence of cortisol the receptor is inactivated by a heat shot protein (hsp 90). Cortisol triggers the release of hsp90 and the activated receptor SR enters the nucleus where it stimulates or inhibits the production or proteins, which then produce the characteristic actions of the hormone.Coritcothrophin releasing hormone (CRH) is a 41 amino acid polypeptide whose action is enhanced by arginine avasopressin (ADH). It is produced in the hypothalamus and reaches the adenopophysis in the hypothalamus-hypophsyial portal system where it stimulates the production of corticotrophin.ACTH is process from large molecular weight precursor, pro-opiomelanocortin (POMC) present in corticotroph cells of the adenohypophosis, its main action is to stimulate the synthesis and release of cortisol.Cortisol Hydrocortisone • Addisons Immediate management.

If acutely sick!Take blood cortisol glucose urea and electrolytes. Give hydrocortisone 100mg as IV bolus. Give saline infusion litre initially over 4-6 hours. Correct hypoglycaemia iwth IV bolus of 20% glucose.Continue with with IM hydrocortisone 100mg 6 hourly.Long term Hydrocortisone orally 10mg on waking, 5mg at lunch and evening (dose varies)Fludrocortisone 0.1-0.2mg per day.

• Moon face• Striae• Fat redistribution• Hirsutsim• Infection• Proximal muscle

wasting• Bruising

Synthetic Aldosterone

Fludrocortisone • Addisons Synthetic mineralcorticoid derivative of aldosterone. Plasme rennin acitivity should be measured 2 hours after the flurdrocortisone dose and maintained in the normal range.

• Hypertension • Oedema• Peptic ulcers• Mood changes• GI upset• Glaucoma

Cushings Syndrome Excess production of cortisol

Ketoconazole • Cushings• Anti fungal

Well absorbed orally, wide spectrum anti fungal drug which has adrenal suppression effects

• Hepatic necrosis• Adrenal suppression

Metirapone • Cushings Metyrapone blocks cortisol synthesis by inhibiting steroid 11β-hydroxylase.

• Nausea vomiting, abdominal cramping pain.

Mitotane • Cushings• Adrenal adenoma

Unknown mechanism of action but inhibits adrenal steroidal action

• Dizzyness, drowsyness nausea and vomiting.

Hyperparathyroidism and Malignancy account for 90% of HypercalcaemiaRehydration IV Saline • Hypercalcaemia Hydration must be

maintained with IV intravenous saline. This will prevent severe hypercalcaemia. Once volume status is normal use bisphosphonates

• Hypernaetremia

Bisphosphonates

AlendronateEtidronate

• Hypercalcaemia Bind to hyrdoxyapatite crystals and reduce bone resorption.

• GI upset, Erosion of Oesophagus

Hypocalaemia Commonest cause is Vit D deficiencyCalcium Supplements

CalcicaOsteocare

• Hypocalaemia • Hypercalcaemia• Stomach pain• Diarrhoea

Vitamin D analogue

Ergocalciferol Vit D2Cholecalciferol Vit D3Alfacalcidol 1-hydroxyvitamin DCalcitriol 1,25 Dihydroxy D

• Hypocalcaemia• Vit D deficiency

Vitamin D analogues allow absorption of calcium from the gut.

• Hypercalcaemia

Recombinant PTH analogue

Teriparatide • Hypocalcaemia • Hypoparathyriodism

Stimulates bones resorption, Kindey to re absorb calcium, stimulates production of 1.25 Dehydroxyvit D at kidney.

• Dizzyness• Leg Cramps• Nausea

Phaeochromocytoma Neoplasm of the adrenal medulla. 10% are malignant, 10% are extra-adrenal, 10% are bilateral, 10% are familial. Blockage of adreno receptors must be started first. a-adrenoreceptor antagonist

PhenoxybenzamineLabetalolDoxazosin Phentolamine Prazosin Tamsulosin Terazosin

• Tumours of adrenal medulla

An irreversible antagonist is used to block the a-effects of the large amounts of catecholamines from tumours of the adrenal medulla.

• Reflex tachycardia

b-blockers Atenolol (see above)

• •

Conns excess production of aldesteroneAldosterone receptor blockers

Spironolactone (see above)Eplernone

• Conns• Liver disease with

ascites

Blocks the binding of aldosterone to its receptor and increases the excretion of Na+ and decreases the electrically coupled K+ secretion.

• Severe Hyperkaleamia

• Painful Gyanocamastia

Postassium Sparing Diuretic

AmilorideTriamterene

• Potassium sparing diuretic

• Conns

Decrease the luminal membrane Na+ permeability in the distal nephron by combining with Na+ channels and blocking them 1:1 basis. This increases Na+ (Cl- and H2O) excretion and decreases K+ excretion.

• Severe Hyperkalaemia

Zero Order Kinetics

Common drugsPhenytoin, Aspirin, Ethanol, Theophylline, Thiopentone

• •

Anti-Epileptics – Epilepsy is a chronic disease in which seizures result from abnormal discharge of cerebral neurones. Epilepsy is defined as a tendency to recurrent seizures i.e. two or more seizures. Partial seizures (seizures begin focally) Simple (consciousness not impaired) Complex (with impairment of consciousness) Beginning as a simple partial seizure and progressing to a complex partial seizure. Impairment of consciousness at onset. Partial seizure becoming secondary generalised. Generalised Seizures Absence Seizure Typical (petit mal) Atypical. Others Myoclonic seizure, Clonic seizure, Tonic seizure, Tonic-clonic seizure (grand mal) Atonic seizure.Treatment should be considered when two or more unprovoked seizures have occurred within a short period. Whenever possible, treatment should involve only one drug.Generalised Epilepsy

LamatrogineSodium Valproate

• Lamatrogine and Valpraote have similar mech of action as Phenytoins discussed below. Valproate also seems to in increase GABAergi central inhibition mechanisms that may involve stimulation of glutamic acid decarboxylase activity and/ or inhibition of GABA-T activity.

• Lamatrogine – Blurred vision dizziness and drowsyness. Serious skin reactions can occur especially in children.

• Valproate - Nausea, weight gain, bleeding tendencies and transient hair loss). The main disadvantage is that occasional idiosyncractic reactions cause sever or fatal hepatic failiure.

Focal Epilepsy CarbamazepinePhenytoin

• Phenytoins anticonvulsant action is probably a result of its ability to prevent high frequency repetitive activity. Phenytoin binds prerentially to inactivated (closed) Na+ channels stabilizing them in the inactivated state and preventing them from returning to the resting closed state which they must do before they can open again. High freuquency repetitive depolarisation increases the proportion of Na+ channels in the inactivated state and, because these are susceptible to blockade by phenytoin, the Na+ is progressively reduced until it is eventually insufficient to evoke and action potential. Neruonal transmission at normal frequencies is relatively unaffected by phenytoin because a smaller portion of the Na+ channels are in the inactivated state. Carbamazepine, lamotrigine, valproate, and topiramate. Have similar actions on neuronal Na+ channels.

• Carbamazepine is metabolised in the liver to carbamzepine-10,11- epoxide, an active metabolite that partly contributes to both its anti-convulsant action and neurotoxicity. In contrast to phenytion there is a linear increase in serum concentration with dosage. Mild neurotoxic effects are common (nausea dizziness drowsyness, blurred vision and ataxia) Agranulocytosis is a rarer idyiosyncratic reaction.

• Phenytoin is hyroxylated in the liver by a saturable enzyme system. The rate of metabolism varies greatly in patients. And up to 20 days maybe required for the serum level to stabilize after changing the dose. Dose is increased gradually until fits are prevented , or until signs of cerebellar disturbance occur (nystagmus, ataxia, involuntary movements) One the metabolizing enxymes are saturated , a small

increase in dose may produce toxic side blood levels of the drug. Other effects Gum hypertrophy, acne, greasy skin, coarsening of the facial features and hirsutism.

Absence Epilepsy in Children

EthosuximideSodium Valproate

• Absence seizures involve oscillatory neuronal activity between the thalamus and the cerebral cortex. This oscillation involves (T-type) Ca2+ channels in the thalamic neurones, which produce low threshold spikes and allow the cells to fie in bursts. Drugs (Ethosuximide and Valproate) that control absences reduced this Ca2+ current dampening the thalmacortical osciallations that are critical in the generation of absece seizures.

• Ethosuximide- Nausea vomiting.

Parkinsons – Main pathology is the extensive degeneration of the dopiminergic nigrostriatal tract, but the cause of the degeneration is usually unknown. Replacement therapy alone is not possible in parkinsons because the dopamine does not pass the blood brain barrier. However its precursor levodopa (L-dopa), does penetrate the brain where it is decarboxylated to dopamine. Orally administered, levodopa is largely metabolized outside the brain and so it is given with a selective extracerebral decarboxylase inhibitor (carbidopa or benserazide). Some of the peripheral side effects of dopaminergic drugs can be reduced with domperidone, a dopamine antagonist that does not penetrate the brain. Inhibition of the drug monoamine oxidase B (MAOb) with selegilene potentiates the actions of levodopa. Anti-muscarincs are used for the tremor that occurs with parkinsons. Levodopa Sinemat

MadoparBoth these drugs come with extracerebral decarboxylase inhibitors)

• Parkinsons Levodopa is the immediate precursos of dopamine and is able to penetrate the brain where it is converted to dopamine. The site of the decarboyxlation is uncertain, but as dopa decarboxylase is no rate limiting there maybe sufficient enzyme in the remaining dopaminergic nerve terminals. Another possibility is that the conversion occurs in nor adrenergic or seratonergic

• Nausea and vomiting caused by stimulation of the CTZ.

• Psych effects vivid dreams, hallucinations, psychotic states and confusion.

• Postural hypotension is common.

• Dyskinesias (jerky

terminals. Because the de-carboxylase activity in these neurones is not specific.

or dance like movement) are an important adverse effect.

• Long term after five years treatment about 50% of patients will have lost ground. In some there is a gradual recurrence of parkinsionian akinesia. A second form of deterioration is the shortening of duration of action of each dose. Various dyskinesias may appear and, with time rapid oscillations in mobility and dyskinesias.

Dopamine Receptor Agonists

Bromocriptine (ergot derivative)Ropinirole (non ergot derivative)Apomorphine (very powerful given by parenteral administration)

• Parkinsons• Prolactinomas

Dopamine agonists have no advantage over levopdopa and the adverse effects are similar.Used with young patients, in particular who are given a dopamine agonist as initial therapy (sometimes together with selegeline). This strategy may slow the development of dyskinesias but only 50% of patients show any beneficial response to monotherapy with dopamine agonists.When patients on levodopa therapy start to show deterioiration dopamine agonists are often added to try and reduce the off periods.

• Nausea, psychiatric symptoms, postural hypotension.

• Pulmonary fibrosis and retroperitoneal fibrosis.

• Apomorphine (highly emetogenic) domperidone should be given before treatment started.

Pre Synaptic Re-Uptake inhibitor

Amantadine • Parkinsons Potentiates dopamine by preventing re-uptake in the pre-synaptic terminals. Moderate effect but toleranc

• Dizzyness, Loss of co-ordindation, inability to sleep, nausea,

soon develops nervousnessMonamine oxidase inhibitor type B (MAO-B)

Selegiline • Parkinsons Inhibits monoamine oxidase type B (MAO-B) there by increasing dopamine. This is done by reducing the metabolism of the dopamine in the brain potentiating the levdopa which can be reduced by up to one 1/3. It is used to reduce end of dose akinesia.

• Nausea • Heartburn• Dry mouth

COMT inhibitors

EntacaponeBenzarazide

• Parkinsons Inhibbits catechol-O-methltransferase (COMT) and prevents peripheral conversion of Levodopa to (inactive) 3-O-methyldopa. It increases the plasma half life of levodopa and increases its action.

• Drowsyness• Dizzyness• Stomach upset• Diarrhoea

Antimuscarinics

BenzetropineProcyclidineOrphenadrineBenzhexol

• Parkinsons Produce a modest iimprovement in the early stages of parkison’s disease, but the akinesia responsible for most of the functional disability responds least well.

• Dry mouth • Urinary retention

and constipation.• Effect memory and

concentration.

Myaesthenia Gravis An acquired organ specific autoimmune disorder in which antibodies are directed at the post synaptic acetycholine receptor. This results in weakness and fatiguability of skeletal muscle groups. The most commonly effected muscles are the proximal limbs and the ocular an bulbar muscles. Oral acetycholinesterase

Prydostigmine • Myaesthenia gravis Most widely used drug; it has a duration of about 3-5 hours. Patients response will determine the dose required. Great symptomatic drug but does not alter the natural history of the disease.

• Overdose causes a cholinergic crisis with severe weakness. Colic and diarrhoea may occur.

Motor neurone diseaseRiluzole Rilutek • MND Used to treat amyoptrophic

lateral sclerosis. Delays the onset of ventilator dependence or tracheostomy by 2 months.

• Nausea• Fatigue• Hepatitis

Guillain- Barres syndrome (post-infective polyneuropathy) Inflammtory demyelinating polyradiculoneuropathy. Often follows one to two weeks after infection or diarrhoea, which may have been mild. Campylobacter jejuni has been particularly implicated as a cause of the diarrhoea and is associated with the most severe form. Classic presentation distal paraesthesie, often with little sensory loss, and weakness can occure proximally, distally spreading or generalised. The symptoms ascend up lower limbs and body over days to weeks. Facial weakness present in 50% cases. In sevre cases respiratory and bulbar involvement occurs. IF VC drops to 1 litre of below: artificial ventilation is needed.High dose (IVIg) • Guillen Barres Either high-dose intravenous • Hepatitis

immunoglobulins

immunoglobulins (IVIg) at 400mg/kg for 5 days or plasmapheresis can be administered, as they are equally effective and a combination of the two is not significantly better than either alone. Therapy is no longer effective after 2 weeks after the first motor symptoms appear, so treatment should be instituted as soon as possible. IVIg is usually used first because of its ease of administration and safety profile, with a total of five daily infusions for a total dose of 2 g/kg body weight (.4kg each day).

• Renal failure

Glaucomas- Mixed group of disorders that have some common features: Optic disc cupping, visual field loss and usually, raised intraocular pressure (IOP). Beta-Blockers Timolol, carteolol,

betaxolol, levobunolol

• Glaucoma Reduce aqueous secretion by inhibitory action on beta adrenoreceptors in the cilliary body.

• Ocular irritation• Bronchospasm• Bradycardia• Nightmares• Exacerbation of

hear failureMuscarinic (parasympathetic) simulates .

Pilocarpine (also a differential for bilateral constricted pupils!)

• Glaucoma Increase aqueous outflow via trabecular meshwork by ciliary muscle contraction

• Ocular: Misosis (reduced vision in the presence of a cataract) spasm of accommodation, brow ache

• Systemic: Swaeting, bradycardia, GI disturbance

Alpha2-stimulantsTopical

Brimonidine, Apraclonidine

• Glaucoma Reduces aqueos secretion by selective stimulation of alpha2 and adrenocrecptors in the ciliary body increase outflow by the uveoscleral route

• Ocular: Iris darkening, conjunctival hyperaemia, eyelash growth.

• Systemic: bitter taste, asthma.

Carbonic Anhydrase Inhibitors

Acetazolamide (systemic)Dorzolamide,Brinzolamide

• Glaucoma Reduce aqueous secretion by the cilliary body

• Ocular route: irritation and allergy

• Systemic route: Malaise,

paraesthesia, urea and electrolye disturbance, aplastic anaemia

Mydriatics and cycloplegics – ( Used for retinal examination and objective refraction (retinoscopy)Antimuscarinics

Tropicanamide, cyclopentolate, atropine.

• Eye dilation for exam Inhibit muscarinic receptors of parasympathetic nervous system to paralyse papillary sphincter and ciliary muscle.

• Ocular: Blurred vision, glare, angle closure glaucoma.

• Systemic: Tachycardia, dry mouth, confusion, tremor.

Alpha-stimulant

Phenylephrine • Eye dilation for exam Stimulates dilator muscle of the pupil no cycloplegic effect.

• Ocular: Blurred vision, glare, angle closure, glaucoma, conjunctival blanching.

• Systemic hypertension

Lubricants – There are a wide rangeCarbomers, hyrpmellose, polyvinyl alcohol, liquid paraffin

• Dry eye Exact mechanism depends on the agent

• Ocular: Allergy, blurred vision

Ant-Inflammatory Agents. Most important drugs are corticosteroids, a Variety of other drugs are available including systemic immnosuppressantsCorticosteroids

Prednisolone, betamethasone, dexamethasone

• Suppress Inflammation

Suppresion of broad spectrum of inflammatory processes (see corticosteroids)

• Ocular: Glaucoma (especially with local administration), cataract (especially prolonged systemic use) exacerbation of some infections !!! e.g. herpes simplex.

• Systemic: Negligible with topical use, common and varied with systemic administration.

Mast cell stabilisers

Cromoglicate, nedocromil, lodoxamide.

• Allergy Stabilise mast cells • Occular: Irritation

Anti-histamines

Topical: Antazoline, azelastine, levocabastine.

• Allergy Block histamine receptor • Occular route: Irritation

• Sytemic route: Drowsiness

Systemic (chlorphenamine, terfendaine, cetirisine)

NSAIDS Topical: (ketorolac, diclofenac, fluribiprofen)

• Eye inflammation Modulate prostaglandin production.

• Systemic: Peptic ulceration, asthma.

Anti-Infective agents: Topically applied antibacterial and antiviral drugs are very commonly prescribed. The use of antifungal and antiparastic agents is much less frequent.Antibacterials Topical:

Chloramphenicol, gentamicin, ciprofloxacin,Neomycin, fusidic acid.Occassionally intra-ocular, systemic

• Bacterial Infection Range of activities and specificities

• Vary with agent• Ocular: allergy;

corneal toxicity common with intensive use.

• Systemic: generally only with systemic use.

• •• •

Antivirals Aciclovir, topical or systemic

• Herpes simplex, zoster

Inhibits herpes virus DNA synthesis

• Ocular: blurred vision, corneal toxicity

• Systemic: Rashes: kidney, liver and other effects may occur with systemic use.

Local Anaesthetics: Major uses are to relieve pain and thereby assist with clinical examination and the facilitation of surgical anaesthesiaLocal anaesthesia

Topical or peri-ocular injection. Oxyburprocaine, proxymetacaine. Tetracaine, lidocaine.

• Clinical exam Block conduction along the nerve fibres

• Ocular: Irritation, corneal toxicicty.

• Systemic: generally accidental intravascular or intrathecal (cerebrospinal fluid) injection. During surgical anaesthesia, cardiac arrythmmias, respiratory depression

Botulinum toxin: Used in the management of certain ocular motility disorders amd blepharospasm, and to induce ptosis for corneal protectionBotulinum Injection at site of • Motility disorder Prevents release of the • Dependant on

toxin action neuro-transmitter acetycholine at neuromuscular junctions

treatment sitee.e.g unwanted ptosis or double vision

MigrainePizotifen Serotonin

Antagonist5HT

• Migraine •

Sumatriptan Acute Migraine

Serotonin Antagonist5HT

• Migraine •

Methysergide Long term migraine

Serotonin Antagonist5HT

• Migraine •

Urinary Tract Infection

E.coli, proteus, saprophiticus.

• •

Trimethoprim • UTI • NOT used in pregnancy

• Use nitrofurentoin instead or amoxicillin

Amoxicillin • UTI • Used in pregnancy

Diazoxide • Insulinoma Blocks insulin release •Teriparatide • Hypocalaemia PTH analogue •Corticosteroids Release of cortisol is controlled by negative feedback mechanism involving the hypothalamus and anterior pitruitary. Low plasms cortisol levels result in release of ACTH which stimulates cortisol synthesis and release by activating Adenylate cyclise. cAMP then activates protein kinase A which phosphorylates and inceases the activity of cholesterylester hydrolase, the rate limiting step in steroid synthesis. Aldosterone release is affected by ACTH but other factors (renin angiotensin are more important.Steroids are examples of gene active hormones. Steroid diffuses into cells where it binds to cytoplasmic glucocorticoid receptors. IN the absence of cortisol the receptor is inactivated by a heat shock protein. Cortisol triggers the release of hsp90 and the activated receptor enteres the nucleus where it stimulates the synthesis of proteins, which then produce the characteristic actions of the hormone.Corticotrophin is prcessed from a large molecular weight precursor pro opiomelanocortin (POMC) precent in the corticotroph cells of the adenohypophysis; its main action is tto stimulate the synthesis an release of cortisol. POMC also contains the sequences for B lipoprotein (B-LPH) and B-endorphin, which are co comittantly release into the blood. Corticotrophin is also believed to sensitize the zone glomerulosa to other stimuli which cause aldosterone release. Glucocorticoids:- Mechanism of action-Cortisol and synthetic glucocorticoids diffuse into target cells and binds to a cytoplasmic glucocorticoid receptor that belongs to the superfamily of steroid thyroid and retinoid receptors. The activated receptor-glucocorticoid complex enters the nucleus and binds to the steroid respsones elements on target DNA molecules. This either induces the synthesis of mRNA or represses the genes inhibiting transcription factors e,g, NFkB for most clinical purposes, synthetic glucocoritcoids are used because they have a higher affinity for the receptor are less rapidly inactivated and have little or no salt retaining properties.Effects Glucorticosteroids are essential for life their most important function being facilitating the conversion of protein to glycogen. They inhibit protein synthesis and stimulate protein catabolism to amino acids. Gluconeogenesis glycogen deposition and glucose release from the liver are stimulated, but peripheral glucose uptake is inhibited. During fasting they are essential

for keeping blood sugars level.Anti Inflammtory Effects and Immunosuppresive effects. Cotricosteroids have profound anti-inflamm effects. They suppress all phases of inflammatory response, include the early swelling , redness pain and the later proliferative changes seen in chronic inflammtation. Inflammation is suppressed by several mechanismsCirculating immunocompetent cells and macrophages are reduced and the formation of pro inflammatory mediators, as prostaglandins leukatrienes and platelet activating factor is inhibited. Done by stimulating the synthesis in leucocytes of a protein (lipocortin) that inhibits phospholipase A2. This enzyme in cell membrane is activated in damaged cells adn is responsible for the formation of arachdonic acid. The precursor of many inflammatory mediators. Corticosteroids suppress the genes coding for phospholipase A2, (COX2) and the interleukin-2 (IL-2) receptor. These genes are normally switched on by NFkB but steroids induce the synthesis of IkB that binds to the NFkB and inhibits it by preventing its entry into the nucleus. They also depress monocytemacrophages fintion and decrease T-Cells, IL1 and IL2 is inhibited.Hydrocortisone

Coritcosteroid • Anti Inflamm (iI)s used orally for replacement (ii) intra venously in shock and status asthmaticus and (iii) topically (e.g. ointments in eczema enemas in ulcerative colitis

• Moon face, fat to trunk and face, purple striae, hirsutism,acne, infections

• Osteoporosis, bruise skin, diabetes, hypercalaemia,

• Fluid retention, hypokalaemia.

Prednisolone Corticosteroid • Anti Inflamm Is the most widely used drug driven orally in inflammatory and allergic diseases.

• A s above

Betamethasone and Dexamethasone

Corticosteroid • Anti Imflamm Are very potent and have so salt-retaining actions. This makes them especially useful for high dose therapy in conditions, such as cerebral oedema where water retention would be a disadvantage.

• As above

Beclometasone and Budesonide

Corticosteroid • Anti Inflamm Pass membranes poorly and are more active topically than when given orally. They are used in asthma and topically in sever eczema to provide a local anti inflammatory action with minimal systemic effects.

• As above

Triamcinolone Corticosteroid • Anti Inflamm Used in sever asthma and by intra articular injection for local inflammation of the joints.

• As above

NSAIDS inhibit COX and inihibit prostaglandin synthesis. COX exists in tissue as constitiutive isoform (COX-1) but at sites of inflammation cytokines stimulate the induction of a second isoform (COX-2) Inhibition of of COX-2 is thought to be responsible

for the anti-flamm effects of NSIADS. Inhibition of COX 1 is responsible for GI problems. Most current NSAIDS are COX 1 inhibitors, but selective COX 2 are on the market (Celecoxib, eterocoxib, valdecoxib) are selective COX 2 inhibitors incidence of gastric perforation obstruction and bleeding is reduced by at least 50%. Aspirin is long standing NSAID and anti analgesicParacetamol is just analgesic

• •• •