DRUG ACE inhibitors

EXAMPLES Ramipril, Lisinopril

USES Hypertension Heart Failure Post MI

MECHANISM Block ATIATII by binding to the site on the enzyme that normally accommodates the terminal leucine of ATI. Inhibits vasoconstriction. block -adrenergic receptors inhibiting the effects of adrenaline and nonadrenaline. 1 (heart) blockage decreases HR and contractility, 2 (bronchial and vascular smooth muscle) blockage causes vasodilation. Vasodilation block cellular entry of Ca+ by preventing opening of voltage-gated L-type and Ttype calcium channels

Beta-Blockers

Atenolol, Propanolol

Hypertension Angina Arrhythmias Stable heart failure

SIDE EFFECTS Hypotension Dry cough (increased bradykinin) Renal failure in pts with bilateral renal stenosis Provocation of asthma, heart failure. Cold hands Bradycardia - fatigue

Calcium Channel Blockers

Dihydropines Amlodipine, Phenyalkylamines Verapamil, Benzthiazepines Diltiazem Bendrofluazide, hydrochlorothiazide

Hypertension Angina Supraventricular arrhythmia (Phenylalkylamines only)

Thiazide Diuretics

Hypertension Combined with loop for Heart Failure

Loop Diuretics

Frusemide, Bumetanide

Potassium-sparing diuretics Angiotensin II receptor antagonists Alphaadrenoreceptor antagonists

Spironolactone, Amiloride Losarten, Valsarten

Hypertension (but less effective than thiazides used when renal impairment or resistant to multiple drug Tx) Heart Failure Secondary Hypertension Severe heart Failure Hypertension Alternative to ACE inhibitor in heart failure Hypertension (in addition to other hypertensives)

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

Flushing, headache, P.oedema Phenyalkylamines can worsen heart failure Gynaecomastia Impotence Hypokalaemia Hyponatraemia Hypotension Gout Type II DM Hypokalaemia Hyponatraemia Hypotension Gout Hypokalaemia Hyponatraemia Abdominal discomfort Usually mild No cough like in ACE inhibitors Postural Hypotension Dizziness

Blocks action of aldosterone in distal convoluted tubule diuretic effect Vasodilation by inhibition at the angiotensin II receptor Reduces peripheral resistance by inhibiting 1-adrenoreceptor-mediated vasoconstriction.

Doxazosin, Prazosin

Fibrinolytics

Streptokinase

Thrombolysis Acute MI, stroke, PE

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

Nausea/vomiting Bleeding

Antiplatelet agents Asprin

Prevention and treatment of MI and stroke. Prevention and treatment of MI and stroke.

Clopidogrel

Irreversibly inhibits COX and so stops synthesis of Thromboxane A2 from Arachidonic Acid which leads to platelet aggregation. Inhibits activation of the glycoprotein IIb/IIIa receptor on the surface of platelets which is required for aggregation to occur. Blocks reduction of Vit. K epoxide necessary for synthesis of factors II, VII, IX and X.

Haemorrhage

Haemorrhage

Anticoagulants Warfarin

Prophylaxis+treatment DVT, PE Prophylaxis of embolization in AF, Rheumatic disease + prosthetic valves. Treatment of DVT, PE. Prophylaxis of DVT/PE post op. MI. Prevention of cardiovascular disease

Haemorrhage

Heparin

Activates antithrombin III, which limits blood clotting by inactivating thrombin and factor X. Reversibly inhibit enzyme HMG CoA reductase which catalyses the ratelimiting step in the synthesis of cholesterol: HMG CoAmevalonic acidcholesterol. This in synthesis LDL receptors so LDL levels. 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. Relaxation of smooth muscle and vasodilation. Activates K+ channels of vascular smooth muscle causing K+ to flow out of cells causing hyperpolarization. This therefore inhibits influx of Ca2+ and so inhibits contraction.

Haemorrhage

Statins

Atorvastatin, Simvastatin, Pravastatin

Myopathy (muscle ache) Disturbed LFTs Abdominal pain

Nitrates

Glyceral trinitrate (GTN), Isosorbide mononitrate

Prophylaxis and Treatment of angina. LVF

Postural hypotension Tachycardia Headache Flushing Dizziness Headache

Potassium channel activators

Nicorandil (only licensed one)

Prophylaxis of angina

Antiarrythmics Class Ia

Quinidine, Disopyramide, Procainamide Lignocaine, Mexiletine, Phenytoin

VT WPW Ventricular arrythmi, especially VT

Class Ib

Block Na2+ channels which increases refractory period and in addition there is a blockade of K+ channels which delays repolarisation. Block Na2+ channels but little effect on refractory period as K+ channels not blocked. duration of the action potential. Marked Na2+ channel blockage refractory period, no effect on the duration of the action potential.

GI disturbances Hypotension Nausea and Vomiting CNS toxicity Hypotension Bradycardia CNS toxicity Hypotension Proarrythmogenic after recent MI may increase mortality Provocation of asthma, heart failure. Cold hands Amiodarone : GI disturbances. Corneal microdeposits, throtoxicosis, photosensitivity Flushing, headache P.oedema Phenyalkylamines can worsen heart failure Gynaecomastia Impotence Intracellular Ca2+ overload junctional escape beats, junctional tachycardia, ventricular ectopic beats, VT. Increased vagal activity can cause AT with 2:1 AVN block GI disturbances Neurological disturbances Gynaecomastia

Class Ic

Flecainide

Pre-excitation AF cardioversion of paroxsms,AVNRT ,AVRT, WPW, AF , AT , NSVT (nonsustained VT) Junctional tachyarrhythmias, Paroxysmal events,AF, Flutter, NSVT, SVTs. AF, AT, AVRT, AVNRT, WPW, NSVT

Class II

Beta blockers (see above also)

rate of spontaneous depolarisation of SA and AV nodal tissue conduction through AV node Block K+ channels so prolong the duration of the action potential.

Class III

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

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.

Digoxin

AF Atrial Flutter

Not strictly antiarrythmic indirect actions on the Action potential through stimulation of the vagus nerve: automaticity of the SA node which slows sinus rate refractory period of the AVN which AV conduction

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-Diabetes Insulin: 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 Regimes 1) 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 Insulin Soluble Insulin Actrapid Simple solution of insulin (onset 30 mins, IV for hyperglycaemic peak activities 2-4hrs, subsides by 8hrs) emergencies. If IV effects only last 30 minutes. Subcutaneous injection Insulin lispro and Insulin aspart (Rapid Acting) Humalog and Novorapid Blood glucose control Insulin analogues have a faster onset and shorter 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 Suspension of amorphous insulin zinc. 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) 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 Hypoglycaemia Insulin auto antibodies Lipohypertrophy

Intermediate and Long Acting Insulin (duration of action between 16-35 hours) Semilente (amorphous insulin zinc) Lente Humulin L or Monotard

Blood glucose control Blood glucose conrol

Hypoglycaemia Hypoglycaemia

Isophane Insulin (NPH)

Insulatard

Hypoglycaemia

Biphasic fixed mixtures

Human mixed (shortand intermediateacting) 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 ultrashort and intermediateacting properties): These include Humalog Mix25 (insulin lispro) and NovoMix 30 (insulin aspart).

Lente Onset of action (30-90 mins) Peak action (4-6 hrs) Duration action (8-16 hrs) 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 intermediateacting 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 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.

Hypglycaemia

Ultralente

Humulin UL Ultratard

Insulin glargine

Lantus

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

Hypoglycaemia

Hyoglycaemia

Oral Anti Diabetic Drugs Tablets 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 The exact mechanism of action of Type 2 diabetes Lactic acidosis rare and Only diabetic drug that metformin is uncertain. It appears to act limited to those with PCOS reduces cardiovascular mainly by reducing hepatic impaired liver of kidney Non Alcoholic fatty liver risks. gluconeogenesis, it also decreases function. disease It reduces weight. absorption of glucose from the GI upset diarrhoea, gastrointestinal tract and increases vomiting cramps. 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 '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. 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 insulin sensitive genes. GI disturbance Rashes Hypoglycaemia Hypoglycaemic coma Contraindicated in severe hyperglycaemia, surgery and major illness Weight gain Fluid retention Contraindicated in pregnancy

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.

Inhibits intestinal a-glycosidases, Flautlence delaying the digestion of starch and Diarrhoea sucrose. It is taken with meals and Abdominal Pain lowers the post prandial increase of blood gluocose. Prolactinomas- oligomenorrhoea, amenoffhoea, galactorrhea, infertility, loss of libido, erectile dysfunction, osteoporosis. TRH stimulates prolactin, Dopamine inhibits it. Dopamine agonist Bromocriptine (ergot Stimulates dopamine receptors in the Prolactinoma Nausea drugs derivative) brain. Acromegaly Psyhchiatric Symptoms Cabergoline Hypogandism Postural Hypotension Galactorrhea Fibrotic changes which can lead to valvular heart disease. a- Glucosidase inhibitors Acarbose Type II diabetes

Acromegaly Over secretion of GH =gigantism before puberty, acromegaly after puberty. (growth of hands feet, tightening of rings) Somatostatin Somatuline Autogel Somatostatin analogue. Inhibits the Acromegaly analogues Sandostatin LAR production of GH. Ocreotide Diabetes Insipidus (no ADH produced so leads to excretion of large volumes of isotonic water) ADH analogue Desmopressin (nasal Desmopressin is preferred to Diabetes Insipidus spray, tablets, or vasopressin because it is a longer acting subcutaneous injection) analogue. Make sure to reduce fluid intake.

Gallstones Conratindicated in liver and kidney failure, diabetes mellitus, Insulinoma.

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 Administered orally is the treatment of Hypothyroidism Concomitant conditions choice. Synthetic T4 is the sodium salt of worsened by thyroxine levothyroxine (L-thryoxine). Its effects therapy. Heart disease, are delayed until the plasma protein and heart failure, infarction, tissue binding sites are occupied. angina, chronic lung Treatment is assessed by monitoring disease, breathlessness, TSH levels, which fall to normal when adrenal disease. Due to optimum dose is achieved. Daily dose increase in oxygen demand 100 and 150ug best take on waking. of most tissues as well as myocardium Liothyronine Is the sodium salt of T3 and because it Hypothyrioidism See above 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. 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 Rapidly converted to methimazole in Hyperthyroidism Rashes vivo Agranulocytosis Once daily doses, 40mg for 1 month, Patients should report a then 30mg for 1 month, 20mg for 1 sore throat! month and then 10 mg daily until reassessed.. Onset of action 3-4 weeks Thionamides Possess a thiocarbamide group that is Hyperthyroidism ? immunosuppressive 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 Propylthiouracil Reserved for patients intolerant of Hyperthyroidism ?immunosupressive carbimazole. Also inhibits the peripheral

deiodination of t4 Have poorly understood actions on the Skin rashes thyroid. They inhibit organification and Nausea and hormone release. In addition iodide Vomiting decreases the size and vascularity of the Allergic reaction. hyperplastic gland, effects which are useful in 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 Immediate management. If acutely Addisons Moon face sick! Striae Take blood cortisol glucose urea and Fat redistribution electrolytes. Give hydrocortisone 100mg Hirsutsim as IV bolus. Give saline infusion litre Infection initially over 4-6 hours. Correct Proximal muscle wasting hypoglycaemia iwth IV bolus of 20% Bruising 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. Synthetic Fludrocortisone Synthetic mineralcorticoid derivative of Addisons Hypertension Aldosterone aldosterone. Plasme rennin acitivity Oedema should be measured 2 hours after the Peptic ulcers flurdrocortisone dose and maintained in Mood changes the normal range. GI upset Glaucoma Cushings Syndrome Excess production of cortisol Ketoconazole Well absorbed orally, wide spectrum anti Cushings Hepatic necrosis fungal drug which has adrenal Anti fungal Adrenal suppression suppression effects Metirapone Metyrapone blocks cortisol synthesis by Cushings Nausea vomiting, Iodides Hyperthyroidism

 Cushings Adrenal adenoma Hyperparathyroidism and Malignancy account for 90% of Hypercalcaemia Rehydration IV Saline Hypercalcaemia Mitotane

inhibiting steroid 11-hydroxylase. Unknown mechanism of action but inhibits adrenal steroidal action Hydration must be maintained with IV intravenous saline. This will prevent severe hypercalcaemia. Once volume status is normal use bisphosphonates Bind to hyrdoxyapatite crystals and reduce bone resorption.

abdominal cramping pain. Dizzyness, drowsyness nausea and vomiting. Hypernaetremia

Bisphosphonates

Alendronate Etidronate Hypocalaemia Commonest cause is Vit D deficiency Calcium Calcica Supplements Osteocare Vitamin D analogue Ergocalciferol Vit D2 Cholecalciferol Vit D3 Alfacalcidol 1hydroxyvitamin D Calcitriol 1,25 Dihydroxy D Teriparatide

Hypercalcaemia

GI upset, Erosion of Oesophagus Hypercalcaemia Stomach pain Diarrhoea Hypercalcaemia

Hypocalaemia

Hypocalcaemia Vit D deficiency

Vitamin D analogues allow absorption of calcium from the gut.

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 Phenoxybenzamine An irreversible antagonist is used to Tumours of adrenal medulla Reflex tachycardia antagonist Labetalol block the a-effects of the large amounts Doxazosin of catecholamines from tumours of the adrenal medulla. Phentolamine Prazosin Tamsulosin Terazosin Recombinant PTH analogue Hypocalcaemia Hypoparathyriodism Stimulates bones resorption, Kindey to re absorb calcium, stimulates production of 1.25 Dehydroxyvit D at kidney. b-blockers Atenolol (see above) Conns excess production of aldesterone Aldosterone receptor Spironolactone (see blockers above) Eplernone Postassium Sparing Diuretic Amiloride Triamterene Conns Liver disease with ascites Potassium sparing diuretic Conns Blocks the binding of aldosterone to its receptor and increases the excretion of Na+ and decreases the electrically coupled K+ secretion. 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 Hyperkaleamia Painful Gyanocamastia Severe Hyperkalaemia

Zero Order Kinetics

Common drugs Phenytoin, 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 Lamatrogine Lamatrogine and Valpraote have Lamatrogine Blurred Sodium Valproate similar mech of action as Phenytoins vision dizziness and discussed below. Valproate also seems drowsyness. Serious skin to in increase GABAergi central reactions can occur inhibition mechanisms that may involve especially in children. stimulation of glutamic acid Valproate - Nausea, weight decarboxylase activity and/ or inhibition gain, bleeding tendencies of GABA-T activity. and transient hair loss). The main disadvantage is that occasional idiosyncractic reactions cause sever or fatal hepatic failiure. Focal Epilepsy Carbamazepine Phenytoins anticonvulsant action is Carbamazepine is Phenytoin probably a result of its ability to prevent metabolised in the liver to high frequency repetitive activity. carbamzepine-10,11Phenytoin binds prerentially to epoxide, an active inactivated (closed) Na+ channels metabolite that partly stabilizing them in the inactivated state contributes to both its antiand preventing them from returning to convulsant action and the resting closed state which they must neurotoxicity. In contrast to do before they can open again. High phenytion there is a linear freuquency repetitive depolarisation increase in serum increases the proportion of Na+ concentration with dosage. channels in the inactivated state and, Mild neurotoxic effects are because these are susceptible to common (nausea dizziness blockade by phenytoin, the Na+ is drowsyness, blurred vision progressively reduced until it is and ataxia) Agranulocytosis eventually insufficient to evoke and is a rarer idyiosyncratic action potential. Neruonal transmission reaction. at normal frequencies is relatively Phenytoin is hyroxylated in unaffected by phenytoin because a the liver by a saturable smaller portion of the Na+ channels are enzyme system. The rate of in the inactivated state. Carbamazepine, metabolism varies greatly in lamotrigine, valproate, and topiramate. patients. And up to 20 days Have similar actions on neuronal Na+ maybe required for the channels. 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,

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. 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 Levodopa is the immediate precursos of Parkinsons Nausea and vomiting Madopar dopamine and is able to penetrate the caused by stimulation of the Both these drugs come brain where it is converted to dopamine. CTZ. with extracerebral The site of the decarboyxlation is Psych effects vivid dreams, decarboxylase inhibitors) uncertain, but as dopa decarboxylase is hallucinations, psychotic no rate limiting there maybe sufficient states and confusion. enzyme in the remaining dopaminergic Postural hypotension is nerve terminals. Another possibility is common. that the conversion occurs in nor Dyskinesias (jerky or dance adrenergic or seratonergic terminals. like movement) are an Because the de-carboxylase activity in important adverse effect. these neurones is not specific. 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 Absence Epilepsy in Children Ethosuximide Sodium Valproate

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. Ethosuximide- Nausea vomiting.

Dopamine Receptor Agonists

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

Parkinsons Prolactinomas

Pre Synaptic ReUptake inhibitor Monamine oxidase inhibitor type B (MAO-B)

Amantadine

Parkinsons

Selegiline

Parkinsons

COMT inhibitors

Entacapone Benzarazide

Parkinsons

Antimuscarinics

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 Prydostigmine Most widely used drug; it has a duration Myaesthenia gravis Overdose causes a acetycholinesterase of about 3-5 hours. Patients response cholinergic crisis with will determine the dose required. Great severe weakness. Colic and symptomatic drug but does not alter the diarrhoea may occur. natural history of the disease. Motor neurone disease Riluzole Rilutek Used to treat amyoptrophic lateral MND Nausea

Benzetropine Procyclidine Orphenadrine Benzhexol

Parkinsons

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. Potentiates dopamine by preventing reuptake in the pre-synaptic terminals. Moderate effect but toleranc soon develops 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. Inhibbits catechol-O-methltransferase (COMT) and prevents peripheral conversion of Levodopa to (inactive) 3O-methyldopa. It increases the plasma half life of levodopa and increases its action. Produce a modest iimprovement in the early stages of parkisons disease, but the akinesia responsible for most of the functional disability responds least well.

appear and, with time rapid oscillations in mobility and dyskinesias. Nausea, psychiatric symptoms, postural hypotension. Pulmonary fibrosis and retroperitoneal fibrosis. Apomorphine (highly emetogenic) domperidone should be given before treatment started.

Dizzyness, Loss of coordindation, inability to sleep, nausea, nervousness Nausea Heartburn Dry mouth

Drowsyness Dizzyness Stomach upset Diarrhoea

sclerosis. Delays the onset of ventilator Fatigue dependence or tracheostomy by 2 Hepatitis months. 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) Either high-dose intravenous Guillen Barres Hepatitis immunoglobulins immunoglobulins (IVIg) at 400mg/kg for Renal failure 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). 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, Reduce aqueous secretion by inhibitory Glaucoma Ocular irritation betaxolol, levobunolol action on beta adrenoreceptors in the Bronchospasm cilliary body. Bradycardia Nightmares Exacerbation of hear failure Muscarinic Pilocarpine (also a Increase aqueous outflow via trabecular Glaucoma Ocular: Misosis (reduced (parasympathetic) differential for bilateral meshwork by ciliary muscle contraction vision in the presence of a simulates . constricted pupils!) cataract) spasm of accommodation, brow ache Systemic: Swaeting, bradycardia, GI disturbance Alpha2-stimulants Brimonidine, Reduces aqueos secretion by selective Glaucoma Ocular: Iris darkening, Topical Apraclonidine stimulation of alpha2 and conjunctival hyperaemia, adrenocrecptors in the ciliary body eyelash growth. increase outflow by the uveoscleral route Systemic: bitter taste, asthma. Carbonic Anhydrase Acetazolamide Reduce aqueous secretion by the cilliary Glaucoma Ocular route: irritation and Inhibitors (systemic) body allergy Dorzolamide, Systemic route: Malaise, Brinzolamide paraesthesia, urea and electrolye disturbance, aplastic anaemia Mydriatics and cycloplegics ( Used for retinal examination and objective refraction (retinoscopy) Antimuscarinics Tropicanamide, Inhibit muscarinic receptors of Eye dilation for exam Ocular: Blurred vision, cyclopentolate, atropine. parasympathetic nervous system to glare, angle closure paralyse papillary sphincter and ciliary

muscle. Alpha-stimulant Phenylephrine Eye dilation for exam Stimulates dilator muscle of the pupil no cycloplegic effect.

Lubricants There are a wide range Carbomers, Exact mechanism depends on the agent Dry eye hyrpmellose, polyvinyl alcohol, liquid paraffin Ant-Inflammatory Agents. Most important drugs are corticosteroids, a Variety of other drugs are available including systemic immnosuppressants Corticosteroids Prednisolone, Suppresion of broad spectrum of Suppress Inflammation betamethasone, inflammatory processes (see dexamethasone corticosteroids)

glaucoma. Systemic: Tachycardia, dry mouth, confusion, tremor. Ocular: Blurred vision, glare, angle closure, glaucoma, conjunctival blanching. Systemic hypertension Ocular: Allergy, blurred vision 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. Occular: Irritation

Cromoglicate, Stabilise mast cells Allergy nedocromil, lodoxamide. Anti-histamines Topical: Antazoline, Block histamine receptor Allergy Occular route: Irritation azelastine, Sytemic route: Drowsiness levocabastine. Systemic (chlorphenamine, terfendaine, cetirisine) NSAIDS Topical: (ketorolac, Modulate prostaglandin production. Eye inflammation Systemic: Peptic ulceration, diclofenac, fluribiprofen) 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: Range of activities and specificities Bacterial Infection Vary with agent Chloramphenicol, Ocular: allergy; corneal gentamicin, toxicity common with ciprofloxacin, intensive use. Neomycin, fusidic acid. Systemic: generally only Occassionally intrawith systemic use. ocular, systemic Antivirals Aciclovir, topical or Inhibits herpes virus DNA synthesis Herpes simplex, zoster Ocular: blurred vision, systemic corneal toxicity Systemic: Rashes: kidney, liver and other effects may Mast cell stabilisers

occur with systemic use. Local Anaesthetics: Major uses are to relieve pain and thereby assist with clinical examination and the facilitation of surgical anaesthesia Local anaesthesia Topical or peri-ocular Block conduction along the nerve fibres Clinical exam injection. Oxyburprocaine, proxymetacaine. Tetracaine, lidocaine. Ocular: Irritation, corneal toxicicty. Systemic: generally accidental intravascular or intrathecal (cerebrospinal fluid) injection. During surgical anaesthesia, cardiac arrythmmias, respiratory depression Dependant on treatment sitee.e.g unwanted ptosis or double vision

Botulinum toxin: Used in the management of certain ocular motility disorders amd blepharospasm, and to induce ptosis for corneal protection Botulinum toxin Injection at site of action Prevents release of the neuro Motility disorder transmitter acetycholine at neuromuscular junctions Migraine Pizotifen Serotonin Antagonist Migraine 5HT Sumatriptan Acute Serotonin Antagonist Migraine Migraine 5HT Methysergide Long Serotonin Antagonist Migraine term migraine 5HT Urinary Tract Infection Trimethoprim E.coli, proteus, saprophiticus. UTI

NOT used in pregnancy Use nitrofurentoin instead or amoxicillin Used in pregnancy

Amoxicillin

UTI

Diazoxide Blocks insulin release Insulinoma Teriparatide PTH analogue Hypocalaemia 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 actionCortisol 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 effect s. 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 mechanisms Circulating 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 (iI)s used orally for replacement (ii) intra Anti Inflamm Moon face, fat to trunk and venously in shock and status face, purple striae, asthmaticus and (iii) topically (e.g. hirsutism,acne, infections ointments in eczema enemas in Osteoporosis, bruise skin, ulcerative colitis diabetes, hypercalaemia, Fluid retention, hypokalaemia. Prednisolone Corticosteroid Is the most widely used drug driven Anti Inflamm A s above orally in inflammatory and allergic diseases. Betamethasone and Corticosteroid Are very potent and have so salt Anti Imflamm As above Dexamethasone retaining actions. This makes them especially useful for high dose therapy in conditions, such as cerebral oedema where water retention would be a disadvantage. Beclometasone and Corticosteroid Pass membranes poorly and are more Anti Inflamm As above Budesonide 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. Triamcinolone Corticosteroid Used in sever asthma and by intra Anti Inflamm As above articular injection for local inflammation of the joints.

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 analgesic Paracetamol is just analgesic