DRUG ACE inhibitors
EXAMPLES Ramipril, Lisinopril
• • •
USES Hypertension Heart Failure Post MI
Beta-Blockers
Calcium Channel Blockers
Atenolol, Propanolol
• • • •
Hypertension Angina Arrhythmias Stable heart failure
Dihydropines – Amlodipine, Phenyalkylamin es Verapamil, Benzthiazepine sDiltiazem Bendrofluazide, hydrochlorothiazi de
• • •
Hypertension Angina Supraventricular arrhythmia – (Phenylalkylamines only)
Vasodilation block cellular entry of Ca+ by preventing opening of voltage-gated L-type and Ttype calcium channels
• •
Hypertension Combined with loop for Heart Failure
Loop Diuretics
Frusemide, Bumetanide
•
Potassiumsparing diuretics
Spironolactone, Amiloride
Hypertension (but less effective than thiazides – used when renal impairment or resistant to multiple drug Tx) Heart Failure Secondary Hypertension Severe heart Failure
Thiazide Diuretics
• • •
MECHANISM Block ATIATII by binding to the site on the enzyme that normally accommodates the terminal leucine of ATI. Inhibits vasoconstriction.
SIDE EFFECTS Hypotension Dry cough (increased bradykinin) • Renal failure in pts with bilateral renal stenosis block β -adrenergic receptors inhibiting • Provocation of the asthma, heart effects of adrenaline and nonadrenaline. failure. β 1 (heart) blockage decreases HR• Cold hands and • Bradycardia contractility, β 2 (bronchial and fatigue vascular smooth muscle) blockage causes vasodilation. • •
• • • • •
Flushing, headache, P.oedema Phenyalkylamines – can worsen heart failure Gynaecomastia Impotence
increase water excretion by decreasing reabsorption of Na+ and Cl- in the distal tubule by binding to the Clsite 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.
• • • • •
Hypokalaemia Hyponatraemia Hypotension Gout Type II DM
• • • •
Hypokalaemia Hyponatraemia Hypotension Gout
Blocks action of aldosterone in distal convoluted tubule – diuretic effect
• • •
Hypokalaemia Hyponatraemia Abdominal discomfort
Angiotensin II receptor antagonists
Losarten, Valsarten
• •
Alphaadrenorecepto r antagonists
Doxazosin, Prazosin
•
Hypertension Alternative to ACE inhibitor in heart failure Hypertension (in addition to other hypertensives)
Vasodilation – by inhibition at the angiotensin II receptor
• •
Usually mild No cough like in ACE inhibitors
Reduces peripheral resistance by inhibiting α 1adrenoreceptor-mediated vasoconstriction.
•
Postural Hypotension Dizziness
•
Fibrinolytics
•
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.
•
Haemorrhage
Clopidogrel
•
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. Inhibits activation of the glycoprotein IIb/IIIa receptor on the surface of platelets which is required for aggregation to occur.
•
Haemorrhage
Anticoagulants Warfarin
•
Prophylaxis+treatme nt DVT, PE Prophylaxis 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. Prevention of cardiovascular disease
Activates antithrombin III, which limits blood clotting by inactivating thrombin and factor X. 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. 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
•
Haemorrhage
•
Myopathy (muscle ache) Disturbed LFTs Abdominal pain
Statins
Nitrates
Potassium channel activators
Streptokinase
Atorvastatin, Simvastatin, Pravastatin
• •
Glyceral trinitrate (GTN), Isosorbide mononitrate
•
Nicorandil (only licensed one)
•
•
Prophylaxis and Treatment of angina. LVF
Prophylaxis of angina
• •
• • • • •
Postural hypotension Tachycardia Headache Flushing Dizziness
•
Headache
causing K+ to flow out of cells causing hyperpolarization. This therefore inhibits influx of Ca2+ and so inhibits contraction. Antiarrythmics Class Ia
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.
Quinidine, Disopyramide, Procainamide
• •
VT WPW
Lignocaine, Mexiletine, Phenytoin
•
Ventricular arrythmi, especially VT
Class Ic
Flecainide
• •
Pre-excitation AF cardioversion of paroxsms,AVNRT ,AVRT, WPW, AF , AT , NSVT (nonsustained VT)
Marked Na2+ channel blockage ↑refractory period, no effect on the duration of the action potential.
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
•
Class Ib
• •
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
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 Intracellular Ca2+ overload – junctional escape beats, junctional
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
Atropine
•
• • •
Supraventricular arrythmias
Sinus bradycardia AV block Cardiopulmonary resuscitation
Potent effect on SA node producing sinus bradycardia. Slows impulse conduction through the AVN but has no effect on conduction in the ventricles. 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.
• • •
• • •
tachycardia, ventricular ectopic beats, VT. Increased vagal activity can cause AT with 2:1 AVN block GI disturbances Neurological disturbances Gynaecomastia Bradycardia and AV block Malaise, flushing, headache chest pain, bronchospasm 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 • IV for (onset 30 mins, peak hyperglycaemic activities 2-4hrs, subsides by emergencies. 8hrs) • Subcutaneous If IV effects only last 30 injection minutes. Insulin lispro Humalog and Insulin analogues have a • Blood glucose • Hypoglycaemia and Insulin Novorapid faster onset and shorter control
aspart (Rapid Acting)
Intermediate and Long Acting Insulin (duration of action between 16-35 hours) Semilente • (amorphous insulin zinc) Lente Humulin L or • Monotard
Isophane Insulin (NPH)
Insulatard
•
Biphasic fixed mixtures
Human mixed (short- and 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 ultra-
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
Blood glucose control
Suspension of amorphous insulin zinc.
•
Hypoglycaemia
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) 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 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 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
•
Hypoglycaemia
•
Hypoglycaemia
•
Hypglycaemia
short and intermediateacting 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 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 • Type 2 diabetes • Lactic acidosis rare Only diabetic action of metformin is and limited to those • PCOS drug that reduces uncertain. It appears to act with impaired liver • Non Alcoholic fatty cardiovascular mainly by reducing hepatic of kidney function. liver disease risks. gluconeogenesis, it also • GI upset diarrhoea, It reduces weight. decreases absorption of vomiting cramps. 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
'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 AMPactivated 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
Glitazones
Glipizide (short half life) Glicazide (short half life) Glibenclamide (longer duration of action) Tolbutamide.
•
Rosiglitazone and Pioglitazone
•
Type II diabetes (people with ideal weight)
Type II diabetes given alone or in combination with metofrmin or sulphonyreas in patients who cannot tolerate metformin or sulphonyreas combinations.
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
• • • • •
• • •
GI disturbance Rashes Hypoglycaemia Hypoglycaemic coma Contraindicated in severe hyperglycaemia, surgery and major illness Weight gain Fluid retention Contraindicated in pregnancy
insulin sensitive genes. a- Glucosidase inhibitors
Acarbose
Inhibits intestinal a• Flautlence glycosidases, delaying the • Diarrhoea digestion of starch and • Abdominal Pain sucrose. It is taken with meals and 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 Bromocriptine Stimulates dopamine • Prolactinoma • Nausea agonist drugs (ergot derivative) receptors in the brain. • Acromegaly • Psyhchiatric Cabergoline Symptoms • Hypogandism • Postural • Galactorrhea 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 Somatuline Somatostatin analogue. • Acromegaly • Gallstones analogues Autogel Inhibits the production of GH. • Conratindicated in Sandostatin LAR liver and kidney Ocreotide failure, diabetes mellitus, Insulinoma. Diabetes Insipidus (no ADH produced so leads to excretion of large volumes of isotonic water) ADH analogue Desmopressin Desmopressin is preferred to • Diabetes Insipidus • Water retention (nasal spray, vasopressin because it is a • Hyponatremia tablets, or longer acting analogue. Make • Contraindicated in subcutaneous sure to reduce fluid intake. heart failure, people injection) 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 • Hypothyroidism • Concomitant treatment of choice. conditions Synthetic T4 is the sodium worsened by salt of levothyroxine (Lthyroxine therapy. thryoxine). Its effects are Heart disease, heart delayed until the plasma failure, infarction, protein and tissue binding angina, chronic lung sites are occupied. disease, Treatment is assessed by breathlessness, •
Type II diabetes
monitoring TSH levels, which adrenal disease. fall to normal when optimum Due to increase in dose is achieved. Daily dose oxygen demand of 100 and 150ug best take on most tissues as well waking. as myocardium Liothyronine Is the sodium salt of T3 and • Hypothyrioidism • See above 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. 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 • Hyperthyroidism • Rashes methimazole in vivo • Agranulocytosis Once daily doses, 40mg for 1 • Patients should month, then 30mg for 1 report a sore month, 20mg for 1 month throat! and then 10 mg daily until reassessed.. Onset of action 3-4 weeks Thionamides Possess a thiocarbamide • Hyperthyroidism • ? group that is essential for immunosuppressive 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 • Hyperthyroidism • ?immunosupressive intolerant of carbimazole. Also inhibits the peripheral deiodination of t4 Iodides Have poorly understood • Hyperthyroidism • Skin rashes actions on the thyroid. They • Nausea inhibit organification and and • Vomiting hormone release. In addition • Allergic reaction. iodide decreases the size and vascularity of the 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. • Addisons • Moon face If acutely sick! • Striae Take blood cortisol glucose • Fat redistribution urea and electrolytes. Give • Hirsutsim hydrocortisone 100mg as IV • Infection bolus. Give saline infusion • Proximal muscle litre initially over 4-6 hours. wasting Correct hypoglycaemia iwth • Bruising IV bolus of 20% glucose.
Synthetic Aldosterone
Fludrocortisone
•
Addisons
Cushings Syndrome Excess production of cortisol
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 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
Ketoconazole
Well absorbed orally, wide spectrum anti fungal drug which has adrenal suppression effects Metirapone Metyrapone blocks cortisol • Cushings synthesis by inhibiting steroid 11β-hydroxylase. Mitotane Unknown mechanism of • Cushings action but inhibits adrenal • Adrenal adenoma steroidal action Hyperparathyroidism and Malignancy account for 90% of Hypercalcaemia Rehydration IV Saline Hydration must be • Hypercalcaemia maintained with IV intravenous saline. This will prevent severe hypercalcaemia. Once volume status is normal use bisphosphonates Bisphosphona Alendronate Bind to hyrdoxyapatite • Hypercalcaemia tes Etidronate crystals and reduce bone resorption. Hypocalaemia Commonest cause is Vit D deficiency Calcium Calcica • Hypocalaemia Supplements Osteocare Vitamin D analogue
Recombinant PTH analogue
• •
Ergocalciferol Vit D2 Cholecalciferol Vit D3 Alfacalcidol 1hydroxyvitamin D Calcitriol 1,25 Dihydroxy D Teriparatide
• •
Cushings Anti fungal
Hypocalcaemia Vit D deficiency
Vitamin D analogues allow absorption of calcium from the gut.
• •
Hepatic necrosis Adrenal suppression
•
Nausea vomiting, abdominal cramping pain. Dizzyness, drowsyness nausea and vomiting.
•
•
Hypernaetremia
•
GI upset, Erosion of Oesophagus
• • • •
Hypercalcaemia Stomach pain Diarrhoea Hypercalcaemia
Stimulates bones resorption, • Kindey to re absorb calcium, • stimulates production of 1.25 • Dehydroxyvit D at kidney. Phaeochromocytoma Neoplasm of the adrenal medulla. 10% are malignant, 10% are extra-adrenal, 10% are familial. Blockage of adreno receptors must be started first. aPhenoxybenzami An irreversible antagonist is • Tumours of adrenal • adrenorecepto ne used to block the a-effects of medulla r antagonist Labetalol the large amounts of catecholamines from Doxazosin Phentolamine tumours of the adrenal Prazosin medulla. Tamsulosin Terazosin • •
Hypocalcaemia Hypoparathyriodism
Dizzyness Leg Cramps Nausea are bilateral, 10% Reflex tachycardia
b-blockers
Atenolol (see • above) Conns excess production of aldesterone Aldosterone Spironolactone • Conns receptor (see above) • Liver disease with blockers Eplernone ascites
Postassium Sparing Diuretic
Zero Order Kinetics
Amiloride Triamterene
• •
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
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 Lamatrogine Lamatrogine and • • Lamatrogine – Epilepsy Sodium Valproate Valpraote have similar Blurred vision mech of action as dizziness and Phenytoins discussed drowsyness. Serious below. Valproate also skin reactions can seems to in increase occur especially in GABAergi central inhibition children. mechanisms that may • Valproate - Nausea, involve stimulation of weight gain, glutamic acid decarboxylase bleeding tendencies activity and/ or inhibition of and transient hair GABA-T activity. loss). The main disadvantage is that occasional idiosyncractic reactions cause sever or fatal hepatic failiure.
Focal Epilepsy
Carbamazepine Phenytoin
•
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 carbamzepine10,11- 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
Absence Epilepsy in Children
Ethosuximide Sodium Valproate
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. EthosuximideNausea vomiting.
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 • Parkinsons • Nausea and Madopar precursos of dopamine and is vomiting caused by Both these drugs able to penetrate the brain stimulation of the come with where it is converted to CTZ. extracerebral dopamine. The site of the • Psych effects vivid decarboxylase decarboyxlation is uncertain, dreams, inhibitors) but as dopa decarboxylase is hallucinations, no rate limiting there maybe psychotic states sufficient enzyme in the and confusion. remaining dopaminergic • Postural nerve terminals. Another hypotension is possibility is that the common. conversion occurs in nor • Dyskinesias (jerky adrenergic or seratonergic •
terminals. Because the decarboxylase activity in these neurones is not specific. •
Dopamine Receptor Agonists
Pre Synaptic Re-Uptake inhibitor
Bromocriptine (ergot derivative) Ropinirole (non ergot derivative) Apomorphine (very powerful given by parenteral administration)
• •
Amantadine
•
Parkinsons Prolactinomas
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 re-uptake in the pre-synaptic terminals. Moderate effect but toleranc
• • •
•
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. Nausea, psychiatric symptoms, postural hypotension. Pulmonary fibrosis and retroperitoneal fibrosis. Apomorphine (highly emetogenic) domperidone should be given before treatment started.
Dizzyness, Loss of co-ordindation, inability to sleep, nausea,
soon develops nervousness Inhibits monoamine oxidase • Nausea type B (MAO-B) there by • Heartburn increasing dopamine. This is • Dry mouth 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. COMT Entacapone Inhibbits catechol-O• Parkinsons • Drowsyness inhibitors Benzarazide methltransferase (COMT) and • Dizzyness prevents peripheral • Stomach upset conversion of Levodopa to • Diarrhoea (inactive) 3-O-methyldopa. It increases the plasma half life of levodopa and increases its action. Antimuscarini Benzetropine Produce a modest • Parkinsons • Dry mouth cs Procyclidine iimprovement in the early • Urinary retention Orphenadrine stages of parkison’s disease, and constipation. Benzhexol but the akinesia responsible • Effect memory and for most of the functional concentration. disability responds least well. 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 • Myaesthenia gravis • Overdose causes a acetycholinest a duration of about 3-5 cholinergic crisis erase hours. Patients response will with severe determine the dose required. weakness. Colic and Great symptomatic drug but diarrhoea may does not alter the natural occur. history of the disease. Motor neurone disease Riluzole Rilutek Used to treat amyoptrophic • MND • Nausea lateral sclerosis. Delays the • Fatigue onset of ventilator • Hepatitis dependence or tracheostomy by 2 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 Monamine oxidase inhibitor type B (MAO-B)
Selegiline
•
Parkinsons
immunoglobul ins
immunoglobulins (IVIg) at • Renal failure 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). 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 • Glaucoma • Ocular irritation betaxolol, inhibitory action on beta • Bronchospasm levobunolol adrenoreceptors in the • Bradycardia cilliary body. • Nightmares • Exacerbation of hear failure Muscarinic Pilocarpine (also Increase aqueous outflow via • Glaucoma • Ocular: Misosis (parasympath a differential for trabecular meshwork by (reduced vision in etic) bilateral ciliary muscle contraction the presence of a simulates . constricted cataract) spasm of pupils!) accommodation, brow ache • Systemic: Swaeting, bradycardia, GI disturbance Alpha2Brimonidine, Reduces aqueos secretion by • Glaucoma • Ocular: Iris stimulants Apraclonidine selective stimulation of darkening, Topical alpha2 and adrenocrecptors conjunctival in the ciliary body increase hyperaemia, outflow by the uveoscleral eyelash growth. route • Systemic: bitter taste, asthma. Carbonic Acetazolamide Reduce aqueous secretion by • Glaucoma • Ocular route: Anhydrase (systemic) the cilliary body irritation and allergy Inhibitors Dorzolamide, • Systemic route: Brinzolamide Malaise,
paraesthesia, urea and electrolye disturbance, aplastic anaemia Mydriatics and cycloplegics – ( Used for retinal examination and objective refraction (retinoscopy) Antimuscarini Tropicanamide, • Eye dilation for exam Inhibit muscarinic receptors cs cyclopentolate, of parasympathetic nervous atropine. system to paralyse papillary sphincter and ciliary muscle.
Alphastimulant
Phenylephrine
•
Eye dilation for exam
Stimulates dilator muscle of the pupil no cycloplegic effect.
• •
•
• Lubricants – There are a wide range Carbomers, • hyrpmellose, polyvinyl alcohol, liquid paraffin Ant-Inflammatory Agents. Most important immnosuppressants Corticosteroid Prednisolone, • s betamethasone, dexamethasone
Dry eye
Exact mechanism depends on the agent
•
Antihistamines
Cromoglicate, nedocromil, lodoxamide. Topical: Antazoline, azelastine, levocabastine.
Ocular: Allergy, blurred vision
drugs are corticosteroids, a Variety of other drugs are available including systemic Suppress Inflammation
Suppresion of broad spectrum of inflammatory processes (see corticosteroids)
•
•
Mast cell stabilisers
Ocular: Blurred vision, glare, angle closure glaucoma. Systemic: Tachycardia, dry mouth, confusion, tremor. Ocular: Blurred vision, glare, angle closure, glaucoma, conjunctival blanching. Systemic hypertension
•
Allergy
Stabilise mast cells
•
•
Allergy
Block histamine receptor
• •
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 Occular route: Irritation Sytemic route: Drowsiness
Systemic (chlorphenamine, terfendaine, cetirisine) NSAIDS Topical: • Eye inflammation (ketorolac, diclofenac, fluribiprofen) Anti-Infective agents: Topically applied antibacterial and antiviral and antiparastic agents is much less frequent. Antibacterials Topical: • Bacterial Infection Chloramphenicol, gentamicin, ciprofloxacin, Neomycin, fusidic acid. Occassionally intra-ocular, systemic • • Antivirals Aciclovir, topical • Herpes simplex, or systemic zoster
Modulate prostaglandin production.
•
Systemic: Peptic ulceration, asthma.
drugs are very commonly prescribed. The use of antifungal Range of activities and specificities
• •
•
Inhibits herpes virus DNA synthesis
• • •
Vary with agent Ocular: allergy; corneal toxicity common with intensive use. Systemic: generally only with systemic use.
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 anaesthesia Local Topical or periBlock conduction along the • Clinical exam • Ocular: Irritation, anaesthesia ocular injection. nerve fibres corneal toxicicty. Oxyburprocaine, • Systemic: generally proxymetacaine. accidental Tetracaine, intravascular or lidocaine. 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 protection Botulinum Injection at site of Prevents release of the • Motility disorder • Dependant on
toxin Migraine Pizotifen Sumatriptan Acute Migraine Methysergide Long term migraine Urinary Tract Infection Trimethoprim
action
neuro-transmitter acetycholine at neuromuscular junctions
treatment sitee.e.g unwanted ptosis or double vision
Serotonin Antagonist 5HT Serotonin Antagonist 5HT Serotonin Antagonist 5HT
•
Migraine
•
•
Migraine
•
•
Migraine
•
E.coli, proteus, saprophiticus.
• •
• UTI
• •
Amoxicillin
•
UTI
•
NOT used in pregnancy Use nitrofurentoin instead or amoxicillin Used in pregnancy
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 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 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. Hydrocortison Coritcosteroid (iI)s used orally for • Anti Inflamm • Moon face, fat to e replacement (ii) intra trunk and face, venously in shock and status purple striae, asthmaticus and (iii) topically hirsutism,acne, (e.g. ointments in eczema infections enemas in ulcerative colitis • Osteoporosis, bruise skin, diabetes, hypercalaemia, • Fluid retention, hypokalaemia. Prednisolone Corticosteroid Is the most widely used drug • Anti Inflamm • A s above driven orally in inflammatory and allergic diseases. Betamethason Corticosteroid Are very potent and have so • Anti Imflamm • As above e and salt-retaining actions. This Dexamethaso makes them especially ne useful for high dose therapy in conditions, such as cerebral oedema where water retention would be a disadvantage. Beclometason Corticosteroid Pass membranes poorly and • Anti Inflamm • As above e and are more active topically Budesonide 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 • Anti Inflamm • As above intra 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 • • • •
