Therapeutics Study Notes

Therapeutics Cardiology pg2 NSAID (aspirin) Thrombolytics (streptokinase) Cardiac glycosides (digoxin) Thiazide diuretics (bendrofluazide) Loop diuretics (frusemide) Nitrates (GTN, isosorbide) Potassium channel activators (nicorandil) ACEi’s (captopril) Beta Blockers (atenolol) Calcium channel blockers (diltiazem, nifedipine, verapamil) Alpha blockers (Doxazosin) HMG Co-A reductase inhibitors (simvastatin) Anticoagulants (heparin, warfarin) Respiratory pg8 Short & long acting B2 agonists (salbutamol, salmeterol) Anticholinergics (ipratropium bromide) Methylxanthines (aminophylline) Inhaled and oral steroids (prednisolone, budesonide) Oxygen Endocrine pg11 Insulin (soluble, isophane, lente) Sulphonylureas (glicazide) Biguanides (Metformin) Alpha-glucosidase inhibitors (acarbose) Glitazones (rosiglitazone) Thyroid (carbimazole, thyroxine) Steroids (hydrocortisone, fludrocortisone) Gastrointestinal disease pg15 Antactids (gaviscon) Motility stimulants (metoclopromide) H2-receptor blockers (cimetidine) PPI (omeprazole) Helicobacter therapy (clarithromycin, metronidazole) Aminosalicylates (mesalazine) Local and systemic steroids (colifoam, predsol, prednisolone) Neurology pg18 Antiepileptics (phenytoin, Carbemazepine, sodium valproate) Dopamine agonists (levodopa, carbidopa, bromocriptine) Antibiotics pg20 Resp infections TB UTIs Biliary infections Divertculitis Surgical wound infections Cellulitis Bacterial meningitis Infective endocarditis Anaesthesia pg26 Local anaesthetics (lignocaine, bupivicaine, EMLA) Opioids (morphine, diamorphine, codeine) Simple analgesia (paracetamol, ibuprofen, diclofenac) Benzodiazepines (diazepam, temazepam, midazolam) Antiemetics (ondanzetron, cyclizine, prochlorperazine) Anticholinergics (atropine, glycopyrrolate) Sympathomimetics (adrenaline, ephedrine) Therapeutics 1 Cardiology • Aspirin Action – irreversible COX inhibitor à inhibition of PG (TXA 2) synthesis. Platelets have no DNA so cannot synthesize new COX. Effects of aspirin last until new platelets produced (approx 10 days). Dose – 300mg single dose after ACS, 75mg od as antiplatelet prophylaxis Indications – prophylaxis of cerebrovascular disease or MI Cautions – asthma, uncontrolled hypertension, previous peptic ulceration, hepatic or renal impairment, pregnancy Contraindications – under 16’s (à Reye syndrome), active peptic ulcer, haemolphilia and other bleeding disorders, breast feeding Side effects – bronchospasm, GI haemorrhage Ulcerogenic effects of NSAIDS ¼ of ulcers are associated with NSAIDs NSAIDs are irreversible cox inhibitors Steroids have similar effect by à lipocortin à inhibiting PLA2 NB: ibuprofen is preferable to aspirin as analgesic as fewer side effects 2 forms of COX COX1 = physiological à gastric protection COX2 = pathological à inflammation Most NSAIDs inhibit both enzymes COX2 selective e.g. clopidogrel have fewer GI side effects • Thrombolytics (streptokinase) Of greatest benefit <12hrs (can be used upto 24hrs) Indications (within 12 hrs) • ST elevation >2mm in > chest leads • ST elevation >1mm in > limb leads • Posterior infarct (dominant R & ST depression in V1-V3) • New LBBB • Continuing chest pain or ST elevation (12-24hrs) Contraindications • Internal bleeding (inc prolonged CPR) • Suspected aortic dissection • Previous allergic reaction • Heavy PV bleed / Pregnant / <18 weeks PN • Acute Pancreatitis • Severe lung disease / active lung disease with cavitation • Oesophageal varices • Recent trauma/surgery (<2 weeks) • Cerebral neoplasm • Severe hypertension (>200/120 Relative contraindications • Peptic ulcer • History of CVA • Bleeding diathesis • Anticoagulated • Cardiac glycosides (digoxin) DIGOXIN - from foxglove (digitalis) Therapeutics 2 Action – cardioactive steroid. Affects Na+/K+/ATPase à increase in intracellular Na+ à increase in intracellular Ca2+ à +ve ionotropic effect à enhances vagal inhibition of Sinus node & AV node conduction. è 3 main effects +ve ionotrope Decreases ventricular rate in AF / flutter (decreases AV conduction) Increased myocardial automaticity in high (toxic concentrations) NB:NARROW therapeutic range. NB: Effects worsened by low K (NB: beware if used with non K sparing diuretic). Excreted by kidney (Ouabain eliminated by liver) Indications – heart failure, supreventricular arrhythmias (esp AF) Cautions – recent infarct, sick sinus syndrome, reduce dose in elderly, avoid hypokalamia or hypomagnesaemia, beware renal impairment, pregnancy Contra-indications – intermittent complete heart block, 2nd degree AV block, WPW syndrome, VF / VT, hypertrophic cardiomyopathy Side effects – usually if high dose. Anorexia, N, V & D, abdo pain, visual disturbance, headache, fatigue, drowsiness, dizziness, heart block • Thiazide diuretics (bendrofluazide) Thiazides (act on early distal tubule) à K+ loss due to Na+/K+ Cheap & widely used pump in distal tubule Bendroflumethiazide – 2.5mg is optimal dose in most BUT not all Na+ reabsorbed à patients low Na+ à H2O loss Non K+ sparing Action - Block Na+/Cl- cotransport in early distal tubule. Also act as vasodilators systemically è lower BP. Take effect within 1-2 hrs of administration. Indications – oedema, hypertension Cautions – renal & hepatic impairment, monitor electrolytes if concerned. May exacerbate DM, gout, or SLE. Pregnancy and breast feeding Contraindications – refractory hypokalaemia, hyponatraemia, hypercalcaemia, symptomatic hyperuricaemia, Addisons disease Side effects – postural hypotension, mild GI effects, impotence, effects on electrolytes. • Loop diuretics (frusemide) Frusemide – 40mg Action - Act on the thick ascending limb. Inhibit Na+/2Cl-/K+ pump à decrease concentration of fluid at tip from 1200 to 500 mosmol / kg à decrease H2O reabsorption & increase urine production Non K+ sparing Very potent & short acting (frusemide used to clear fluid from lungs in CCF) Act within 1 hour of administration Indications – oedema (pulmonary) and heart failure. Occasionally used for hypertension Cautions – hypotension, prostatic enlargement, renal impairment, hepatic impairment, pregnancy Contraindications – renal failure with Anuria, liver cirrhosis Side effects – hyponatraemia, hypokalaemia, hypomagnesaemia, hypotension, some GI disturbance, hyperuricaemia, gout • Nitrates (GTN, isosorbide) Nitrates GTN spray or sublingual tablets up to every ½ hr – short acting Isosorbide Mononitrate 10-30mg bd – long acting used a prophylaxis. ENSURE a nitrate free period overnight or tolerance will develop Action – produce NO in vascular cells. NO is a vasodilator. à reduce preload & by increasing coronary flow Therapeutics 3 Indications – prophylaxis and treatment of angina, left ventricular failure Cautions – hypothyroidism, malnutrition, hypothermia, head trauma, cerebral haemorrhage, recent MI, hypoxaemia, V/Q mismatch Contraindications – hypersensitivity to nitrates, hypotension, hypovolaemia, aortic stenosis, cardiac Tamponade, mitral stenosis, marked anaemia Side effects – postural hypotension, tachycardia, throbbing headache, dizziness, less commonly N&V, heartburn, flushing • Potassium channel activators (nicorandil) Nicorandil has a nitrate component à arterial & venous V/D Indications – prophylaxis & treatment on angina Cautions – hypovolaemia, low systolic BP, acute pulmonary oedema, acute MI (with LVF), pregnancy Contraindications – cardiogenic shock, LVF with low filling pressures, hypotension, breast feeding Side effects – headache (esp on initiation, usually temporary), flushing, N&V, dizziness • ACEi’s (captopril, enalapril, ramipril) Mechanism of action ACE converts Angiotensin I (inactive) to Angiotensin II (active v/c) AND bradykinin (active v/d) to bradykinin 1-7 (inactive) Therefore - Lower angiotensin II à reduce v/c à reduce aldosterone à reduce Na & H2O retention à potentiates bradykinin à v/d Uses Heart failure – in all grades, usually combined with a diuretic. Discontinue K+ supplements and K-sparing diuretics. Hypertension – for younger, Caucasian patients. Esp good for DM with nephropathy DM nephropathy Cautions – care required in starting therapy when on diuretic (risk of hyperkalaemia). Give first dose as night – risk of hypotension. Avoid if on dialysis (risk of anaphylactoid reaction) Contraindications – hypersensitivity to ACEi’s, known / suspected renovascular disease, pregnancy Side Effects Cough – bradykinin increases airway sensitivity & à inflammation 1st dose hypotension – give first dose at night Reduce GFR due to effect of angiotensin antagonism. If renal artery stenosis à pre renal failure due to drop in perfusion pressure. ALWAYS monitor creatinine before starting and after 1 week to check renal function Can increase K+ & cause renal damage. Angioedema – more common in black Africans • Beta Blockers (atenolol, propranalol, sotalol, bisoprazole) B – adrenoceptor antagonists (B-blockers) e.g. propranolol – non selective (B1 & B2) for angina & HT e.g. atenolol / metoprolol – B1 selective (for action on heart) Mechanism of Action Block receptors in SA node and ventricular muscle à decrease HR & force à reduce O2 demand. Decreased rate à increased filling time & coronary blood flow – used in angina Decrease renin secretion (& therefore angiotensin II & aldosterone) Decrease sympathetic activity (some cross BBB) Decrease NA release (blocks presynaptic B receptors which increase NA release) Uses Hypertension – mechanism not fully understood Therapeutics 4 Angina – reduce cardiac workload à improve exercise tolerance & reduce Sx MI – improve mortality & reduce recurrence rate Arrhythmias – can be used with digoxin Heart failure – by blocking sympathetic activity Thyrotoxicosis – reverse some symptoms, used pre-thyroidectomy Contraindications – asthma (bronchospasm), uncontrolled heart failure, marked bradycardia, hypotension, 2nd / 3rd degree heart block, cardiogenic shock Side Effects Bronchoconstriction – block B2 mediated bronchodilatation (less with B1 selective). AVOID in asthma / COPD Can reduce hypoglycaemic awareness so avoid in DM Poor execise tolerance, muscle cramps, cold extremities – blocked B2 mediated vasodilatation (skeletal muscle) à unopposed A-mediated v/c. Should be less with B1 selective Others – GI disturbance, bradycardia, hypotension, peripheral vasoconstriction, bronchospasm, impotence • Calcium channel blockers (diltiazem, nifedipine, verapamil) Action – Acts on the heart and smooth muscle to block the movement and propagation of action potentials à v/d & lower BP of Ca2+ into cells via the slow channels à reduced contractility Uses Verapamil – angina, hypertension and arrhythmias. A highly negative ionotrope à reduces CO, HR and may impair AV conduction. NEVER use with B-blockers Diltiazem – angina. And hypertension in its long acting form. NEVER use with Bblockers Dihydropyridines (Nifedipine, Amlodipine) – relaxes vascular smooth muscle and dilates coronary and peripheral arteries. No antiarrhythmic activity. NOT used for angina Cautions – hepatic and renal impairment, pregnancy, heart block, heart failure Contraindications – cardiogenic shock, aortic stenosis Side effects – vary with each drug • Alpha blockers (Doxazosin) A-Adrenoceptor Antagonists (A-blockers) e.g. doxazosin, prazosin – A1 selective Mechanism of action Post synaptic blockade à Reduce A-mediated vasoconstriction Uses Hypertension Pheochromocytoma (catecholamine secreting tumour of adrenal medulla) – used with B-blocker pre & post op Peripheral vascular disease – raynauds Hypertensive emergencies – cheese reaction Sx relief from prostatic hypertrophy Benign Prostatic hypertrophy – relaxes smooth muscle à reduce obstruction Cautions – care with initial dose (postural hypotension), hepatic impairment, heart failure, pregnancy, breast feeding Side Effects Postural Hypotension – loss of A-mediated v/c with baro reflex Dizziness, vertigo, headache, fatigue, oedema Rarely - Angina, Arrhythmias, Tachycardia – reduced A2 mediated presynaptic inhibition of NA release à more NA available to act on cardiac B-receptors • HMG Co-A reductase inhibitors (simvastatin) Therapeutics 5 Statins (e.g. simvastatin, pravastatin, atorvastatin, fluvastatin) Mechanism Statins are heavily hepatoselective Only 5% reaches the systemic circulation due to high 1st pass metabolism Hydroxymethylglutary ê (HMG-CoA reductase) Mevalonate Statins are HMG-CoA reductase inhibitors ê Cholesterol By reducing the plasma cholesterol à increase LDL receptors in the liver à LDL uptake (NB: less effective in familial cases as unable to make the receptors) Evidence & advice Some evidence that statins à regression of atherosclerosis Statins do slow athersclerotic progression à reduces stroke, CVS disease & death Statins should be considered for ALL patients with high risk of CVS disease, irrespective of their cholesterol level BUT are rationed according to priority and are given to Post angine / MI Those with 30% 10yr risk of CVS disease (e.g. DM, HT) with cholesterol > 5mmol/l Should be taken at night Contraindications Active liver disease Pregnancy & Lactation Adverse effects Derangement of LFTs - Should monitor LFTs if any liver disease Diarrhoea Can à myopathy à rhabdomyolysis so REPORT any muscle pains Have a range of interactions (ciclosporin, fibrates, itroconazole, warfarin) • Anticoagulants (heparin, warfarin) Warfarin = 4-hydroxycoumarin Blocks regeneration of Vit K Vit K is a cofactor for gamma carboxylation of factors II, VII, IX & X Clotting factors are still produced but not in active form Dosing Takes 48-72 hours to take effect – should be on LMWH until then ONLY comes in 3mg tablets in Notts area Starting regime = 9, 9, 6 and check INR on day 3 Check INR weekly until stable then 2-weekly or more as appropriate Target INR based on reason for treatment: 2.5 for DVT / PE 3.0 for AF & mechanical aortic valves 3.5 for recurrent DVT / PE & mechanical mitral valves Cautions / Contraindications Caution – recent surgery, hepatic & renal impairment, breast feeding Contraindications – active peptic ulcer, severe hypertension, bacterial endocarditis NB: contraindicated in pregnancy due to teratogenic effects 6-12 weeks gestation MUST stop warfarin 4 days before surgery (convert to heparin) Therapeutics 6 AVOID – Vit K containing foods (leafy green veg) and enzyme inducers (alcohol, cranberry juice) Side effects – haemorrhage, hypersensitivity, rash, allopecia, diarrhoea Key interactions – erythromycin, coproxamol, amidoarone, antoconvulsants, NSAIDs Emergency reversal – Immediate with FFP (but will only last 8 hrs so give Vit K as well) Normal reversal = 12 hrs. IV or PO Vit K 10mg for complete reversal Heparin = Glycosaminoglycan (GAG) = Polysaccharide Naturally present in mast cells – Lung or gut Clinically used unfractionated heparin isloated from lung of pigs or cows Action Potentiates Antithrobin 3 (NB wont work in rare state of antithrombin 3 deficiency) à Inhibition IIa and Xa Pharmacokinetics Destroyed in the gut – Parenteral administration required T1/2 60 mins – Increases with dose (longer in LMWH than standard heparin) Should monitor APTT if on heparin infusion Renal clearance Uses Rapid anticoagulation in PE/DVT until warfarin is started During thrombolysis for MI Before surgery in place of warfarin (shorter action & easier to control) Anticoagulation / DVT/PE prophylaxis during pregnancy (warfarin is teratogenic) Side effects Longterm can à osteoporosis Heparin induced thrombocytopenia / Thrombosis (HITT) Develops after 4-5 days treatment Causes reduction in platelets (can be complicated by thrombus) Hyperkalaemia Aldosterone secretion is reduced by heparin can à high K+ (esp if on K+ sparing diuretics) Reversing heparin Emergency – Protamine sulphate (binds heparin) NB: FFP wont work due to inhibition of clotting Routine - T1/2 of unfractionated heparin is 90mins – so just switch off! Therapeutics 7 Respiratory • Short & long acting B2 agonists (salbutamol, salmeterol) Selective beta2 agonists produce bronchodilation. Short-acting beta2 agonists - Mild to moderate symptoms of asthma respond rapidly to the inhalation of a selective short-acting beta2 agonist such as salbutamol or terbutaline. If beta2 agonist inhalation is needed more often than once daily, prophylactic treatment should be considered, using a stepped approach. Long-acting beta2 agonists - Formoterol (eformoterol) and salmeterol are longer-acting beta2 agonists which are administered by inhalation. Added to regular inhaled corticosteroid treatment, they have a role in the long-term control of chronic asthma and they can be useful in nocturnal asthma. Salmeterol should not be used for the relief of an asthma attack; Formoterol is licensed for short-term symptom relief and for the prevention of exercise-induced bronchospasm; its speed of onset of action is similar to that of salbutamol. Inhalation – Pressurised-metered dose inhalers are an effective and convenient method of drug administration in mild to moderate asthma. A spacer device may improve drug delivery. At recommended inhaled doses the duration of action of salbutamol, terbutaline and fenoterol is about 3 to 5 hours and for salmeterol and formoterol 12 hours. The dose, the frequency, and the maximum number of inhalations in 24 hours of the beta2 agonist should be stated explicitly to the patient. The patient should be advised to seek medical advice when the prescribed dose of beta2 agonist fails to provide relief. Nebuliser (or respirator) solutions of salbutamol and terbutaline are used for the treatment of severe acute asthma in hospital or in general practice. Patients with a severe attack of asthma should preferably have oxygen during nebulisation since beta2 agonists can increase arterial hypoxaemia. CFC-free inhalers are replacing the old style. Oral - Oral preparations of beta2 agonists may be used by patients who cannot manage the inhaled route (e.g. young children & elderly) Parenteral - Salbutamol or terbutaline are given by intravenous infusion for severe asthma. Cautions - hyperthyroidism, cardiovascular disease, arrhythmias, susceptibility to QTinterval prolongation, and hypertension. Diabetes—monitor blood glucose (risk of ketoacidosis, especially when beta2 agonist given intravenously). Hypokalaemia - potentiated by concomitant treatment with theophylline and its derivatives, corticosteroids, and diuretics, and by hypoxia. Plasma-potassium concentration should therefore be monitored in severe asthma Side-effects - Side-effects of the beta2 agonists include fine tremor (particularly in the hands), nervous tension, headache, muscle cramps, and palpitation. Other sideeffects include tachycardia, arrhythmias, peripheral vasodilation, and disturbances of sleep and behaviour. Paradoxical bronchospasm, urticaria, angioedema, hypotension, and collapse have also been reported. High doses of beta2 agonists are associated with hypokalaemia. • Anticholinergics (ipratropium bromide) Ipratropium can provide short-term relief in chronic asthma, but short-acting beta2 agonists act more quickly and are preferred. Tiotropium, a long-acting antimuscarinic bronchodilator, is effective for the management of chronic obstructive pulmonary disease; it is not suitable for the relief of acute bronchospasm. Cautions - Antimuscarinic bronchodilators should be used with caution in patients with prostatic hyperplasia, bladder outflow obstruction, and those susceptible to angleclosure glaucoma Therapeutics 8 Side-effects - Dry mouth is the most common side-effect of antimuscarinic bronchodilators; less commonly nausea and headache occur. Constipation, tachycardia, palpitation, paradoxical bronchospasm, urinary retention, blurred vision, angle-closure glaucoma, and hypersensitivity reactions including rash, urticaria, and angioedema occur rarely. Indications - reversible airways obstruction, particularly in chronic obstructive pulmonary disease; rhinitis • Methylxanthines (aminophylline) Bronchodilator used for asthma and stable chronic obstructive pulmonary disease; Pharmacokinetics - metabolised in the liver. Considerable variation in plasma-theophylline concentration particularly in smokers (decreased), in patients with hepatic impairment or heart failure (increased), or if certain drugs are taken concurrently. Toxic dose is close to therapeutic dose so care required Theophylline is given by injection as aminophylline, a mixture of theophylline with ethylenediamine, which is 20 times more soluble than theophylline alone. Aminophylline injection is needed rarely for severe attacks of asthma. It must be given by very slow intravenous injection (over at least 20 minutes); it is too irritant for intramuscular use. Measurement of plasma theophylline concentration may be helpful, and is essential if aminophylline is to be given to patients who have been taking theophylline, because serious side-effects such as convulsions and arrhythmias can occasionally precede other symptoms of toxicity. • Inhaled and oral steroids (prednisolone, budesonide) Corticosteroids are used for the management of reversible & irreversible airways disease. Asthma Reduce airway inflammation (and hence reduce oedema and secretion of mucus into the airway). If patients require a beta2 agonist more than twice a week, or if symptoms disturb sleep more than once a week, or if the patient has suffered exacerbations in the last 2 years requiring a systemic corticosteroid or a nebulised bronchodilator Used as prophylaxis Can take 3-7 days to act so must be used regularly for best effect Systemic corticosteroid therapy may be necessary during episodes of infection or if the asthma is worsening, when higher doses are needed and access of inhaled drug to small airways may be reduced; patients may need a reserve supply of tablets. Chronic obstructive pulmonary disease May reduce exacerbations. An inhaled corticosteroid [unlicensed indication] should be considered (in addition to bronchodilator treatment) if the forced expiratory volume in 1 second (FEV1) is less than 50% of the predicted value and if the patient has had 2 or more exacerbations in a year which require antibacterial treatment or an oral corticosteroid. Inhaled steroids Cautions - Systemic therapy may be required during periods of stress or when either airways obstruction or mucus prevent drug access to smaller airways; Side-effects - considerably fewer systemic effects than oral corticosteroids, but adverse effects have been reported. High doses of inhaled corticosteroid have been associated with lower respiratory tract infections, including pneumonia, in older patients with chronic obstructive pulmonary disease. Bone mineral density may be reduced following long-term inhalation of Therapeutics 9 higher doses of corticosteroids, predisposing patients to osteoporosis. Candidiasis can occur Oral steroids An acute attack of asthma should be treated with a short course of an oral corticosteroid starting with a high dose, e.g. prednisolone 40–50 mg daily for a few days. In chronic continuing asthma, when the response to other drugs has been inadequate, longer term administration of an oral corticosteroid may be necessary. Parenteral For the use of hydrocortisone injection in the emergency treatment of acute severe asthma • Oxygen High concentration O2 therapy, with concentrations of up to 60%, is safe in uncomplicated cases of conditions such as pneumonia, pulmonary thromboembolism, and fibrosing alveolitis. In such conditions low arterial oxygen (PaO2) is usually associated with low or normal arterial carbon dioxide (PaCO2), and therefore there is little risk of hypoventilation and carbon dioxide retention. In acute severe asthma, the arterial carbon dioxide (PaCO2) is usually subnormal but as asthma deteriorates it may rise steeply (particularly in children). These patients usually require high concentrations of oxygen and if the arterial carbon dioxide (PaCO2) remains high despite other treatment, intermittent positive-pressure ventilation needs to be considered urgently. Where facilities for blood gas measurement are not immediately available, for example while transferring the patient to hospital, 40 to 60% oxygen delivered through a high-flow mask is recommended. Low concentration oxygen therapy (controlled oxygen therapy) is reserved for patients with ventilatory failure due to chronic obstructive pulmonary disease or other causes. The concentration of oxygen administered should not exceed 28% and in some patients a concentration above 24% may be excessive. The aim is to provide the patient with enough oxygen to achieve an acceptable arterial oxygen tension without worsening carbon dioxide retention and respiratory acidosis. Treatment should be initiated in hospital because repeated blood gas measurements are required to determine the correct concentration. Long term Usually for COPD Assessment for long-term oxygen therapy requires measurement of arterial blood gas tensions. Measurements should be taken on 2 occasions at least 3 weeks apart to demonstrate clinical stability, and not sooner than 4 weeks after an acute exacerbation of the disease. Short burst Oxygen is occasionally prescribed for short-burst (intermittent) use for episodes of breathlessness not relieved by other treatment in patients with severe chronic obstructive pulmonary disease, interstitial lung disease, heart failure, and in palliative care. It is important, however, that the patient does not rely on oxygen instead of obtaining medical help or taking more specific treatment. Short-burst oxygen therapy can be used to improve exercise capacity and recovery. Short-burst oxygen should only be continued if there is proven improvement in breathlessness or exercise tolerance. Therapeutics 10 Endocrine • Insulin (soluble, isophane, lente) Indications - diabetes mellitus; diabetic ketoacidosis Side-effects - transient oedema; local reactions and fat hypertrophy at injection site; rarely hypersensitivity Types of insulin Soluble insulin Acts within 30-60 minutes (give 15-30 minutes before meal) Lasts 4-6 hours Used mainly during surgery or in emergencies Rapid Acting Insulin (human insulin analogue) Acts within 15 minutes Lasts 2-4 hours Used as a pre meal bolus to increase flexibility. Good if prone to low BP pre meals Prolonged acting Insulin Intermediate = 12-24 hrs Long = > 24 hrs Mixed with Protamine or Zinc to delay absorption Administration routes IV – used only in hospital Subcut – by syringe / pen. MUST rotate site to prevent lipohypertrophy à unpredictable absorption Insulin pumps – sub cut. Continuous infusions with increase at meals. Insulin regimes Twice daily 30 minutes before breakfast (2/3 of daily dose) before evening meal Mixture of short and long acting insulin Most common regime Basal-Bolus regime Single dose of long acting and then short acting before each meal. Allows increased flexibility of meals Single daily regimes Single daily dose of intermediate Used for Type II unable to use tablets NB: Insulin requirements increase with stress, infection, trauma, puberty and the lastter 2/3 of pregnancy NB: Requirements decrease in coeliac disease, renal / hepatic impairment & Addisons disease • Sulphonylureas (chlopropamide, glibenclamide, gliclazide, tolbutamide) Can be used in patients who Metformin is contraindicated Action - Promote insulin secretion (but only when there is some remaining B-cell function) High glucose à ATP production à inactivate K-ATP à depolarisation à Ca2+ influx & insulin secretion Low glucose à decrease ATP à channels open à hyperpolarisation à decreases insulin secretion Sulphonylureas à channel inhibition à increase insulin secretion Therapeutics 11 Cautions – some weight gain so avoid where possible in obese. Elderly, hepatic & renal impairment. Contra-indications - severe hepatic and renal impairment and porphyria. Pregnancy and breast-feeding. Presence of ketoacidosis. Side-effects - mild and infrequent gastro-intestinal disturbances. Can --> liver disturbance -> cholestatic jaundice, hepatitis & hepatic failure. Some hypersensitivity may occur in 1st 6 weeks. Rarely marrow failure NB: If used with B-Blockers à loss of hypoglycaemic awareness (esp in elderly). Particular problem with glibenclamide (long acting sulphonylureas) Meglitinide analogues Promote insulin secretion because also cause K-ATP closure but act at a different site to sulphonylureas Rapid onset so used at meal times Effects are enhanced by high glucose Can à obesity and do not improve plasma lipid profile Is a risk of hypoglycaemia • Biguanides (Metformin) 1st choice in obese patients (doesn’t cause weight gain). Doesn’t cause hypoglycaemia Action - Decrease gluconeogenesis & increases peripheral utilization of glucose but mechanism unclear - Requires endogenous insulin Indications - diabetes mellitus; polycystic ovary syndrome [unlicensed - improves insulin sensitivity, may aid weight reduction, helps to normalise menstrual cycle (increasing the rate of spontaneous ovulation), and may improve hirsutism] Cautions - determine renal function (using an appropriately sensitive method) before treatment and once or twice annually (more frequently in the elderly or if deterioration suspected) Contra-indications - renal impairment, ketoacidosis, withdraw if tissue hypoxia likely (e.g. sepsis, respiratory failure, recent myocardial infarction, hepatic impairment), use of iodine-containing X-ray contrast media (do not restart metformin until renal function returns to normal) and use of general anaesthesia (suspend metformin on the morning of surgery and restart when renal function returns to normal), pregnancy and breast-feeding Side-effects - anorexia, nausea, vomiting, diarrhoea (usually transient), abdominal pain, metallic taste; rarely lactic acidosis (withdraw treatment), decreased vitamin-B12 absorption, erythema, pruritus and urticaria; hepatitis also reported NB: Metformin can provoke lactic acidosis which is most likely to occur in patients with even mild renal impairment • Glitazones (rosiglitazone) Actions - Decrease insulin resistance by genetic effect Activate nuclear peroxisome proliferator activated receptors (PPARs) à Altered gene expression à Insulin like effects (reduce peripheral insulin resistance --> reduce blood glucose Effects - Decrease hepatic glucose output, increase peripheral uptake & increase fatty acid uptake into adipose cells Indications - type 2 diabetes mellitus (alone or combined with metformin or with a sulphonylurea or with both) Cautions - monitor liver function (rare reports of toxicity); cardiovascular disease (risk of heart failure); substitute insulin during peri-operative period (omit rosiglitazone on morning of surgery and recommence when eating and drinking normally); increased risk of bone fracture in females; renal impairment Therapeutics 12 Contra-indications - hepatic impairment, history of heart failure, combination with insulin (risk of heart failure), pregnancy, breast-feeding Side-effects - gastro-intestinal disturbances, cardiac ischaemia, headache, anaemia, altered blood lipids, weight gain, oedema, hypoglycaemia, bone fracture; see also Liver Toxicity above • Alpha-glucosidase inhibitors (acarbose) Action - inhibitor of intestinal alpha glucosidases --> delays the digestion and absorption of starch and sucrose. Indications - diabetes mellitus inadequately controlled by diet or by diet with oral antidiabetic drugs (used either on its own or as an adjunct to metformin or to sulphonylureas when they prove inadequate) Cautions - monitor liver function; may enhance hypoglycaemic effects of insulin and sulphonylureas (hypoglycaemic episodes may be treated with oral glucose but not with sucrose) Contra-indications - inflammatory bowel disease, predisposition to partial intestinal obstruction; hernia, previous abdominal surgery; hepatic impairment; renal impairment; pregnancy; breast-feeding Side-effects - flatulence, soft stools, diarrhoea (may need to reduce dose or withdraw), abdominal distention and pain; rarely, nausea, abnormal liver function tests and skin reactions; very rarely ileus, oedema, jaundice, and hepatitis • Thyroid (carbimazole, thyroxine) Antithyroid drugs – carbimazole Action - Blocks thyroid hormone biosynthesis – block iodination of thyroperoxidase. Will also suppress the graves process Takes 10-20 days to act – due to long t1/2 of hormone Indications – hyperthyroidism (1st episode in pats under 40 yrs) Cautions - liver disorders, pregnancy, breast-feeding Side-effects - nausea, mild gastro-intestinal disturbances, headache, rashes and pruritus(2%), arthralgia; rarely myopathy, alopecia, bone marrow suppression (including pancytopenia and agranulocytosis (0.2%)), jaundice > 50% will relapse on stopping drug Throxine Action – to replace endogenous thyroid hormone Uses - hypothyroidism (myxoedema), and also in diffuse non-toxic goitre, Hashimoto's thyroiditis (lymphadenoid goitre), and thyroid carcinoma. NB: Neonatal hypothyroidism requires prompt treatment for normal development. Indications - hypothyroidism Cautions - panhypopituitarism or predisposition to adrenal insufficiency (initiate corticosteroid therapy before starting levothyroxine), elderly, cardiovascular disorders (including hypertension, myocardial insufficiency or myocardial infarction), long-standing hypothyroidism, diabetes insipidus, diabetes mellitus (dose of antidiabetic drugs including insulin may need to be increased); pregnancy NB: Start slowly with baseline ECG. If metabolism increases too rapidly (causing diarrhoea, nervousness, rapid pulse, insomnia, tremors and sometimes anginal pain where there is latent myocardial ischaemia), reduce dose or withhold for 1–2 days and start again at a lower dose Contra-indications - thyrotoxicosis Side-effects - usually at excessive dosage include D&V, anginal pain, arrhythmias, palpitation, tachycardia, tremor, restlessness, excitability, insomnia; headache, flushing, sweating, fever, heat intolerance, weight-loss, muscle Therapeutics 13 cramp, and muscular weakness; transient hair loss in children; hypersensitivity reactions including rash, pruritus and oedema also reported • Steroids (hydrocortisone, fludrocortisone) Action The adrenal cortex normally secretes hydrocortisone (cortisol) which has glucocorticoid activity and weak mineralocorticoid activity. It also secretes the mineralocorticoid aldosterone. In deficiency states (e.g. addisons), physiological replacement is best achieved with a combination of hydrocortisone and the mineralocorticoid fludrocortisone Hydrocortisone Indications - adrenocortical insufficiency; shock; hypersensitivity reactions e.g. anaphylactic shock and angioedema; asthma; severe inflammatory bowel disease; haemorrhoids; rheumatic disease Cautions – Adrenal suppression and infection Children and adolescents (growth retardation possibly irreversible) Elderly (close supervision required particularly on long-term treatment) Frequent monitoring required if history of tuberculosis (or X-ray changes) Hypertension, recent myocardial infarction (rupture reported), congestive heart failure Liver failure or renal impairment DM including family history Osteoporosis (post-menopausal women at special risk) Glaucoma (including family history) Contra-indications - systemic infection (unless specific antimicrobial therapy given); avoid live virus vaccines in those receiving immunosuppressive doses (serum antibody response diminished) Side-effects GI - include dyspepsia, peptic ulceration, distension, acute pancreatitis, oesophageal ulceration and candidiasis; MSK- include proximal myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, tendon rupture; Endocrine - include adrenal suppression, menstrual irregularities and amenorrhoea, Cushing's syndrome (with high doses), hirsutism, weight gain, negative nitrogen and calcium balance, increased appetite; increased susceptibility to and severity of infection; Neuropsychiatric effects include psychological dependence, increased intracranial pressure with papilloedema in children (usually after withdrawal), aggravation of schizophrenia, aggravation of epilepsy; Ophthalmic effects include glaucoma, papilloedema, posterior subcapsular cataracts, corneal or scleral thinning and exacerbation of ophthalmic viral or fungal disease; Other side-effects include impaired healing, skin atrophy, bruising, striae, telangiectasia, acne, myocardial rupture following recent myocardial infarction, fluid and electrolyte disturbance, leucocytosis, hypersensitivity reactions (including anaphylaxis), thromboembolism, nausea, malaise, hiccups Fludrocortisone Indications - mineralocorticoid replacement in adrenocortical insufficiency Cautions – as for hydrocortisone Contra-indications - as for hydrocortisone Side-effects - hypertension, sodium and water retention and potassium loss. Therapeutics 14 Gastrointestinal disease • Antactids (gaviscon) NB: gaviscon is a combination of antacid with alginate Antacids – give relief not cure HCO3- + H+ à CO2 + H2) à bloating and belching Al (OH)3 + 3HCl à AlCl3 + 3H2O à constipation Mg(OH)2 + 2HCl à MgCl2 + 2H2O à laxative Use Al and Mg together to even out effects Ca2+ salts à gastrin release so not used (Alginates - Forms a foam raft on gastric contents which protects from reflux) • Motility stimulants (metoclopromide) Prokinetic drugs Cause gastric emptying Benefit GORD Domperidone = closure of oesophageal sphincter & opens lower sphincter Metoclopromide = local increase in gastric motility to hasten emptying Metclopromide Indications – Adults - nausea and vomiting, particularly in gastro-intestinal disorders and treatment with cytotoxics or radiotherapy; migraine. Patients under 20 years - Use restricted to severe intractable vomiting of known cause, vomiting of radiotherapy and cytotoxics, aid to gastrointestinal intubation, pre-medication; also, dose should be determined on the basis of body-weight Cautions - hepatic impairment, renal impairment; elderly, young adults, and children (measure dose accurately, preferably with a pipette); may mask underlying disorders such as cerebral irritation; epilepsy; pregnancy; porphyria; Contra-indications - gastro-intestinal obstruction, perforation or haemorrhage; 3–4 days after gastro-intestinal surgery; phaeochromocytoma; breast-feeding Side-effects - extrapyramidal effects (especially in children and young adults, hyperprolactinaemia, occasionally tardive dyskinesia on prolonged administration; also reported, drowsiness, restlessness, diarrhoea, depression, neuroleptic malignant syndrome, rashes, pruritus, oedema; cardiac conduction abnormalities reported following intravenous administration; rarely methaemoglobinaemia (more severe in G6PD deficiency) • H2-receptor blockers (cimetidine ranitidine, famtodine) Low dose available OTC (xantac), high dose = POM Best given at night Action – reduce gastric acid output by blocking H2 receptors. Indications – GORD, Zollinger-Ellison syndrome (PPI preferred), recurrent H.Pylori, ulcer complications, healing NSAID ulcers Cautions - renal impairment, pregnancy, and in breast-feeding. May mask symptoms of gastric cancer Side-effects - diarrhoea and other gastro-intestinal disturbances, altered liver function tests (rarely liver damage), headache, dizziness, rash, and tiredness. Rare side-effects include acute pancreatitis, bradycardia, AV block, confusion, depression, and hallucinations particularly in the elderly or the very ill, hypersensitivity reactions (including fever, arthralgia, myalgia, anaphylaxis), blood disorders Therapeutics 15 Interactions - cimetidine inhibits CYP450 (so interactions with warfarin, phenytoin, theophylline etc), ranitidine doesn’t • PPI (Omeprazole (OTC), pantoptrazole, lansoprazole) Widely used - More effective than H2 antagonists (hits end process, not just one factor) Action – activated by low pH. Inhibit gastric acid secretion by 90% by blocking the hydrogen-potassium adenosine triphosphatase enzyme system (the ‘proton pump’) of the gastric parietal cell. Indications – gastric and duodenal ulcers, H.Pylori eradication (used with Abx), dyspepsia, GORD, NSAID ulcer healing, Zollinger-Ellison syndrome Cautions - liver disease, in pregnancy and in breast-feeding. Proton pump inhibitors may mask the symptoms of gastric cancer Side-effects - GI disturbances (including D, N & V, abdominal pain, flatulence, constipation), headache, and dizziness. Less frequent side-effects include dry mouth, insomnia, drowsiness, malaise, blurred vision, rash, and pruritus. decreasing gastric acidity, may increase the risk of gastro-intestinal infections. • Helicobacter therapy (clarithromycin, metronidazole) Triple therapy for a week, then PPI alone 2 from metronidazole, amoxycillin and clarithromycin + PPI +/- H2 antagonist Bismuth chelate – kills H-pylori, coats the ulcer, absorbs pepsin, increases PG production, increased HCO3If fully treated recurrence risk is reduced BUT increases risk of food poisoning (due to decreased acid) Requires good compliance Successful in 90% of patients, 1% recurrence Should also stop smoking to aid healing Recheck with breath test to ensure success If gastric ulcer re-endoscope at 6 weeks Clarithromycin Indications - respiratory-tract infections, mild to moderate skin and soft tissue infections, otitis media; Helicobacter pylori eradication Cautions - neonate under 2 weeks (risk of hypertrophic pyloric stenosis); predisposition to QT interval prolongation (including electrolyte disturbances, concomitant use of drugs that prolong QT interval); avoid in porphyria; hepatic impairment; renal impairment; pregnancy (not known to be harmful) and breast-feeding (only small amounts in milk) Side-effects - dyspepsia, tooth and tongue discoloration, smell and taste disturbances, stomatitis, glossitis, and headache; less commonly hepatitis, arthralgia, and myalgia; rarely tinnitus; very rarely pancreatitis, dizziness, insomnia, nightmares, anxiety, confusion, psychosis, paraesthesia, convulsions, hypoglycaemia, renal failure, leucopenia, and thrombocytopenia; on intravenous infusion, local tenderness, phlebitis Metronidazole Indications - anaerobic infections (including dental), protozoal infections; Helicobacter pylori eradication; skin Cautions - disulfiram-like reaction with alcohol, hepatic impairment and hepatic encephalopathy; pregnancy and breast-feeding; avoid in porphyria); clinical and laboratory monitoring advised if treatment exceeds 10 days; Side-effects - gastro-intestinal disturbances (including nausea and vomiting), taste disturbances, furred tongue, oral mucositis, anorexia; very rarely hepatitis, jaundice, pancreatitis, drowsiness, dizziness, headache, ataxia, psychotic Therapeutics 16 disorders, darkening of urine, thrombocytopenia, pancytopenia, myalgia, arthralgia, visual disturbances, rash, pruritus, and erythema multiforme; on prolonged or intensive therapy peripheral neuropathy, transient epileptiform seizures, and leucopenia Amoxycillin Cautions - maintain adequate hydration with high doses (particularly during parenteral therapy), history of allergy; renal impairment; erythematous rashes common in glandular fever, cytomegalovirus infection, and acute or chronic lymphocytic leukaemia (see notes above); Contra-indications - penicillin hypersensitivity Side-effects - nausea, vomiting, diarrhoea; rashes (discontinue treatment); rarely, antibiotic-associated colitis; see also under Benzylpenicillin • Aminosalicylates (mesalazine) Action – 5ASA (5-aminosalicylic acid) is the active molecule which supresses the immune process in the cells. Sulfasalazine is a combination of (‘5-ASA') and sulfapyridine (carrier). Mesalazine is a newer drug avoiding the sulphonamide effects of sulphasalazine. Indications Sulphasalazine - treatment of mild to moderate and severe ulcerative colitis and maintenance of remission; active Crohn's disease; rheumatoid arthritis Mesalazine - treatment of mild to moderate ulcerative colitis and maintenance of remission Cautions - renal impairment, during pregnancy and breast-feeding; blood disorders can occur (Patients should be advised to report any unexplained bleeding, bruising, purpura, sore throat, fever or malaise that occurs during treatment. A blood count should be performed and the drug stopped immediately if there is suspicion of a blood dyscrasia.). Contra-indications - avoid in salicylate hypersensitivity. Side-effects - diarrhoea, nausea, vomiting, abdominal pain, exacerbation of symptoms of colitis, headache, hypersensitivity reactions (including rash and urticaria); sideeffects that occur rarely include acute pancreatitis, hepatitis, myocarditis, pericarditis, lung disorders (including eosinophilia and fibrosing alveolitis), peripheral neuropathy, blood disorders (including agranulocytosis, aplastic anaemia, leucopenia, methaemoglobinaemia, neutropenia, and thrombocytopenia), renal dysfunction (interstitial nephritis, nephrotic syndrome), myalgia, arthralgia, skin reactions (including lupus erythematosus-like syndrome, Stevens-Johnson syndrome), alopecia. • Local and systemic steroids (colifoam, predsol, prednisolone) IBD – first line Rx is local application of a corticosteroid or an aminosalicylate. foam preparations and suppositories are especially useful where patients have difficulty retaining liquid enemas. Diffuse IBD may require oral steroid (e.g. prednisolone). Severe IBD requires admission with IV hydrocortisone or methylprednisolone Colifoam – rectal foam & Predsol – rectal preparation Indications - ulcerative colitis and Crohn's disease, proctitis, proctosigmoiditis Cautions - systemic absorption may occur; prolonged use should be avoided Contra-indications - use of enemas and rectal foams in obstruction, bowel perforation, and extensive fistulas; untreated infection Side-effects – general steroid effects + local irritation Therapeutics 17 Management of Status Epilepticus Neurology • Antiepileptics (phenytoin, Carbemazepine, sodium valproate) Rapidly repeated seizures without regaining consciousness Ensure airway – intubate if required O2 100% +/- suction IV access & bloods Thiamine if malnourished / alcoholic IV glucose unless known to be normal Correct low BP with iv fluids IV lorazepam / rectal diazepam OR slow phenytoin infusion OR GA à paralysis + ventilate Phenytoin Indications - all forms of epilepsy except absence seizures; status epilepticus; trigeminal neuralgia if carbamazepine inappropriate) Cautions - avoid abrupt withdrawal; manufacturer recommends FBCs; avoid in porphyria; hepatic impairment; pregnancy; breast-feeding; Blood (leukopenia) or skin disorders Side-effects – N&V, constipation, insomnia, transient nervousness, tremor, paraesthesia, dizziness, headache, anorexia; gingival hypertrophy and tenderness; rash (discontinue; if mild re-introduce cautiously but discontinue immediately if recurrence). Rarely hepatoxicity, peripheral neuropathy, dyskinesia, lymphadenopathy, osteomalacia, blood disorders, StevensJohnson syndrome, and toxic epidermal necrolysis; Carbemazepine Indications - partial and secondary generalised tonic-clonic seizures, some primary generalised seizures; trigeminal neuralgia; prophylaxis of bipolar disorder unresponsive to lithium Cautions - hepatic impairment or renal impairment; cardiac disease, skin reactions, history of haematological reactions to other drugs; manufacturer recommends FBC, LFTs and U&Es; may exacerbate absence and myoclonic seizures; susceptibility to angle-closure glaucoma; pregnancy, breast-feeding; avoid abrupt withdrawal; Contra-indications - AV conduction abnormalities (unless paced); history of bone marrow depression, porphyria Side-effects – N&V, dizziness, drowsiness, headache, ataxia, confusion and agitation (elderly), visual disturbances (especially diplopia and often associated with peak plasma concentrations); constipation or diarrhoea, anorexia; mild transient generalised erythematous rash may occur in a large number of patients (withdraw if worsens or is accompanied by other symptoms); leucopenia and other blood disorders. Other side-effects include cholestatic jaundice, hepatitis and acute renal failure, Stevens-Johnson syndrome, toxic epidermal necrolysis. Valproate Weak GABA transaminase inhibitor, ? also Na+ channel blockers Indications - all forms of epilepsy Cautions - monitor LFTs before therapy and during first 6 months especially in patients most at risk; measure FBC count and ensure no undue potential for bleeding before starting and before surgery; systemic lupus erythematosus; false-positive urine tests for ketones; avoid abrupt withdrawal; renal impairment; pregnancy; breast-feeding; Liver toxicity (monitor LFTs, discontinue if abnormal); Pancreatitis Contra-indications - active liver disease, family history of severe hepatic dysfunction; porphyria Side-effects - nausea, gastric irritation, diarrhoea; weight gain; hyperammonaemia, thrombocytopenia; transient hair loss (regrowth may be curly); less frequently increased alertness, aggression, hyperactivity, behavioural disturbances, ataxia, tremor, and vasculitis; rarely hepatic dysfunction, Therapeutics 18 Lamotrigine Indications - monotherapy and adjunctive treatment of partial seizures and primary and secondarily generalised tonic-clonic seizures; seizures associated with Lennox-Gastaut syndrome; trigeminal neuralgia [unlicensed indication] Cautions - closely monitor and consider withdrawal if rash, fever, or other signs of hypersensitivity syndrome develop; avoid abrupt withdrawal (taper off over 2 weeks or longer) unless serious skin reaction occurs; hepatic impairment; renal impairment; pregnancy; breast-feeding; Blood disorders (marrow failure) Side-effects – rash (inc stevens-Johnson syndrome); hypersensitivity syndrome (possibly including rash, fever, lymphadenopathy, hepatic dysfunction, blood disorders, disseminated intravascular coagulation and multi-organ dysfunction); nausea, vomiting, diarrhoea, hepatic dysfunction; headache, fatigue, dizziness, sleep disturbances, tremor, movement disorders, agitation, confusion, hallucinations, occasional increase in seizure frequency; blood disorders • Dopamine agonists (levodopa, carbidopa, bromocriptine) L-dopa + Dopa-decarboxylase inhibitor (e.g. carbidopa) Actions Dopamine is ionised at pH7.4 (cant cross BBB) and metabolised by MAO (found on cells of BBB) L-dopa (precursor) is unionised at 7.4 so can cross BBB but is converted to DA in periphery Dopa-decarboxylase Inhibitors prevent conversion peripherally & cannot cross BBB as ionised Restores function in corpus striatum & benefits hypokinesias Indications - parkinsonism (but not drug-induced extrapyramidal symptoms) Cautions - pulmonary disease, peptic ulceration, cardiovascular disease, diabetes mellitus, osteomalacia, glaucoma, history of skin melanoma (risk of activation), psychiatric illness (avoid if severe); warn patients about excessive drowsiness; in prolonged therapy, psychiatric, hepatic, haematological, renal, and cardiovascular surveillance is advisable; warn patients to resume normal activities gradually; avoid abrupt withdrawal; Contra-indications - pregnancy; breast-feeding Side Effects After 2 years can develop on/off (bec short ½ life) and choreic movements Nausea & anorexia (due to peripheral effect) Hypotension Psychotic effects Eventually à dyskinesias & loss of control Dopamine agonist e.g. bromocriptine Actions D2 receptors = inhibitory (mainly in BG) D1 receptors = excitatory (few in BG) Post synaptic DA receptors not affected by disease so use a D2 agonists to treat symptoms Indications - parkinsonism (but not drug-induced extrapyramidal symptoms); endocrine disorders (inhibits prolactin release) Side-effects – Used alone less SE than levodopa treatments But more neuropsychiatric Ses Can cause excessive daytime sleepiness, hypotensive reactions and fibrotic reactions (pulmonary, retroperitoneal and pericardial Therapeutics 19 Antibiotics • Common Antibiotics Penicillins – affects ability to make cell wall. Only effective on Gr+ve Action - The penicillins are bactericidal and act by interfering with bacterial cell wall synthesis. They diffuse well into body tissues and fluids, but penetration into the cerebrospinal fluid is poor except when the meninges are inflamed. They are excreted in the urine in therapeutic concentrations. Hypersensitivity reactions - --> rashes and anaphylaxis, can be fatal. Incidence of reactions 1–10%; anaphylactic reactions < 0.05%. Higher risk if history of atopic allergy. If previous reaction avoid penicillins, cephalosporins and other B-lactams. Rarely can develop encephalopathy due to cerebral irritation (usually if high doses / renal failure. NEVER give intrathecally. Benzylpenicillin (Penicillin G) is inactivated by bacterial beta-lactamases. It is effective for many streptococcal (including pneumococcal), gonococcal, and meningococcal infections and also for anthrax, diphtheria, gas-gangrene, leptospirosis, and treatment of Lyme disease in children. Pneumococci, meningococci, and gonococci which have decreased sensitivity to penicillin have been isolated; Benzylpenicillin is inactivated by gastric acid and absorption from the gut is low; therefore it is best given by injection. Indications - throat infections, otitis media, endocarditis, meningococcal disease, pneumonia, cellulitis; anthrax; prophylaxis in limb amputation; Cautions - history of allergy; false-positive urinary glucose (if tested for reducing substances); renal impairment Contra-indications - penicillin hypersensitivity Side-effects - hypersensitivity reactions; rarely CNS toxicity including convulsions (see above), interstitial nephritis, haemolytic anaemia, leucopenia, thrombocytopenia, and coagulation disorders; also reported diarrhoea (including antibiotic-associated colitis) Ampicillin is active against some Gr+ve and Gr-ve bacteria but is inactivated by penicillinases including those produced by S. aureus and by common Gramnegative bacilli such as E. coli. High levels of resistance in staphs and E.coli are now resistant. Uses – well excreted in the bile and urine. It is principally indicated for the treatment of exacerbations of chronic bronchitis and middle ear infections, both of which may be due to S. pneumoniae and H. influenzae, and for urinary-tract infections Route - Ampicillin can be given by mouth but less than half the dose is absorbed, and absorption is further decreased by the presence of food in the gut. SE - Maculopapular rashes commonly occur with ampicillin (and amoxicillin) but are not usually related to true penicillin allergy. They almost always occur in patients with glandular fever Amoxycillin – Wont work if penicillin resistance is a derivative of ampicillin and has a similar antibacterial spectrum, But better absorbed orally, producing higher plasma and tissue concentrations; absorption is not affected by full stomach. Amoxicillin is used for endocarditis prophylaxis; it may also be used for the treatment of Lyme disease [not licensed], Indications - UTI, otitis media, sinusitis, oral infections, bronchitis, uncomplicated CAP, H. influenzae infections, invasive salmonellosis; listerial meningitis, endocarditis prophylaxis & Rx; anthrax; Helicobacter pylori eradication, Therapeutics 20 Cautions - maintain adequate hydration with high doses (particularly during parenteral therapy), history of allergy; renal impairment; erythematous rashes common in glandular fever, cytomegalovirus infection, and acute or chronic lymphocytic leukaemia (see notes above) Contra-indications - penicillin hypersensitivity Side-effects - nausea, vomiting, diarrhoea; rashes (discontinue treatment); rarely, antibiotic-associated colitis; Macrolides – (e.g.) Erythromycin (macrolide) Action - Inhibits protein synthesis, but no effect on nucleic acid synthesis. Mainly Gr+ve Erythromycin similar spectrum to penicillin; therefore an alternative in penicillinallergy. Indications - respiratory infections, whooping cough, legionnaires' disease, and campylobacter enteritis. Some penicillin-resistant staphylococci; NB: poor activity against H. influenzae. SE - nausea, vomiting, and diarrhoea in some patients; reduced if dose decreased. Azithromycin - enhanced activity against some Gram-negative organisms inc H. influenzae. Plasma concentrations are very low but tissue concentrations are much higher. It has a long tissue half-life so once daily dosage. Fewer GI SE Clarithromycin - slightly greater activity than erythromycin & higher tissue concentrations Fewer GI SE Indications - susceptible infections in patients with penicillin hypersensitivity; oral infections; campylobacter enteritis, syphilis, non-gonococcal urethritis, respiratory-tract infections (including Legionnaires' disease), skin infections, chronic prostatitis; prophylaxis of diphtheria, group A streptococcal infection, and whooping cough; acne vulgaris and rosacea Cautions - neonate under 2 weeks (risk of hypertrophic pyloric stenosis); predisposition to QT interval prolongation (including electrolyte disturbances, concomitant use of drugs that prolong QT interval); avoid in porphyria; hepatic impairment; renal impairment; pregnancy (not known to be harmful) and breast-feeding (only small amounts in milk); Side-effects – N&V, abdominal discomfort, diarrhoea (antibiotic-associated colitis reported); less frequently urticaria, rashes and other allergic reactions; reversible hearing loss reported after large doses; cholestatic jaundice, pancreatitis, cardiac effects (including chest pain and arrhythmias), myasthenia-like syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis also reported Tetracyclines – blocks protein synthesis. Generally broad spectrum (+ > -) Broad-spectrum antibiotics but increasing bacterial resistance. Treatment of choice for infections caused by chlamydia, rickettsia, brucella, and Borrelia burgdorferi (Lyme disease). They are also used in respiratory and genital mycoplasma infections, in acne, in destructive (refractory) periodontal disease, in exacerbations of chronic bronchitis (because of their activity against H. influenzae), and for leptospirosis in penicillin hypersensitivity (as an alternative to erythromycin). Little difference between them except minocycline which has a broader spectrum; it is active against Neisseria meningitidis Oral infections - development of resistance (especially by oral streptococci) has reduced their usefulness for the treatment of acute oral infections Cautions - hepatic impairment or those receiving potentially hepatotoxic drugs. May increase muscle weakness in patients with myasthenia gravis, and Therapeutics 21 exacerbate SLE. Antacids, and aluminium, calcium, iron, magnesium and zinc salts decrease the absorption of tetracyclines; milk also reduces the absorption of demeclocycline, oxytetracycline, and tetracycline. Contra-indications - Deposition of tetracyclines in growing bone and teeth (by binding to calcium) causes staining and occasionally dental hypoplasia, and they should not be given to children under 12 years, or to pregnant / breastfeeding women. With the exception of doxycycline and minocycline, the tetracyclines may exacerbate renal failure and should not be given to patients with kidney disease. Side-effects - nausea, vomiting, diarrhoea (antibiotic-associated colitis reported occasionally), dysphagia, and oesophageal irritation. Other rare side-effects include hepatotoxicity, pancreatitis, blood disorders, photosensitivity (particularly with demeclocycline), and hypersensitivity reactions (including rash, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria, angioedema, anaphylaxis, pericarditis). Headache and visual disturbances may indicate benign intracranial hypertension (discontinue treatment); bulging fontanelles have been reported in infants. Aminoglycoside – (e.g. Gentamycin) Action - blocks protein synthesis. Generally broad spectrum (Gr- > Gr+) Amikacin, gentamicin, neomycin, netilmicin, streptomycin, and tobramycin. MUST be given IV - not absorbed from the gut Excretion is principally via the kidney (caution in renal impairment.) Dosing - If there is impairment of renal function (or high pre-dose serum concentrations) the interval between doses must be increased; if the renal impairment is severe the dose itself should be reduced as well. Loading and maintenance doses of gentamicin may be calculated on the basis of the patient's weight and renal function (e.g. using a nomogram); adjustments are then made according to serum-gentamicin concentrations. High doses are occasionally indicated for serious infections, especially in the neonate, in the patient with cystic fibrosis, or in the immunocompromised patient. Whenever possible treatment should not exceed 7 days. Indications - septicaemia and neonatal sepsis; meningitis and other CNS infections; biliary-tract infection, acute pyelonephritis or prostatitis, endocarditis; pneumonia in hospital patients, adjunct in listerial meningitis eye; ear Cautions - pregnancy, renal impairment, neonates, infants and elderly (adjust dose and monitor renal, auditory and vestibular function together with serum gentamicin concentrations); avoid prolonged use; conditions characterised by muscular weakness; obesity (use ideal weight for height to calculate dose and monitor serum-gentamicin concentration closely); Contraindications – MG (can impair neuromuscular transmission), avoid use with potentially ototoxic diuretics (e.g. furosemide (frusemide)) Side-effects - mostly dose related - vestibular and auditory damage, nephrotoxicity; rarely, hypomagnesaemia on prolonged therapy, antibiotic-associated colitis, stomatitis; also reported, nausea, vomiting, rash, blood disorders; Cephalosporins – cell wall synthesis inhibitors. Broad spectrum Broad-spectrum antibiotics used for the treatment of septicaemia, pneumonia, meningitis, biliary-tract infections, peritonitis, and urinary-tract infections. Cefuroxime is a ‘second generation' cephalosporin, less susceptible to inactivation by beta-lactamases. It is, therefore, active against certain bacteria which are Therapeutics 22 resistant to the other drugs and has greater activity against Haemophilus influenzae and Neisseria gonorrhoeae. Cefotaxime, ceftazidime and ceftriaxone are ‘third generation' cephalosporins with greater activity than the ‘second generation' cephalosporins against certain Gram-negative bacteria. However, they are less active than cefuroxime against Gram-positive bacteria, most notably Staphylococcus aureus. Their broad antibacterial spectrum may encourage superinfection with resistant bacteria or fungi. Ceftazidime has good activity against pseudomonas. It is also active against other Gram-negative bacteria. Ceftriaxone has a longer half-life and therefore needs to be given only once daily. Indications - infections due to sensitive Gram-positive and Gram-negative bacteria, Cautions - sensitivity to beta-lactam antibacterials (avoid if history of immediate hypersensitivity reaction); renal impairment; pregnancy and breast-feeding (but appropriate to use); false positive urinary glucose (if tested for reducing substances) and false positive Coombs' test Contra-indications - cephalosporin hypersensitivity Side-effects - hypersensitivity and about 10% of penicillin-sensitive patients will also be allergic to the cephalosporins. diarrhoea and rarely antibioticassociated colitis (CSM has warned both more likely with higher doses), nausea and vomiting, abdominal discomfort, headache; allergic reactions including rashes, pruritus, urticaria, serum sickness-like reactions with rashes, fever and arthralgia, and anaphylaxis; Stevens-Johnson syndrome, toxic epidermal necrolysis reported; disturbances in liver enzymes, transient hepatitis and cholestatic jaundice; other side-effects reported include eosinophilia and blood disorders (including thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia and haemolytic anaemia); reversible interstitial nephritis, hyperactivity, nervousness, sleep disturbances, hallucinations, confusion, hypertonia, and dizziness Colistin – acts as detergent to cell membrane – therefore acts on GrIndications - the polymyxin antibiotic, colistin, is active against Gram-negative organisms including Pseudomonas aeruginosa, Acinetobacter baumanii, and Klebsiella pneumoniae. Route - Not absorbed if given PO – must be injected (unless using for bowel sterilisation in neutropenic patients, or being administered as nebulised for CF) Cautions - renal impairment, porphyria; risk of bronchospasm on inhalation—may be prevented or treated with a selective beta2 agonist; Contra-indications - myasthenia gravis; pregnancy; breast-feeding Side-effects - neurotoxicity reported especially with excessive doses (including apnoea, perioral and peripheral paraesthesia, vertigo; rarely vasomotor instability, slurred speech, confusion, psychosis, visual disturbances); nephrotoxicity; hypersensitivity reactions including rash; injection-site reactions; inhalation may cause sore throat, sore mouth, cough, bronchospasm Nalidixic acid – affects DNA replication. Gr-ve Basis for quinolone Abx (e.g. ciprofloxacin) Indications - urinary-tract infections Cautions - avoid in porphyria; liver disease; false positive urinary glucose (if tested for reducing substances); monitor blood counts, renal and liver function if treatment exceeds 2 weeks; Therapeutics 23 Side-effects - reported toxic psychosis, increased intracranial pressure, cranial nerve palsy, metabolic acidosis • Resp infections Community – strep pneumoniae, H.influenzae, S. Aureus, Mycoplasma Pneumoniae, Legionella Pneumoniae Hospital – coliforms (e.coli etc), MRSA, Pseudomonas (CF’s & imm compromised) URTI Bordetella pertussis à whooping cough à no Rx Candida Albicans à thrush à nystatin Corynebacterium Diptheriae à diptheria à antitoxin + benzylpenicillin H.Influenzae à epiglotitis, otitis à ampicillin & cefotaxime S.Pneumoniae à sinusitis, otitis à benzylpenicillin S. Pyogenes à pharyngitis à benzylpenicillin LRTI H.Influenzae à chronic bronchitis à ampicillin / tetracycline L. Pneumoniae à legionnaires disease à erythromycin M. TB à TB à RIPE M. Pneumoniae à atypical pneumonia à tetracycline & erythromycin Pneumocystis carinii à interstitial pneumonitis à cotrimoxazole S. Aureus à bronchopneumonia à fluclox S. Pneumonia à lobar pneumonia à Benzylpenicillin • UTIs E.coli – trimethoprim, ampicillin, nitroflurantoin Proteus mirabilis - trimethoprim, ampicillin, a quinolone K. aerogenes - trimethoprim, nitroflurantoin, a quinolone Staphylococci – trimethoprim, cephalexin Enterococci – ampicillin, trimethoprim P. Aeurginosa – azolocillin, gentamicin, ciprofloxacin (NB: usually hospital acquired) C. Albicans – fluconazole (NB: usually hospital acquired) M. TB – RIPE etc • Divertculitis & GI tract Common GI infections Campylobacter jejuni à enteritis à erythromycin Salmonella (others) à food poisoning à none E.coli à infant & travellers diarrhoea à fluids Clost. Difficile à pseudomembranous colitis à vancomycin & metronidazole Shigella à dysentery à Ampicillin Other GI infections Bacillus cereus à Food poisoning à none (self limiting) S.Aureus à food poisoning (none) and entercollitis (flucloxacillin) Clost. Perfingens à food poisoning à none Clost. Botulinum à botulism à antitoxin Entamoeba histiolytica à amoebic dysentery à metronidazole Giardia lamblia à chronic diarrhoea à metronidazole Salmonella typhii à typhoid à ciprofloxacin / chloramphenicol V.Cholerae à cholera à fluids & tetracycline Yersina enterocolitic à mesenteric Adenitis à co-trimoxazole Rota-virus à diarrhoea à none Therapeutics 24 • Bacterial meningitis Neonatal – Group B strep, E.coli, Listeria monocytogenes, Staph epidermidis. 30% mortality (50% in prems) Infants – Neisseria meningitides, H. influenza, strep pneumonia Children & young adults – Neisseria meningitides, strep pneumonia Adults - strep pneumonia, Neisseria meningitides, mycobacteria (TB), cryptococci (immunosupressed) • Infective endocarditis 65% of cases are strep mitior, mutans or sanguis 25% have history of dental procedures ALWAYS preceeded by bacteraemia Common with CHD / RF / prosthetic valves High mortality Native valves Viridans strep Enterococci Other streps S.Aureus Haemophilus Valve / IVDU Streptococci S.Aureus S.Epidermidis Enterobacter Therapeutics 25 Anaesthesia • Local anaesthetics (lignocaine, bupivicaine, EMLA) Action - Inhibit sodium ion channels in the neuronal membranes preventing conduction of the action potential (carrying the pain signal) Uses: Can be used topically (mucous membrane e.g. eye / urethra), sub cutaneously, IV after application of the tourniquet, directly around nerves (regional block). Use with epinephrine if large dose or prolonged effect required BUT NOT around end arteries (fingers, toes, penis etc) EMLA (mixture of 50:50 lignocaine & prilocaine) Used as a cream for skin sites and has effect in approx 60 mins Ametop (4% amethocaine) Used like EMLA but acts in a shorter time Lignocaine - (0.5%) for short procedures 3mg/kg plain 200mg max, 6mg/kg (with epinephrine) 500mg max Rapid onset, 60-180 min duration Used for topical infiltration, nerve blocks, IVRA, epidural and intrathecally Bupivicaine - (0.5%) for pain relief from surgical incision 2mg/kg (+/- epinephrine), 150mg max in 4hrs Nerve block onset in 40 mins, duration upto 24hrs Epidural onset in 15-20 mins, duration 3-4 hrs Intrathecal in 30s, duration 2-3 hrs Mainly used for nerve blocks, epidural and intrathecal. *** Relatively CARDIOTOXIC *** Procedure Calculate volume that can be used Clean skin surrounding & allow to dry Insert needle, aspirate to check not in vein Inject as withdrawing Toxicity signs Mild - Perioral paresthesia, numbness of tongue, visual disturbances, light headedness. Slurred speech, twitching, restlessness, mild hypotension, bradycardia Severe – grand mal convulsions fb coma, respiratory depression, and eventual CVS collapse, profound hypotension & bradycardia & cardiac arrest Management – A, B, C & treat convulsions with 5-10mg diazepam IV • Opioids (morphine, diamorphine, codeine) Opioids = any drug acting on opioids receptors Opiate = any naturally occurring opioid (e.g. morphine) Produce euphoria, analgesia & sleep Stimulation of μ (mu) & κ (kappa) leads to analgesia & depression of ventilation(both), euphoria (μ), sedation (κ), and physical dependence (μ) ALL opioid receptors are inhibitory Inhibit adenylate cyclase & decreased cGMP ALL OPIOIDS ARE ANTAGONISED BY NALOXONE Side Effects Constipation (40% or oral users, no tolerance) Anti-tussive Dependence Tolerance (Receptors change à decreased effect à require é dose à resp ê) Morphine – strongest but most likely to cause nausea & vomiting Diamorphine – (heroin) causes less N&V than morphine Therapeutics 26 Alifentanil – analgesia for short procedures (e.g. out pat / day case). Will suppress ventilation. Can cause hypertension & myoclonic movements Fentanyl – analgesic used in surgery Remifentanil – Rapidly metabolised & non-cumulative so used as an infusion during long surgery to allow a more rapid recovery than fentanyl Pethidine – prompt short acting analgesia, less potent than morphine. Used in labour. Also used to reduce / stop shaking due to spinal / GA. Codeine – for mild – moderate pain but too constipating for long term use Nalbuphine (nubaine) – synthetic agent. Antagonist at μ & partial agonist at κ. Good but cant be followed by morphine because is antagonist Tramadol – complex analgesia. Weak agonist at μ, inhibits NA uptake & 5HT release. 1/10 strength of morphine = approx equal to pethidine but less resp depression. Not a controlled drug. Naloxone (narcan) – pure antagonist. IV dose in adults 0.1-0.4mg, acts in < 60s, last 35-40mins. Limited effect on complex opioids. For severe OD may require infusion. • Simple analgesia (paracetamol, ibuprofen, diclofenac) o Paracetamol - simple analgesic (1g QDS oral or IV) Analgesic & antipyretic properties Indirectly blocks COX enzyme à analgesic without NSAID effects Metabolised by the liver & then the metabolites are excreted by the kidneys Cyt P450 converts paracetamol to an active metabolite Then conjugated to harmless metabolite & excreted renally Toxicity due to active metabolite (builds up due to saturation of pathway) – more information in the overdose notes o Non-steroidal anti-inflammatory drugs Eicosanoids (PG, TX, LT) (NSAIDs) Phosholipids à arachiodonic acid à eicosanoid Analgesic, antipyretic & antiContribute to inflammatory response inflammatory Rate limiting step = PLA2 (liberation of AA) Blocks COX1 & 2 à blocks Synthesis is driven by different stimuli in cell damage AA metabolised by COX enzymes (Cox 1 & 2) prostaglandin synthesis PGI2 & PGE2 are hyperalgesics Anti-inflammatory à v/d & decreases oedema Analgesic à decreases pain Antipyretic à affect PG COX1 production in Constituative hypothalamus (resets most tissues blood platelets thermostat) by v/d & tissue homeostasis increasing sweatting COX2 Can be used with opioids = induced in inflammatory cells by IL1 & TFNa reduce amount responsible for producing PG mediators of required = “opioid inflammation sparing” Interactions Should not be used if on warfarin Can decrease effectiveness of ACEi’s Can oppose diuretics à fluid retention Contraindications Previous allergy Peptic ulcers - as PG is protective for the stomach Renal impairment – as can affect renal afferent arterial flow Asthma – reduction of PG production à increased leukotriene production (alternative pathway) à bronchospasm Therapeutics 27 o o • Coagulopathy – haemophilia, warfarin, heparin etc (due to reduced platelet aggregation) Aspirin 300-900mg every 4-6 hours (max 4g daily) Irreversible inactivation of COX1 & COX2 1st order elimination 75% metabolism in liver Rapid absorption T1/2 = 4 hrs Myocardial infarction therapy (75mg od) Side effects due to the COX1 effects Diclofenac (volterol) Max daily dose 150mg (in 2-3 divided doses) Used for MSK pain (esp rheumatoid arthritis) Can be given PO, IM, IV, PR Opioids (see notes on anaesthetic principles) Local anaesthetics (see notes on anaesthetic principles) Benzodiazepines (diazepam, temazepam, midazolam) Anxiolytics Temazepam 20-30 mg à sedation & amnesia Diazepam 10-20 mg Well absorbed from the GI Tract Lorazepam 2-4 mg Given orally 45-90 minutes before surgery Amnesia If a patient requests not to remember the events before theatre Use lorazepam = anteriorgrade amnesia Benzodiazepines: Relieve anxiety, cause sedation and amnesia BUT no analgesic properties so require separate analgesia Can cause respiratory depression in high dose Diazepam – long acting (slow metabolism) causing mild sedation & amnesia. Painful on injection Temazepam – shorter duration (approx 90 mins), more rapid onset than diazepam. Midazolam – 40-70s onset, 10-15min duration Dose dependent hypotension, some ventilatory depression, mild anticonvulsant, causes amnesia • Antiemetics (ondanzetron, cyclizine, prochlorperazine) Emesis = inappropriate gastric emptying Stimulated by bacterial toxins, alcohol (15%), drugs, motion sickness, smells, migraine, pregnancy Motion sickness Menieres Labyrinth VIII Block with sedatives Drugs – morphine, L-dope, postanoids Sensory afferents (sight, smell, pain) BBB window Nucleus tractus solitarus Vestibular N H1 + Muscarinic receptors CTZ D2 & 5HT3 receptors Vomiting Centre Muscarinic receptors VOMIT Therapeutics 28 Anticholinergics Antihistamine D2 / 5HT3 antag No BBB @ CTZ so peripheral D2 antag will work anticholinergics Anti emetics H1 receptor antagonists – e.g. promethazine Act on vestibular nuclei Effective in motion sickness Also has antimuscarinic actions Antimuscarinic Agents – e.g. hyoscine Effective in motion sickness and heartburn Has antimuscarinic SE (blurred vision, urinary retention etc) Dopamine antagonists – e.g. metoclopromide Acts in CTZ Has unwanted CNS side effects Effective against anti cancer induced emesis 5HT antagonists – e.g. ondansetron blocks 5HT at 5HT3 receptors Effective against anti-cancer induced emesis and post operative N&V Nabilone Canabinoid (synthetic cannabis based) § § § § § § • Antihistamines (H1) = IM cyclizine – also has anticholinergic effects & can cause tachycardia when given IV. Used for labyrinthine induced 5HT3 antagonists = IV / PO ondansetron – blocks 5HT3 receptors in the gut’s mucosal vagal afferents. Used as 2nd line Dopamine antagonists = IV / IM / PO Metoclopromide – minimally effective against PONV. Acts in the CTZ increasing gastric motility. Work for opioid Phenothiazine derivatives = IM / PO procholorperazine – can cause hypotension due to alpha blockade. Some antihistamine activity. May cause dystonic movements Anticholinergic = atropine, hyoscine – cause dry mouth, blurred vision etc. Work well for vagally induced nausea Steroids = dexamethasone may be useful in resistant cases Anticholinergics (atropine, glycopyrrolate) Anticholinergic (e.g. glycopyrrolate, atropine, hyoscine) § Reduce salivation – for fibre optic intubation or surgery on oral cavity § Reduce vagolytic effects on heart – before suxamethonium, surgery on eye muscles or zygoma surgery § Can be used with neostigmine (to prevent its SE of bradycardia excessive salivation) during reversal of depolarising neuromuscular blockade Antisympathomimetic § Avoids tachycardia & hypertension on intubation Therapeutics 29