Fitz’ Pharm for Finals – 2009 Feel free to use this, and share it with others. If you have any additions, comments or (I am sure many) corrections, please let me know. [I know it’s obvious, but these are just my notes, and not intended as prescription recommendations, so do not prescribe from them.] Thanks, Fitz Abciximab (and others) Drug Name(s) Abciximab, (Tirofiban, Eptifibatide) Drug Class GPIIb/IIIa inhibitors. Abciximab is a Monoclonal AntiBody, the others are small peptides. Mode of Action Inhibits the GPIIb/IIIa fibrinogen receptors on the surface of platelets, decreasing their adhesions Benefits and Indications • Prevention of cardiac events in patients awaiting PCI, and for the prevention of stent stenosis. (Abciximab) • Prevention of early MI following unstable angina or NSTEMI. (Tirofiban, eptifibatide) Risks and Adverse effects • Bleeding • N+V • Hypotension, bradycardia • Hypersensitivity and ARDS Interactions Any other anti-platelet or anti-clotting agent - bleeding Susceptible groups • Previously exposed individuals - immunogenic • Risk of serious bleeds (active bleeding, recent trauma or surgery, stroke, brain tumour, aneuryms, severe hypertension, bleeding disorders, thrombocytopenia, vasculitis – very much like contraindications for thrombolysis) Kinetics Administration (routes, doses) IV – loading dose and infusion – complex and based on body weight. Information (Patient and staff) Monitoring Check clotting and FBC before administration, and in the 24 hours afterwards. Stopping Acarbose Drug Name(s) Acarbose Drug Class alpha – glucosidase inhibitors Mode of Action Inhibits intestinal alpha glucosidase, leading to delayed carbohydrate absorption. Benefits and Indications • Small effect in lowering blood glucose (especially post-prandial hyperglycaemia) • Sometimes used in overweight type II DM patients. Risks and Adverse effects Common: • Flatulence • Diarrhoea • Abdominal Pain Uncommon: • Changes in LFTs or hepatitis • Ileus Interactions Susceptible groups Avoid if risk of intestinal obstruction or inflammation: • Inflammatory Bowel Disease • Previous bowel obstruction • Hernia • Previous abdominal surgery Use with caution in hepatic or renal impairment Kinetics Administration (routes, doses) 50mg-200mg TDS just before food. Information (Patient and staff) Discuss common side effects Monitoring LFTs Stopping ACE inhibitors Drug Name(s) Captopril, Lisinopril/ Losartan Drug Class ACE inhibitor/ Angiotensin receptor anagonist Mode of Action ACEis – Competitive inhibitors of ACE, leading to less ATI ATII, and an accumulation of bradykinin. Less ATII reduces circulating aldosterone. peripheral dilatation lower BP decreases aberrant myocardial remodelling neurohormonal responses in heart failure Benefits and Indications • Hypertension • Cardiac Failure • Post-MI to reduce mortality • Diabetic Nephropathy (even in normotensives) Risks and Adverse effects • Hypotension, especially for the first dose and with concurrent use of other hypotensives • Hyperkalaemia • Rashes (10%) with or w/o fever and eosinophilia • Dry cough (10%) due to bradykinin accumulation – ARBs do not have this effect • Impaired renal function in those with renal artery stenosis • Transient change in taste • Proteinuria and nephrotic syndrome (0.3%) due to membranous glomerulonephritis • Neutropenia (0.3%) Interactions • Hypotension with other antihypertensive drugs, and in patients volume depleted by diuretics. • Hyperkalaemia, exacerbated by other drugs with this effect – potassium supplements and potassium-sparing diuretics • NSAIDS can reduce the effectiveness of ACE inhibitors • ACE inhibitors inhibit the excretion of lithium Susceptible groups • Patients on other anti-hypertensives • Patients with renal artery stenosis • Doses of ARBs must be reduced in hepatic impairment Kinetics Well absorbed PO, but absorption decreased by food. Long half lives Administration (routes, doses) Start with low doses, taken in bed, at night. Increase at 2 week intervals according to response e.g. Captopril – 6.25-12.5mg BD. Up to 25mg BD to 50mg TDS. Losartan – 25-100 OD NB: doses vary dependant on indication – see BNF Information (Patient and staff) Hypotension Cough Rashes and taste changes Monitoring U+Es before and during treatment, esp. if high risk of hypokalaemia or renal disfunction Stopping Activated charcoal Drug Name(s) Activated charcoal Mode of Action Certain drugs are adsorbed to the surface of the charcoal molecules, decreasing their absorption. It also hastens secretion of drugs that are secreted into the gut or into the bile. Benefits and Indications Used to decrease absorption of drugs within 2 hours of administration (unless modified release): • Salicylates • Barbiturates • TCAs • Digitalis • Paraffin • Dextropropoxyphene Used to hasten elimination of drugs excreted into the gut (can be effective many hours after administration): • Aspirin • Carbamazepine • Dapsone • Digoxin • Phenobarbital • Quinine • Theophylline Risks and Adverse effects • A safe drug • Black stools • Not effective in poisoning with petroleum products, alcohols, iron, lithium, acids and alkalis Interactions Susceptible groups Some patients are intolerant – reduce dose Kinetics Not absorbed Administration (routes, doses) To stop absorption: 50-100g To aid elimination: 50g every 4 hours Information (Patient and staff) Black stool Monitoring Monitor effects of toxic drug Adenosine Drug Name(s) Adenosine Drug Class Endogenously produced purine Mode of Action Agonist at A1, A2 and A3 receptors. Cardiac effects (A1): • Negative chronotropic and inotropic effects • Decreased SA and AV nodal conduction Other effects: • Vascular effects (A2) – vasodilatation (except kidney) hypotension • Inhibition of platelet aggregation (A2) • Bronchoconstriction (A1, A3) • Neuroprotection (A1) Benefits and Indications • Terminate SVTs • Distinguish between VT and SVT with aberrant conduction • Coronary vasodilator in cardiac radionucleotide imaging Risks and Adverse effects Mild, transient (1-2 minutes) effects • Chest pain • Dyspnoea • Flushing • Headache Serious effects: • Cardiac – AV block, bradycardia, asystole, increase condn in accessory pathways • Vascular – hypotension • Respiratory - bronchospasm Interactions • Inhibit effect - Theophyllines/ xanthines – A1 and A2 receptor antagonists • Potentiate effect – Dipyridamole – inhibit cellular uptake 6x efficacy Susceptible groups • Asthmatics – bronchospasm (avoid) • 2nd or 3rd degree heart block – only use if pacemaker in situ • Transplanted hearts are more sensitive to the effects Kinetics Not absorbed orally Taken up into cells, with an IV half life of 10 seconds Administration (routes, doses) IV For SVT:3mg over 2 secs, increase to 6mg, then 12mg if no effect after 1-2 minutes Information (Patient and staff) Ask asthma and cardiac history Inform about transient side effects (esp. chest pain, headache) Monitoring - ECG Stopping - Only used for short periods Adrenaline Drug Name(s) Adrenaline Drug Class Adrenoreceptor agonist Mode of Action Acts on both alpha and beta receptors, leading to, amongst others: • Positive chronotropic and inotropic effects on the heart • Relaxation of bronchial smooth muscle • Pupil dilatation Benefits and Indications Shock (as an inotrope) Cardiac arrest Anaphylaxis Risks and Adverse effects Mild: • N+V • Tremor, restlessness, headache • Sweating • Urinary retention Severe: • Tachycardia arrythmias (and therefore palpitations) • Hypertension cerebral haemorrhage • Pulmonary oedema Interactions Drugs that inhibit Mono-amine oxidase greatly increase the drug’s effect: • MAOIs • Linezolid (an antibiotic with these effects) Tricyclic antidepressants will also increase the drug’s effect Beta blockers will lead to unopposed alpha effects, leading to severe hypertension. Susceptible groups Patients with Phaeochromocytoma may have a catecholamine storm when given adrenaline. Hyperthyroidism (increased sensitivity and side effects) Patients with known heart disease, stroke disease and hypertension Kinetics Half life of 2 minutes Administration (routes, doses) • In cardiac arrest – 1mg (10ml of 1:10,000) IV, preferably through a central line, or well flushed through a peripheral line. Normally repeated every 2nd cycle of the ALS algorithm • Anaphylaxis – 500 micrograms (0.5ml 1:1000) IM, repeated every 5 minutes according to response. Epipens are available in 150 or 300 microgram automated injectors, prescribed according to size of the patient and severity of their allergic symptoms. Information (Patient and staff) Warn of side effects if conscious Monitoring Monitor BP and cardiac rhythm, and consider invasive monitoring. Bisphosphonates Drug Name(s) Alendronate, pamidronate Drug Class Bisphosphonates Mode of Action • The drug adsorbs onto hydroxyapatite crystals and enter osteoclasts, leading to a decrease in their function and survival. This increases bone density. • They also lead to sequestration of calcium in bone. Benefits and Indications • Prevention and treatment of osteoporosis (alendronate) • Hypercalcaemia (pamidronate) • Paget’s disease of bone Risks and Adverse effects Common: • Oesophageal reactions (dyspepsia, ulceration, stenosis) • Abdominal pain/distension • Myalgia/Arthralgia • Hypophosphataemia (esp. IV preparations) • Hypocalcaemia (esp. IV preparations) Rarely: • Fever at initiation of treatment • Hypersensitivity reactions (Stevens-Johnson syndrome) • Osteonecrosis of the jaw (esp. IV forms) Interactions Absorption of oral bisphosphonates decreased by antacids, iron and calcium salts Aminoglycosides increase risk of hypocalcaemia Do not give in IV infusion containing calcium with an IV bisphosphonate Susceptible groups Contraindicated in patients with: • Oesophageal disorders (achalasia, stenosis) • Hypocalcaemia • Pregnancy Caution in: • Upper GI symptoms, including GI bleeding history and PUD • Renal impairment Kinetics What does not adsorb to bone is excreted unchanged in the urine Administration (routes, doses) Osteoporosis: Alendronate 70mg PO once weekly or 10mg PO OD [swallow whole with water whilst sitting 30 minutes before breakfast] Hypercalcaemia: 15-90mg in slow IV infusion in divided doses over 2-4 days according to calcium levels (no more than 60mg in a single infusion). NB: there are some long-acting forms for OP used, with monthly or even yearly injections Information (Patient and staff) Side effects Monitoring Calcium and phosphate levels (esp. with IV infusion) before starting therapy, and during treatment Amiloride Drug Name(s) Amiloride Drug Class K+ sparing diuretic Mode of Action Blocks Na+ channels in the DCT. independently of Aldosterone Benefits and Indications In combination with loop of thiazide diuretics to increase diuresis and to moderate K+ losses Risks and Adverse effects • ↑K+ (5%), even with loop of thiazide diuretics • • • ↓Na+ Dehydration N+V (rare) Interactions Anything that retains K+ increases risk of hyperkalaemia: • ACE inhibitors • Trimethopirm • K+ supplements • Renal impairment • Spironolactone Susceptible groups Kinetics Poorly absorbed Excreted unchanged in the urine (half life 6h) Administration (routes, doses) 10-20mg OD PO Information (Patient and staff) Monitoring U+Es Stopping Amiodarone Drug Name(s) Amiodarone Drug Class Class III Anti-arrhythmic drug – contains iodine Mode of Action • Prolongs the AP by slowing repolarisation (Phase 3) – similar to hypothyroidism • Acts on K+ channels • Refractory period prolonged • QT interval prolonged • Does not affect Phase 4 depolarisation • Effects seen in all areas of the heart Benefits and Indications • SVT – paroxysmal atrial fibrillation and flutter, as well as WPW syndrome • VT - recurrent Risks and Adverse effects Common - Corneal deposits of lipofucsin seen on slit lamp. May cause visual halos. Reversible - Photosensitisation suntan, slate grey colour, or erythematous rxns - Headache, N + V, constipation, fatigue, tremor - Thyroid: o Inhibits t4t3 leading to increased t4 and reduces t3. Normally euthyroid o Can cause hypo or hyper thyroidism (in 4%) o 2 types of hyperthyroidism – XS iodine (type 1) or gland effects (type2) hard to treat Rare - Peripheral demyelination and neuropathy – reversible - Interstitial pneumonitis due to lipofucsin deposits. May be fatal. Treat with steroids - Hepatitis Interactions - Inhibits warfarin metabolism – BLEEDING - Inhibits renal secretion of digoxin – DIGOXIN TOXICITY - Prolongs QT – don’t give with others like class Ia drugs – long QT Torsades de Pointes Susceptible groups - Hereditary long QT syndrome torsades de pointes - Thyroid Dx - caution Kinetics Hepatic metabolism – long half life – about 50 days Administration (routes, doses) IV – 5mg/kg infusion over at least 20 mins in 250ml 5% dextrose - max dose 15mg/kg in 24 hours PO – complex initial doses – maintenance dose of 100-200mg OD Information (Patient and staff) Side effects – risks versus benefits Monitoring TFTs not routinely recommended and difficult to interpret Stopping Amlodipine and the dihydropyridine Calcium channel blockers Drug Name(s) Amlodipine, Nimodipine, nifedipine Drug Class Ca2+ channel blocker - Dihydropyridine Mode of Action - Inhibit L-type Ca2+ channels - Decreases peripheral and cardiac vascular tone - Little or no negative inotropic or chronotropic effect (Amlodipine < Nifedipine) - [Nimodipine is preferentially effective in the cerebral arterioles] Benefits and Indications - Treatment of hypertension - Some use in angina (esp. Amlodipine as it is safe in heart failure) - Treatment of Prinzmetal’s angina and Raynaud’s phenomenon/Dx NB: Nimodipine used in cerebral spasm after SAH, to prevent or treat neurological deficit Risks and Adverse effects Common – due to vasodilatation and tolerance may develop: • Headache • Flusing • Peripheral oedema • Dizzyness Rare (Nifedipine): • May exacerbate Angina (dose related) • May exacerbate heart failure • Gingival hypertrophy Rare (All) • Urinary or GI disturbance? • Impotence? Interactions May decrease secretion of digoxin (P-glycoprotein) toxicity Susceptible groups - Angina (esp. unstable) - CAUTION - Heart Failure - CAUTION - AF patients on LT digoxin - Cardiogenic shock/ advanced AS – Contra indicated? - (Pregnancy and breast feeding) Kinetics - Well absorbed orally and sub-lingually - Extensive first pass metabolism - Amlodipine half life is long 36 hours (nifedipine 5 hours) Administration (routes, doses) - Angina and hypertension: Amlodipine PO 5-10mg OD - Hypertension: Nifedipine PO 5-20 mg TDS - Sub-arachnoid haemorrhage: Nimodipine PO 60mg every 4 hours for 3 weeks (different treatment if neurological deficit already present – lower dose, IV infusion) Amoxicillin and similar Drug Name(s) Amoxicillin, Ampicillin, Co-amoxiclav with clavulanic acid Drug Class – Broad spectrum β-lactamase-sensitive β-lactam antibiotic Mode of Action Bacteriocidal Inhibits cell wall synthesis (prevents X-linking enzyme) Benefits and Indications - Lots of G+ bacteria: o Streptococcus spp. o Staphylococcus spp. - Haemophilus influenzae (G- bacilli): Bronchitis, bronchopneumonia, otitis media, sinusitis, CAP (esp. in COPD) o Therefore an empirical Rx for CAP - Part of triple Rx for Helicobacter pylori eradication Risks and Adverse effects Common: - Rashes(18%) but 90% in EBV (infectious mononucleosis) - Diarrhoea (bacterial overgrowth?) incl. C. difficile - N+V - Candida vaginits Rare: - Anaphylaxis (1 in 5000? 10% mortality) and other hypersensitivity (more common) - Blood dyscrasias Interactions - Probenecid – prolongs excretion - Other drugs decreasing renal excretion - indomethacin - COC pill – decreases contraceptive effectiveness - Clavulanic acid – inhibits beta-lactamase. Used therapeutically Susceptible groups Renal insufficiency Kinetics Renal excretion – short half life – 30-60mins Administration (routes, doses) PO – 250mg – 1g TDS Also given IV, IM Also co-amoxiclav (similar dose of amoxicillin equivalents) Information (Patient and staff) Hypersensitivity Importance of finishing course Monitoring Stopping Appropriate ABx course length Amphotericin Drug Name(s) Amphotericin Drug Class Antifungal Mode of Action Amphotericin decreases the permeability of cell membranes Benefits and Indications Broad spectrum antifungal for local and systemic infections with: • Candida • Coccidioides • Histoplasma • Cryptococcus • Aspergillus Risks and Adverse effects • Renal impairment is universal – arteriolar vasospasm and direct tubular effect o hypokalaemia o acidosis • Fever (50%) • Bone marrow suppression – anaemia, leucopenia Interactions Narrow therapeutic ratio (liposomal preparations are less toxic) Some drugs increase renal toxicity: • Aminoglycosides • Vancomycin • ciclosporin Risk of hypokalaemia • Diuretics • Steroids Susceptible groups Previous renal impairment Kinetics Not absorbed orally Metabolised with a 24 hour half life Administration (routes, doses) • Local therapy – deoxycholate lozenges – 10mg QDS • Systemic therapy (non-liposomal preparation) test dose of 1mg over 30 mins Then 0.25-1mg/kg daily by continuous infusion • However, liposomal preparations are better for parenteral administration - BNF Information (Patient and staff) Monitoring Monitor FBCs, U+Es regularly Antihistamines – H1 Drug Name(s) Cyclizine, Chlorphenamine, Loratidine Drug Class Antihistamines – H1 receptor antagonists Mode of Action - Decreases the effects of histamine – vasodilation, capillary permeability, itching (but does not reverse them) - They do not have the gastric benefits of the H2 receptor antagonists - They have central effects, including decreased N+V, sedation, and muscarinic effects. These may be therapeutic, or side effects - Cinnarizine has vasodilator properties, leading to its use for PVD (although not recommended by SIGN) Benefits and Indications Allergic rxns – hayfever, urticaria, angio-oedema, bites and stings, drug and transfusion reactions Prevention of motion sickness Relief of nausea and vomiting (incl. motion sickness) Treatment of Meniere’s Dx and vertigo Relief of pruritis - Treatment of PVD (cinnarizine) (although not recommended by SIGN) Risks and Adverse effects - Sedation - Anti-muscarinic effects (dry eyes and mouth, blurry vision, constipation, urinary retention) - Rarely more serious CNS effects occur – tremor, nervousness, insomnia, convulsions) Interactions Potentiate other CNS depressants (alcohol, BDZ, barbiturates) Susceptible groups Care should be taken with drugs with antimuscarinic properties in patients with glaucoma and prostatic disease. May exacerbate severe heart failure Kinetics Well absorbed PO. Metabolised rapidly Administration (routes, doses) All PO, some can be given IV or IM Drug Doses/Routes 4mg TDS PO (and Chlorpheniramine can be given IM/IV) Sedation Anti- Musc Notes ++ - Common OTC Cinnarizine PO + + Nausea, PVD (but not very effective) Cyclizine 50mg TDS PO/IM/IV ++ ++ Anti emetic Loratadine 10mg OD PO - - Promethazine PO/IM/IV ++++ +++ Information (Patient and staff) Warn about sedation – don’t drive machinery. Monitoring Symptom relief? Newer. OTC. with few S/Es Antiemetic Aspirin Drug Name(s) Aspirin (acetyl salicylic acid) Drug Class Salicylate Mode of Action It is a COX inhibitor decreased PG synthesis decreased TXA2 decreased platelet aggregation at low dose analgesia anti- inflammatory action anti- pyretic Benefits and Indications - Mild analgesia - Anti-pyrexic in infections (esp. viral) - Anti- inflammatory – RA, OA, Acute Rheumatic Fever, Dressler’s Syndrome - Prevention of thromboembolic events – CVA, MI - Acute treatment of MI Risks and Adverse effects - Bleeding – occult blood loss (few mL) is normal, but large bleeds from erosions and ulcers do occur - Hypersensitivity - Gout – can be precipitated by changes in uric acid excretion esp. at low doses - Toxicity in overdose Interactions - Warfarin/ Clopidogrel, etc bleeding - Increases Methotrexate concentrations - Decreases effectiveness of uricosuric drugs – probenecid, sulfinpyrazone Susceptible groups C/I in children below 12yo – Reye’s syndrome – (hepatic steatosis and CNS S+S) Asthmatics, nasal polyps, hypersensitivity Hx increased risk of hypersensitivity Gout Haemophilias Severe renal impairment, liver impairment Kinetics Well absorbed PO, then metabolised to salicylic acid Salicylic acid is further metabolised, and shows saturation kinetics (half life is 3-6 hours in low dose, 20 hours in high dose) Metabolites renally excreted Administration (routes, doses) Analgesia – 300-900mg PO 4-6 hourly (max 4g/day) Prevention of thromboembolic events – 75mg OD PO Treatment of AMI – 300mg stat Rheumatic fever, Dressler’s, OA, RA – high dose 900mg PO 4 hourly (8g/day) Information (Patient and staff) Bleeding risk Toxicity - symptoms Monitoring Only if used in high doses for chronic conditions (U+Es), or if toxicity suspected (levels) Stopping Stop analgesic levels as soon as it is not needed to reduce the chance of GI bleeds For prevention this is a chronic drug Atropine Drug Name(s) Atropine Drug Class Muscarinic receptor antagonist Mode of Action Blocks action of ACh at muscarinic receptors, effectively decreasing parasympathetic activity. • Increased heart rate • Bronchiolar dilatation • Decreased secretions • Relaxation of smooth muscle • Pupilary dilatation Benefits and Indications - Cardiac arrest - Bradycardia - Organophosphate and neurotoxin poisoning Risks and Adverse effects Common: • Antimuscarinic – dry eyes, dry mouth, blurred vision, constipation Rare: • Acute urinary retention (esp. in prostatic hyperplasia) • Glaucoma in susceptible patients • Confusion • Palpitations (tachycardia) Interactions TCAs, MAOIs, antihistamines – may potentiate anti-muscarinic effects Neostigmine / Physostigmine – reverses adverse effects (AChase inhibitor) Susceptible groups Avoid in the following: • Prostatic hyperplasia • Closed-angle glaucoma • Myasthenia gravis • Pyloric stenosis • Paralytic ileus Kinetics Significant first pass metabolism Some excreted in urine IV Half life – 24hours Administration (routes, doses) Cardiac arrest (asystole and slow PEA) – IV 3mg once only (max. vagal blockade) Bradycardia – IV 500micrograms repeat until response to max 3mg Preoperatively – IM 600 micrograms Information (Patient and staff) Monitoring Stopping Azathioprine Drug Name(s) Azathioprine, Mercaptopurine Drug Class Cytotoxic/ Immunosuppressant Mode of Action Azathioprine metabolised to Mercaptopurine decreased DNA synthesis cytotixic and immunosuppressant effects Benefits and Indications • To prevent rejection of organ transplant • Steroid sparing effect in the treatment of autoimmune disorders: o PAN, Wegener’s o Rheumatoid Arthritis, Dermatomyositis, SLE o Ulcerative colitis, Crohn’s disease • Cytotoxic chemotherapy in acute leukaemias (Mercaptopurine) Risks and Adverse effects • Bone marrow suppression – Neutropenia, Anaemia, Thrombocytopenia o infections, bleeding, • Nausea, Vomiting, Diarrhoea • Probable teratogenic effect • Risk of progression of present malignancy • Long term risk of malignancy, particularly lymphoma Interactions Toxicity is increased by some antibiotics – rifampicin and trimethoprim Metabolism greatly decreased by allopurinol – lower dose by 75% Susceptible groups - Those with low TPMT activity, especially those homozygous. - Pregnancy - Those with present malignancy Kinetics Azathioprine well absorbed (better than mercaptopurine) Mercaptopurine is metabolised by Thiopurine Methyl Transferase (TPMT) (this enzyme has several alleles in the population, some of which have greatly decreased activity, which leads to increased toxicity) Administration (routes, doses) PO – 1-5mg/kg/day (usual maintenance doses in autoimmune diseases 1-3mg/kg/day) Information (Patient and staff) Need for blood tests Risks of bone marrow suppression – to look for bleeding, bruising, sore throat Long term risk of malignancy Monitoring TPMT levels before starting FBCs regularly Bendroflumethiazide Drug Name(s) Bendroflumethiazide Drug Class Thiazide diuretic Mode of Action • Diuretic action – Inhibits Na+/Cl- channel in DCT reduced NaCl reabsorption, and a diuresis. K+ secretion is increased as a consequence in the DCT. • Antihypertensive action – Decreased volume is compensated over weeks, but permanent haemodynamic changes occur. Na+ in smooth muscle is decreased, inhibiting SNS effects of vasoconstriction. There is also a direct vasodilatory effect. Benefits and Indications • Oedema from heart failure, liver disease, nephrotic syndrome and from drugs • Hypertension • [Nephrogenic diabetes insipidus – where it paradoxically decreases urine output] Risks and Adverse effects • Hypovolaemia • ↓K+ • ↓Na+ • ↓Mg2+ • Rarely: • • • ↑uric acid gout in susceptible cases Erectile dysfunction Thrombocytopenia Pancreatitis Interactions • ↓K+ made worse with laxatives and steroids • • • • ↓K+ can trigger digixin toxicity Lithium excretion decreased – half the Lithium dose and monitor ↓K+ can trigger torsades de pointes with class I antiarrhythmics Increased risk of dehydration/hypotension with other diuretics and drugs with hypotensive effects Susceptible groups Hepatic insufficiency - ↓K+ can precipitate hepatic encephalopathy Kinetics Well absorbed PO Excreted unchanged in urine – half life – 10 hours Administration (routes, doses) Hypertension – 2.5mg OD PO mane Oedema – 5-10mg OD PO mane Information (Patient and staff) Give in morning to avoid diuresis Monitoring U+Es Li+ if relevant Stopping Normally a long term therapy Beta blockers Drug Name(s) Propranolol, Atenolol, Bisoprolol, Metoprolol Drug Class – Beta blockers Mode of Action Competitive antagonists of adrenaline and noradrenaline at β1 and β2 adrenoreceptors - β1 – heart and kidney - β2 – lung, blood vessels, muscle HEART – negative inotropic and chronotropic effect reduces work by the heart – decreased angina and ischaemia reduces destructive sympathetic remodelling in heart failure (but short term worsening if introduced rapidly) - esp. carvedilol and bisoprolol prevents SVTs Hypertension – complex mechanism, starts with the heart – role of baroreceptors and RAA system Thyrotoxicosis – decreases sympathomimetic symptoms but complex mechanism Vary in selectivity for β1 over β2, with bisoprolol>atenolol>metoprolol. Some are partial agonists, others penetrate the CNS Carvedilol – has α1 antagonist properties also, which causes peripheral vasodilation and is useful in heart failure. Benefits and Indications Hypertension IHD: • Angina prophylaxis • In AMI to reduce infarct size • Prevent recurrence of AMI SVTs Symptomatic relief of thyrotoxicosis and anxiety LT treatment of Heart Failure Risks and Adverse effects - CNS effects (depression, hallucinations, sleep probs) - use one with less CNS penetration - Peripheral vasoconstriction and raynaud’s Dx – poorly understood mechanism - Dry eyes (and peritoneal fibrosis with practolol and MAYBE others) - Can mask sympathetic response to hypoglycaemia – avoid if frequent hypos - Sexual dysfunction - Lipid changes – increased TGs, decreased HDLs Interactions - Cimetidine inhibits liver metabolism of propranolol, metoprolol, bisoprolol - Verapamil and β-blockers lead to bradycardias, heart failure and asystole - AVOID - May increase activity of oral hypoglycaemic agents and insulin - Digoxin levels may increase with carvedilol Susceptible groups - In patients with phaeochromocytoma, β-blockers are used with an alpha-blocker to control heart rate and blood pressure, use with β-blockers alone can precipitate a hypertensive crisis - Can depress myocardium – don’t give if 2nd or 3rd degree heart block - Bronchospasm due to β2 effects – even selective drugs avoid in ASTHMA - Can worsen heart failure (esp. if introduced rapidly) esp. if unstable Kinetics Most are well absorbed orally (except atenolol and sotalol – 50% PO absorption) Atenolol and sotalol – eliminated unchanged in the urine (polar) Carvedilol, metoprolol and propranolol - first pass metabolism (lipid soluble) Bisoprolol – hepatic metabolism but not first pass (lipid soluble) Administration (routes, doses) PO – most are BD or TDS for anginal or cardiac effects Bisoprolol has advantageous dosing as it is once daily. Max dose 10mg Information (Patient and staff) SEs are important to mention, as is the importance of not stopping suddenly Monitoring Stopping Stop slowly as sympathetic rebound can lead to angina or MI Bupropion Drug Name(s) Bupropion Drug Class Atypical antidepressant Mode of Action NaRI and DopamineRI, and nicotinic antagonist Benefits and Indications - Smoking cessation – reduces cravings by half, and reduces mood swings and weight gain. No evidence that it is better in combination with NRT. - Depression - Sexual dysfunction Risks and Adverse effects - S/Es – Nausea (5%), Dry eyes (10%), insomnia (5%) - Seizures – dose dependant – less that 0.3% in recommended doses. - Hypertension (infrequently) Interactions MAOI – avoid combination Caution with drugs that lower the seizure threshold (antimalarials, antidepressants, quinolones, steroids, sedating antihistamines, theophylline). Possibly lower dose. Susceptible groups - Epilepsy - contraindicated - CNS tumours, eating disorders, alcohol or BDZ withdrawal – seizure risk so contraindicated - Liver and kidney impairment – raised levels of the drug. - Hypertension – can exacerbate it. Kinetics Metabolised by the liver. Excreted in the urine The drug is similar to amphetamines, so will show positive for these on drug tests. Administration (routes, doses) 150-300mg OD or BD (150mg per dose) for 12 weeks, starting 2 weeks before stop date. NHS funded for patients who set a stop date, and then for only a 4 week course, continuing for those who have not restarted. Only to be given once every 6 months. Information (Patient and staff) Risks and S/Es OD risks Take doses min 8 hours apart Smoking cessation counselling Monitoring Stopping Stop after 10-12 weeks for smoking cessation. Carbapenems Drug Name(s) Imipenem Also Meropenem Drug Class Carbapenems Mode of Action Inhibits cell wall synthesis Benefits and Indications Very broad spectrum against: • Gram positive and negative organisms • Anaerobic and aerobic organisms (Meropenem is best against anaerobic organisms) • This includes anti-Pseudomonal activity However they are not active against MRSA Risks and Adverse effects • Hypersensitivity – often rash (esp. in those with reactions to Penicillins) • Imipenem lowers seizure threshold – don’t give Imipenem in meningitis • Can cause confusion • Diarrhoea • Deranged LFTs Rare: • Haemolytic anaemia Interactions Imipenem is rapidly metabolised in the kidney, so is given with cilastatin which inhibits this. Ganciclovir and imipenem seizures Susceptible groups Those with Penicillin allergy (50% cross-reactivity) Kinetics Not absorbed orally – give IV Renal metabolism and excretion Administration (routes, doses) Imipenem: 500mg TDS/QDS IV Meropenem: 500mg TDS Information (Patient and staff) Check about Penicillin allergy Monitoring Stopping Stop as soon as there is a suitable narrow spectrum alternative Mucolytics Drug Name(s) Carbocisteine – ‘Mucodyne’ Also Erdosteine Drug Class Mucolytics Mode of Action Systemically reduce mucus viscosity Benefits and Indications • Reduce exacerbations in some patients with COPD and with chronic cough • Decrease viscous secretions in: o Tracheostomy o Cystic fibrosis Risks and Adverse effects Rarely: • GI bleeding from PUD (decrease in gastric mucosal barrier) • Rashes • GI symptoms Interactions Susceptible groups Patients with a history of peptic ulcer disease Kinetics Administration (routes, doses) Carbocisteine – 2.25g daily in divided doses PO (reducing to 1.5g when condition improves) Erdosteine (during acute exacerbations) – 300mg OD PO for 10 days Information (Patient and staff) Monitoring Monitor clinical response for the first 4 weeks. Stopping Stop if no improvement after 4 weeks. Cephalosporins Drug Name(s) Cefadroxil (1st generation) Cefuroxime (2nd generation) Cefotaxime, ceftazidime, ceftriaxone, cefaclor (3rd generation) Drug Class Cephalosporin Mode of Action Bacteriocidal Beta-lactam cell wall synthesis inhibition Benefits and Indications Generally a 2nd choice anti-biotic used in hospital for a range of G+ and G- infections (Pneumonia, meningitis, septicaemia, biliary tract infections, peritonitis, UTI, prophylaxis for surgery) Active against: G+ • S. aureus - skin infections • Most Streptococci – ENT infections, pneumonia G• Neisseria spp. – meningitis or gonorrhoea (cefotaxime, ceftriaxone) • H. influenzae – Pneumonia (esp. cefuroxime and cefaclor) • E. coli – Nosocomial UTIs • Klebsiella spp. – G- sepsis • Proteus spp. – G- sepsis • Pseudomonas aeruginosa (esp Ceftazidime) 3rd generation more effective against G- organisms Risks and Adverse effects Common: • Antibiotic associated diarrhoea and C. diff. • Thrombophlebitis at IV site • Candida superinfection, especially in the elderly Rare: • • • • • Hypersensitivity (10% of those with penicillin reaction) N+V LFT derangement and hepatitis Accumulation of Na+ and K+ from quantity in the solution in renal failure Haemolytic anaemia/ bone marrow suppression Interactions Risk of nephrotoxicity so caution with furosemide and gentamicin Susceptible groups - Porphyria - Renal failure - Penicillin hypersensitivity Kinetics Cefaclor and cefalexin – well absorbed orally (all others for IV/IM use) Renal elimination (cefuroxime - 1.5 hour half life) – may need to reduce doses in renal insufficiency Administration (routes, doses) Meningitis – Cefotaxime Severe CAP – Cefotaxime (or cefuroxime) + erythromycin Community acquired septicaemia - Cefotaxime Surgical prophylaxis – cefuroxime (often with metronidazole) Cefotaxime • 1-2g BD-QDS IV/IM Cefuroxime • IM - 750mg TDS • IV – up to 1.5g QDS Information (Patient and staff) Report diarrhoea Monitoring Consider monitoring renal function Stopping Stop broad spectrum antibiotics as soon as sensitivities offer a narrower alternative. Cholestyramine Drug Name(s) Cholestyramine Drug Class Exchange resin Mode of Action Sequesters bile acids in the GI tract less bile acids reabsorbed in the enterohepatic circulation decreased cholesterol breakdown decreased plasma concentrations BUT – increase in TGs Benefits and Indications - Familial hypercholesterolaemia type IIa - Pruritis of obstructive jaundice - Diarrhoea from ileal disease or resection (from XS bile acids) - Digoxin toxicity Risks and Adverse effects - Constipation in 50% - A range of other GI symptoms - Decreased vitamin A and K absorption - Worsens hypertriglycerideaemia Interactions Inhibits the absorption of: • Warfarin • Digitoxin • Thyroxine Susceptible groups Patients with high triglycerides Digoxin/Warfarin/ Thyroxine treated patients Kinetics Not absorbed – stays in lumen Administration (routes, doses) For cholesterol lowering and diarrhoea – 12-24g OD (or divided) PO For pruritis – 4-8g OD PO Information (Patient and staff) Monitoring Digoxin or TFTs if worried Stopping Often long term Stop after the resolution of obstructive jaundice Ciprofloxacin and the quinolones Drug Name(s) Ciprofloxacin, Levofloxacin, Ofloxacin, Nalidixic acid Drug Class Quinolone antibiotics Mode of Action Inhibit the supercoiling of bacterial DNA - bactericidal Benefits and Indications • The class is used for treatment of both G+ and G- organisms, particularly: o UTIs o Biliary tract sepsis o Food poisoning – esp. Shigella, Salmonella, Campylobacter • However, they have poor activity against Staphylococcus • • • Only levofloxacin has any cover against Streptococcus pneumoniae Ciprofloxacin the only oral medication with good Pseudomonas cover Ciprofloxacin is also used for: o Treatment and prophylaxis of anthrax o Some TB regimes if there is resistance o An alternative to rifampacin for meningococcal prophylaxis Risks and Adverse effects Common: - GI problems, such as nausea, vomiting and abdominal pain occur in up to 10% - LFT changes occur in 5%, with a small number progressing to hepatitis Uncommon: - Photosensitive rash – 1-2% - Anaphylaxis - CNS effects - confusion, hallucinations, convulsions (lower seizure threshold) - Tendon rupture – esp. elderly, those with tendonitis, and those on corticosteroids Rare: - Hypoglycaemia - Haemolytic anaemia Interactions Enhance warfarin effects – BLEEDING Drugs that lower seizure threshold - SEIZURES Susceptible groups Renal and hepatic dysfunction – need lower dose Those prone to seizures – caution Pregnancy, breast feeding – AVOID – arthropathy Children – AVOID IF POSSIBLE – arthropathy Tendonitis – TENDON RUPTURE Kinetics Well absorbed orally, IV only needed if PO not possible Hepatic metabolism – increases potency of drugs metabolised by P450 enzymes (reduce dose in hepatic insufficiency) Renal excretion – halve dose in renal insufficiency Administration (routes, doses) (doses are condition specific – see BNF) Ciprofloxacin – 250-750mg BD PO (200-400mg BD IV over 1 hour) Levofloxacin – 250-500mg OD or BD PO (500mg OD or BD IV over 1 hour) Information (Patient and staff) N+V common, No energetic exercise – tendon damage, Rash Monitoring Consider renal and hepatic function before administration Consider monitoring hepatic function Clopidogrel Drug Name(s) Clopidogrel (Plavix) Drug Class ADP – dependant aggregation inhibitor Mode of Action Inhibits ADP – dependant platelet aggregation Has additive effects with aspirin Benefits and Indications Prevention of atherosclerotic events in patients with: • PVD • Post – ischaemic stroke • Post-MI Treatment of NSTEMI and STEMI Prevention of stent thrombosis Risks and Adverse effects Common: - Rash - Diarrhoea, dyspepsia, other GI effects - Bleeds (2% GI haemorrhage, less than 1% cerebral haemorrhage) Rare: - Blood dyscrasias (neutropenia – 5/10,000, TTP – 4/1,000,000) Hypersensitivity Liver failure Interactions Increased risk of bleeding with anticoagulants, antiplatelets and NSAIDs Susceptible groups Avoid in severe liver disease – bleeding risk Caution in renal impairment Kinetics Oral absorption (50% availability) Renal and liver excretion – 8 hour half live Administration (routes, doses) PO 75mg OD (with 300mg loading dose in patients with acute events) Information (Patient and staff) Risks Monitoring Stopping For treatment following NSTEMI, treatment should be 1-12 months. Corticosteroids (systemic) Drug Name(s) Prednisolone, Hydrocortisone, Methylprednisolone Drug Class Systemic Corticosteroids Mode of Action Binds to nuclear receptors, and leads to the suppression and induction of certain genes’ transcription. This process takes several hours, so changes from steroids often take 6-12 hours to start to take effect. Therapeutic effects are: • Anti-inflammatory (decreased activity of neutrophils, T-cells and fibroblasts) • Immunosuppressive (Decreased COX-2 expression, decreased cytokine production, decreased complement production, decreased histamine release, and decreased IgG) Benefits and Indications Replacement of deficient corticosteroid release: • Addison’s disease or adrenalectomy (hydrocortisone) • Hypopituitarism • Specialised use in septic shock, and other ITU patients Anti-inflammatory/Immunosupressive: • Management of cerebral oedema secondary to malignancy (dexamethasone) • Management of nausea from chemotherapy (dexamethasone) • Acute hypersensitivity reactions (e.g. anaphylaxis – hydrocortisone) • Acute asthma and COPD (Prednisolone PO, Hydrocortisone IV) • Chronic severe asthma and COPD (Prednisolone) • Nephrotic syndrome (minimal change disease) • Rheumatoid arthritis, autoimmune hepatitis, SLE, PAN • Sarcoidosis • Temporal arteritis and other vasculitides Risks and Adverse effects Most side effects are dose dependant, increasing at doses above 7.5mg Prednisolone Metabolic: • Adrenal suppression can last for years, and continued corticosteroid adminstration is needed to avoid an addisonian crisis • Fat deposition changes – centripedal obesity, facial changes • Hyperglycaemia • Hyperlipidaemia • High BP • Growth suppression GI: • • • Pancreatitis Gastritis/ Peptic ulceration Oesophageal candidiasis Infectious: • Increased susceptibility to infections • Changed presentation of infections (especially TB and septicaemia) • Risk of severe varicella disease • Decreased efficacy of vaccines • Risk of infection with live vaccines Musculoskeletal and skin • Thin skin, striae, bruising • Acne • Poor wound healing • Muscle wasting • • • Osteoporosis Avascular necrosis of the femoral head Tendon rupture (increased with quinolones) Neurological/Psychological • Cataracts • Steroid psychosis, and milder psychiatric reactions Interactions - Antagonise the action of anti-hypertensive medications Antagonise the action of diabetic drugs May decrease levels of some anti-retroviral drugs May enhance or reduce anticoagulant effect of warfarin (enhanced at high doses) May increase levels of ciclosporin Decreases efficacy of vaccines Corticosteroid actions increased (Metabolism decreased) by: - Macrolide antibiotics (esp clarithromycin) - Itraconazole and Ketoconazole - Ritonavir - oestrogens Corticosteroid actions decreased (Metabolism increased) by: - Rifampicin - Phenytoin - Carbamazepine - Barbiturates - Increased risk of gastric ulceration with NSAIDs and aspirin Risk of hypokalaemia higher with amphotericin, digoxin, loop and thiazide diuretics, theophylline Risk of haematological toxicity with methotrexate increased with steroids Risk of severe illness with live vaccines if long-term use of steroids - AVOID Susceptible groups - Patients with, or at risk from, osteoporosis - The elderly - Children (growth suppression) - Diabetes, or those at risk - Hypertension - Heart Disease (especially recent MI) - Glaucoma - Peptic ulcer disease - History of TB or other chronic infection - Renal impairment - Severe affective disorders, or previous steroid psychosis - Pregnancy (although generally safe – no evidence for malformations or severe adrenal suppression - Breast feeding (generally safe, but monitor baby if maternal dose > 40mg Prednisolone or equivalent) Kinetics Some absorbed orally (Prednisolone), others only IV (hydrocortisone) Metabolised by P450 enzymes Administration (routes, doses) Give steroids in the morning where possible to mimic physiological peak Equivalent doses: 5mg Prednisolone = 25mg Cortisone acetate (good mineralocorticoid activity) = 20mg Hydrocortisone (good mineralocorticoid activity) = 4mg Methylprednisolone = 750micrograms Dexamethasone Prednisolone – up to 60mg OD (PO only) – commonest long term oral treatment Hydrocortisone – PO,IM or IV, needed to be given 3-4 times daily. (20-30mg PO, or 100-500mg IV/IM) Dexamethasone – PO, IM or IV, up to 24mg daily (IV). Some standard doses in certain conditions: Acute asthma – 40-50mg Prednisolone OD PO for 5 days (or 100mg hydrocortisone stat IV, with Prednisolone PO started when possible) Cerebral oedema from malignancy – 10mg stat, 4mg QDS, tapering to stop at 7 days. Adjunctive treatment for bacterial meningitis – 10mg IV QDS for 4 days Information (Patient and staff) - Side effects - Necessary prophylaxis if needed (antibiotics (esp. in children), ADCAL D3, Bisphosphonates) - Avoiding infections/chicken pox/vaccinations - What to do for surgery - Don’t stop suddenly - Carry steroid card Monitoring That which is relevant to patient’s Risk factors, length of treatment and underlying condition. May include: - FBC - U+Es - DEXA scan - Blood glucose - Cholesterol and lipids - Blood pressure Stopping Gradual withdrawal is needed in patients who: • Have received more than 40mg Prednisolone • Have had treatment for more than 3 weeks • Have had multiple doses in the evening • Have had repeated short courses (esp if adding to 3 weeks) • Have a short course within 1 year of stopping long term steroids To stop, taper the dose rapidly down to physiological levels (7.5mg Prednisolone) and then more slowly. E.g. 40mg for treatment Dose reducing by 5mg each week until 10mg Then 7.5mg for two weeks Then 5 mg for 2 weeks Then 5mg every other day for 2 weeks Then stop Desferrioxamine Drug Name(s) Desferrioxamine Drug Class Iron chelator Mode of Action Chelates iron, mole for mole (1g of desferrioxamine chelates 85mg of iron). It removes iron bound to ferritin and haemosiderin, but not from haemoglobin, myoglobin and cytochromes. Benefits and Indications - Iron poisoning - Iron overload from repeated transfusions (e.g. SCA, thalassaemia) - Haemochromatosis Risks and Adverse effects - IV infusion – hypotension, erythema and pruritis, especially if given fast. - Rashes, dizziness and pain can occur. - Iron deficiency anaemia can occur if there is not iron overload. - Urine will be discoloured brown. - Long term use can increase the chances of opportunistic infections including: o PCP, Staph aureus, and others. This is due to the importance of iron to bacterial metabolism. Interactions Vitamin C (100-200mg OD) improves the effect of the drug in reducing iron overload, even though it also improves the absorption of iron. Susceptible groups Kinetics Poorly absorbed PO, so given parenterally. Excreted in urine. Administration (routes, doses) Iron poisoning: Gastric lavage – 2g/L, followed by leaving 10g in 50mL in the stomach 2g IM, repeated after 12 hours. 15mg/kg/h by IV infusion (max 80mg/kg/day). Chronic iron overload: IM injection – 25mg/kg/day SC – 2g daily by infusion over 6-12h. Dose may need to be increased in some patients. Information (Patient and staff) Monitoring For reactions. Digoxin Drug Name(s) Digoxin (digitoxin) Drug Class Cardiac Glycoside (digitalis) Mode of Action - Inhibit Na+/K+ ATPase Ca2+ changes in the cell (theory) - Slows heart rate (decreased condn speed and AV node delay) - Positive inotrope - Does not act on accessory pathways Benefits and Indications - AF – slow ventricular rate (and may return sinus rhythm) - SVTs – slow ventricular rate and return sinus rhythm (not in WPW) - Heart failure – evidence that is reduces admissions, but not mortality Risks and Adverse effects Non-cardiac are common: anorexia, N+V, diarrhoea, confusion and psych disturbance, visual disturbances Cardiac – Any arrythmia – normally dose dependant • Ectopic arrythmias • Heart block • Bradycardia (rare) Interactions Adverse effects increased by: • Low K+ (may be due to diuretics, etc) • High Ca2+ • Low Mg2+ • Low O2 and low pH • Hypothyroidism • Old age Excretion decreased by (renal P-glycoprotein mediated): • Quinidine • Amiodarone • Ciclosporin • Ca2+ chanel blockers Susceptible groups • Hyperthyroidism – partly resistant to digoxin therapy • HOCM – can exacerbate it • Cor pulmonale – little value and increased toxicity • Accessory pathways (e.g. WPW) – affects normal condn tissue only Kinetics Renal elimination (half life 40 hours) – relies on p-glycoprotein Good absorption depending on formulation (tablets<elixir<capsules) [Digitoxin – metabolic elimination] Administration (routes, doses) PO – loading dose 15mg/kg in 3 doses over 12 hours - maintenance dose 5mg/kg OD (less if abnormal renal function) IV - 2/3 oral doses, infused over 30 mins Information (Patient and staff) S/Es Toxicity S+S and what they should do Monitoring Plasma concns < 3ng/ml but toxicity can occur below this Stopping – Usually long term Diltiazem Drug Name(s) Diltiazem Drug Class Ca2+ channel blockers - benzothiapines Mode of Action Block L-type Ca2+ channels Acts on myocardial and smooth vascular muscle Acts mainly in Phase 2 of the cardiac AP – prolongs it and the refractory period Negatively chronotropic (delayed SA + AV condn) and inotropic Decreases peripheral arteriolar tone decreased preload Benefits and Indications - Angina or Hypertension, if rate reduction is needed and beta blockade is contraindicated - Prinzmetal’s angina - Raynaud’s phenomenon/Dx Risks and Adverse effects Common – vasodilatation: • Headache • Dizzness • Hypotension • peripheral oedema Rare and serious: • Sinus bradycardia • Heart block • teratogenic Interactions • Propranolol – Diltiazem reduces its clearance – avoid combo • Ciclosporin – Diltiazem reduces its metabolism – reduce ciclosporin doses 40% • Digoxin – Diltiazem reduces its excretion (P-glycoprotein) Susceptible groups - Sinus bradycardia and sick sinus syndrome - Heart block - Pregnancy and breast feeding - Elderly - decreased metabolism – lower dose - Heart Failure??? Kinetics Absorbed orally 50% first pass metabolism half life 5 hours – long acting preparations are good Administration (routes, doses) Drug alone – 60-120mg TDS (BD in elderly) Long acting formulations are better long term – once or twice daily Information (Patient and staff) Monitoring Stopping Dipyridamole Drug Name(s) Dipyridamole Drug Class ‘Antiplatelet’ Mode of Action Phosphodiesterase inhibitor, as well as inhibiting adenosine breakdown Benefits and Indications Secondary prevention of Stroke (i.e. following TIA and stroke) Modified release form of dipyridamole has been shown to reduce the risk of stroke and death by 15%. It has an additive effect to aspirin It is also sometimes used for additional thromboembolic prophylaxis in prosthetic heart valves Risks and Adverse effects Minor: - Headaches - Nausea and vomiting - Postural hypotension Major: - Rash, urticaria and bronchospasm - Increases the risk of bleeding during surgery Interactions Potentiates and prolongs the effects of adenosine If given with clopidogrel, it increases the risk of bleeding Susceptible groups May worsen heart failure in those with recent MI, aortic stenosis, worsening angina, or pre-existing heart failure. May worsen myasthenia gravis Kinetics Hepatic metabolism Administration (routes, doses) Dipyridamole modified release capsules – 200mg BD Information (Patient and staff) Risk of allergy, warning of headaches, warning of feeling faint (esp. if working, driving) Monitoring Stopping Normally used for 2 years following TIA/Stroke. Diuretics – general information Diuretics have 2 broad functions: • To decrease oedema in: o Cardiac failure o Renal failure o Cirrhosis o Nephotic syndrome • To decrease blood pressure Types: Urinary excretion of Type Example and mechanism Thiazides Bendroflumethiazide – Inhibits Na+/Cltransporter in DCT Loop diuretics K+ sparing Aldosterone antagonists Mannitol Furosemide – inhibits Na+/K+/2Cltransporter in ascending Loop of Henle Amiloride – inhibits Na+ channels in the DCT Spironolactone – Na+ excretion and K+ retention by antagonising aldosterone Osmotic diuretic Na+ loss Potency ↓ ++ ++ ↑ ↓or ↔ +++ +++ ↓ ↔ ↑ + + ↑ ↓ ↔ ↑ + + ↑ ↔ ↑ ↑ + +++ Na+ K+ Cl- HCO3- ↑ ↑ ↑ ↑ ↑ ↑ Others exist, including the Carbonic anhydrase inhibitor, acetazolamide. There are also various combination preparations, including thiazide and loop diuretics with either K+ supplements, or a K+ sparing agent, however these should, in general, not be used in favour of individual balancing of K+ needs. Their differences: Efficacy and high ‘ceiling’ Furosemide and other loop diuretics are most effective. They also have other benefits, for instance they are venodilators, explaining their rapid onset in acute LVF. Thiazides are less strong (2-3x), but more gentle, preventing the complications of high ceiling diuretic therapy: • Discomfort • Nocturia, frequency • Acute urinary retention • Incontinence The exception is metolazone, a potent thiazide which has a high ceiling, and is used with furosemide in severe heart failure. Antihypertensive action Thiazides are more effective than loop diuretics. The mechanism is complex, but involves direct vasodilation, inhibition of the SNS through intracellular sodium levels, and haemodynamic compensation to the initial, transient diuresis. K+ balance Thiazide and loop diuretics decrease K+ equally. ↓K+ is dangerous below 3.5mmol/l, some even say below 4mmol/l. It is particularly dangerous with Cardiac glycosides (exacerbates toxicity) and with class I antiarrhythmic drugs (VT, VF, Torsades de pointes). Other things that lower the K+: • Vomiting • Diarrhoea • Laxatives • Steroids • Secondary hyperaldosteronism (e.g. from cirrhosis) K+ sparing and aldosterone antagonists both increase K+, and can lead to hyperkalaemia even when with a K+ lowering diuretic. Other things that raise K+: • Renal impairment • K+ supplements • ACE inhibitors • Trimethoprim One can prescribe a K+ supplement or a K+ sparing diuretic with a loop or thiazide. A K+ sparing diuretic is generally a better option, as it corrects Mg2+ also, is easier to take than unpleasant K+ pills, and aids the diuresis. Resistance to diuretics – three main reasons: • Secondary hyperaldosteronism from heart failure, nephrotic syndrome, cirrohsis. Add spironolactone. This will also aid mortality in severe heart failure. • Decreased renal blood flow, e.g. in severe heart failure. Treat with bedrest, inotropes, DA to increase renal blood flow, but consult first! • Decreased absorption in heart failure, especially with the already poorly absorbed furosemide. Test this pseudoresistance with some IV furosemide, then change to bumetanide, a better absorbed loop diuretic. Docusate sodium Drug Name(s) Docusate sodium Drug Class Stimulant and softening laxative Mode of Action Acts as a surfactant, but also has stimulant properties Benefits and Indications - Constipation - Used in some abdominal radiological procedures Risks and Adverse effects • Abdominal cramp • Diarrhoea Hypokalaemia Interactions Do not give with liquid paraffin or oil based treatments for constipation (can lead to absorption of these agents) Susceptible groups Avoid in intestinal obstruction Kinetics Should take effect in 1-3 days Administration (routes, doses) • Up to 500mg daily in divided doses • Encourage increased intake of liquids Information (Patient and staff) Cramps Monitoring Symptoms and stool chart Stopping Domperidone Drug Name(s) Domperidone, ‘Motilium’ Drug Class Peripheral dopamine receptor antagonist Mode of Action Acts on the chemoreceptor trigger zone Benefits and Indications - Nausea and vomiting - Particularly good for drug related nausea - Has a lower incidence of central side effects like sedation and dystonic reactions than metaclopramide as it does not cross the blood brain barrier. Particular uses: • With analgesia for Migraine (relieves nausea and speeds gastric transit) • Prevent vomiting with emergency contraception and post-exposure prophylaxis • Prevent nausea with apomorphine and other dopaminergic drugs It is also used in gastro-oesophageal reflux, especially in kids, and in diabetic gastroparesis. Risks and Adverse effects Better side effect profile than metoclopramide Rarely: • GI upset (pain, cramps) • Hyperprolactinaemia Very rarely: • Extra pyramidal SEs • Rashes • QT prolongation Torsades des pointes Interactions • Domperidone increases absorption of drugs from the small bowel, and decreases absorption of drugs from the stomach. • Arrythmias may be increased with drugs that prolong the QT • May antagonise hypoprolactinaemic effect of bromocritpine • May increase the risk of EPSEs with amantadine and typical antipsychotics Susceptible groups Contraindicated in: • Prolactinomas • Hepatic impairment • Conditions where increased gastric motility is harmful (obtruction, perforation, haemorrhage) Use with care in: • Children • Renal impairment (lower dose) • Pregnancy Kinetics Mainly metabolised in the liver, with mixed faecal and urinary excretion. Administration (routes, doses) PO - 10-20mg max QDS PR – 60mg BD Doxazosin and other alpha blockers Drug Name(s) Doxazosin Tamsulosin Drug Class Alpha adrenoreceptor antagonists (alpha blockers) Mode of Action These drugs antagonise the post synaptic alpha-1 receptors on smooth muscle, blocking the effects of noradrenaline. This leads to: • Peripheral arteriolar vasodilation and a drop in systemic vascular resistance, with reduces blood pressure and cardiac afterload. They do not cause a reflex tachycardia as there is no effect on alpha-2 receptors. • Relaxation of other sympathetically controlled smooth muscle, such as in the urinary tract, leading to a decrease of obstructive symptoms and an improved flow. Benefits and Indications • Hypertension • Cardiac failure (specialist) • Urinary symptoms in Benign Prostatic Hypertrophy • To aid the passage of a ureteric stone Risks and Adverse effects Common/important: - Postural hypotension (especially first dose hypotension) - Syncope Rarer: - Drowsiness - Headache - Failure of ejaculation Interactions All other antihypertensives increase the risk of hypotension, syncope and falls Susceptible groups • Renal impairment (increased sensitivity) • Patients with a history of postural hypotension and micturition syncope • Elderly (increased risk of falls) Kinetics Well absorbed orally, hepatic metabolism Administration (routes, doses) Doxazosin (for hypertension): 1mg OD PO increasing every 2 weeks to therapeutic dose (max. dose 16mg) Tamsulosin (for BPH): 400micrograms OD PO. Information (Patient and staff) Warn of postural hypotension, particularly for the early dose. Monitoring Assess response with BP monitoring. Flow studies for prostatism Erythromycin and the macrolides Drug Name(s) Erythromycin Also azithromycin, Clarithromycin Drug Class Macrolide antibiotics Mode of Action Inhibit the 50S subunit of bacterial ribosome Benefits and Indications The class: - Similar spectrum of antibiotic activity to the simple Penicillins (Penicillin G and V) o used in those with Penicillin allergy - Cannot be used for meningitis as they do not penetrate the blood-brain barrier - Active against atypical pneumonias – Mycoplasma, Chlamydia, Legionella Azithromycin: - Good coverage against Haemophilus influenzae - Can be used as a stat dose against chlamydial urethritis Erythromycin: - Used as a topical therapy for acne - Also stimulates gut motility – used in ICU Clarithromycin: - Used as part of triple therapy for H. pylori eradication. Risks and Adverse effects - Nausea and vomiting – common (the dose can be lowered for some infections) - Allergic rash – may be severe - Antibiotic associated diarrhoea - Prolongation of the QT interval, predisposing to Torsades de Pointes, especially if administered with other drugs that prolong the QT interval. - Cholestatic jaundice Interactions - Any drug that prolongs the QT interval – arrythmias - Inhibit P450 enzymes – potentiate effect of other medications including warfarin - Clarithromycin decreases the absorption of zidovudine Susceptible groups - Hepatic insufficiency – avoid if possible as increases risk of hepatic toxicity - Avoid in porphyria - Renal insufficiency – halve dose of clarythromycin, limit erythromycin to 1.5g/day - Avoid in pregnancy unless essential - Avoid in cardiac conduction abnormalities Kinetics Quickly absorbed, but must be enteric coated Eliminated by hepatic metabolism and excreted in the bile Administration (routes, doses) - many specific doses – see BNF Erythromycin – 500mg – 1g every 12 hours PO (can also be given IV) Azithromycin (for Chlamydia) – 1g stat dose PO Clarithromycin (for H. pylori) – 250mg BD PO Information (Patient and staff) Warn about risk if Nausea Monitoring Consider if hepatic or renal insufficiency is likely, especially with longer therapy (a week+) Consider an ECG to measure the QT interval in a patient with cardiac problems, or who is unstable. Fibrates Drug Name(s) Gemfibrozil Drug Class Fibrates Mode of Action Inhibitor of cholesterol synthesis decreasing VLDL secretion strongly lowers TGs, lowers LDLs, raises HDLs, Benefits and Indications - Hyperlipoproteinaemias - Primary prevention of CHD in patients with hyperlipidaemia – Gemfibrozil (in 40-55 yo men) Risks and Adverse effects - Myositis rhabdomyolysis - Increased risk of cholesterol gallstones especially with some of the older drugs Interactions Increased risk of myopathy/myositis i Susceptible groups Caution in renal impairment Avoid in pregnancy and breast feeding Kinetics Well absorbed PO Partly metabolised by the liver, and metabolites and drug excreted in urine. Administration (routes, doses) PO Information (Patient and staff) Risk of myositis Monitoring Stopping Normally a long term therapy Flecainide Drug Name(s) Flecainide Drug Class Class Ic antiarrhythmic drug Mode of Action Longer acting used dependent Na+ channel blocker Has little effect on AP but does effect the conducting system widened QRS Benefits and Indications - SVTs – AV nodal rhythms, paroxysmal AF, aberrant conduction pathways(WPW) - (Ventricular arrythmias – but only as last resort due to CAST study findings that they increase mortality after MI) Risks and Adverse effects CNS effects - minor Prolongs QT interval – arrythmogenic. Esp. if low K+ or poor LVF Interactions - Drugs increase concn – amiodarone, cimetidiine, fluoxetine, quinine, ritonavir - Drugs increase risk of heart failure – negativ inotropes – beta blockers and Ca2+ channel blockers - Hypokalaemia and other antiarrhythmics – increased arrhythmias Susceptible groups DO NOT USE following MI or in heart failure Hepatic or severe renal impairment Kinetics Metabolised by P450 system (14 hours) 25% excreted unchanged in urine Administration (routes, doses) PO – 50mg BD up to a max of 300mg BD Information (Patient and staff) Monitoring Opt pre-dose (trough) plasma concn is 0.2-1mg/l Flucloxacillin Drug Name(s) Flucloxacillin Drug Class Penicillase resistant Penicillin Mode of Action Inhibits peptidoglycan cell wall synthesis in G+ bacteria Benefits and Indications s Used against Staphylococcus infections as these typically produce Penicillase e.g.: • Cellulitis • Infective endocarditis (blind therapy or if staphylococcus is isolated, normally with gentamicin) • Septic arthritis (usually with fusidic acid) • Osteomyelitis • Otitis externa • Widespread impetigo Risks and Adverse effects Common: Rashes(10%), diarrhoea (bacterial overgrowth?) Rare: - Anaphylaxis (1 in 5000? 10% mortality) and other hypersensitivity - Cholestatic jaundice - Seizures and coma - High K+ and Na+ if large IV doses given (they are salts!) - Blood dyscrasias Interactions Susceptible groups Those with previous true Penicillin allergy Those with hepatic impairment - CAUTION Kinetics Renal excretion – can accumulate in renal insufficiency Administration (routes, doses) PO or IM - 250-500mg QDS IV – 250mg – 2g QDS Information (Patient and staff) Monitoring Consider monitoring renal and hepatic function, especially if therapy will last longer than a week Furosemide Drug Name(s) Furosemide (also bumetanide) Drug Class Loop diuretic Mode of Action Inhibits the Na+/K+/2Cl- transporter in the ascending loop if Henle, leading to increased NaCl excretion, with water following. A profound diuresis ensues. More K+ is excreted, as it is exchanged for Na+ in the DCT in proportion to the quantity lost. The drugs also has a venodilatory effect, useful in the treatment of acute pulmonary oedema in heart failure. Benefits and Indications • ↓ oedema in congestive cardiac failure, nephotic syndrome and cirrhosis • Treatment of acute pulmonary oedema • Treatment of acute and chronic renal failure (to ↑ urine output under expert supervision) Risks and Adverse effects • Hypovolaemia • ↓K+ • ↓Na+ • ↓Mg2+ • ↑blood sugar (small effect) • • • ↑uric acid gout in susceptible cases Acute urinary retention Cochlear damage (with rapid infusion >4mg/min) Interactions • ↓K+ made worse with laxatives and steroids • Aminoglycosides increase the risk of oto and nephrotoxicity • ↓K+ from furosemide can trigger digixin toxicity • Lithium excretion decreased by furosemide – half the Lithium dose and monitor • ↓K+ from furosemide can trigger torsades de pointes with class I antiarrhythmics Susceptible groups Hepatic insufficiency - ↓K+ can precipitate hepatic encephalopathy Benign prostatic hypertrophy – increases chance of retention Kinetics Poorly absorbed (50%) PO (less in congestive heart failure) Excreted in the urine unchanged Administration (routes, doses) Oedema and pulmonary oedema – 20-160mg IV, or 40-160mg OD PO mane Renal failure – 250-200mg IV (slow infusion) or PO Information (Patient and staff) Take in morning – avoid nocturia, or a bit later if awkward Interactions – inform other HCPs Monitoring Electrolytes, BM, Lithium in specific patients Stopping Normally long term therapy Fusidic acid Drug Name(s) Fusidic Acid Drug Class Anti-staphylococcal antibiotic Mode of Action Inhibits bacterial protein synthesis Benefits and Indications Treatment of staphylococcal infections, including some MRSA strains (in combination with another antibiotic) e.g. • osteomyelitis and septic arthritis • cellulitis • some skin infections Risks and Adverse effects Cholestatic jaundice Resistance rapidly develops, so use with other ABx Interactions Anatgonistic with quinolones (they inhibit each other’s antibiotic effect) Synergistic with rifampicin, with which it is often used Susceptible groups Hepatic dysfunction Kinetics Well absorbed PO Concentrates in bone, therefore good in osteomyelitis Administration (routes, doses) Sodium fusidate: 500mg TDS PO or IV However, as resistance develops quickly, it is usually given with another antibiotic Information (Patient and staff) Fybogel Drug Name(s) ‘Fybogel’ – Ispaghula Husk Drug Class Bulking laxative Mode of Action Indigestible fibre increases bulk in the stool, which retains water and increases peristalsis Benefits and Indications Constipation Particularly useful for patients with: • Intestinal stomas • Haemorrhoids and anal fissure • Diverticular disease • Irritable bowel syndrome • Sometimes used in Ulcerative colitis Risks and Adverse effects Risk of intestinal obstruction in patients with tight stenoses of their bowel, and if fluid intake is not adequate Interactions Susceptible groups Contraindicated in: • Intestinal obstruction (or patients at risk of obstruction) • Colonic atony • Faecal impaction Kinetics Not absorbed Administration (routes, doses) 1 sachet or 2x 5ml spoonfuls in water BD Maintain good fluid intake Information (Patient and staff) Monitoring Symptoms and stool chart Stopping Gaviscon Drug Name(s) Gaviscon Drug Class Mixed alginate and antacid preparation Mode of Action Neutralises stomach acid and forms alginate ‘raft’ on stomach contents, reducing reflux symptoms Benefits and Indications Relief of dyspepsia Risks and Adverse effects - Diarrhoea or constipation - Cramps - Masking symptoms of a more serious condition – peptic ulcer disease Interactions Antacids impair the absorption of many important medications, including: • Antibiotics • Antiepileptics • Antisychotics • Cardiac drugs • Iron and lithium • Thyroxine This can be reduced by not administering at the same time as other medications Susceptible groups Kinetics Alginate not absorbed Administration (routes, doses) Tablets – 1-2 tablets after meals and at bedtime Liquid – 5-10ml after meals and at bedtime Information (Patient and staff) Monitoring Symptoms Gentamicin and other aminoglycosides Drug Name(s) Gentamicin Also Neomycin, Tobramycin, Amikacin, Streptomycin Drug Class Aminoglycoside antibiotic Mode of Action Inhibit the 30S unit of the bacterial ribosome – bacteriocidal Benefits and Indications - Given for serious Gram negative infections - Some have activity against Pseudomonas - Have a synergistic effect with Penicillins against Streptococcal endocarditis - Tobramycin is used nebulised to treat Pseudomonas aeruginosa in CF patients - Neomycin is used for bacterial gut clearance in hepatic encephalopathy Risks and Adverse effects - Nephrotoxicity and Ototoxicity (both related to trough concentrations above 2mg/l) - Hypersensitivity is common, with a rash in 5% - They can have a neuromuscular blocking action Interactions - Nephrotoxicity increased with loop diuretics, antifungal drugs, cytotoxic drugs and ciclosporin. - Neomycin reduces vit K metabolism, potentiating warfarin effects - Neomycin reduces digoxin absorption - Aminoglycosides potentiate neuromuscular blocking drug effects. Susceptible groups - Those with renal insufficiency - Those with myasthenia gravis - Pregnant women Kinetics Not absorbed from the gut – give parenterally Normally given once daily Administration (routes, doses) Typically it is given in once daily doses, as the drug shows a post-antibiotic effect, and this strategy may be more efficacious and less toxic. The dose is body weight and height dependant, and dosing will be changed based on peak and trough levels. Some individuals are not suitable for once daily dosing, including: - Those being treated for G+ infections, who need 2-3 daily dosing - Pregnancy - Severe liver or kidney disease - Neutropenia - Extensive burns Information (Patient and staff) Check levels can be done at necessary times, esp. weekends Inform about possible allergic reactions such as rash, and the need for regular blood tests. Monitoring Before starting, check culture and sensitivities of infection, and check renal function. Measure peak (1 hour after administration) and trough (just before next dose) concentrations. Stopping Heparins Drug Name(s) Heparins Unfractionated Heparin, LMWH (enoxaparin, tinzaparin, daltaparin) Drug Class Acidic mucopolysaccharide 2-20kDa (LMWH – 2-7kDa) Mode of Action Unfractionated Heparin – enhances anti-thrombin III against thrombin and the intrinsic cascade, decreasing fibrin formation and prolonging the APTT LMWH – main action on factor Xa – no change in the APTT Benefits and Indications - Treatment of DVT and PE - Prophylaxis of DVT - Treatment of ACS Risks and Adverse effects - Haemorrhage – can be reversed with protamine (1mg per 100iu if within 15mins), and works with LMWH also. - Heparin-induced thrombocytopenia, immune related, 6-12 days after starting treatment it can (counterintuitively) lead to thromboses, DIC, bleeding, etc – uncommon with heparin, and rare with LWMH - Allergies Interactions Increased bleeding risk with other anticoagulants and antiplatelets Heparin’s effects can be rapidly reversed with protamine, LMWH less so Susceptible groups Any that are a bleeding risk Kinetics Unfractionated heparin undergoes liver metabolism Administration (routes, doses) DVT prophylaxis – 5000iu Heparin every 8-12 hours SC or 40mg OD SC of LMWH (20mg OD SC in moderate risk surgical patients) DVT Rx – 75iu/kg loading dose of Heparin, 18iu/kg per hour infusion (modified based on APTT) or 1.5mg/kg LMWH OD SC for at least 5 days and until adequate oral anticoagulation is established Rx of NSTEMI or UA – 1mg/kg BD SC of LMWH for 2-8 days Information (Patient and staff) Monitoring APTT, or the APT Ratio is used to monitor the levels of Heparin, normally daily Factor Xa activity can be measured in cases where LMWH levels are concerning, and in patients with poor GFR. Stopping Hyoscine Drug Name(s) Hyoscine Alternative – scopolamine (stereoisomer of atropine) Drug Class Muscarinic receptor antagonist Mode of Action Blocks action of ACh at muscarinic receptors, effectively decreasing parasympathetic activity. • Increased heart rate • Bronchiolar dilatation • Decreased secretions • Relaxation of smooth muscle • Pupilary dilatation Benefits and Indications - Travel sickness prophylaxis - Intestinal or renal colic, and for preventing bowel spasm in radiological procedures - IBS - Decrease secretions pre-operatively Risks and Adverse effects Common: • Antimuscarinic – dry eyes, dry mouth, blurred vision, constipation Rare: • Acute urinary retention (esp. in prostatic hyperplasia) • Glaucoma in susceptible patients • Confusion Interactions TCAs, MAOIs, antihistamines – may potentiate anti-muscarinic effects Neostigmine / Physostigmine – reverses adverse effects (AChase inhibitor) Alcohol – potentiates sedative effect Susceptible groups Avoid in the following: • Prostatic hyperplasia • Closed-angle glaucoma • Myasthenia gravis • Pyloric stenosis? • Paralytic ileus? Kinetics Well absorbed and metabolised – half life 2 hours Administration (routes, doses) Travel sickness – PO 300 micrograms 30mins before travel, repeat 6hourly doses, max 900micrograms/day Ipratropium and tiotropium Drug Name(s) Ipratropium/Tiotropium Drug Class Acetylcholine muscarinic receptor antagonists Mode of Action Antagonise Ach muscarinic receptors decrease the effects of the parasympathetic nervous system. As these are inhaled agents they work to dilate the bronchiolar tree. Benefits and Indications - COPD – significant improvements in FEV1 (about 15%) and FVC are seen. Some studies show greater patient benefit and greater FEV1 results for tiotropium. Combined with its once daily use, it may be both better used and more effective. - Asthma – ipratropium can be used in acute asthma. Risks and Adverse effects - Dryness, cough and irritation from the inhaler - Hypersensitivity - Headache, dizziness, blurred vision, tachycardia - Could precipitate closed angle glaucoma, and hypotension and urinary retention Interactions CAUTION with other anti-muscarinic drugs Susceptible groups - BPH – urinary retention - Closed angle glaucoma – exacerbation - BUT it seems unlikely that the risks are that great Patients hypersensitive to soy, peanuts or atropine Kinetics Ipratropium is minimally absorbed, both from the gut and from mucous membranes, so the risk of antimuscarinic side-effects is low. Administration (routes, doses) Ipratropium - 1-2 puffs of 20 micrograms TDS Tiotropium – 1 inhaled capsule OD (18 micrograms) Information (Patient and staff) Don’t spray into eyes, and contact GP if you get sudden eye pain. Monitoring Stopping Lactulose Drug Name(s) Lactulose Drug Class Osmotic laxative Mode of Action • This synthetic disaccharide is not absorbed from the GI tract, leading to fluid retention in the bowel. • This leads to a low pH diarrhoea, which handily also discourages bacteria that produce ammonia. Benefits and Indications • Constipation • Hepatic encephalopathy Risks and Adverse effects Flatulence Cramps/ Abdo pain Interactions Lactulose may increase warfarin effect Susceptible groups Contraindicated in: • Intestinal obstruction • Galactosaemia Caution in lactose intolerance Kinetics Not absorbed Administration (routes, doses) Constipation: Initially 15ml BD PO, adjusted to symptoms Hepatic encephalopathy: 30-50ml TDS PO, adjusted to maintain 2-3 soft stools a day Encourage oral intake of liquids to aid the laxative effect Information (Patient and staff) Side effects Monitoring Symptoms and stool chart Stopping Laxatives Type Example Bulking Bran/Ispaghula Softening Stimulating Osmotic Arachis oil/ glycerol/ docusate Senna/ Castor oil/ picosulfate/ docusate Lactulose/ Mg2+ salts/ phosphate enemas Mode of Action Absorb water – increasing stool bulk and stimulating natural rectal reflexes Lubricate and soften the stools Act on bowel, increasing peristalsis, decreasing water and electrolyte absorption Keep water in the bowel – increased transit time and ease of defaecation Benefits and Indications Bulking – good in simple chronic constipation, or with diverticular Dx, IBS, pregnancy, stomas and anal fissure or haemorrhoids. Softeners – Good in cases where a bulking laxative cannot be used due to intestinal pathology (see risk section below). Also particularly good in patients with anal fissure or haemorrhoids where pain is preventing defaecation. Stimulants – These cause rapid evacuation, and are good for bowel prep for radiological or surgical interventions. Also used post faecal impaction. Osmotic – good additional drugs (lactulose orally, salts rectally). Lactulose is also used in hepatic encephalopathy to decrease ammonia absorption from the gut (lowers pH decreasing ammonia producing organisms) . Risks and Adverse effects Bulking – commonly cause flatulence, and can lead to obstruction in patients with stenosis, adhesions, ulceration, scleroderma and autonomic neuropathy). Softeners – Given rectally and give few side effects. Stimulants – repeated use leads to fluid and electrolyte depletion, colonic atony. Hypokalaemia is a particular risk with abuse. Osmotic – giving salts can fluid deplete the patient, and can lead to increased absorption of those salts. Interactions Susceptible groups Those with bowel pathology mentioned above should not be given bulk forming laxatives, as this can lead to obstruction. Patients with stomas need special attention – bulking laxatives can be used, and in severe cases a small dose of senna can be be given. Children may be afraid and concerned about both constipation and the treatments, avoid treatment if possible, and care should be managed by someone experienced. Enemas should be avoided where possible. Information (Patient and staff) All patients (except those at risk of intestinal obstruction) should be advised to increase fibre and fluid intake, and told that bowel habits vary widely. Tell patients that laxatives should not be used long term. Lidocaine Drug Name(s) Lidocaine Old name lignocaine Benzocaine Tetracaine (Ametop cream) Drug Class Class Ib antiarrhythmic drug. Local anaesthetic Mode of Action Fast dissociating used dependent Na+ channel blocker. Cardiac: Slight decrease in automaticity Decreases conduction in ischaemic tissues but not normal tissues. Main action in ventricles and abnormal conduction tissue Benefits and Indications Stops ventricular arrhythmias – VF, VT, fibrillation Produces effective local anaesthesia Risks and Adverse effects - 6% get side effects if they have an IV infusion – DOSE related - CNS toxicity – Nausea and Vomiting, decreased consciousness, coma, convulsions - Cardiac toxicity – brady and tachyarrhythmias, asystole, hypotension - Digit ischaemia if with adrenaline as local anaesthetic Interactions High hepatic clearance ratio drugs reducing hepatic blood flow decrease clearance (cimetidine, propranolol) Arrythmogenic activity increased by hypokalaemia – measure and correct it Adrenaline in local anaesthetic formulations leads to vasocontriction and increases maximum dose of lidocaine that can be used Susceptible groups Sick sinus syndrome and preexisting conduction system problems – CAUTION Liver disease and Heart failure patients may need decreased doses Kinetics First pass metabolism – don’t give PO Liver metabolism with short half life (1.5 hours) Metabolites cause CNS toxicity – limit treatment to less than 48 hours Administration (routes, doses) Cardiac: 100mg IV injection (10 ml of 1% over 2 mins) Follow with infusion tapering down (due to rapid metabolism) Local anaesthetic: 0.5, 1 and 2% solutions with and without 1 in 200,000 adrenaline (500µg/100ml) Max. dose of 200mg, or 500mg with adrenaline, with max adrenaline dose of 500µg. Check that the needle is not in a vein, and do not give adrenaline preparations to digits Also creams, gels and sprays are available Monitoring Plasma concentration not useful to measure Measure K+ Monitor for toxicity for at least 30 minutes Stopping – Do not give for more than 24-48 hours. Magnesium salt laxatives Drug Name(s) Magnesium hydroxide laxative Drug Class Osmotic laxative Mode of Action Salt leads to retained water in the bowel Benefits and Indications - Constipation – best for occasional use - [Dyspepsia (although other magnesium salts are more commonly used)] Risks and Adverse effects - Abdominal pain - Hypokalaemia NB: Milpar is a mixture of magnesium hydroxide and liquid paraffin Liquid paraffin can lead to serious problems, including: • Anal irritation • Granulomatous reactions in the bowel • Lipoid pneumonia if aspirated • Decreased absorption of fat-soluble vitamins It is therefore not recommended for regular use Interactions Magnesium (and aluminium) salts are also antacids and impair the absorption of many important medications, including: • Antibiotics • Antiepileptics • Antisychotics • Cardiac drugs • Iron and lithium • Thyroxine This can be reduced by not administering at the same time as other medications Susceptible groups Contraindicated in acute GI conditions Renal impairment - AVOID Hepatic impairment – AVOID if severe Kinetics Administration (routes, doses) Constipation: 30-45ml with water, usually at bedtime Give at a different time to other drugs Information (Patient and staff) Monitoring Symptoms and stool chart Stopping Best for short term use only – abused by some Magnesium sulphate Drug Name(s) Magnesium sulphate Drug Class Elemental ion Mode of Action Used in many enzyme systems. Magnesium stores often mirror Potassium stores Benefits and Indications - Treatment of acute severe asthma - Treatment of some arrhythmias such as Torsades des pointes - Treatment of hypomagnesaemia (e.g from diuretics) - Treatment of eclampsia/ pre-eclampsia – treatment and prevention of seizures Risks and Adverse effects Uncommon – hypermagnesaemia - Muscle weakness and reduced reflexes - Nausea - Flushing - CNS effects – diplopia, slurred speech Interactions - Magnesium and calcium channel inhibitors can cause severe hypotension - Potentiate the effect of non-depolarising muscle blockers Susceptible groups Renal insufficiency Kinetics Excreted renally (however only accumulates in severe renal insufficiency) Administration (routes, doses) - Arrhythmia and Asthma – 8mmol (2g) IV over 10 minutes. - Eclampsia – 16mmol (4g) IV over 5-10 minutes, followed by 4mmol/h for 24hours. Information (Patient and staff) Monitoring Assess clinically and biochemically for hypermagnesaemia Stopping Mesalazine and other aminosalicylates Drug Name(s) Mesalazine, Sulfasalazine, Olsalazine Drug Class Aminosalicylates Mode of Action Inhibits inflammation in the gut, possibly through inhibiting prostaglandin synthesis. However, Sulfasalazine’s mechanism in Rheumatoid arthritis may be through the sulfapyridine moiety. Benefits and Indications - Ulcerative colitis – treatment of acute attacks and for maintenance therapy. - Crohn’s Disease – mainly for acute treatment - Rheumatoid arthritis (only Sulfasalazine) Risks and Adverse effects Risks of aminosalicycates in general: - Interstitial nephritis - Blood dyscrasias - Hepatic damage Risks of Sulfasalazine (due to sulfapyridine moiety): - Nausea, Vomiting - Abdo pain - Reversible sterility - Allergic reactions o Fixed drug reactions o Erythema nodosum, erythema multiforme, SLE-like syndrome Interactions - It decreases folic acid absorption - Lactulose changes the gut pH, leading to decreased release of the drug from pH sensitive capsules Susceptible groups Mesalazine crosses the placenta in negligible quantities, so it is safe in pregnancy, but should be used with caution like all drugs. Sulfasalazine in pregnancy can lead to haemolytic anaemia Kinetics Mesalazine (5-ASA) is well absorbed orally, but as it is wanted in the lower gut lumen, it is either: - Put in pH sensitive capsules - Made into a dimer, that is hydrolysed by colonic bacteria (olsalazine) - Joined to sulfapyridine, that is hydrolysed by colonic bacteria (sulfasalazine) That which is absorbed is renally excreted rapidly Administration (routes, doses) e.g. UC Mesalazine PO – 1.5-4g/day in divided doses Enemas can also be used Information (Patient and staff) Side effects – esp. signs of bone marrow or liver toxicity (bruising, bleeding, sore throat, jaundice). Monitoring Monitor FBCs and LFTs regularly for the first 3 months Monitor clinical response Metformin Drug Name(s) Metformin Drug Class Biguanide Mode of Action • Poorly understood mechanism that decreases blood glucose. • It seems to aid uptake of glucose into skeletal muscle (decreasing insulin resistance) and decreases gluconeogenesis in the liver. • As such, it is only effective if there is endogenous insulin secretion. Benefits and Indications Hypoglycaemic agent in Type II DM - Prevents weight gain in overweight patients with DM - It does not cause hypoglycaemia It is also used in Polycystic Ovarian Syndrome, where it aids weight loss, hirsutism and ovulation Risks and Adverse effects Minor: - GI side effects common initially: anorexia, nausea, diarrhoea, abdo pain Major: - Lactic acidosis (rare) - Allergic symptoms (urticaria) - Hepatitis (rare) Interactions Interaction with drugs that may affect renal function: • General anaethesia • Iodine containing IV contrast Susceptible groups Any renal impairment (increased risk of lactic acidosis) Ketoacidosis Any condition with likely tissue hypoxia • Sepsis • Respiratory Failure • MI Kinetics Excreted unchanged in the urine Administration (routes, doses) Metformin 500mg OD to 2g in 3 divided doses PO – Start 500mg at breakfast, increasing by 500mg each week until adequate effect achieved. Information (Patient and staff) Monitoring Metoclopramide Drug Name(s) Metoclopramide – ‘Maxolon’ Drug Class Dopamine receptor antagonist (+/- serotonin receptor effects) (closely related to phenothiazines) Mode of Action Acts at the chemoreceptor trigger zone, and in the gut, leading to antiemetic and prokinetic properties. Benefits and Indications Nausea and vomiting from many causes (less useful for motion sickness, post-op nausea and chemotherapy nausea) Increased gastric motility • With analgesia to aid absorption (e.g. migraine, ACS) • Sometimes before emergency surgery • In barium studies Risks and Adverse effects Sometimes: • Extrapyramidal side effects, especially oculogyric crises • Hyperprolactinaemia • Drowsiness • Restlessness • Hypertension Very rarely: • Neuroleptic malignant syndrome • Tardive dyskinesias • Allergies • Arrythmias Interactions Increases absorption of drugs from small intestine, and decreased absorption of drugs from stomach Susceptible groups • The young, especially women under 30 (dystonias) • The elderly (dystonias) • G6PD deficiency (methaemoglobinaemia) Contraindicated in: • Conditions where increased GI motility dangerous: obstruction, haemorrhage, perforation, 4 days following GI surgery • Phaeochromocytoma Kinetics Hepatic metabolism, renal excretion Administration (routes, doses) PO/IM/IV – 10mg TDS Information (Patient and staff) Monitoring Observe for dystonic reactions – if they occur stop drug and give procyclidine. N-Acetyl cysteine Drug Name(s) N-Acetyl cysteine Drug Class Mode of Action • Paracetamol poisoning: conjugates the toxic hydroxylamine metabolite of paracetamol that builds up when hepatic glutathione reserves are depleted. This stops it binding to hepatic proteins and causing damage. • Before Angiogram: ? Benefits and Indications Paracetamol overdose where the dose exceeds treatment level on the nomogram, or when the nomogram cannot be used but toxic levels suspected (e.g. staggered overdose, or lack of history to determine timing of overdose). Decreases risk of renal failure in patients needing IV contrast whose Creatinine clearance in less than 50ml/min Risks and Adverse effects Hypersensitivity reactions – reduce infusion rate, and treat rash with antihistamine or asthma with salbutamol. Interactions Susceptible groups Certain patients need treatment with NAC at a lower paracetamol concentration on the nomogram – the high risk groups: • Malnurished • Anorexic • High alcohol intake (acutely or chronically) • HIV positive • Those on enzyme inducing drugs (carbamazepine, Phenobarbital, phenytoin, rifampacin, alcohol, St. John’s wart) Asthma may be exacerbated – use with caution Kinetics Administration (routes, doses) For Paracetamol toxicity (IV infusion in 5% glucose): • 150mg/kg in 200mL over 15 minutes • 50mg/kg in 500mL over 4 hours • 100mg/kg in 1L over 16 hours o continue as necessary Information (Patient and staff) Monitoring Monitoring is for signs of hepatic toxicity from Paracetamol – U+Es, LFTs, Clotting Stopping Naloxone Drug Name(s) Naloxone, Naltrexone Drug Class Opioid antagonist Mode of Action Competitive antagonists at opioid receptors, reversing their pharmacological effects Benefits and Indications Naloxone is used to reverse the toxic effects of opioids: • Drug overdose • Post-operative respiratory depression Naltrexone is generally reserved for relapse prevention in previously opioid dependant patients Risks and Adverse effects Naloxone administration leads to rapid withdrawal syndrome: - Sweating - Lacrimation and rhinorrhoea - Restlessness, irritability and tremor - Anorexia - Dilated pupils, - Goosebumps - Nausea andvomiting - Cramps and diarrhoea. Interactions Susceptible groups Kinetics Naloxone is given IV, and it has a short half life (1 hour), so repeated administation will be needed as most opiates have a longer half life than this. Administration (routes, doses) Naloxone 0.4-2 mg IV repeated every 2-3 minutes, repeated as necessary to max. 10mg (then reconsider diagnosis before continuing treatment). Information (Patient and staff) Monitoring Observations for the patient’s response, and for the drug wearing off are needed. Nicorandil Drug Name(s) Nicorandil Drug Class Potassium channel agonist Mode of Action Activation of Potassium channels relaxes smooth muscle. Its main action is on the venous system, reducing pre-load. Benefits and Indications Prevention and long term treatment of angina Risks and Adverse effects Common: • Flushing, palpitation, dizziness, headache (esp. on initiation) • nausea and vomiting Rare: mouth ulcers, rash, myalgia Toxicity: low BP, angioedema, hepatic toxicity Interactions Hypotension increased with: • Sildenafil (and similar drugs) – AVOID • MAOIs • TCAs • Alcohol Susceptible groups C/I in: - cardiogenic shock - left ventricular failure with low filling pressures - hypotension - breast-feeding Also care should be taken in acute pulmonary oedema and in MI Kinetics Orally absorbed Metabolised in the liver – 1 hour half-life Some renal excretion Administration (routes, doses) 10-20mg BD PO Information (Patient and staff) Headaches Avoid large amounts of alcohol Monitoring BP Symptoms of angina Nitrates Drug Name(s) Glyceryl trinitrate, Isosorbide mononitrate Drug Class Nitrates Mode of Action Relieves the pain of angina pectoris through 3 mechanisms; - Peripheral arteriolar vasodilatation decreased SVR Cardiac work - Peripheral venous vasodilatation reduction in LVEDP increased coronary blood flow in diastole - Vasodilating effects in coronary artery collaterals redistribute blood flow The reduction in preload and afterload is also beneficial in heart failure Benefits and Indications - Angina pectoris and pain in ACS - Heart failure Risks and Adverse effects Common S/Es: Throbbing headache, sinus tachycardia, hypotension Tolerance Interactions Nitrates and sildenafil can lead to severe hypotension, fainting and even death. Susceptible groups Kinetics GTN – extensive first pass metabolism – therefore it is given sub-lingually. Buccal and transdermal routes can be used for slower administration. It has a half-life of a few minutes. IMN – Has a longer half-life and is absorbed well PO. Administration (routes, doses) GTN Angina - Spray – 1-2 400 microgram puffs with pain or anticipated pain. - Sub-lingual tablet – 1-2 0.5mg tablets under tongue - Patch – 5-10mg patch once daily, removed at night Acute LVF - 100-200micrograms/min IV IMN/IDN Tolerance develops quickly, so a nitrate free period is encouraged, typically at night. Information (Patient and staff) Spray and pills – administration techniques. Pills - how to keep it, don’t keep the tablets past sell-by date. Tolerance – nitrate free period If chest pain gets worse - ambulance Monitoring Stopping NSAIDs Drug Name(s) Ibuprofen, Indomethacin, Diclofenac Drug Class NSAIDs Mode of Action Inhibition of COX 1 and 2 leading to decreased PG synthesis analgesia anti-inflammatory action anti-pyrexia Benefits and Indications Analgesia for mild to moderate pain, and, in conjunction with opiates, for moderate to severe pain where they show an opiate sparing effect Analgesia and anti-inflammatory action in RA, OA, Ank Spond, Musculoskeletal pain Ibuprofen - Analgesia and anti-inflammatory action in Still’s Dx and the seronegative arthropathies Diclofenac in acute gout Indomethacin in treatment of PDA in premature neonates [Mefanamic acid for menorrhagia] Risks and Adverse effects - GI disturbance is common - There is a risk of serious GI bleeding – Ibuprofen < Diclofenac < Indomethacin - Hypersensitivity (more in ppts with aspirin hypersensitivity) - Renal Damage Interactions Susceptible groups All renally impaired patients (most elderly patients) Kinetics Administration (routes, doses) PO Ibuprofen 200-800mg TDS or QDS (max 2.4g daily) Diclofenac 25-50mg BD or TDS Indomethacin 50-200mg in BD or TDS divisions (but start at low dose) Information (Patient and staff) Monitoring Renal function if concerned Stopping Stop when not necessary (esp. for analgesia) to decrease risk of GI bleeds and renal impairment Omeprazole and the PPIs Drug Name(s) Omeprazole Lansoprazole, esomeprazole Drug Class Proton Pump Inhibitors Mode of Action Binds irreversibly to H+/K+ ATPase in gastric parietal cells 90% ↓ in acid secretion – more effective and longer lasting that the H2- receptor antagonists. Benefits and Indications • Peptic ulceration - It leads to effective ulcer healing • Erosive reflux oesophagitis - Successful in oesophagitis in 75% of cases • Used as part of the triple therapy for H. pylori eradication • Used in the Zollinger-Ellison syndrome (a gastrin secreting tumour, typically in the pancreas or duodenal wall) • Successful in dyspepsia in over half of cases Risks and Adverse effects - GI disturbance (N + V, Diarrhoea, Constipation, flatulence, pain) - Hypersensitivity (rash, angioedema) - Increased incidence C. difficile diarrhoea Interactions - P450 inhibitor (minor effect at normal doses) - Warfarin bleeding - Phenytoin toxicity Susceptible groups Not known to be harmful in pregnancy – benefit risk ratio Kinetics - Well absorbed - They bind irreversibly to the transporter – so they have a long duration of effect. - They have a short half life Administration (routes, doses) PO – 20-40 mg OD or PRN(average 0.4 tablets a day) IV 72 hours in GI bleed Higher doses needed in the Zollinger-Ellison syndrome Information (Patient and staff) Monitoring Symptoms Endoscopy H.pylori eradication Also INR and phenytoin in relevant patients. Stopping Normally given as a 2 month course. If symptoms return, chronic low doses can be given. Sometimes given long term with ulcer causing drugs. Ondansetron Drug Name(s) Ondansetron Drug Class 5-HT3 receptor antagonists Mode of Action It therefore has both central and peripheral anti-emetic properties. These selective serotonin antagonists have their mode of action in the chemoreceptor trigger zone and on vagal afferents in the GI tract. Benefits and Indications N+V – especially for chemotherapy, radiotherapy and post-op. Risks and Adverse effects Common: • Headache after repeated doses. • Constipation • Flushing can occur if given IV Rarer: • • • • Hypotension Bradycardia Arrythmias Transient visual disturbances (if IV) Interactions Their effects are enhanced by corticosteroids, and this has therapeutic uses, with dexamethasone often being given as a single dose with it. • • • Risk of arrythmias with: o A selection of antiarrythmic drugs including amiodarone and lidocaine o Beta-blockers Odansetron antagonises the analgesic effects of tramadol Levels affected by enzyme inducers (e.g. rifampicin) and enzyme inhibitors (carbamazepine, phenytoin) Susceptible groups Long QT interval Hepatic impairment Kinetics Well absorbed, but extensiely metabolised by the liver (half life 4h). Administration (routes, doses) Emetogenic chemotherapy: 8mg PO/IV/IM (or 16mg PR) before treatment, then if needed this can be repeated twice every 2-4 hours, before starting 8mg BD PO for 5 days Post-op N+V: 8mg PO/IV/IM before surgery, followed by 2 further doses every 8 hours. Information (Patient and staff) Paracetamol Drug Name(s) Paracetamol Drug Class Mode of Action Selective inhibition of PG synthesis Benefits and Indications - Analgesic - Antipyretic Risks and Adverse effects No S/Es in the therapeutic range Toxicity leads to hepatic necrosis within 48 hours, and rarely acute tubular necrosis. Interactions Warfarin – with prolonged max dose (>1 week) it can prolong INR Susceptible groups Severe hepatic impairment, alcohol dependence Kinetics Well absorbed PO Metabolised in the liver and then excreted renally - 80% of a normal dose is conjugated as the glucuronide and renally excreted - 20% is metabolised to the hydroxylamine, which then reacts with glutathione Glutathione supplies are finite, and toxicity occurs when the stores are depleted, and the toxic metabolite accumulates in hepatocytes and reacts with cell structures Glutathione replacements can be given – N-acetylcysteine, methionine Administration (routes, doses) 0.5-1g every 4 hours PO (max 4g/day) Information (Patient and staff) DON’T EXCEED DOSE Other OTC drugs may contain it Monitoring Not necessary except in toxicity Stopping Not dangerous in chronic use Penicillin Drug Name(s) Penicillin G – benzyl penicillin Penicillin V - phenoxymethylpenicillin Drug Class – Penicillinase sensitive β-lactam antibiotic Mode of Action - Bacteriocidal - Inhibits cell wall synthesis (prevents X-linking enzyme) Benefits and Indications Most Streptococus infections (G+ cocci) • S. pyogenes: ENT infections, puerperal sepsis, RF prophylaxis – ALONE • S. viridans, faecalis, etc: Endocarditis – with synergistic GENTAMICIN • S. pneumoniae: Pneumonia, meningitis, bacteraemia - ALONE Neisseria (G- cocci) • N. meningitides – Meningitis • N. gonorrhoeae – Gonorrhoea G+ cocci • Corynebacterium diphtheriae – Diphtheria • Clostridium perfringens and tetani – gas gangrene and tetanus • Bacillus anthracis – Anthrax Others • Treponema pallidum/pertenue – Syphilis/ Yaws • Leptospira spp. – Leptospirosis • Actinomyces israelii - Actinomycosis Risks and Adverse effects Common: Rashes(10%), diarrhoea (bacterial overgrowth?) Rare: - Anaphylaxis (1 in 5000? 10% mortality) and other hypersensitivity - Seizures and coma - High K+ and Na+ if large IV doses given (they are salts!) - Blood dyscrasias Interactions Probenecid – prolongs excretion and is sometimes used therapeutically Other drugs decreasing renal excretion - indomethacin Susceptible groups Renal insufficiency Kinetics Renal excretion – short half life – 30-60mins Administration (routes, doses) Penicillin G - IM - 0.3-6g/day split QDS - IV – up to 24g/day infusion Penicillin V - PO – 250mg QDS (Probenecid - 500mg QDS) Information (Patient and staff) Hypersensitivity Importance of finishing course or telling Dr. if drug stopped Potassium Drug Name(s) Potassium chloride Drug Class Essential ion Mode of Action Intracellular ion used in maintaining electrochemical gradients. Its levels are tightly controlled, and changes can cause serious cardiac side effects: - Low levels cause membrane depolarisation leading to arrhythmias - High levels stabilise membranes, and can lead to asystole Benefits and Indications - Treatment of hypokalaemia from any cause (e.g. diuretics, steroids) - Treatment of digoxin toxicity if there is hypokalaemia (as it exacerbates it) - To keen the K+ level above 4mmol/L in patients with cardiac disease. Risks and Adverse effects - Hyperkalaemia, especially with medications that increase K+ levels (see interactions) - Pain and phlebitis with high peripheral concentrations - Tissue necrosis if there is extravasation - Oral supplements can cause nausea and vomiting Interactions Hyperkalaemia, especially with: • Potassium sparing diuretics • ACE-inhibitors • Angiotensin II receptor inhibitors • NSAIDs Susceptible groups Renal insufficiency Kinetics Renally excreted, so altered by renal function and diuretics Administration (routes, doses) PO: Sando K tablets: 12mmol K+ per tablet – 2 tablets TDS IV: Usual dose 0.5-1mmol/kg/day (max 3mmol/kg/day) - Peripheral line – Max concn 40mmol/L, max rate 20mmol/h - Central line – Max concn 20mmol/100mL, max rate 30mmol/h SC: Although there is some debate, concentrations of 20mmol/L or less can be given SC over 12 hours or longer Information (Patient and staff) Tell patients about dietary sources of potassium – potato, banana. Monitoring Measure K+ before supplementation Measure K+ daily if parenteral K+ is given, and consider regular ECGs to look for tall T waves indicative of hyperkalaemia Stopping Prochlorperazine Drug Name(s) Prochlorperazine Drug Class Phenothiazine antipsychotic Mode of Action D1 and D2 receptor antagonist, especially in the mesolimbic system and in the chemoreceptor trigger zone. Also some alpha adrenergic, and muscarinic inhibition. Benefits and Indications Prevention and treatment of nausea and vomiting • Often used for post-op N+V Treatment of labyrinthitis (both N+V and motion sensation) Generally NOT recommended as an antipsychotic (less effective than alternatives) Risks and Adverse effects Common, and can occur with short term useL • EPSEs, including dystonias and tremor (worse in young, old and ill) • Some sedating effect • CV - Some hypotension seen, risk of arrythmias (increased QT) • Change in body temperature (dose dependant) Rare, or seen with chronic use: • Neuroleptic malignant syndrome • Gynaecomastia, galactorrhoea • Hepatitis, jaundice • Antimuscarinic effects • Blood dyscrasias Interactions Many: • Sedation – with all drugs that cause sedation • Arrythmias – with all drugs that prolong the QT • Hypotension – with all drugs that cause hypotension • Dyscrasias – with other drugs toxic to bone marrow Enzyme inhibitors/inducers – will change levels of these drugs Susceptible groups Contraindicated in: • CNS depression • Phaeochromocytoma Increased side effects in: • Parkinson’s Disease • The young and old • Cardiovascular disease • Epilepsy • Hepatic disease • History of blood dyscrasias • Glaucoma Kinetics Hepatic metabolism, mixed excretion Administration (routes, doses) N+V: • Acute attack – 20mg PO, followed by 10mg 2 hours later (or 12.5mg IM single dose) • Prevention – 10mg PO/IM TDS • A buccal preparation is also available Labyrinthitis: 5mg PO TDS, increased to 10mg PO TDS if needed Information (Patient and staff) Sedating Warn to look for side effects Do not use long term without close supervision Monitoring Short-term – watch for side-effects, particularly hypotension and EPSEs Long-term – consider FBCs, LFTs, RBG, Stopping Use for short periods only Ranitidine and the H2 antihistamines Drug Name(s) Ranitidine Cimetidine – earlier type with worse interaction profile Drug Class H2 receptor antagonists Mode of Action Histamine stimulates gastric acid secretion via the H2 receptors on parietal cells. Benefits and Indications Ulcers: 8 week course heals 90% of DU and 60% GU. Dyspepsia: Symptoms are reduced Risks and Adverse effects Cimetidine was antiadrogenic and prolactin stimulating gynaecomastia, impotence, galacttorrhoea. Interactions Cimetidine is a liver P450 enzyme INHIBITOR leading to increased drug concentrations: • Warfarin bleeding • Phenytoin toxicity • Theophylline arrythmias Ranitidine is not an inhibitor of P450 Susceptible groups Elderly confusion Renal inpairment increased concentrations confusion – half dose? Pregnancy and breast feeding avoid unless essential Kinetics 60% renal elimination half life 2 hours Administration (routes, doses) PO – 105mg BD, but can give single dose nocte for DU (nocturnal acid secretion) IV – GI bleed? Information (Patient and staff) Monitoring Symptomatic relief Endoscopy Stopping For ulcer healing – 6-8 weeks Repaglinide and the meglitinides Drug Name(s) Repaglinide, Nateglinide Drug Class Meglitinides Mode of Action Similar action to sulfonylureas, stimulating insulin secretion from the B cells in the Islets of Langerhans. Benefits and Indications Hypoglycaemic agent in Type II DM where there is still endogenous Insulin production Risks and Adverse effects - Hypoglycaemia - Hypersensitivity reactions (rash, urticaria) Interactions Risks of hypoglycaemia increased by; - Fibrates - Some antibiotics (Clarythromycin) - Some antifungals (Itraconazole, Ketoconazole) Susceptible groups Ketoacidosis Severe hepatic impairment Kinetics Hepatic metabolism, and excretion Administration (routes, doses) Repaglinide 500 micrograms to 4mg TDS-QDS (just before meals) Information (Patient and staff) Risk of hypoglycaemia Risk of interactions Monitoring Regular blood sugars Stopping Rifampicin Drug Name(s) Rifampicin Drug Class Bacteriocidal antibiotic Mode of Action RNA polymerase inhibitor Benefits and Indications • Treatment of Mycobacterium tuberculosis (with Isoniazid and other agents) • Treatment of Mycobacterium leprae (with dapsone and clofazimine) • Treatment of MRSA infections, often in combination with fusidic acid • Prophylaxis of bacterial meningitis in contacts • Also used in Brucellosis, Legionnaire’s disease Risks and Adverse effects Common side effects: • Transient rise in liver transaminases in the first 2 months of treatment • GI disturbances • Rashes and allergic reactions • Orange-red bodily secretions Severe side-effects: • Hepatotoxicity • Influenza-like illness • Renal failure • Haemolytic anaemia and Thrombocytopenia Interactions Rifampicin absorption is decreased by Rifampicin is a potent enzyme inducer, decreasing plasma levels of many drugs, including: • Warfarin • Theophylline • Steroids • Phenytoin • Sulfonylureas • OCP • Benzodiazepines • Digoxin • Calcium channel blockers • Bisoprolol • Carvedilol • Ciclosporin • Imidazole antifungals • Haloperidol • Lamotrigine Susceptible groups Hepatic impairment High alcohol intake Renal impairment Kinetics Well absorbed orally Distributes in all tissues well, including CSF and bone Metabolised in the liver – most excreted in bile and faeces Administration (routes, doses) For TB – 600mg OD for at least six months (with other therapy in initial and continuation phase, according to sensitivities. Therapy longer with meningeal, brain and bone TB) For meningitis prophylaxis – 600 mg PO every 12 hours for 2 days Information (Patient and staff) Risk of liver damage – warn of symptoms Staining of secretions – esp. if wears contact lenses Monitoring LFTs before and during treatment (certainly once in first 2 months) Renal function may be useful before treatment starts Stopping Therapy for TB should be continuous – interruptions can lead to resistance Rosiglitazone and the glitazones Drug Name(s) Rosiglitazone Drug Class Thiazolidinediones (or the Glitzones) Mode of Action Bind to a nuclear receptor (PPAR-gamma) in adipose cells, leading to an upregulation of lipogenesis. This seems to lower insulin resistance. Benefits and Indications In diabetes it: • Lowers insulin resistance (reducing insulin demands by up to 30%) • Lowers free fatty acids and triglycerides However, this effect is slow in onset, taking 1-2 months to reach full effect. Risks and Adverse effects Minor: - GI disturbance - Headache - Fatigue - Weight gain (1-4kg: both through fluid retention, and addition of subcutaneous fat) Major: - Hypoglycaemia Hepatotoxicity (rare) Provocation of heart failure due to fluid retention Small increased risk of myocardial ischaemia Interactions Works synergistically with metformin. Can precipitate heart failure or myocardial ischaemia with Insulin Susceptible groups - Hepatic impairment (avoid) - Heart Failure (avoid) - IHD, PVD (avoid) Kinetics Hepatic metabolism. Administration (routes, doses) Rosiglitazone 4-8mg OD Pioglitazone 15-45mg OD Information (Patient and staff) Monitoring LFTs Blood Sugar Salbutamol Drug Name(s) Salbutamol, Salmeterol, formoterol, terbutaline Drug Class – β2 adrenoreceptor agonists Mode of Action Strong β2 effects causing bronchodilation (and also muscle vasodilatation and uterine relaxation) They also have mild β1 effects, with a positive chronotropic and inotropic cardiac effect. Benefits and Indications - To relieve bronchoconstriction in asthma - To relieve any reversible component of COPD - To prevent and treat premature labour - To treat hyperkalaemia Risks and Adverse effects - Dose related side effects o Anxiety o Tremor o Tachycardia o Palpitations, - Hypokalaemia There is some evidence that inhaled β2 agonists may increase the risk of acute severe asthma – only if nebulised without oxygen, leading to pulmonary vasodilatation in poorly ventilated areas leading to V/Q mismatch. Therefore nebulisers for this indication at home are discouraged. Interactions Corticosteroids, diuretics and theophylline – risk of hypokalaemia Susceptible groups Hyperthyroidism Cardiovascular disease Arrythmias and long QT syndrome Kinetics If used enterally, it is hepatically metabolised, and renally excreted. Administration (routes, doses) Salbutamol: Asthma management – 1-2 100microgram puffs as required, if more that 4 times daily consider review of medication Acute severe asthma 2.5 – 5mg nebulised with oxygen as required Can also be given IV – 5-20micrograms/min infusion Salmeterol: 1-2 puffs of 25-50micrograms BD - NOT PRN Information (Patient and staff) Adminitration and inhaler technique To come back if dose needed increases Monitoring If high doses, monitor K+ PEFR Stopping Senna Drug Name(s) Senna Drug Class Stimulant laxative – (Plant extract containing anthraquinones) Mode of Action Stimulates the local gut nerve plexi Benefits and Indications Constipation – particularly if there is a cause for slowed gastric activity (e.g. opiates) Risks and Adverse effects • Abdominal cramp • Diarrhoea hypokalaemia Interactions Susceptible groups Do NOT use in suspected intestinal obstruction Will be painful and probably ineffective if there is faecal impaction Kinetics Administration (routes, doses) 2-4 tablets daily, usually at night – acts in 8-12 hours Probably best to give regularly rather than PRN to prevent impaction Information (Patient and staff) Cramps Monitoring Stool chart Stopping Once it is not needed Spironolactone Drug Name(s) Spironolactone (also epleronone) Drug Class Aldosterone antagonist Mode of Action Inhibits aldosterone’s effects on Na+ excretion in the DCT, in exchange for K+. The mechanism for decreased mortality in sever heart failure is unknown Benefits and Indications • Decreases oedema in heart failure, nephotic syndrome, liver disease or malignant disease with ascites – normally in conjunction with a loop or thiazide diuretic. • Decreases mortality in severe heart failure • For the diagnosis and treatment of primary hyperaldosteronism Risks and Adverse effects N+V – common in high doses Gynaecomastia in high doses (not with eplerenone) ↑ K+ in 8% of patients using high doses, even with a loop or thiazide Rare: • • • • Menstrual changes Impotence Atrophy of testes PUD Interactions Anything that retains K+: • ACE inhibitors • Trimethopirm • K+ supplements • Renal impairment • Amiloride Susceptible groups Kinetics Well absorbed PO, and changed to active metabolite. Metabolite has a long half life (16h) long duration and onset of action Administration (routes, doses) Severe heart failure – 25mg OD PO Oedema – 100-200mg OD PO Information (Patient and staff) N+V Other S/Es Monitoring K+ if necessary Stopping Normally long term therapy Statins Drug Name(s) Simvastatin, Atorvastatin, Rosuvastatin, Pravastatin Drug Class HMGCoA reductase inhibitor Mode of Action Inhibits the rate limiting enzyme in cholesterol synthesis, which leads to increased LDL receptors decreased LDLs and TGs increased HDLs (unknown mechanism) Benefits and Indications Treatment of primary hypercholesterolaemia Primary and secondary prevention of IHC, PVD, CVD Risks and Adverse effects - Commonly minor S/Es: o Diarrhoea, Constipation o Nausea o Headache o Dyspepsia o Insomnia o Asyptomatic small rises in CK - Reversible myopathy – pain, weakness, increased CK, Myoglobinuria – 0.5% or ppts - Rises in LFTs – normally minor, but stop drug in the 2% who have rises 3x baseline Interactions Myopathy risk is increased with fibrates, niacin, ciclosporin, macrolides - AVOID Susceptible groups Avoid in pregnancy and breast feeding Kinetics Administration (routes, doses) It is more effective given at night, when cholesterol synthesis is at its peak Simvastatin 10mg OD nocte PO (increasing up to 40mg as necessary) Information (Patient and staff) Myopathy – warning symptoms Blood tests - LFTs Monitoring LFTs before starting drug and some time after CK if myopathy suspected Stopping Statins are long term therapy, and only show mortality benefit after 2-3 years Examples 4S study showed the efficacy of statins in secondary prevention of CHD Thrombolytics Drug Name(s) Streptokinase/ tissue plasminogen activator (alteplase) Drug Class Thrombolytics Mode of Action Plasmin degrades fibrin clots. Streptokinase activates plasminogen to plasmin all through the body, reducing clotting. tPA activates plasminogen already bound to fibrin, and so is more clot selective. Benefits and Indications - AMI - Thromboembolic disease of major vessels - Major PE - Thrombosis of AV shunts in dialysis patients - Acute ischaemic stroke (tPA) Risks and Adverse effects - Bleeding, including stroke, GI bleeds, post-surgery bleeding. - Hypotension – posture usually resolves this - Allergic and anaphylactic reactions (with streptokinase) - Reperfusion arrhythmias (same as for PCI) - Backpain - Fever - Convulsions Interactions Positive interaction with aspirin for survival after AMI Interaction with all other antithrombotics on bleeding risk Susceptible groups Contraindications - Recent haemorrhage - Recent trauma - Recent surgery - Bleeding disorders - Aortic dissection - Recent/present PUD/ varices - Severe hypertension - Severe liver damage - Recent delivery or abortion - Recent stroke - Current pancreatitis, endocarditis, pericarditis Cautions - Severe DM with retinopathy - External chest compressions - AAA - Atrial fibrillation (esp. if with thrombus) - Anticoagulant therapy - Pregnancy foetal death - Previous streptokinase administration between 4 days and 1 year (use alteplase) Kinetics Administration (routes, doses) AMI: Alteplase – 100mg in 3 hours, 10% in one min, 50% in one hour, 40% in 2 hours Streptokinase – 1.5 million units over 1 hour Information (Patient and staff) Risks, benefits Monitoring Look for signs of internal or external bleeding ECG monitoring in HDU/CCU Stopping If bleeding is lifethreatening, stop and give an antifibrinolytic (tranexamic acid) along with FFP. Sulphonylureas Drug Name(s) Gliclazide, Tolbtamide (short acting) Glibenclamide, [Chlorpropamide] (long acting) Drug Class Sulfonylureas Mode of Action Increases the release of endogenous Insulin from B cells. Benefits and Indications Effective hypoglycaemic in Type II DM where there is still endogenous Insulin secretion, and the patient is not overweight Risks and Adverse effects Minor: Weight gain Nausea, Diarrhoea, Constipation Major: - Hypoglycaemia – not that common, but can be severe and long-lasting, requiring hospital treatment. Higher risk with long acting drugs. - Disturbance of liver function – can be severe - Allergic reactions (usually in the first 2 months) - Blood dyscrasias (haemolysis, aplastic anaemia, agranulocytosis, thrombocytopenia) NB – Chlorpropamide has more severe side effects, and additional effects including an antabuse type reaction to alcohol. It is no longer recommended. Interactions Several drugs increase the sulfonylurea’s hypoglycaemic effects: - NSAIDs - Warfarin - Alcohol - MAOIs - Some antibiotics (trimethoprim, sulfonamides) - Some antifungals Susceptible groups Porphyria Severe hepatic or renal impairment (high risk of hypoglycaemia) Kinetics Different for each drug, generally a mix of hepatic metabolism and renal excretion Administration (routes, doses) Tolbutamide 0.5-2g daily, OD with breakfast, or sometimes in divided doses Gliclazide 40-320mg daily, OD (or BD with higher doses) Glibenclamide 5-15mg OD with breakfast Information (Patient and staff) BM measurement needed Warning about hypoglycaemia – need to take with food Warning about allergy symptoms Warning about interactions – tell Dr or pharmacist if drugs prescribed or bought Monitoring Titrate to blood sugars Stopping Sulfonamides Drug Name(s) Sulfadiazine Trimethoprim Cotrimoxazole – Trimethoprim and sulfamethoxazole Drug Class Sulfonamides And anti-folates (Trimethoprim) Mode of Action Sulphonamides act as false substrates for folate metabolism Trimethoprim inhibits dihydro-folate reductase inhibition of Purine synthesis Both are bacteriostatic Benefits and Indications Trimethoprim: • UTIs • Prostatitis • Some bacterial gut infections Cotrimoxazole: • Pneumocystis jiroveci pneumonia • Toxoplasmosis Sulfadiazine: • Treatment of cerebral toxoplasmosis • Silver sulfadiazine is used to prevent infection in wounds (normally burns) Risks and Adverse effects Cotrimoxazole is more likely to cause severe effects than trimethoprim Common: - GI upset - Headache - Diarrhoea - Crystalluria Rare (and severe): - Hypersensitivity: Rash, Stevens-Johnson syndrome, anaphylaxis, vasculitis - Bone marrow suppression (due to anti-folate action agranulocytosis) - Haemolytic anaemia with G6PD Interactions Increased risk of toxicity with other anti-folate drugs: (BM suppression, hypersensitivity) • Pyramethamine • Azathioprine and mercaptopurine • Methotrexate • Phenytoin Warfarin effect increased BLEEDING Sulfonamides interact with Amiodarone ventricular arrhythmias Susceptible groups Severe renal and hepatic insufficiency Those with haematological disease – increased risk of BM suppression Avoid in pregnancy – neural tube defects Avoid if patient is folate deficient Avoid in G6PD deficiency haemolysis Avoid cotrimoxazole and sulfadiazine in true sulphonamide allergy Kinetics Hepatic metabolism Renal excretion Administration (routes, doses) Trimethoprim (for UTI) : 200mg BD PO (3 days for simple infections in women, 7 days otherwise) Cotrimoxazole: PJP prophylaxis: 960mg OD PO PJP treatment: 120mg/kg/day in 2-4 doses for 14 days Sulfadiazine: Specialist. However, it will be given with folinic acid to try to prevent side effects. Information (Patient and staff) Warn patients on sulfadiazine and cotrimoxazole to recognise symptoms of BM suppression (bruising, unexpected sore throat, bleeding) and to seek medical attention if they occur. Monitoring Measure FBC before commencing treatment (except for short course trimethoprim) Monitor FBC in patients on sulfadiazine weekly, and cotrimoxazole monthly. Stopping Examples Tetracyclines Drug Name(s) Tetracycline, doxycycline, Minocycline Drug Class Tetracyclines Mode of Action Inhibits the 30S subunit of the bacterial ribosome - bacteriostatic Benefits and Indications Broad spectrum but there is considerable resistance Drug of choice for intracellular organisms: • Chlamydiae (urethritis, trachoma, psittacosis) • Brucellae • Spirochaetes Used to treat moderate acne Doxycycline is used as malarial prophylaxis Risks and Adverse effects Common: - Nausea and vomiting - They are irritant to the oesophagus, and can cause heartburn and even ulceration - Nephrotoxic (except doxycycline) - Hypersensitivity - Problems in developing teeth – brown discolouration or hypoplasia - Photosensitivity Rare: - Idiopathic Intracranial hypertension Blood dyscrasias SLE-like syndrome with minocycline Interactions - Dairy products and some minerals chelate tetracyclines, decreasing absorption, including Zinc, Iron, Magnesium and Aluminium. Avoid supplements, laxatives and antacids in the hour around taking the medication. - P450 enzyme inducers will decrease tetracycline levels. - Tetracyclines increase the effect of warfarin. Susceptible groups - Pregnancy, breast-feeding and in children – tooth hypoplasia/ discolouration - Avoid in hepatic or renal dysfunction - Can exacerate Diabetes insipidus - Can worsen muscle weakness in myasthenia gravis and SLE Kinetics Well absorbed orally, Hepatic metabolism, with urine and biliary excretion Administration (routes, doses) Tetracycline – 250-500mg QDS PO Doxycycline for malaria prophylaxis – 100mg OD PO Minocycline for acne – 100mg OD PO or a topical formulation Information (Patient and staff) Photosensitivity, rash, heartburn - Warn to contact Doctor if they suffer a rash or headaches Instructions to take with water, upright, 30 minutes before food, without dairy, antacids or supplements Monitoring Consider monitoring renal function Monitor hepatic function and possibly inflammatory markers in treatment > 6/12 Theophylline Drug Name(s) Theophylline, Aminophylline Drug Class Xanthine derivatives Mode of Action Xanthine derivatives are phosphodiesterase inhibitors. They may also have inhibitory effects on adenosine receptors. These effects lead to dilatation of the airways. Benefits and Indications Treatment for reversible airways obstruction (asthma, and some patients with COPD). Risks and Adverse effects All effects are dose related: Early symptoms are: • Nausea and vomiting • Tremor, anxiety, nervousness Later symptoms are: • Tachycardia • Arrythmias • Convulsions • Coma Interactions • Theophylline potentiates beta agonists effects on the heart arrythmias • St John’s Wort decreased theophylline levels • Enzyme inhibitors increased theophylline levels: o Cimetidine o Ciprofloxacin o Erythromycin o OCP • Coffee and tea intake also reduces clearance of xanthines Susceptible groups The clearance of theophylline is decreased in the following conditions: • Cardiac failure • Hepatic cirrhosis • COPD • Pulmonary oedema • Pneumonia • Febrile illnesses As the drug is not distributed in fat, obese individuals will need a relatively lower dose. Kinetics All forms are turned into theophylline. Theophylline is metabolised in the liver, with a half life of 6 hours. A therapeutic dose in the acute phase is 50-100 micromol/L (10-20micrograms/L) Administration (routes, doses) IV use – Aminophylline: • Loading dose of 250-500mg (5mg/kg) given by slow injection • Maintenance of 0.9mg/kg/hour (but this is decreased in children, those over 50, and those with COPD, cardiac or hepatic disease, or on enzyme inhibitors) Oral use – Aminophylline or theophylline: • Aminophylline 100-300mg as necessary, or MR forms BD • Theophylline 125-250mg BD or TDS, or MR forms BD. Monitoring – levels needed Vancomycin and the glycopeptides Drug Name(s) Vancomycin and Teicoplanin Drug Class Glycopeptides Mode of Action Sterically inhibit peptidoglycan formation in cell wall - bacteriostatic Benefits and Indications - Treatment of multi-drug resistant Gram positive cocci, especially MRSA - Have NO activity against Gram negative bacteria - Vancomycin used to treat antibiotic associated diarrhoea (C. difficile) (2nd line after metronidazole) Risks and Adverse effects Common: - Nephrotoxic - “red man syndrome” if the infusion is too rapid, due to histamine release. - Hypersensitivity – usually a rash, often severe Rare: - Ototoxic Blood dyscrasias Interactions Nephrotoxicity and ototoxicity risk increased with aminoglycosides, loop diuretics and Susceptible groups Renal insufficiency – can lead to high levels, so close monitoring is required, and the drug may cause further renal damage. Kinetics - Glycopeptides show time-dependant antibacterial properties, meaning that they should be above a certain concentration for as much time as possible to be most effective. Therefore trough levels should be measured. - They are not absorbed in the gut, so systemic therapy is parenteral, and C. difficile therapy is PO, and not absorbed. - They are excreted by the kidney; renal insufficiency can increase concentrations. Administration (routes, doses) Vancomycin: Systemic infection – 1g BD IV – infusion over 60 minutes. Reduce dose according to trough concentrations, in the elderly, and in renal impairment. C. difficile diarrhoea – 125mg QDS PO for 7-10 days. Teicoplanin: Systemic infection – 400mg BD IV – infusion over 60 minutes. Reduce dose according to trough concentrations and in the elderly. Information (Patient and staff) Warn about rash and allergy Monitoring Measure renal function before and during treatment Measure trough concentrations before administration – it should be 5-10mg/l Verapamil Drug Name(s) Verapamil Drug Class Phenylalkamine - Ca2+ channel blocker and Class IV antiarrhythmic drug Mode of Action Prolongs slow Phase 2 stage of cardiac AP prolongs refractory period Slows transmission in the SA and AV node Negative inotropic and inotropic effect Some peripheral vasodilatation Benefits and Indications - SVT – esp paroxysmal and WPW syndrome - Angina - Hypertension (now rarely) - Prinzmetal’s angina and Raynaud’s phenomenon/Dx Risks and Adverse effects Common: • Headache • GI disturbance • Peripheral oedema Rare and serious: • Cardiac failure • Hypotension • Heart block Interactions β-blockers – synergistic cardiac effect low BP, cardiac failure, asystole - AVOID (however β-blocker can be given 30-60mins following verapamil) Amiodarone – increases AV block, bradycardia etc - AVOID Digoxin – verapamil decreases excretion (P-glycoprotein) toxicity Susceptible groups - Heart Failure/Cardiogenic shock – AVOID - Sick sinus syndrome, bradycardia, heart block – AVOID - Hypotension – AVOID - Porphyria – AVOID - Liver Dx – prolonged drug half-life Kinetics Well absorbed orally Extensive first pass metabolism (85%) Half life – 5 hours Administration (routes, doses) SVT • IV – 5-10mg slow injection(2mins), repeat in 10 mins if necessary • PO – 40-120mg TDS Angina – 80-120mg TDS Hypertension – 80-160mg TDS Information (Patient and staff) Monitoring Stopping Warfarin Drug Name(s) Warfarin Drug Class Coumarin - vitamin K antagonist Mode of Action Inhibits the carboxylation of clotting factors II, VII, IX and X in the liver, through competitive inhibition of vitamin K metabolism. Benefits and Indications DVT and PE – prophylaxis and treatment Preventing emboli in patients with: • Prosthetic heart valves • AF • Elective cardioversion for AF • Some cardiomyopathies • Hip surgery Risks and Adverse effects Bleeding – depending on severity warfarin dose can be reduced, stopped, or vitamin K, FFP or coagulation factor precipitates can be given. Hepatotoxicity (rare) Teratogenic Interactions - huge number! INCREASED anticoagulant effect: - P450 enzyme inhibitors: Cimetidine, co-tromoxazole, chloramphenicol, ciprofloxacin, amiodarone, metronidazole, isoniazid - Platelet function inhibitors: Aspirin, NSAIDs, some antibiotics, phenylbutazone - Vitamin K reduction inhibitors: cephalosporins - Decrease vit K availability: broad spectrum antibiotics - Drugs that displace warfarin from albumin: salicylates, NSAIDs, chloral hydrate - Deacreased synthesis or activity of clotting factors: tetracyclines, steroids - Quinine and quinidine DECREASED anticoagulant effect: - Vitamin K – in vitamin tablets, parenteral feeds, etc - P450 enzyme inducers: phenytoin, st. john’s wort, rifampicin, carbamazepine, barbiturates, griseofulvin, alcohol - Drugs that reduce absorption: cholestyramine Susceptible groups - Pregnancy – Teratogenic, so not given in the first trimester. It can cause maternal or foetal bleeds in labour, so it is not given in the third trimester either. - Impaired liver function – increases warfarins effect, as the liver is synthesising less factors, and less bile is excreted leading to less vitamin K absorption. - Congestive Cardiac Failure liver congestion and increases warfarin’s effect - Thyroid function – hyperthyroidism increases warfarin’s effect, hypothyroidism decreases it. Probably due to changes in the rate of clotting factor clearance. Kinetics Absorbed well orally, transported bound to albumin. The effect on the PT or INR does not start for about 16 hours, and lasts about 5 days, as previously synthesised clotting factors must be degraded before the effect of decreased synthesis is seen. Administration (routes, doses) PO – 1,3,5 mg tablets INR measured before (along with Plts) Loading dose given – 10mg daily with daily INR until it reaches 2-2.5 Maintenance dose of about 1-2mg for each 10mg of the loading dose. Regular monitoring needed during early phase. Information (Patient and staff) Bleeding risks – signs of overcoagulation Need for monitoring Warn Drs. and dentists and pharmacists Risks of sports Interactions, both prescribed, OTC and food items Monitoring Important and difficult – as a dose’s effect is only seen 2 days after administration. INR is the tool of choice, with typical target values of 2-3. 2-2.5 – DVT prophylaxis, surgery in high risk patients 2-3 – Treatment of DVT, PE, Systemic embolism 2-3 – Prevention of Embolism from MI, mitral stenosis, AF and hip surgery 3-4.5 – Recurrent DVT/PE, arterial Dx, prosthetic heart valves Stopping Specific lengths of treatment for different indications e.g. 3/12 for single, uncomplicated, unprovoked DVT.
