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By Dr Garry KJ Pettet MBBS/BSc Revision 2 (January 2006)
Copyright Dr Garry KJ Pettet 2005 - 2009
Preface.........................................................................1 Drug development .........................................................2 Adverse drug reactions ...................................................5 Drug interactions ...........................................................7 Pharmacodynamics/pharmacokinetics ..............................9 Prescribing in renal / liver disease ..................................12 Rheumatology .............................................................16 Gastroenterology .........................................................22 Antivirals ....................................................................27 Asthma / COPD ...........................................................30 Analgesics ..................................................................35 The failing heart ..........................................................38 Endocrinology..............................................................46 Lipids .........................................................................57 Clotting ......................................................................60 Mood disorders ............................................................68 Anti-arrhythmic drugs ..................................................74 Hypertension...............................................................81 Antibiotic therapy ........................................................83 Antibiotics ..................................................................86 Diabetes .....................................................................95
Copyright Dr Garry KJ Pettet 2005 - 2009
Epilepsy ....................................................................101 Migraine ...................................................................107 Multiple sclerosis .......................................................109 Parkinson’s disease ....................................................110 Drug-induced movement disorders ...............................115 Myasthenia gravis ......................................................117 Diuretics ...................................................................119 Muscle relaxants ........................................................122 Anti-emetics ..............................................................124 The eye ....................................................................127 Antipsychotics (neuroleptics) .......................................130 Drugs in the elderly, young or pregnant ........................134 Cytotoxic chemotherapy .............................................137 Anti-malarials ............................................................141
garrypettet. Dale. Although every effort has been made to ensure the accuracy of these notes.com 1 . Milson & Tofield) Medical pharmacology at a glance 4th edition (Neal) Oxford handbook of clinical medicine 6th edition (Longmore. Wilkinson & Rajagopalan) Pharmacology 4th edition (Rang.2009 Preface I wrote these notes as a final year medical student in the UK as I found it very difficult to find a good single text to use for my CPT revision. Ritter) I have made sure that everything that has been mentioned in our lectures is in these notes. as some of their material may well be in these notes: Dr Chris Bench Dr Neil Chapman Dr Anton Emmanuel Dr Michael Feher Dr Alun Hughes Prof Sebastian Johnston Prof John MacDermot Dr Janice Main Dr Vias Markides Dr Jamil Mayet Dr Andrew Rice Dr Stephen Robinson Dr Mike Schachter Dr Tom Sensky Prof Peter Sever Dr Colin Tench Dr Simon Thom Dr Roxaneh Zamegar I would also like to thank Dr Wajid Hussain for proofreading the section on anti-arrhythmics. I used the following textbooks in writing these notes: British National Formulary (BNF 47 March 2004) Clinical medicine 5th edition (Kumar. Dr Garry Pettet www. Clark) Hands-on-guide to clinical pharmacology (Chatu. I take no responsibility for errors within (but please let me know as I have to revise from these as well!). We must thank the following lecturers.Copyright Dr Garry KJ Pettet 2005 .
complex studies with several treatments.com .2009 Drug development Surrogate markers: • A biological measurement which substitutes for the therapeutic endpoint • Examples: o BP and stroke o Cholesterol and coronary disease • Characteristics of a “good” surrogate: o Biological feasibility o Dose-related response to intervention o Easy to measure o Reproducible o Specific / sensitive o High predictive value o Acceptable by experts / regulatory authorities Types of clinical trials: • Open: o Subject and researcher know what they are getting • Single-blind: o The subjects do not know what they are getting • Double-blind: o No one knows what they are getting (during the trial) • PROBE: o Prospective o Randomised o Open-labelled o Blinded o End-point o This is used for large. these may be different than in healthy volunteers) • Phase 3: o Patients o Much larger (> 1000) 2 www. It is an open trial where those who analyse the results do not know who got what treatment The phases of a clinical trial: • Phase 1: o Healthy volunteers (not for cancer / HIV trials) o Few subjects (< 50) o Looks at pharmacokinetics / pharmacodynamic activity / safety • Phase 2: o Patients with the target disease o More subjects (100 – 200) o Usually single-blind trials o Looks again at pharmacokinetics / safety (note.garrypettet.Copyright Dr Garry KJ Pettet 2005 .
Copyright Dr Garry KJ Pettet 2005 . 80 – 90% usually) • The higher we set " (i.05) • Type 2 error ("): o Chance of finding 2 treatments are equal when they are not o Usually: ! " = 0.1 or 0.com 3 . the greater our power) the more expensive the trial becomes as we need more subjects www. p < 0.2009 • o o o o Phase o o Usually double-blind or PROBE May be parallel or crossover Multi-centre May use either “hard” (e.e. MI) or “surrogate” end-points 4: Post-marketing Surveillance for: ! Adverse drug reactions ! Rare side-effects ! Drug interactions Parallel vs crossover studies: • Parallel study: A B • o Most randomised controlled trials (RCTs) are parallel Crossover study: A B o o o Need fewer subjects Should normally be used in chronic stable diseases and the interventions should have a rapid onset and short duration Beware of order effects: ! Carry-over effects ! Period effects: • Changes in the patient’s disease over time Power: • Is the study large enough to answer the study’s question? • Type 1 error (!): o Chance of finding 2 treatments are different when they are not o Usually: ! ! = 0.garrypettet.2 (arbitrary) • Power = 1 .05 (i.g.e." (i.e.
com 4 .Copyright Dr Garry KJ Pettet 2005 .2009 “Intention to treat” vs “per protocol” analysis: • Intention to treat: o Ignore whether the subjects actually take the medication (i. just assume they did) • Per protocol: o Only analyse data from subjects who actually took the medication www.e.garrypettet.
com .2009 Adverse drug reactions Significance: • 3 – 40% of inpatient admissions • Affects 10 – 20% of hospital patients • 4th most common cause of death in US hospital patients • Up to 30 – 60% are preventable Types of adverse drug reaction (ADR): • Type 1: o “Predictable” reactions o Common o Dose-related o A consequence of the known pharmacology of the drug • Type 2: o “Idiosyncratic” reactions o Rare o Usually not dose-related o Allergies o Pharmacogenetic variations Classification of ADRs: • Augmented pharmacological effect • Bizarre • Chronic • Delayed • End-of-treatment Determinants of ADRs: • Drug: o Pharmacodynamics o Pharmacokinetics o Dose o Formulation o Route of administration • Patient: o Age o Co-morbidity o Organ dysfunction o Genetic predisposition • Environment: o Mistakes Allergies vs psuedoallergies: • Allergies: o Type I (anaphylaxis): 5 www.Copyright Dr Garry KJ Pettet 2005 .garrypettet.
bronchospasm ! ACE inhibitors – cough ! ! Type ! Long-term ADRs: • Withdrawal: o Opiates o Benzodiazepines o Corticosteroids • Rebound: o Clonidine o "-blockers • Adaptive: o Neuroleptics www.garrypettet.2009 • Penicillins Contrast media (anaphylactoid) o II (cytotoxic antibodies – blood dyscrasias): Haemolytic anaemia: • Methyldopa • Penicillin • Sulphonamides ! Agranulocytosis: • Carbimazole • Clozapine ! Thrombocytopenia: • Quinidine • Heparin o Type III (immune complex formation): ! Penicillin ! Sulphonamides o Type IV (cell mediated): ! Topical antibiotics Pseudoallergies: o Looks like an allergy but is not immune-mediated o Examples: ! Aspirin .com 6 .Copyright Dr Garry KJ Pettet 2005 .
garrypettet.com 7 .Copyright Dr Garry KJ Pettet 2005 .2009 Drug interactions Liver • • • • Liver • • • • • enzyme inducers (cytochrome P450): Carbamazepine Phenobarbitone Phenytoin Rifampicin enzyme inhibitors (cytochrome P450): Cimetidine Ciprofloxacin Grapefruit juice Macrolide antibiotics: o Erythromycin Omeprazole Important drugs metabolised by the liver (cytochrome P450): • Carbamazepine • Cyclosporin A • Combined oral contraceptive (COC) pill • Phenytoin • Theophylline • Warfarin Some important drugs interacting with warfarin: • Drugs increasing the effect of warfarin: o Alcohol o Amiodarone o Antibiotics (many – reduced vitamin K absorption) o Cimetidine o Omeprazole o Simvastatin • Drugs decreasing the effect of warfarin: o Carbamazepine o COC pill o Rifampicin Interactions with diuretics: • General: o Potentiate: ! ACE inhibitors ! Lithium o Metabolic: ! Hypokalaemia enhances digoxin efficacy ! "-blockers potentiate hypokalaemic effects of diuretics • Loop: o Increased risk of ototoxicity with the aminoglycosides • Potassium-sparing: www.
garrypettet. leads to increased concentration of penicillins (can be beneficial) www.2009 o Risk of hyperkalaemia with ACE inhibitors Drugs affecting gastric emptying and hence drug absorption: • Increase emptying: o Metoclopramide • Decrease emptying: o Atropine Impairment of drug excretion: • Probenicid: o Competes with Penicillins for renal tubular excretion.com 8 .Copyright Dr Garry KJ Pettet 2005 .
omeprazole Volume of distribution (Vd): • This is the apparent volume into which the drug is distributed Vd = dose / (initial apparent plasma concentration) • • • • Is used to calculate the clearance of a drug Is high for lipid-soluble drugs Is low for water-soluble drugs Values of Vd: o < 5L drug retained within the vascular system o < 15L drug is restricted to the extracellular fluid (ECF) o > 15L indicates the drug is distributed throughout the total body water Clearance: • The volume of plasma (or blood) cleared of drug per unit time • Depends on drug lipid solubility • Clearance (but not t1/2) provides an indication of the ability of the liver and kidneys to dispose of the drug First vs zero order kinetics: • First-order kinetics: o A metabolic process that depends on the drug concentration at any given time is called a first-order process o I.2009 Pharmacodynamics/pharmacokinetics Half-life (t1/2): • The time taken for the concentration of drug in plasma (or blood) to fall to half it’s original value • Drugs with a short t1/2 may have a long duration of action: o So-called “cell-trapping” o E.g. a non-saturable process • Zero-order kinetics: o If any enzyme system responsible for drug metabolism becomes saturated. but the plasma concentration would not double (may increase to an enormous extent) Bioavailability: • The proportion of administered drug reaching the systemic circulation • IV drugs have 100% bioavailability 9 www.com .e.e.Copyright Dr Garry KJ Pettet 2005 . then the rate of elimination proceeds at a constant rate and is unaffected by an increase in the concentration of the drug o I. a saturable process o Examples include: ! Phenytoin ! Ethanol o The importance of zero-order kinetics is that you could double the dose.garrypettet.
tyramine ! Reduction / Hydrolysis o Usually produces a more reactive compound that will be acted on by phase II components o May activate a prodrug – examples: ! Levodopa " dopamine ! Enalapril " enalaprilat ! Azathioprine " 6-mercaptopurine ! Methlydopa " !-methyl-noradrenaline ! Carbimazole " methimazole • Phase II: o Conjugation of a drug or phase I metabolite with an endogenous substance to form a more polar.g.2009 • • Drugs with high bioavailability: o Ciprofloxacin (near 100%) Drugs with low bioavailability: o Bisphosphonates (~15%) First-pass metabolism: • Also known as pre-systemic metabolism • This is drug metabolism that occurs before the drug reaches the system circulation • Occurs in the liver and gut wall • Some drugs undergo extensive first-pass metabolism: o Levodopa o Lignocaine o Morphine o Nitrates (e.garrypettet.Copyright Dr Garry KJ Pettet 2005 . easily excreted. NA. GTN) o Propranolol o Verapamil • Is generally a nuisance for two reasons: o A larger dose is needed when it is given orally o Marked individual variations occur Post-systemic metabolism: • The main purpose is to increase water-solubility of the drug • Phase I: o Three types of reaction: ! Oxidation: • Most important are the P450 enzymes • Xanthine oxidase metabolises 6-mercaptopurine • Monoamine oxidase inactivates 5-HT.com . compound o May be either: ! Glucuronidation ! Sulphation ! Acetylation (does not alter water-solubility) 10 www.
not drug concentration!) o Antibiotics (aminoglycosides.garrypettet. phenytoin) o Aminophylline / theophylline o Cyclosporin A o Digoxin o Lithium www. vancomycin) o Anticonvulsants (carbamazepine. a steady state concentration is effectively achieved after three plasma half-times • Faster attainment of the steady state is achieved by starting with a larger dose – a loading dose Therapeutic drug monitoring: • Why? o To investigate lack of drug efficacy o Possible poor compliance o Suspected toxicity o Prevention of toxicity • Type of drugs: o Narrow therapeutic index (TI) o Uncertain dose / concentration relationship o Defined plasma concentrations with no active metabolites • Examples: o Not warfarin (this measures the INR.com 11 .2009 ! Glutathione Loading doses: • In practice.Copyright Dr Garry KJ Pettet 2005 .
2009 Prescribing in renal / liver disease Important drugs whose elimination is affected by renal impairment • Half-lives are approximate ranges when renal impairment present • Amoxicillin (t1/2 2 – 14 hours): o Applies to most penicillins o Toxic effects: ! Seizures (especially in meningitis) ! Rashes are more common in renal impairment • Atenolol (t1/2 6 – 100 hours): o Contraindicated in: ! Asthmatics ! Severe heart failure ! Peripheral vascular disease o Toxic effects: ! Bradycardia ! Confusion ! Hypotension • Captopril (t1/2 2 – 14 hours): o Toxic effects: ! # GFR ! Angioedema ! Cough: • Probably due to a direct effect on sensory afferents • Not bradykinin ! GI disturbances ! Hypotension ! Taste disturbances • Digoxin (t1/2 36 – 90 hours): o Requires therapeutic drug monitoring (TDM) o Toxic effects: ! Dysrhythmias (VT.>50 hours): o Increased risk of toxicity when: ! Dehydrated (important as septic patients usually are) ! Hyponatraemic o Toxic effects: ! Nephrotoxicity (renal tubular damage) ! Ototoxicity (can be irreversible) Vitamin D and the kidney: • Vitamin D has to undergo two hydroxylation reactions within the body to become active www. heart block) ! Gynaecomastia ! Nausea (severe) / vomiting ! Xanthopsia (distortion of yellow colour vision) • Gentamicin (t1/2 2! .Copyright Dr Garry KJ Pettet 2005 .garrypettet.com 12 .
garrypettet.2009 • • • • Kidney forms the 1-hydroxy form of vitamin D and requires the enzyme 1!-hydroxylase In renal impairment. thus negating need for 1!-hydroxylase) o Calcitriol (the active 1. the above step may not happen Bone disease caused by renal disease is termed renal osteodystrophy: o Loss of vitamin D activity o $ PTH activity Replacing vitamin D: o Alfacalcidol (the 1-hydroxylated form.com .Copyright Dr Garry KJ Pettet 2005 . 25-hydroxylated form) – rarely used Nephrotoxic drugs: • ACE inhibitors: o # GFR (if the arterial perfusion pressure is low): ! Renal artery stenosis (especially bilaterally) ! Coarctation of the aorta • Cyclosporin A: o Used in renal transplants o Is a substrate for P450 (levels may be increased by other drugs) o # GFR o Damages tubular function • Gentamicin: o Renal tubular damage • Lithium: o Nephrogenic diabetes insipidus o Renal tubular damage • NSAIDs: o # GFR o Papillary necrosis: ! Loss of PG-mediated vasodilatation o Na+ retention • Others: o Urate stones: ! Anticancer drugs (tumour lysis syndrome) o Myoglobinuria: ! Alcohol ! Statins Drugs to watch when patient has impaired hepatic synthetic function: • Hypoalbuminaemia: o Drugs which bind to albumin and are cleared by the liver: ! Diazepam ! Phenytoin ! Tolbutamide • A1-acidic glycoprotein deficiency: o Binds basic drugs: ! Chlorpromazine ! Imipramine 13 www.
IX and X then warfarin’s effects will be potentiated o Antibiotics: ! Interfere with vitamin K production in the gut by bacteria ! May compound the above problem Drugs to watch in a patient with current / recent hepatic encephalopathy: • Antidepressants: o Tricyclic antidepressants (TCAs) are safest (but use a # dose) o Avoid monoamine oxidase inhibitors (MAOIs): ! Idiosyncratic hepatotoxicity • Anti-psychotics: o Chlorpromazine • Anxiolytics / hypnotics: o Oxazepam / temazepam are the safest o Avoid chlormethiazole (especially IV) • Opiates: o Can precipitate coma o Even low levels are dangerous Drugs with a high first-pass metabolism: • These drugs will not be metabolised as much in liver impairment (if given orally).2009 • ! Quinidine Reduced synthesis of clotting factors: o Warfarin: ! If the liver is synthesising even less of factors II.garrypettet. glibenclamide) o Carbimazole • Hepatocellular necrosis: o Antibiotics: ! Isoniazid ! Rifampicin ! Nitrofurantoin o Anticonvulsants: ! Can cause liver damage at normal doses in some patients ! Carbamazepine ! Phenytoin ! Valproate 14 www.com . VII.g.Copyright Dr Garry KJ Pettet 2005 . thus the dose should be # • Chlorpromazine • Chlormethiazole • Imipramine • Morphine / pethidine • Propranolol • Verapamil Hepatotoxic drugs: • Cholestasis: o Chlorpromazine (reversible cholestasis) o Sulphonylureas (e.
Copyright Dr Garry KJ Pettet 2005 .2009 o o o Anti-hypertensives: ! Hydralazine: • Also causes a SLE-like syndrome (ssDNA Abs) ! Methyldopa Halothane (repeated exposures) Paracetamol (overdose) www.com 15 .garrypettet.
garrypettet.Copyright Dr Garry KJ Pettet 2005 .com 16 . the pain-producing effect disappears and nociceptive responses to other stimuli disappear as well – hence it’s use here • Glucosamine • Systemic NSAIDs Drug treatment of rheumatoid arthritis (RA): • NSAIDs • COX-II inhibitors: o Indications: ! Age >65 years ! Previous history of DU / GU or GI bleed ! Large doses of NSAID required to control pain o Absolute contraindications: ! Established IHD ! Cerebrovascular disease ! Heart failure (NYHA II – IV) • Gastroprotection (if on NSAID / long-term steroids): o H2-receptor antagonists o Proton pump inhibitors (PPIs) o Misoprostol • Disease modifying anti-rheumatic drug (DMARD): o Persisting synovitis >6 weeks o Several may have to be tried to find the right one: ! Methotrexate ! Sulphasalazine ! Gold ! Penicillamine ! Hydroxychloroquine • Anti-TNF! therapy: o Progressive RA after 2 DMARD failures • Steroids are controversial but useful in acute flares Drug treatment of osteoporosis: • Bisphosphonates: o Are the mainstay of treatment • Calcium supplements • Vitamin D • Calcitonin (may be considered) • HRT no longer has role www.2009 Rheumatology Drug treatment of osteoarthritis (OA): • Simple analgesics: o Paracetamol (as good as Ibuprofen in early disease) • Topical therapy: o NSAIDs (e. ibuleve) o Capsaicin: ! Potent pain-producing agent ! After a few applications.g.
garrypettet.Copyright Dr Garry KJ Pettet 2005 .2009 Glucosamine: • Unclear mechanism of action • Probably similar efficacy to simple NSAIDs • Better tolerated than NSAIDs but not free of side-effects: o Headache o Rash o Drowsiness Non-steroidal anti-inflammatory drugs (NSAIDs): • (Non.hypertension ! Interstitial nephritis ! Hyperkalaemia ! Papillary necrosis (chronic use) o Other: ! Bronchospasm (especially in asthmatics) ! Allergies Aspirin as a NSAID: • Aspirin is a NSAID but the large doses required to control the inflammation in the arthritides led to an unacceptable number of adverse effects 17 www.com .COX-I and COX-II: o COX-I is a constitutional enzyme and is important in the maintenance of the protective GI mucus barrier in the stomach and of renal blood flow o COX-II is expressed at sites of inflammation • NSAIDs are: o Analgesic o Antipyretic (inhibits the rise in brain PGs that cause pyrexia) o Anti-inflammatory (at higher doses) • Adverse effects: o GI: ! Peptic ulceration (major adverse effect) o Renal: ! Reduced renal blood flow ! Sodium retention .selectively) inhibit cyclo-oxygenase (COX) • COX converts arachidonic acid (derived from membrane phospholipids) into endoperoxides • The endoperoxides are further converted into: o Prostaglandins (PGs): ! Potentiate the activity of other pain mediators ! Vasodilatation o Thromboxane A2: ! Platelet aggregation ! Vasoconstriction o Prostacyclin: ! Inhibits platelet aggregation ! Vasodilatation • There are 2 isoforms of COX .
g. paracetamol is a NSAID • It’s mechanism of action is not fully understood and it has no antiinflammatory activity • It works.garrypettet. Celecoxib (Rofecoxib (Vioxx) has been withdrawn in the UK)) • No better at improving symptoms of pain / inflammation than NSAIDs • 50% reduction in GI: o Ulceration o Perforation o Bleeds • (Probable) increased risk of: o Myocardial infarction o Stroke Methotrexate: • Indications: o Malignancy o Psoriasis (when conventional therapy fails) o Rheumatoid arthritis www. paracetamol works best when there is little or no leucocyte infiltration (as leucocytes produce high levels of peroxide) Relative risk of GI toxicity with NSAIDs: • From least toxic to most toxic: o Ibuprofen o Diclofenac o Aspirin o Naproxen o Indomethacin o Ketoprofen COX-II inhibitors: • E.2009 • It irreversibly inactivates COX – activity returns only when new enzyme is synthesised: o Hence it’s effectiveness in platelets (cannot synthesise new enzyme) Paracetamol as a NSAID: • Like aspirin.com 18 . by reducing COX tone: o This activity is only seen in areas of low peroxide concentration o Hence.Copyright Dr Garry KJ Pettet 2005 . act least partly.
garrypettet.com .2009 • • • • • Mechanism of action: o Inhibits dihydrofolate reductase o Leads to a reduction in the production of tetrahydrofolic acid (which is essential for nucleic acid synthesis) o Prevents cells from dividing Administer concurrent folic acid to minimise symptoms Adverse effects: o Nausea o Fatigue o Pneumonitis (rare but can be life-threatening) Contraindications: o Renal / hepatic impairment o Pregnancy Interactions: o NSAIDs / probenicid: ! Reduce the excretion of methotrexate Sulphasalazine: • Mechanism of action in RA is unknown • Adverse effects: o Nausea / abdominal discomfort o Reduced sperm count o Marrow suppression • Contraindications: o Salicylate allergy o Renal impairment Gold: • Adverse effects: o Marrow suppression o Proteinuria o Hepatitis Penicillamine: • Adverse effects: o Marrow suppression o Proteinuria o Reduction in taste o SLE • Contraindications: o Penicillin allergy o SLE Hydroxychloroquine: • Adverse effects: o Rash o Retinopathy (rare) o Tinnitus • Cautions: 19 www.Copyright Dr Garry KJ Pettet 2005 .
alendronate. pamidronate • Are enzyme-resistant analogues of pyrophosphate • Bind to hydroxyapatite crystals and reduce bone resorption (via inhibition of osteoclasts) • Indications: o Osteoporosis (both primary and steroid-induced) o Paget’s disease o Malignant hypercalcaemia • Adverse effects: o Alendronate can cause oesophagitis: ! Swallow the tablet whole with a full glass of water on an empty stomach and remain upright for at least 30 mins Vitamin D supplementation: • Usually given as ergocalciferol (vitamin D2 – the usual dietary source of vitamin D) • Is a fat-soluble vitamin so bile salts are necessary for absorption • Adverse effects: o Hypercalcaemia • Interactions: www.com 20 . inhibit progression and improve radiological Sharp score (a measure of radiological RA severity) • Adverse effects: o Local reactions o Increased risk of infections: ! Especially tuberculosis (need to screen before therapy) o Demyelination syndromes o SLE-like syndrome: ! Avoid in SLE-sufferers o Worsening of pre-existing heart failure • Other disease indications: o Ankylosing spondylitis o Psoriatic arthritis o Crohn’s disease Bisphosphonates: • E.g.Copyright Dr Garry KJ Pettet 2005 .2009 • o Hepatic impairment Very toxic in overdose Anti-TNF! therapy: • TNF! is the major mediator of inflammation • Used in RA when patient has failed to respond to >=2 DMARDs (including methotrexate) • Can be either: o Soluble TNF! receptors (etanercept) o Anti-TNF! receptors (infliximab) • Reduce inflammation.garrypettet.
garrypettet.2009 o Some anticonvulsants (carbamazepine. phenytoin) increase the requirement of vitamin D www.Copyright Dr Garry KJ Pettet 2005 .com 21 .
loperamide) • Autonomic neuropathy (e. PPI) Drug treatment of Crohn’s disease: • Acute exacerbations: o Steroids (oral / rectal / IV) o Elemental diet o Anti-TNF! therapy (infliximab): ! Severe (especially fistulating) disease • Maintenance: o 5-Aminosalicylic acid (5-ASA) compounds o Azathioprine (if 5-ASA fails) o Methotrexate (if azathioprine intolerant) Drug treatment of ulcerative colitis: • Acute exacerbations: 22 www. tegaserod) o Probiotics Drug treatment of diarrhoea: • General: o Opioids (e. diabetes. diabetes): o Clonidine o Octreotide (for secretory diarrhoea) • Bacterial overgrowth: o Treat underlying cause o Cyclical antibiotics if above fails (e.2009 Gastroenterology Drug treatment of GORD / PUD: • Antacids • Acid suppression: o H2-receptor antagonists o Proton pump inhibitors (PPIs) • Helicobacter pylori eradication Drug • • • • • • treatment of constipation (laxatives): Bulk laxatives Stimulant laxatives Osmotic agents Stool softeners Suppositories / enemas Novel: o Motilin analogues (e.g.g.com .g.garrypettet.g. erythromycin) o 5-HT4 antagonists (e.g. neuropathy) • Pancreatic insufficiency (e.Copyright Dr Garry KJ Pettet 2005 .g. chronic pancreatitis): o Pancreatin + acid-suppressant (e.g.
g.2009 • o Rectal 5-ASA (evidence shows benefit over steroids) o Steroids (oral / rectal / IV) Maintenance: o 5-ASA compounds Antacids: • Increase gastric pH (this increases rate of emptying thus action is short) • All antacids can interfere with drug absorption – should be taken separately • Sodium bicarbonate: o Only useful water-soluble antacid o May cause metabolic alkalosis • Magnesium hydroxide: o May cause diarrhoea • Aluminium hydroxide: o May cause constipation • Alginate-containing compounds (e. ranitidine.g.g. valproate) ! Theophylline ! Warfarin o Hyperprolactinaemia o Anti-androgenic activity (gynaecomastia) Proton pump inhibitors (PPIs): • E. Gaviscon): o Form a “raft” on top of stomach contents and prevent reflux H2-receptor antagonists: • E. lansoprazole • Inactive at neutral pH but are activated in the stomach and irreversibly inhibit the H+/K+-ATPase (proton pump) • Are more effective than H2-receptor antagonists and more costeffective • Indications: o GORD o PUD o Zollinger-Ellison syndrome • Adverse effects: o Liver enzyme inhibitor (increases levels of): 23 www. phenytoin.Copyright Dr Garry KJ Pettet 2005 .com .garrypettet. omeprazole. cimetidine • Block histamine receptors on the gastric parietal cell membrane and reduce acid secretion • Indications: o GORD o PUD • Adverse effects (mainly cimetidine): o Liver enzyme inhibitor (increases levels of): ! Anticonvulsants (carbamazepine.
bran.g. picosulphate. Lactulose.com 24 .g. pylori eradication therapy: • One PPI and two antibiotics for two weeks • Usual combination (but there are many): o Omeprazole o Clarithromycin o Amoxicillin (or metronidazole) • Resistance to metronidazole is common Bulk laxatives: • E.2009 ! ! • Cautions: o Achlorhydria is associated with gastric cancer – unsure of longterm effects of acid suppression Phenytoin Warfarin H. bisacodyl. magnesium salts • Poorly absorbed solutes that maintain a large stool volume by osmosis • Lactulose: o Is a disaccharide (fructose-galactose) o Cannot be cleaved by human disaccharidases – is cleaved by bacteria in the colon www. ispaghula • Only good for mild constipation • Are usually indigestible polysaccharides • Increase the volume of the intestinal contents – thus stimulating peristalsis by stretching mechanoreceptors • Gradual onset of action (~1 week) • Increase stool output as a function of initial stool weight: o If stool volume is low initially then won’t see much of an increase • Adverse effects: o Exacerbates bloating in slow-transit constipations Stimulant laxatives: • E.garrypettet. senna • Are inactive glycosides that are activated in the colon by bacteria • Once in colon – have direct stimulant effect on the myenteric plexus: o Smooth muscle contraction (peristalsis) • Also increase secretion of water and electrolytes • Rapid onset of action (~8 hours) – give in evening for morning stool • Adverse effects: o Colic o Colonic atony o Hypokalaemia o Pseudomelanosis coli (colonic pigmentation with chronic use) o Unpredictable effect Osmotic agents: • E.Copyright Dr Garry KJ Pettet 2005 .g.
arachis oil • Act like detergents in the colon and facilitate mixing of fat and water in the stool • Adverse effects: o Passive faecal leakage • Not effective enough to be used on their own Suppositories / enemas: • E. sulphasalazine 25 www. morphine • Stimulate µ-receptors on myenteric neurones and lead to hyperpolarization: o Inhibits Ach release from myenteric plexus and reduces peristalsis • Loperamide is most appropriate as it does not cross the blood-brain barrier and is unlikely to cause dependence Pancreatin: • Pancreatic enzyme supplement of porcine origin • Must be taken with an anti-acid drug (usually a H2-receptor antagonist) to prevent it’s destruction in the stomach • Is inactivated by heat – caution if mixing pancreatin in with food • Indications: o Cystic fibrosis o Chronic pancreatitis o Diabetes mellitus o Pancreatectomy • Adverse effects: o Nausea / vomiting o Abdominal discomfort o Irritation of buccal / perianal mucosa 5-Aminosalicyclic acid (5-ASA) compounds: • E. loperamide.g.g.g. mesalazine. codeine. phosphate enemas • Probably as effective as oral osmotic laxatives Opioids and diarrhoea: • E.2009 • • These sugars are poorly absorbed by the colon and act as osmotic laxatives Onset of action: o Salts – hours o Lactulose – 2 or 3 days Adverse effects: o Cramps o Flatulence o Hypermagnesaemia (especially in renal impairment) with Mg salts o Stool softeners: • E.com .Copyright Dr Garry KJ Pettet 2005 . glycerine suppositories.garrypettet. sodium docusate.g. olsalazine.
Copyright Dr Garry KJ Pettet 2005 . only 30% of those who heal remain healed at 1 year • Adverse effects: o Local reactions o Increased risk of infections: ! Especially tuberculosis (need to screen before therapy) o Demyelination syndromes o SLE-like syndrome: ! Avoid in SLE-sufferers o Worsening of pre-existing heart failure www.2009 • • • • • Unknown mechanism of action Indications: o Induction of remission in UC (rectal preparation) o Maintenance of remission in UC and CD: ! 1 year relapse rate (73% placebo vs 21% sulphasalazine) Probably reduce the cancer risk associated with UC Drug structures: o Olsalazine: ! Two 5-ASA molecules joined by an azo bond that is cleaved by bacteria in the colon o Sulphasalazine: ! 5-ASA with sulphapyridine (a sulphonamide) ! The sulphapyridine carries the 5-ASA to the colon ! Most of the adverse effects are caused by sulphapyridine Adverse effects: o Few with the newer agents (lacking sulphapyridine) Infliximab: • An anti-TNF! monoclonal antibody • Indications: o Crohn’s disease not controlled by steroids and a conventional immunosuppressant o Refractory fistulating Crohn’s disease • 65% of patients initially respond to infliximab • 30% will go on to remission • Of those that respond to a single treatment – 50% maintain remission when treated for 1 year • Infliximab closes 50% of refractory fistulas within 2 weeks and improves healing in 65%: o However.com 26 .garrypettet.
com . 4: ! Worse prognosis ! Treat for 12 months • If HCV RNA has not decreased after 12 weeks treatment to <1% of initial level then consider discontinuing Drug treatment of influenza: • Influenza A only: 27 www.2009 Antivirals Treatment of herpes simplex virus (HSV) and varicella zoster virus (VZV): • Aciclovir (topical / oral / IV) • Second-line: o Famciclovir (good for genital herpes) o Valaciclovir Treatment of cytomegalovirus (CMV): • Ganciclovir (IV) (can cause myelosuppression) • Second-line: o Valaciclovir o Foscarnet Treatment of human immunodeficiency virus (HIV): • Highly active anti-retroviral therapy (HAART): o Two NRTIs plus either an NNRTI or a PI • NRTI = nucleoside reverse transcriptase inhibitor • NNRTI = non.garrypettet.Copyright Dr Garry KJ Pettet 2005 .nucleoside reverse transcriptase inhibitor • PI = protease inhibitor • Treatment of opportunistic infections Drugs treatment of chronic hepatitis B (HBV) infection: • 40% success rate • Interferon-! (IFN-!) given as a subcutaneous injection • Lamivudine • Second-line: o Famciclovir Drug treatment of chronic hepatitis C (HCV) infection: • Combination therapy (most effective. 3: ! Better prognosis ! Treat for 6 months o Genotypes 1. up to 60% ‘cured’): o Peginterferon-! ($ bioavailability – once weekly) o Ribavirin • Treatment depends on HCV genotype: o Genotypes 2.
where it is converted to the triphosphate: o Inhibits viral DNA polymerase and terminates the nucleotide chain • Adverse effects: o Rash (topical preparations) o Drip site inflammation o Renal damage o Bone marrow suppression (with parenteral administration • Interactions: o Probenicid decreases excretion of aciclovir Adverse effects of the NRTIs: • All of these drugs have many side-effects. only important ones for each are listed here • Abacavir: o Hypersensitivity (rash.garrypettet.com .2009 • • • o Amantadine Influenza A and B: o Neuraminidase inhibitors: ! Olseltamivir ! Zanamivir Only used in at-risk adults who can start treatment within 48 hours of the onset of symptoms At-risk adults: o Chronic respiratory disease o Significant cardiovascular disease (excluding hypertension) o Chronic renal disease o Immunocompromised o Diabetes mellitus Aciclovir: • Is a guanosine analogue and an example of a prodrug • Aciclovir is converted to the monophosphate by thymidine kinase • Viral thymidine kinase has a much greater affinity for aciclovir than the human enzyme • Aciclovir is therefore only activated in virally-infected cells. Stevens-Johnson syndrome) o Hepatic impairment (lactic acidosis.Copyright Dr Garry KJ Pettet 2005 . hepatomegaly) • Didanosine: o Pancreatitis • Lamivudine: o Well tolerated o Caution in hepatic disease • Stavudine: o Lipodystrophy o Peripheral neuropathy • Zalcitabine: o Pancreatitis o Peripheral neuropathy 28 www.
Copyright Dr Garry KJ Pettet 2005 - 2009
Zidovudine (AZT): o Bone marrow suppression (initially developed as an anticancer agent)
Adverse effects of the NNRTIs: • All of these drugs have many side-effects, only the important ones for each are listed here • Efavirenz: o Psychiatric manifestations • Nevirapine: o Hypersensitivity (rash, Stevens-Johnson syndrome) o Many drug interactions: ! E.g. methadone is metabolised much faster Adverse effects of the PIs: o Many side effects although an important one is lipodystrophy • Amprenavir: o Hypersensitivity (rash, Stevens-Johnson syndrome) • Indinavir: o Renal calculi • Ritonavir: o Peripheral and circumoral paraesthesia • Saquinavir: o Liver impairment • Combination: o Kaletra (lopinavir + ritonavir): ! The ritonavir $ the concentration of the lopinavir ! Diarrhoea Lipodystrophy: • Also known as the fat redistribution syndrome • A common side effect of the PIs and stavudine • Features: o Decreased subcutaneous fat o Buffalo hump o Breast enlargement o Hyperlipidaemia o Insulin resistance - hyperglycaemia Amantadine: • Indications: o Influenza A in at-risk adults within 48 hours of symptoms o Parkinson’s disease • It’s anti-viral actions arise from it’s ability to inhibit a viral ion-channel • The putative mechanism in Parkinson’s disease is an increase in dopamine release
Copyright Dr Garry KJ Pettet 2005 - 2009
Asthma / COPD
Severe asthma: • Unable to complete sentences • Respiratory rate >25/min • Pulse >110/min • PEFR <50% best or predicted Life-threatening asthma: • PEFR <33% best or predicted • Bradycardia • Hypotension • Silent chest • Feeble respiratory effort • Confusion • Blood gases: o pCO2 > 5kPa o pO2 <8kPa o pH <7.35 BTS guidelines for the management of acute severe asthma in adults • Initial management: o 100% High flow oxygen o Nebulised salbutamol (5mg) or terbutaline (10mg) o Add in nebulised ipratropium bromide (0.5mg) if poor response o IV hydrocortisone (100mg) • No improvement: o Consider ITU referral o Continue repeating nebulised salbutamol o IV magnesium sulphate (1.2-2g over 20 mins) o Aminophylline: ! Omit loading dose if patient is taking theophylline o IV Salbutamol (but not with Aminophylline) BTS 5 steps approach to the management of asthma: • Step 1 (mild intermittent asthma): o Inhaled short-acting "2-agonist as required • Step 2 (regular preventer therapy): o Step 1 + low dose inhaled steroid • Step 3 (add-on therapy): o Step 2 + long-acting "2-agonist (LABA) o If partial response to LABA then: ! Continue with LABA and increase dose of inhaled steroid o If no response to LABA then: ! Stop LABA and increase dose of inhaled steroid ! Consider adding in leukotriene antagonist or theophylline • Step 4 (persistent poor control):
Copyright Dr Garry KJ Pettet 2005 - 2009
Step 3 + either: ! High-dose inhaled steroid ! Leukotriene antagonist (if not on one already) ! Oral theophylline Step 5 (continuous or frequent use of oral steroids): o Step 4 + daily oral steroids o Refer patient for specialist care o
General principles of drug treatment of COPD: • Discontinue drugs which may worsen COPD: o E.g. "2-blockers for hypertension • Maintenance therapy: o Inhaled bronchodilators: ! "2-agonists (short-/long-acting) ! Anti-muscarinics (short-/long-acting): • These are more important than in asthma o Inhaled corticosteroids: ! If FEV1 <50% predicted ! Repeated exacerbations o Theophylline • Exacerbations: o Oral steroids o Antibiotics (if infection suspected) • Vaccination: o Influenza (definite benefit shown) o Pneumococcal (probable benefit) Drug treatment of COPD by stage: • Stage 0: o No COPD (but at risk) • Stage 1 (mild COPD): o FEV1 <80% predicted o Short-acting "2-agonist • Stage 2: o FEV1 50-80% predicted o Long-acting "2-agonist • Stage 3: o FEV1 <50% predicted o Inhaled steroids (1000 - 2000µg daily) • Stage 4: o FEV1 <30% predicted o Risk of cor pulmonale o May need oxygen therapy if hypoxic at rest
Inhaled "2-agonists: • Short-acting (last 4-6 hours): o Salbutamol
leading to smooth muscle relaxation Adverse effects: o Tachycardia o Tremor Interactions (Hypokalaemia with high doses of): o Corticosteroids o Diuretics (loop and thiazide) o Theophylline Inhaled anti-muscarinics: • Short-acting (last 3-6 hours): o Ipratropium bromide (Atrovent) • Long-acting (once daily): o Tiotropium (Spiriva) • Indications: o Asthma o COPD with reversible component (especially tiotropium) • Mechanism of action: o Inhibits the parasympathetic nervous supply of the bronchioles by binding to muscarinic receptors • Adverse effects (uncommon as poorly absorbed systemically): o Dry mouth o Constipation • Cautions: o Glaucoma o Prostatic hypertrophy Inhaled corticosteroids: • E.Copyright Dr Garry KJ Pettet 2005 .2009 • • • • • o Terbutaline Long-acting (last ~12 hours): o Salmeterol Indications: o Asthma o COPD with reversible component Mechanism of action: o Stimulate "2-receptors on airway smooth muscle o Leads to $ cAMP which # intracellular Ca2+. fluticasone • Indications: o Asthma (from BTS step 2 onwards) • Mechanism of action: o Decrease formation of numerous cytokines important in asthma o Inhibit generation of prostaglandins / leukotrienes o Inhibit the allergen-induced influx of eosinophils into the lung o Up-regulate "2-receptors • Take up to 12 weeks to reach maximum efficacy • Reduce morbidity and mortality of asthma • Improve quality of life • Prevent long-term decrease in airway function 32 www.garrypettet.g. beclomethasone. budesonide.com .
Aminophylline. must be by very slow IV injection • Indications: o Asthma (BTS step 3 onwards) as theophylline o Severe acute asthma (as aminophylline) • Mechanism of action: o Are phosphodiesterase inhibitors and lead to an $ cAMP and hence bronchial smooth muscle relaxation o May also increase cGMP levels and cause smooth muscle relaxation • Adverse effects: o Nausea / vomiting o Hypokalaemia o CNS stimulation • Interactions (many – is metabolised by liver enzymes): o Adenosine: ! Actions of adenosine are inhibited by the methylxanthines o Plasma concentration increased by: ! COC pill ! Erythromycin ! Cimetidine ! Verapamil o Plasma concentration decreased by: ! Carbamazepine ! Phenytoin ! Rifampicin • Caution: 33 www.2009 • • • • Inhaled steroids work best at a moderate dose combined with bronchodilators Adverse effects (fewer than systemic corticosteroids): o High dose: ! Adrenal suppression (give patients steroid card) ! Cataracts ! Glaucoma ! Growth suppression (probably just initial growth velocity) ! Osteoporosis o Low dose: ! Candidiasis (reduced by using a spacer device) ! Hoarse voice Interactions: o Very few when inhaled Cautions: o Active or quiescent TB o Oral steroids may be required during times of high stress if on long-term high dose inhaled steroids Methylxanthines: • E.garrypettet. theophylline • Aminophylline is a soluble form of theophylline: o If given IV.com .Copyright Dr Garry KJ Pettet 2005 .g.
2009 o o Half-life is increased by: ! Cardiac failure ! Liver disease ! Viral infections Half-life is decreased by: ! Alcoholism ! Smoking Leukotriene antagonists: • E. LTD4 and LTE4) in the airways • Advantages: o Improved compliance (oral and don’t have the steroid stigma) o Some patients respond well to them o Well tolerated • Disadvantages: o Poor efficacy compared to inhaled steroids o Unpredictable response o Expensive • Adverse effects: o GI disturbances o Drug-induced Churg-Strauss syndrome www.com 34 .Copyright Dr Garry KJ Pettet 2005 .g.g.garrypettet. LTC4. montelukast • Taken orally • Indications: o Asthma (BTS step 3 onwards) • Mechanism of action: o Block the effects of cysteinyl leukotrienes (e.
% and & receptors in the: o Dorsal horn o Peri-aqueductal grey matter o Midline raphe nuclei Contraindications to the use of strong opioids: • Severe respiratory disease (e.garrypettet. COPD) • Head injury / raised intracranial pressure: o Interfere with neurological assessment • Hepatic failure • Acute alcohol intoxication WHO analgesic ladder: • Step 1: o Non-opioid analgesics: ! Aspirin ! Paracetamol ! NSAIDs • Step 2: o Weak opioids /partial opioid agonists: 35 www.2009 Analgesics Taxonomy of opioids: • Opioid: o A compound acting at an opioid receptor • Opiate: o An alkaloid derived from opium Adverse effects of opioids: • CNS: o Respiratory depression: ! Decreased respiratory rate ! Relief of dyspnoea o Sedation o Euphoria o Meiosis o Anti-tussive o Nausea / vomiting • Non-CNS: o Pruritis o Constipation o Urinary retention • Opiates only: o Histamine release: ! Not opioid receptor mediated Mechanism of action of opioids: • Mimic endogenous opioids by acting on µ.g.Copyright Dr Garry KJ Pettet 2005 .com .
patient can go home ! Renal impairment (creatinine >200µmol/L) ! Blood pH <7.Copyright Dr Garry KJ Pettet 2005 .5 at 72 hours: • If INR is normal at 48 hours. U&Es o Treatment: ! Remove the drug: • If >12g and <1 hr since ingestion .gastric lavage • If <8 hrs since ingestion .garrypettet. FBC.com .3 ! Systolic BP <80mmHg • Cautions: o Hepatic / renal impairment o Alcohol dependence Codeine phosphate: • Indications: o Cough suppression o Diarrhoea o Mild to moderate pain • Half-life of 3.0 at < 48 hrs or INR >3.2009 ! ! • Step 3: o Strong opioids: ! Morphine ! Diamorphine Codeine Tramadol Paracetamol (acetaminophen): • Indications: o Mild to moderate pain o Pyrexia • Adverse effects: o Dangerous in overdose • Overdose: o Signs / symptoms: ! None (generally) ! Abdominal pain ! Hypoglycaemia ! Vomiting o Investigations: ! ABG.activated charcoal ! Find the time vs paracetamol concentration graph in A&E: • If above treatment line start N-acetylcysteine o Rule of thumb: ! If PT (secs) > time since od (hrs) then bad prognosis o Criteria for transfer to specialist liver unit: ! Encephalopathy / $ ICP ! INR > 2.5 hours • Adverse effects: o Constipation (prominent) o See “adverse effects of opioids” 36 www. INR. glucose. LFTs (ALT).
2009 Tramadol: • Synthetic analogue derived from codeine • Indications: o Moderate to severe pain • Mechanism of action: o µ-receptor agonist (like most opioids) o Inhibits uptake of noradrenaline and 5-HT • Advantages over other opioids: o Does not depress respiration • Disadvantage over other opioids: o Can cause seizures Morphine: • Indications: o Pain: ! Acute (e. malignancy) o Acute pulmonary oedema o Intractable cough in terminal care • Half-life of 3 hours • Tolerance to morphine occurs after about 2 weeks of continuous use • Titration of morphine dose: o Assess individual 24 hour requirement to relieve pain at rest and on movement o Convert to modified release morphine (MST) bd with rapid release morphine prn for breakthrough pain o Increase the dose of MST based on the basis of breakthrough requirements www. myocardial infarction) ! Chronic (e.com 37 .g. chronic pancreatitis) ! Terminal (e.garrypettet.g.Copyright Dr Garry KJ Pettet 2005 .g.
Copyright Dr Garry KJ Pettet 2005 .garrypettet.com .g. atenolol 5mg IV) unless contraindicated Thrombolysis: o Indications: ! Presentation within 12 hours of chest pain and ! ST elevation >2mm in 2 or more chest leads or ! ST elevation >1mm in 2 or more limb leads or ! New left bundle branch block or ! Posterior infarction o Contraindications: ! Bleeding ! Prolonged / traumatic CPR ! Trauma / surgery (within 2 weeks) ! Recent haemorrhagic stroke ! Severe hypertension (>200/120mmHg) ! Pregnancy ! Suspected aortic dissection o Thrombolytic agent: ! Streptokinase (SK): • 1.9% saline over 1 hour • Usual first choice • Risk of allergy / anaphylaxis ! Tissue plasminogen activator (tPA): • Give if patient already received SK • Alteplase " infusion • Tenecteplase " bolus injection • Heparin: o DVT / PE prophylaxis Drug treatment post-myocardial infarction: • Aspirin 75mg od 38 www.2009 The failing heart Heart failure: • Acute: o Myocardial infarction (MI): ! Acute ! Post-MI o Pulmonary oedema without MI • Chronic: o Chronic stable angina o Heart failure Drug • • • • • • treatment of acute myocardial infarction: Oxygen Aspirin 300mg (chewed) or clopidogrel (if aspirin contraindicated) Morphine 5-10mg IV + metoclopramide 10mg IV GTN 2 puffs or 1 tablet prn "-blocker (e.5 million units in 100mls 0.
5 – 5mg slow IV) GTN 2 puffs or 2x0.2009 • • • • • Drug • • • • • • • "-blocker (e. benefit shown even if “normal” cholesterol levels) Treat other risk factors: o Diabetes mellitus o Hypertension Think of the 4 A’s (Aspirin.g.g.garrypettet.3mg tablets If systolic BP >100mmHg start nitrate infusion (keep >90mmHg) If patient worsening: o Repeat furosemide 40 – 80mg slow IV o Consider ventilation o Consider increasing nitrate infusion Drug treatment of chronic stable angina: • Aspirin • Nitrates: o Relief: ! GTN o Prevention: ! Long-acting nitrates • "-blockers (e.com . ACE inhibitor and Atorvastatin) treatment of acute pulmonary oedema: Sit patient upright Oxygen Furosemide (40 – 80mg slow IV) Diamorphine (2.g. Atenolol. atenolol 50-100mg/24 hours po) • Calcium-channel blockers: ! Caution with concomitant use of "-blocker o Dihydropyridines: ! Amlodipine o Non-dihydropyridines: ! Diltiazem ! Verapamil (caution with "-blockers) • Potassium channel activator: o Nicorandil Drug treatment of chronic heart failure: • Diuretics: o Furosemide (symptomatic only) ± o Spironolactone: ! Potassium-sparing ! Shown to reduce mortality o Metolazone: ! Thiazide diuretic ! Synergistic with furosemide for refractory oedema • ACE inhibitors: o Shown to reduce mortality 39 www. atenolol) or verapamil if contraindicated ACE inhibitor (especially if evidence of heart failure) Statin (e.Copyright Dr Garry KJ Pettet 2005 .
garrypettet. go slow” – needs careful titration Digoxin: o Can be used even if the patient is in sinus rhythm o No reduction in mortality o # in hospital admissions Angiotensin II receptor antagonists: o Probably similar to ACEIs but little conclusive evidence Nitrates: o Probably reduce mortality (but less so than ACEIs) o Used in those in whom ACEIs are contraindicated Nitrates: • All function as nitric oxide (NO) donors • Cause mainly venous dilatation (hence # preload) • Mechanism of action of NO: o NO stimulates guanylyl cyclase which leads to an $ cGMP o $ cGMP leads to smooth muscle relaxation • Glyceryl trinitrate (GTN): o Onset is rapid and lasts for ~30 mins o Usually given sublingually • Long-acting nitrates (isosorbide mono-/dinitrate): o More stable than GTN and last several hours o Isosorbide mononitrate is the active metabolite of isosorbide dinitrate: ! The mononitrate avoids the unpredictable first-pass metabolism of the dinitrate o Tolerance develops after as little as 24 hours – avoid by omitting the evening dose (permits an 8 hour drug-free interval) • Adverse effects: o Headaches (frequently dose-limiting) o Hypotension / fainting o Reflex tachycardia (prevented by administration of a "-blocker) • Contraindications: o Constrictive pericarditis o Hypotension o Head trauma o Hypertrophic obstructive cardiomyopathy (HOCM) o Valvular stenosis (aortic / mitral) • Interactions: o Sildenafil (Viagra): ! Profound hypotension "-blockers: • Non-selective: o Propranolol: ! Is a full antagonist o Pindolol / oxprenolol: 40 www.com .2009 • • • • "-blockers: o Shown to reduce mortality (probably via # arrhythmias) o Synergistic with ACEIs o “Start low.Copyright Dr Garry KJ Pettet 2005 .
Copyright Dr Garry KJ Pettet 2005 . heart rate) but prevent the exercise-induced cardiovascular changes caused by sympathetic stimulation o Anti-hypertensive action probably arises from an alteration in the CNS “set-point” Adverse effects: o Lethargy / fatigue (usually improves with use) o Bradycardia o Cold hands / feet o Hypotension o Bronchospasm (including cardio-selective agents) o Nightmares o Worsened / precipitated heart failure Contraindications: o Asthma / COPD o Bradycardia / heart block Interactions: o Diltiazem / verapamil: ! $ risk of bradycardia / AV block o Insulin / oral anti-diabetic agents: ! "-blockers mask the signs of hypoglycaemia o Calcium-channel blockers: • Two classes: o Dihydropyridines: ! Nifedipine (short-acting) ! Amlodipine (longer-acting) Non-dihydropyridines: ! Diltiazem ! Verapamil Indications: o All: ! Angina (especially vasospastic angina) o 41 • www.garrypettet.2009 • • • • • • ! Are partial agonists Labetolol: ! " and ! antagonist (" > !) “Cardio-selective” ("1-antagonists): o Atenolol o Metoprolol Indications: o Angina o Heart failure o Hypertension o Post-MI o Prevention of variceal bleeding in liver disease (propranolol) o Prophylaxis of migraine o “Stress”-induced arrhythmias Mechanism of action: o Most do not affect resting parameters (e.g.com .
2009 • • • • • • • ! Hypertension Nifedipine: ! Raynaud’s phenomenon o Verapamil: ! Supraventricular arrhythmias: • Adenosine has largely replaced in acute situation • Can be used as prophylaxis against SVTs Mechanism of action: o Block L-type voltage-sensitive Ca2+ channels in: ! Arterial smooth muscle (vasodilatation): • Both classes • Can cause a reflex tachycardia ! Myocardial conduction system (negative inotropism): • Non-dihydropyridines (as they have a high affinity for channels in the activated state Amlodipine causes less tachycardia than nifedipine Verapamil (and to a lesser extent diltiazem) depress the sinus node: o Mild resting bradycardia Verapamil slows conduction at the AVN Diltiazem has actions in between verapamil and nifedipine: o Popular in treatment of angina – does not cause tachycardia Adverse effects: o Fluid retention (ankle oedema): ! Can be severe enough to merit withdrawal ! Is a local effect that has nothing to do with Na+ retention o Headaches o Hypotension o Flushing o Gum hypertrophy Contraindications: o All: ! Cardiogenic shock o Dihydropyridines: ! Severe aortic stenosis / HOCM ! Unstable angina o Non-dihydropyridines: ! Myocardial conduction defects (e.Copyright Dr Garry KJ Pettet 2005 . bradycardia) ! Heart failure: • Further depression of cardiac function o Nifedipine: ! Angina (short-acting preparation may $ mortality) o Verapamil: ! Ventricular tachycardia (potentially lethal) ! AF with Wolff-Parkinson-White syndrome Interactions: o Diltiazem: ! Digoxin: • Diltiazem $ plasma concentration of digoxin o 42 • www.g.garrypettet.com .
severe hypotension.g.2009 ! Carbamazepine: • Diltiazem $ plasma concentration of carbamazepine o o Phenytoin: • Diltiazem $ plasma concentration of phenytoin Nifedipine: ! Diltiazem: • $ plasma levels of nifedipine ! Phenytoin: • Nifedipine $ plasma levels of phenytoin ! Grapefruit juice: • $ plasma levels of nifedipine (and other dihydropyridines but not Amlodipine) Verapamil: ! "-blockers (asystole.com . thus reduce circulating angiotensin II • Actions of angiotensin II (mediated via the AT1 receptor): o Potent vasoconstrictor o Aldosterone secretion: ! Na+ retention ! K+ excretion • Advantages: o Do not affect blood lipids o May improve cardiac remodelling • Adverse effects: o Postural hypotension: ! Usually first-dose ! More common in sodium-depleted patients o Dry cough (Chinese are more susceptible) o Hyperkalaemia o Angioedema (in 1 – 2% of patients) • Contraindications: o Poor renal arterial perfusion pressure: ! Renal artery stenosis / coarctation of the aorta: • Loss of renal efferent arteriole tone (caused by the ACEI) and # afferent arteriole pressure leads to renal ischaemia 43 www. lisinopril • Indications: o Diabetic nephropathy o Hypertension o Heart failure o Post-MI • Inhibit ACE. captopril. enalapril.garrypettet. heart failure) ! Digoxin: • Verapamil $ plasma concentration of digoxin ! Cyclosporin: • Verapamil $ plasma concentration of cyclosporin ! Angiotensin converting enzyme inhibitors (ACEIs): • E.Copyright Dr Garry KJ Pettet 2005 .
irbesartan.2009 • o Aortic stenosis o Pregnancy Interactions: o NSAIDs: ! $ risk of renal impairment o Potassium-sparing diuretics: ! $ risk of hyperkalaemia o Lithium: ! ACEIs # excretion of lithium o Diuretics: ! $ risk of hypotension Angiotensin II (AII) receptor antagonists: • E.g. inhibiting the actions of angiotensin II o As they do not block ACE. losartan.Copyright Dr Garry KJ Pettet 2005 . candesartan • Indications: o Diabetic nephropathy o Hypertension o Heart failure (unlicensed indication) • Mechanism of action: o Block the AT1 receptor.garrypettet.com 44 . they do not affect the metabolism of bradykinin – possibly why they do not cause a cough • Adverse effects/contraindications/interactions – as for ACE inhibitors Digoxin: • Indications: o Supraventricular dysrhythmias (esp. AF) for ventricular rate control o Heart failure (improves symptoms not mortality) • Mechanism of action: o Is a cardiac glycoside extracted from foxglove leaves o Inhibits cardiac membrane Na+/K+-ATPase: ! $ intracellular Na+ ! Secondary $ in intracellular Ca2+ • Clinical effects: o $ force of cardiac contraction o $ cardiac vagal activity: ! # heart rate ! # AV conductance ! $ AVN refractory period • Common adverse effects: o Anorexia o Nausea o Vomiting • Toxic levels: o Digoxin requires therapeutic drug monitoring o Risk of toxicity increased with: ! Hypokalaemia (reduced competition for pump binding) ! Hypercalcaemia www.
com 45 . thus $ risk of digoxin toxicity o o Nicorandil: • Indications: o Angina • Mechanism of action: o Potassium channel activator with a nitrate component o Causes both arterial and venous vasodilatation • Adverse effects: o Headache o Flushing o Oral ulceration (rarely) • Interactions: o Sildenafil: ! Profound hypotension – avoid concomitant use www.2009 • • • ! Hypothyroidism May require digoxin specific antibody fragments (Fab) Features: ! Nausea (severe) ! Dysrhythmias: • VT • Heart block ! Xanthopsia (distortion of yellow colour vision) Contraindications: o Complete heart block o HOCM o Wolff-Parkinson-White syndrome Caution in renal impairment: ! Digoxin is excreted by the kidneys Drugs increasing risk of digoxin toxicity: o Anti-arrhythmics: ! Amiodarone ! Quinidine o Calcium channel blockers (non-dihydropyridines)): ! Diltiazem ! Verapamil o Diuretics (loop and thiazide): ! Cause hypokalaemia.garrypettet.Copyright Dr Garry KJ Pettet 2005 .
chlorpromazine • Propranolol (oral or IV if no contraindications) • Digoxin: o May be needed to slow the heart • Anti-thyroid drugs: o Carbimazole o Lugol’s solution • Corticosteroids (IV hydrocortisone or oral dexamethasone) Drug treatment of hypothyroidism: • Hypothyroidism: o Levothyroxine (T4) • Myxoedema coma: o Liothyronine (T3) Drug treatment of Addison’s: • Disease: o Oral hydrocortisone: ! 20mg in the morning ! 10mg in the evening ! Double during febrile illness.Copyright Dr Garry KJ Pettet 2005 . $K+ or $ renin ! Give every second day • Crisis: o Hydrocortisone 100mg IV stat o IV fluids (colloid to resuscitate then crystalloids) o Glucose IV if hypoglycaemic o Antibiotics if infection present 46 www.g. T4 (and cultures if infection suspected) • Sedate if necessary: o E.com . stress or injury o Fludrocortisone: ! Only needed if: • Postural hypotension • # Na+.garrypettet.2009 Endocrinology Drug treatment of hyperthyroidism: • Immediate symptom control: o Propranolol • Long-term treatment: o Thionamides: ! Carbimazole or ! Propylthiouracil o Radioiodine (131I) • Prior to surgery to decrease thyroid vascularity: o Lugol’s iodine solution Immediate management of thyrotoxic storm: • IV fluids • Take blood for T3.
garrypettet. LH: o Testosterone .2009 Drug treatment of Cushing’s syndrome: • Treat the underlying cause – rarely need drug therapy long-term • Suppression of plasma cortisol level: o Aminoglutethemide o Ketoconazole o Metyrapone Drug treatment of Conn’s syndrome: • Definitive treatment is with surgery • Spironolactone Drug treatment of diabetes insipidus (DI): • Cranial DI: o Treat the underlying cause o Intranasal desmopressin (DDAVP) • Nephrogenic DI: o Treat the underlying cause o Bendrofluazide (paradoxically.Copyright Dr Garry KJ Pettet 2005 .females • TSH: o Thyroxine (if hypothyroid.males o Oestrogen (via COC pill) . but can’t use to TSH to monitor) • No need to replace prolactin Drug treatment of hypogonadism: • Males: o Testosterone 47 www.com . as this is a diuretic) Drug treatment of acromegaly: • Best treated with trans-sphenoidal surgery or irradiation • Somatostatin analogues (first line): o Octreotide (short-acting) o Lanreotide (long-acting) • Dopamine agonists: o Bromocriptine o Cabergoline Drug treatment of hypopituitarism: • Need to replace what is missing • ACTH: o Hydrocortisone • GH: o Recombinant GH is available • FSH.
garrypettet. sandocal) • Severe: o 10mls 10% calcium gluconate IVI over 30 mins o Repeat as necessary • Must correct magnesium levels – will never correct Ca2+ otherwise Drug treatment of phaeochromocytoma crisis: • Control BP with IV phentolamine (short-acting !-antagonist) • When BP controlled.g.Copyright Dr Garry KJ Pettet 2005 .2009 • Females: o COC pill Drug treatment of hyperprolactinaemia: • Definitive treatment is surgical • Dopamine agonists: o Bromocriptine o Cabergoline Drug • • • • treatment of hypercalcaemia: Treat underlying cause if possible IV fluids Bisphosphonates Salmon calcitonin: o Rarely used o Faster onset than bisphosphonates • Steroids: o E. propylthiouracil • Indications: o Carbimazole: ! Hyperthyroidism o Propylthiouracil: ! Usually reserved for patients intolerant to carbimazole • Mechanism of action: o All: ! Inhibition of thyroid peroxidase ! Immunosuppressive properties (controversial) 48 www.g. carbimazole.g. for sarcoidosis • Furosemide (once rehydrated) Drug treatment of hypocalcaemia: • Mild: o Oral calcium supplements (e. give phenoxybenzamine (irreversible !antagonist) • Give "1-blocker • Arrange for surgery within next few weeks Thionamides: • E.com .
1%) ! Propylthiouracil (0.garrypettet.Copyright Dr Garry KJ Pettet 2005 .g. pregnancy must not be allowed to occur within 3 months) o Mothers who are unable to leave their children in others care for at least 10 days (to avoid exposure) Thyroxine: • May be either T4 (Levothyroxine) or T3 (liothyronine) • T3 is faster acting than T4 but with a shorter half-life 49 www.com . sore throat): • If neutropenia confirmed " stop treatment Cautions: o Pregnancy: ! Low doses should be used as carbimazole crosses the placenta and can cause neonatal hypothyroidism / goitre ! PTU is less problematic in pregnancy o Radioiodine (131I): • Treatment of choice in pts >40 years (can be used in younger pts) • Indications: o Hyperthyroidism o Disseminated thyroid malignancy • Mechanism of action: o The radioactive iodine is localised to the thyroid where it destroys thyroid tissue via "-radiation • Treatment renders the pt euthyroid within 4-6 weeks.2009 • • • Carbimazole: ! Is a prodrug (converted to methimazole) o Propylthiouracil: ! Inhibits peripheral conversion of T4 " T3 How to use: o Aim is to render the patient euthyroid and then give a # dose for maintenance o It is often possible to stop treatment after 1 or 2 years (50% relapse rate) Adverse effects: o GI disturbances o Carbimazole: ! Pruritis ! Rash o Agranulocytosis: ! Carbimazole (0. when thyroxine replacement therapy can be undertaken (lifelong) • Adverse effects: o Causes hypothyroidism o May precipitate thyroid storm • Contraindications: o Children o Pregnancy (also.4%) ! Patients should be told to seek medical attention if they develop symptoms of infection (e.
temporal arteritis) ! Leukaemia ! Sarcoidosis ! Transplant rejection o Replacement: ! Addison’s disease ! Congenital adrenal hyperplasia • Mechanism of action: o Bind to cytoplasmic receptor that diffuses into nucleus and binds to steroid-response elements on DNA: ! Either increases or decreases transcription with numerous effects o Inhibits phospholipase A2 (thus # production of arachidonic acid) o # B and T cell responses to antigens • Adverse effects (many): o CNS: ! Depression ! Psychosis o Endocrine: ! Adrenal suppression ! Hirsuitism 50 www.g. prednisolone. hydrocortisone.Copyright Dr Garry KJ Pettet 2005 .garrypettet.g.g.com . eczema) ! Systemic: • Anaphylaxis • IBD • Rheumatoid arthritis o Immunosuppression: ! Connective tissue diseases (e.2009 • • • Adverse effects (mainly in overdose): o Angina o Dysrhythmias (including AF) o MI o Tachycardia o Hyperthyroid symptoms (even when TSH in normal range) Cautions: o Thyroxine should be introduced slowly in those with IHD Interactions: o Warfarin: ! Thyroxine $ the effect of warfarin Corticosteroids: • E. dexamethasone • Indications (many): o Anti-inflammatory: ! Topical: • Asthma • Skin disorders (e.
phenytoin) Withdrawal of glucocorticoids – withdrawal gradually in the following: o Course duration >3 weeks o Received >40mg prednisolone (or equivalent) daily o Been given repeated doses in the evening o Taken a short course within 1 year of taking long-term therapy Notes: 51 www.g.Copyright Dr Garry KJ Pettet 2005 .garrypettet. gut) Interactions: o Enhances activity of warfarin o Live vaccines (impairs response) o Reduces activity of anticonvulsants (carbamazepine. aerosol.g.2009 • • • • ! Impotence ! Oligo-/amenorrhoea ! Weight gain o Eyes: ! Cataracts ! Glaucoma o Gastrointestinal: ! Candidiasis ! Peptic ulceration ! Pancreatitis o Immune system: ! $ susceptibility to and $ severity of infections o Metabolic: ! Hyperglycaemia ! Hypertension o Musculoskeletal: ! Growth suppression ! Myopathy ! Osteoporosis o Skin: ! Abdominal striae ! Buffalo hump ! Easy bruising ! Poor wound healing ! Thinning Differences between the different steroids: o Hydrocortisone: ! Replacement therapy ! IV in shock / status asthmaticus o Prednisolone: ! Orally for anti-inflammatory effects o Dexamethasone: ! No salt-retaining properties ! Very potent ! Useful when high doses required (e.com . cerebral oedema) o Budesonide / beclomethasone: ! Pass membranes very poorly ! Much more active topically (e.
Copyright Dr Garry KJ Pettet 2005 .5mg prednisolone Patients should be given a steroid card Metyrapone: • Indications: o Cushing’s syndrome: ! Especially that not amenable to surgery (e.g.com . lanreotide (given once monthly) • Indications: o Acromegaly o Carcinoid syndrome o Variceal bleeding (octreotide. unlicensed indication) • Mechanism of action in acromegaly: o Inhibits GH release from the pituitary gland o 90% of patients respond and 60% have GH level normalisation 52 www.garrypettet. octreotide (given tds).2009 o o “Physiological” dose of steroid is ~7.g. lung ca) o Resistant oedema due to aldosterone secretion in: ! Cirrhosis ! Congestive cardiac failure • Mechanism of action: o Competitive inhibitor of 11"-hydroxylase o Inhibits endogenous production of cortisol (and to a lesser extent aldosterone) by the adrenals • Contraindications: o Adrenocortical insufficiency o Pregnancy / breast feeding • Adverse effects: o Hypoadrenalism Desmopressin (DDAVP): • Synthetic vasopressin (ADH) analogue • Indications: o Cranial diabetes insipidus (diagnosis and treatment) o Haemophilia o Persistent enuresis • Mechanism of action: o Selectively agonises V2 receptors on renal tubular cells: ! Leads to increased reabsorption of water ! Thus devoid of vasoconstrictor activity (V1) o Also increases the plasma concentration of factor VIII • Adverse effects: o Dilutional hyponatraemia o Fluid retention • Contraindications: o Heart failure Somatostatin analogues: • E.
cabergoline (long-acting) • Indications: o Acromegaly o Hyperprolactinaemia o Idiopathic Parkinson’s disease o Suppression of lactation o Cyclical benign breast disease • Mechanism of action: o Directly stimulate dopamine receptors in the CNS (antiParkinson’s effect) o Inhibits release of prolactin from anterior pituitary o Inhibits the release of GH in acromegalics: ! Increases GH levels in non-acromegalics • Lead to a maximum # of GH of 7-60%: o Only 10-15% of patients achieve GH normalisation • Adverse effects: o Nausea / vomiting o Postural hypotension o Drowsiness / confusion o Dyskinesia o Fibrotic reactions (rare): ! Pericardial / pulmonary and retroperitoneal fibrosis • Domperidone (D2 antagonist): o Can be used to relieve the peripheral adverse effects of bromocriptine (does not cross the BBB so has no effect on CNS effects) • Interactions: o Erythromycin and sympathomimetics (e.com . somatrophin • Indications: o Adults: ! GH deficiency o Children: ! GH deficiency ! Chronic renal impairment ! Turner’s syndrome Testosterone: 53 www.g.g. bromocriptine (short-acting).garrypettet.2009 • • Adverse effects: o Gallstones o GI disturbances Interactions: o Anti-diabetic agents (oral and insulin): ! Octreotide may # requirements for these drugs Dopamine agonists: • E.g.Copyright Dr Garry KJ Pettet 2005 . dobutamine): ! Increase the plasma concentration of bromocriptine Growth hormone: • E.
and thus inhibits ovulation • Adverse effects: o Major: ! $ risk of venous thromboembolism (VTE) ! $ risk of hypertension ! $ risk of breast carcinoma (small) o Minor: ! Breast tenderness ! Headaches ! Nausea ! Weight gain • Contraindications: o Absolute: ! History of CVA / IHD / VTE ! Migraine (severe / focal) ! Blood clotting disorders ! Active breast / endometrial cancer o Relative: 54 www.com .garrypettet.g.2009 • • • • • E. restandol (oral). andropatch (transdermal patch) Indications: o Male androgen deficiency Adverse effects: o Androgenic effects: ! Fusion of epiphyses in prepubertal boys (stunted growth) ! Hirsuitism ! Male pattern baldness ! Acne o Prostate abnormalities (enlargement ± malignancy) o Cholestatic jaundice Contraindications: o Cancers: ! Male breast ! Primary liver tumour ! Prostate Interactions: o Warfarin: ! Potentiates actions of warfarin Combined oral contraceptive (COC) pill: • E.g. microgynon • Are preparations containing both an oestrogen and a progestogen • Indications: o Contraception o Menstrual cycle control / menorrhagia o Mild endometriosis o Premenstrual symptoms • Mechanism of action: o Exerts a negative feedback on the pituitary and inhibits gonadotrophin release.Copyright Dr Garry KJ Pettet 2005 . sustanon (IM). cilest.
garrypettet.Copyright Dr Garry KJ Pettet 2005 . calcitonin (porcine natural).com . long-acting) • !1: o Prazosin o Doxazosin o Tamsulosin (Flomax) • Indications: o Non-selective !-blockers: ! Phaeochromocytoma o !1-blockers: 55 www.2009 • • ! Age > 40 years ! Obesity ! Smokers Interactions: o Drugs reducing the efficacy of the COC pill: ! Broad-spectrum antibiotics ! P450 inducers: • Carbamazepine • Phenytoin • Rifampicin o Warfarin: ! Oestrogens (including the COC pill) reduce the effect of warfarin The COC pill should be stopped several weeks prior to an elective surgical procedure to # risk of VTE Calcitonin: • E.g. salcatonin (synthetic salmon calcitonin) • Indications: o Hypercalcaemia (rarely) o Malignant bone pain o Osteoporosis o Paget’s disease of bone (especially pain relief) • Mechanism of action: o Lowers serum calcium: ! Inhibits osteoclast activity ! Increases renal Ca2+ excretion • Adverse effects: o Facial flushing o Nausea / vomiting o Tingling sensation in the hands o Unpleasant taste in the mouth !1-antagonists: • Non-selective (!1 and !2): o Phentolamine (short-acting) o Phenoxybenzamine (irreversible.
tamsulosin) Mechanism of action: o Antagonism of post-synaptic !1-adrenoceptors leads to vasodilatation o !1 blockade also leads to relaxation of the internal urethral sphincter.2009 • • • ! Hypertension ! Benign Prostatic hypertrophy (doxazosin. resulting in $ urinary flow Adverse effects: o First-dose hypotension Interactions: o Other hypotensive agents .Copyright Dr Garry KJ Pettet 2005 .garrypettet.$ risk of hypotension www.com 56 .
Copyright Dr Garry KJ Pettet 2005 .garrypettet. simvastatin. pravastatin • Usually taken at night • Reduce incidence of all cardiovascular events and total mortality • Mechanism of action: o Are HMG-CoA reductase inhibitors – block the rate-limiting step in hepatic cholesterol synthesis o Due to the # concentration of cholesterol in the hepatocytes.com . there is an $ in the number of hepatic LDL receptors o This leads to a # in plasma LDL o Those with homozygous familial hypercholesterolaemia do not respond to statins (as they have no LDL receptors) • Adverse effects (all uncommon): o Myositis: o Patients complain of weakness / aching muscles ! If CK >5x upper limit of normal discontinue ! Can lead to rhabdomyolysis and renal failure ! If this occurs.2009 Lipids Which patients require lipid-lowering therapy? • Primary prevention: o Guidelines are frequently changing ! Total [chol] >5mmol/L and CHD risk >30% over 10yrs or ! 10yr CHD risk >=15% • Secondary prevention: o History of CVS event (angina. MI.g. cannot use a statin again o Altered LFTs • Contraindications: o Liver disease o Pregnancy • Interactions: o Drugs increasing the risk of myositis: 57 www. PVD. not just eat it) Drugs used to treat obesity: • Orlistat • Sibutramine Statins: • E. CVA) ± o [chol] >=5mmol/L • Choice of drug: o First choice therapy: ! Statin o Second choice therapy: ! Fibrates ! Anion exchange resins • Note about diet: o Diet lowers [cholesterol] only by ~10% (as we endogenously synthesise cholesterol. atorvastatin.
garrypettet. cholestipol • Mechanism of action: o Bind bile acids in the bowel o Forces the liver to synthesise more bile acids – causes an increase in the expression of LDL receptors and lowering of LDL • Adverse effects: o GI disturbance: ! Bloating ! Constipation ! Nausea / vomiting o May aggravate hypertriglyceridaemia o Impairs the absorption of many drugs o May impair the absorption of fat soluble vitamins: ! May require supplements of vitamins A.g.g. gemfibrozil • Actions: o Unclear mechanism – possibly stimulate lipoprotein lipase o # TGs (~30%) o # LDL (~10%) o $ HDL (10%) • Are first line drugs in patients with hypertriglyceridaemia (who are at risk of pancreatitis and retinal vein thrombosis) • Adverse effects: o GI disturbance o Myositis o Gallstones • Contraindications: o Hepatic / renal impairment o Pregnancy • Interactions: o Statins: ! $ risk of myositis o Warfarin: ! Potentiate the actions of warfarin Anion exchange resins: • E.2009 • ! Cyclosporin ! Fibrates o Warfarin: ! Statins potentiate the actions of warfarin Patients should have their LFTs monitored regularly whilst on a statin Fibrates: • E. cholestyramine. D and K Omega-3-oils (fish oils): • Can be effective in hypertriglyceridaemia • Adverse effects: 58 www. bezafibrate.Copyright Dr Garry KJ Pettet 2005 .com .
Copyright Dr Garry KJ Pettet 2005 . mainly cardiovascular www. D and K • Contraindications: o Cholestasis o Pregnancy • Interactions: o Warfarin: ! Difficulty in controlling the INR Sibutramine: • Indications: o As for orlistat • Mechanism of action: o Centrally acting anorectic o Inhibits reuptake of noradrenaline and 5-HT • Adverse effects: o Hypertension o Many others • Contraindications: o Many.garrypettet.2009 o Fish-like odour to the patient Orlistat: • Indications: o Adjunct in obesity management: ! BMI >30 if no diabetes ! BMI >27 if diabetic • Mechanism of action: o Pancreatic lipase inhibitor o Impairs absorption of dietary fat • Adverse effects: o GI disturbance: ! Probably why the drug works as patients reduce their fat intake to reduce the side-effects o May impair the absorption of fat soluble vitamins: ! May require supplements of vitamins A.com 59 .
Copyright Dr Garry KJ Pettet 2005 .2009 Clotting Antiplatelet drugs: • Aspirin • Dypyridamole • Clopidogrel • GP IIb/IIIa receptor antagonists: o Abciximab Anticoagulants: • Oral: o Warfarin • Parenteral: o Unfractionated heparin o Low molecular weight heparin (LMWH) Thrombolytic agents: • Streptokinase • Tissue plasminogen activator (tPA) Indications for antiplatelet drugs: • Acute coronary syndromes • Primary prevention of cardiovascular events: o If 10yr CVD risk >=20% (with a controlled blood pressure) • Secondary prevention of cardiovascular events: o CVA / TIA o IHD o PVD • Heart valve replacements • AF (in those who cannot be anti-coagulated) Indications for oral anti-coagulants: • AF • Prophylaxis / treatment of VTE: o DVT o PE • Mechanical heart valve replacements • Dilated cardiomyopathy / left ventricular aneurysm • ? TIAs Indications for parenteral anti-coagulants: • Acute coronary syndromes • Acute arterial obstruction • Treatment of VTE: o DVT o PE Indications for thrombolytic agents: • Acute myocardial infarction 60 www.com .garrypettet.
com .Copyright Dr Garry KJ Pettet 2005 . Glucose. may have taken both): • Levels >700mg/L are potentially fatal ! ABG. LFTs. U&Es o Treatment: ! Remove drug: • Gastric lavage if od <1 hour ago 61 www.garrypettet. INR. FBC.2009 • • • Arterial thrombus Life-threatening PE Occluded lines / shunts Aspirin: • Indications: o Mild to moderate pain o Pyrexia o Anti-platelet: ! Acute myocardial infarction ! History of: • Angina • Intermittent claudication • Myocardial infarction • Stroke • TIA ! AF (in patients where warfarin is contraindicated) ! Kawasaki syndrome (only childhood indication) • Mechanism of action: o Irreversibly inactivates platelet COX o Platelets cannot synthesise new COX: ! Takes 4 – 7 days for new platelets to be synthesised following a single dose (300mg) ! Reduction in production of the platelet aggregating compound thromboxane A2 • Adverse effects: o Bleeding o Bronchospasm o GI irritation / bleeding o Dangerous in overdose • Overdose: o Signs / symptoms: ! Coma ! Dehydration ! Hyperventilation ! Tinnitus ! Seizures ! Sweating ! Vertigo ! Vomiting o Investigations: ! Levels (salicylate and paracetamol.
haemophilia) Interactions: o Warfarin: ! Increased risk of bleeding o Methotrexate: ! Aspirin $ risk of toxic effects of methotrexate Correct acidosis with 1.com .26% HCO3>500mg/L: • Consider alkalinization of the urine Consider dialysis when: • Levels >700mg/L • Cardiac / renal failure • Seizures Dipyridamole: • Indications: o Secondary prevention of CVA / TIA: ! Some synergistic benefit with aspirin ! Used in those patients who have had a CVA on aspirin o Prevention of thromboembolism from prosthetic heart valves: ! Adjunct to oral anti-coagulation • Mechanism of action: o Phosphodiesterase inhibitor o Leads to an $ in cAMP and potentiation of prostacyclin • No increased risk of bleeding (cf aspirin) • Adverse effects: o Headache • Contraindications: o Myasthenia gravis (risk of exacerbation) • Interactions: o Adenosine: ! Dipyridamole prolong / enhances the effects of adenosine Clopidogrel: • Indications: o Secondary prevention of CVD: ! Within 35 days of MI ! Within 6 months of CVA o Acute coronary syndrome (without ST elevation): ! Given with aspirin ! Not for >12 months o Coronary artery stents 62 www.garrypettet.g.Copyright Dr Garry KJ Pettet 2005 .2009 ! ! ! • • • Cautions: o Asthma o Uncontrolled hypertension Contraindications: o Children <16 years (unless Kawasaki’s syndrome): ! Risk of Reye’s syndrome o Active peptic ulceration o Bleeding disorders (e.
com . IX and X o Also inhibits formation of protein C and S: ! Has an initial procoagulant effect o Takes at least 2–3 days to work (due to the half-life of preexisting clotting factors in the circulation) o Prolongs the prothrombin time (PT) • Pharmacokinetics: o Long half-life (40 hours) o Takes ~5 days after stopping treatment for INR to normalise o Highly protein-bound (albumin) • Dosage: o Loading: ! Warfarin therapy begins with a loading dose. VII.Copyright Dr Garry KJ Pettet 2005 .2009 • • • • Mechanisms of action: o Irreversibly blocks the action of ADP on platelets – leading to a reduction of platelet aggregation Adverse effects: o Bleeding o Bone marrow suppression (rare) Cautions: o First few days following MI / CVA Interactions: o Warfarin: ! Increased risk of bleeding Abciximab: • Indications: o Patients awaiting PTCA: ! Short-term prevention of MI in those with ACS o Patients undergoing PTCA: ! Adjunct to aspirin and heparin • Mechanism of action: o Monoclonal antibody to GP IIb/IIIa o Inhibit platelet aggregation • Adverse effects: o Bleeding o Thrombocytopenia Warfarin: • Indications: o Prevention / treatment of VTE: ! DVT ! PE o Prevention of thromboembolism: ! AF ! Prosthetic heart valves • Mechanism of action: o Vitamin K antagonist o Inhibits the vitamin K-dependent synthesis of clotting factors II. usually: 63 www.garrypettet.
5: • Prophylaxis of DVT ! 2.Copyright Dr Garry KJ Pettet 2005 .5: • Recurrent DVT / PE • Mechanical prosthetic heart valves o Monitoring the INR: ! The INR should be determined daily (or alternate days) in the early days of therapy.garrypettet.com .5 units above target value: ! Reduce or stop warfarin and restart when INR <5 Contraindications: o Pregnancy: ! Teratogenic (1st trimester) ! Foetal haemorrhage (3rd trimester) o Peptic ulcer o Severe hypertension 64 www.2009 • • • • • Day 1 .10mg • Day 2 – 10mg # measure INR and adjust dose • Day 3 – 5mg (if still not target INR) o Daily dose: ! Daily maintenance is usually 3-9mg daily (taken at same time each day) INR (International Normalised Ratio): o Prothrombin results can vary depending on the thromboplastin reagent used o The INR is a conversion unit that takes into account the different sensitivities of thromboplastins o Target INRs: ! 2 – 2.5: • AF • Treatment of DVT / PE • Rheumatic mitral valve disease ! 3. then at longer intervals (depending on response) then up to every 12 weeks Adverse effects: o Bleeding / bruising o Skin necrosis o Alopecia o Liver damage o Pancreatitis Management of warfarin-induced haemorrhage: o Major bleeding: ! Stop warfarin ! Give vitamin K (phytomenadione) by slow IV injection ! FFP o INR >8 (no bleeding or minor bleeding): ! Stop warfarin and restart when INR <5 ! Vitamin K (either IV or oral) o INR 6-8: (no bleeding or minor bleeding): ! Stop warfarin and restart when INR <5 o INR <6 but >0.
Copyright Dr Garry KJ Pettet 2005 .garrypettet.g. cardiac bypass surgery) • Mechanism of action: o Heparin potentiates the actions of antithrombin III o Antithrombin III inactivates factor IIa (thrombin) o Prolongs the APTT • Structure: o Both types of heparin are extracted from bovine lung or hog intestine o Unfractionated heparin: ! Mixture of sulphated glycosaminoglycans with a range of molecular weights up to 40.000 • Unfractionated or LMWH? o Unfractionated heparins are best used when there is a high risk of bleeding as their effect can be terminated rapidly by stopping the infusion o LMWHs do not require monitoring of the APTT and only need to be given once-daily o LMWHs have a more predictable subcutaneous absorption • Adverse effects: o Thrombocytopenia: ! Immune-mediated ! Develops ~6 days after starting treatment o Hyperkalaemia: ! Heparin inhibits aldosterone activity o Haemorrhage 65 www.000 o LMWH: ! Fragments of heparin with weights 4000 – 15.com .2009 • Interactions (many!): o Drugs that $ the efficacy of warfarin: ! Alcohol ! Cimetidine ! Omeprazole ! Simvastatin o Drugs that # the efficacy of warfarin: ! Carbamazepine ! COC pill ! Rifampicin o Drugs increasing risk of haemorrhage: ! Aspirin Heparin: • Low molecular weight heparins (LMWHs) include: o Enoxaparin o Tinzaparin • Indications: o Treatment of VTE o Unstable angina o Acute peripheral arterial occlusion o Prophylaxis in surgery o Extracorporeal circuits (e.
g.Copyright Dr Garry KJ Pettet 2005 . tenecteplase (bolus) 66 www.g. haemophilia) o Thrombocytopenia o Peptic ulcer o Recent cerebral haemorrhage o Severe hypertension o Severe liver disease (especially variceal disease) o Hypersensitivity The effects of heparin can be reversed by IV protamine sulphate: o A strongly basic protein that forms an inactive complex with heparin Streptokinase (SK): • Indications: o Acute MI o Thromboembolic events: ! PE ! Thrombosed arteriovenous shunts • Mechanism of action: o Binds circulating plasminogen and converts it to plasmin o Plasmin then lyses fibrin within the thrombus and dissolves it • Adverse effects: o Allergic reactions: ! Rash (common) ! Anaphylaxis o Hypotension o Guillain-Barre syndrome • Contraindications: o Bleeding o Prolonged / traumatic CPR o Trauma / surgery (within 2 weeks) o Recent haemorrhagic stroke o Severe hypertension (>200/120mmHg) o Pregnancy o Suspected aortic dissection • • Interactions: o Warfarin (increased risk of haemorrhage) Patients develop antibodies to streptokinase: o If a patient requires thrombolysis and has received SK in the past – they should be given recombinant tPA Tissue plasminogen activator (tPA): • E.com .2009 • • o Osteoporosis o Skin necrosis o Hypersensitivity o Alopecia Contraindications: o Bleeding disorders (e. alteplase (requires infusion).garrypettet.
2009 • • Indications: o As for SK but in those patients who cannot receive SK In contrast to SK.garrypettet. co-administration of tPA and heparin produces added benefit (but increases the risk of stroke) www.com 67 .Copyright Dr Garry KJ Pettet 2005 .
com . although TCAs and SSRIs are generally first choice • All antidepressants take 2-6 weeks to work • Antidepressants should be continued for 4-6 months after resolution of symptoms • When to use a TCA: o Severe depression o When insomnia is prominent symptom • When to use a SSRI: o Suicidal patient (safer in overdose) o Intolerance to TCAs: ! Prostatism ! Dementia (TCAs can cause confusion) ! Cardiac illness • When to use a MAOI: o “Atypical” depression o Depression refractory to first-line drugs • When to use venlafaxine: o Severe depression with hypersomnia Drugs used as mood stabilisers: • Lithium carbonate • Anticonvulsants: o Carbamazepine o Valproate Tri-Cyclic Antidepressants (TCAs): • More sedating: o Amitriptylline o Clomipramine o Dothiepin • Less sedating: o Imipramine • Indications: o Moderate to severe depression o Neuropathic pain (amitriptylline – unlicensed indication) o Nocturnal enuresis (children) • Mechanism of action: o Inhibit noradrenaline (NA) and serotonin (5-HT) uptake in central nerve terminals o Most TCAs act on several other neurotransmitter receptors and this is the reason for their large side-effect profile: ! Anti-muscarinic # most TCAs ! Histamine receptor blockade • Adverse effects: 68 www.Copyright Dr Garry KJ Pettet 2005 .2009 Mood disorders Which antidepressant? • No hard and fast rules.garrypettet.
thus increasing it’s concentration 69 www. fluoxetine (prozac). citalopram • Indications: o Depression: ! High suicide risk ! Those intolerant to TCAs (e.garrypettet.Copyright Dr Garry KJ Pettet 2005 . paroxetine (seroxat).com .g.2009 • • • o Sedation (some more than others) o Confusion o Seizures (# seizure threshold) o Blurred vision (loss of accommodation) o Dry mouth (can lead to # dental hygiene) o Heart block o Postural hypotension o Constipation o Impotence Contraindications: o Dysrhythmias (especially heart block) o Epilepsy o Severe coronary heart disease o Suicidal patient (danger in overdose) TCA overdose: o Clinical features: ! Tachycardia ! Mydriasis ! Convulsions ! Arrhythmias ! Hypotension o Management: ! Treat convulsions with diazepam ! Treat SVT / VT with sodium bicarbonate (even in absence of acidosis) Interactions: o MAOIs: ! Danger of potentially fatal hyperthermia syndrome o Anti-arrhythmics: ! Increased risk of ventricular dysrhythmias o Anticonvulsants: ! TCAs lower the seizure threshold and thus antagonise the effect of anticonvulsants o Antipsychotics: ! Increased risk of ventricular dysrhythmias Selective Serotonin Reuptake Inhibitors (SSRIs): • E.g. Prostatism) o Obsessive compulsive disorder (OCD) o Eating disorders • Mechanism of action: o “Selectively” block the uptake of 5-HT by central nerve terminal.
Copyright Dr Garry KJ Pettet 2005 . phenytoin): ! SSRIs $ plasma levels of these drugs o Haloperidol: ! SSRIs $ plasma levels of haloperidol o Monoamine Oxidase Inhibitors (MAOIs): • Non-selective (inhibit MAO-A and MAO-B): o Phenelzine • MAO-AIs (reversible): o Moclobemide • MAO-BIs: o Selegiline • Indications: o “Atypical” depression (especially in young patients): ! Weight gain ! Hypersomnia o Second-line use in depression (after TCA / SSRI) • Mechanism of action: o MAO is found throughout body tissues (including the gut) o There are 2 isoforms of MAO .com .g.garrypettet.2009 • • • Fewer side-effects than the TCAs: ! Less anti-muscarinic effects ! Safer in overdose Adverse effects: o Nausea / anorexia o Insomnia o Sexual dysfunction: ! Loss of libido ! Failure of orgasm Contraindications: o Children <18 years of age: ! $ risk of self-harm / suicidal behaviour o Mania Interactions: o MAOIs: ! Do not start an SSRI until at least 2 weeks after stopping a MAOI ! Risk of hyperthermia syndrome: • Hyperthermia • Tremor • Collapse o Anticonvulsants (e. carbamazepine.A and B o MAO-A has a preference for 5-HT (this is seen to be beneficial in depression) o MAO-B has a preference for dopamine (hence an anti-Parkinson effect with selegiline) o MAO regulates intra-neuronal concentration of it’s substrates (it is not involved in the inactivation of released transmitter) • Adverse effects: o Hypotension 70 www.
venlafaxine • Indications: o Severe / refractory depression o Anxiety disorders • Adverse effects: o Nausea o Insomnia o Hypertension (at high doses) o Withdrawal problems common • Interactions: o MAOIs: ! Risk of hyperthermia syndrome Fewer side-effects than the TCAs but no more efficacious • www. thus preventing it reaching the systemic circulation ! In the presence of a MAOI.g. SSRIs): ! Avoid concomitant use (allow washout period in between) ! Potentiation of all side-effects and risk of hyperthermia syndrome o Pethidine: ! Hyperthermia ! CNS depression or excitement o Carbamazepine: ! MAOIs can # the plasma levels of carbamazepine The selective MAO-AIs have a much smaller risk of the “cheese reaction” Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs): • E.g.garrypettet. tyramine reaches the circulation and acts as a sympathomimetic (triggers the release of NA) and can lead to severe hypertension ! Treat with: • !1-antagonist (e. phentolamine) or • Nifedipine o Antidepressants (TCAs. marmite) • Red wine / beer ! MAO in the gut wall usually metabolises tyramine.g.Copyright Dr Garry KJ Pettet 2005 .com 71 .2009 • • • o Weight gain o Sedation o Anti-muscarinic effects Contraindications: o Hepatic impairment o Phaeochromocytoma o Non-compliant patients (unable to monitor diet) Interactions: o Main hazard is with foods – the “cheese reaction”: ! Caused by foods containing high levels of tyramine: • Hard cheeses • Yeast extracts (e.
Copyright Dr Garry KJ Pettet 2005 .0mmol/L: ! Nausea ! Diarrhoea ! Polyuria / polydipsia (nephrogenic DI) ! Weight gain o 1.g.0mmol/L • Adverse effects: o 0.0mmol/L: ! Blurred vision ! Anorexia / vomiting ! Ataxia / dysarthria / tremor ! Drowsiness o >2.0 – 2.2009 Noradrenaline and Specific Serotenergic Antidepressants (NaSSAs): • E.4 – 1.4 – 1.death • Long-term effects: o Can cause renal tubular damage and hypothyroidism • Contraindications: o Pregnancy (although consider relative risks of drug cessation) o Renal impairment o Thyroid disease o Sick sinus syndrome o Poor compliance • Interactions: o Lithium levels increased by: 72 www.0mmol/L: ! Convulsions ! Hyperreflexia ! Oliguria ! Circulatory failure . mirtazapine • Indications: o Depression (especially with insomnia) • Adverse effects: o Drowsiness (even at low doses) o $ appetite / weight gain o Blood dyscrasias (rarely) • Interactions: o Other sedatives (including alcohol) o MAOIs • Safe in overdose • Minimal effects on sexual function Lithium carbonate: • Indications: o Acute mania o Prophylaxis of bipolar disorder o Recurrent depression o Aggressive / self-mutilating behaviour • Toxicity: o Lithium requires therapeutic drug monitoring: ! Normal range is 0.garrypettet.com .
theophylline) ! Antacids ! Acetazolamide www.Copyright Dr Garry KJ Pettet 2005 .garrypettet.com 73 .g.2009 o ! Diuretics (thiazides > loop) ! ACEIs ! NSAIDs ! Alcohol Lithium levels decreased by: ! Xanthines (e.
g. AVN. sotalol (a "-blocker) o All have effects on various K+ channels o $ AP duration o $ refractory period • Class IV (SAN.g.Copyright Dr Garry KJ Pettet 2005 . SAN. amlodipine) have no role in arrhythmias • Unclassified: o Digoxin (AVN) o Adenosine (AVN) Supraventricular arrhythmias: • Supraventricular tachycardias (SVTs) are often due to re-entry: o SNRT (sinus node re-entry tachycardia) o AVNRT (atrioventricular node re-entry tachycardia) o AVRT (atrioventricular re-entry tachycardia): ! Caused by an accessory pathway • Atrial arrhythmias: o Atrial tachycardia o Atrial flutter o Atrial fibrillation (AF): ! Paroxysmal ! Persistent www. amiodarone. V): ! E.garrypettet. verapamil) o Dihydropyridines (e.g. V): ! E. flecainide ! AP duration slightly $ ! Primarily act by slowing conduction • Class II (A. SAN. procainamide ! $ AP duration ! Hardly ever used in the UK (but used in the USA) o Ib (V only): ! E. AVN): o Ca2+ channel blockers (e. V): o E.com 74 .g. SAN. quinidine. SAN.2009 Anti-arrhythmic drugs Vaughan-Williams classification: • Class I: o Are all Na+ channel blockers (local anaesthetics) o Ib only works in the ventricles o Ia (A. V): o "-blockers (e. AVN. disopyramide. lidocaine (lignocaine) ! AP duration unaffected or slightly # o Ic (A.g. AVN.g.g. propranolol) o # automaticity o # AP duration acutely (may prolong it with prolonged use) o # refractory period • Class III (A. AVN.
Copyright Dr Garry KJ Pettet 2005 .2009 ! Permanent Treatment of SVTs: • Vagal manoeuvres • Adenosine: o 6mg " 12mg " 12mg • If adenosine fails: o Cardiovascular instability: ! Synchronised cardioversion o No cardiovascular instability: ! Verapamil or ! Digoxin or ! Amiodarone • Prophylaxis: o "-blockers o Flecainide (AVRT) o Verapamil (AVNRT) • Wolff-Parkinson-White (WPW) syndrome: o If pt with WPW has AF and fast ventricular rate: ! Adenosine.g. but can try: o Amiodarone: ! Drug most likely to work o Digoxin: ! Rate control only o "-blockers: ! Rate control ! Chance of return to sinus rhythm (SR) o Verapamil: ! Rate control ! Chance of return to SR • DC cardioversion ± anticoagulation can work • RFA is the treatment of choice Treatment of atrial fibrillation (AF): • Acute: o Treat underlying cause (e. digoxin and verapamil are absolutely contraindicated ! Use Flecainide Treatment of atrial tachycardia: • Treat underlying coronary / structural heart disease if present • Exclude digoxin toxicity • "-blockers • Verapamil • Often refractory to drug treatment – treat with radiofrequency ablation (RFA) Treatment of atrial flutter: • Drugs are generally ineffective. pneumonia) o DC cardioversion (first-line choice): 75 www.garrypettet.com .
2009 • Anticoagulation is not essential if AF is of recent onset (<48 hours) with a structurally normal heart (but most people do) ! If required.5) ! <65 years with no risk factors or > 65 years and unable to be warfarinised: • Aspirin ! Treatment of ventricular tachycardia (VT): • Acute: o Haemodynamically stable: ! Amiodarone or ! Lidocaine o Not haemodynamically stable: ! Synchronised DC cardioversion ! Amiodarone • Recurrent / paroxysmal: o Drugs: ! Amiodarone ! "-blocker (works synergistically with amiodarone) ! Sotalol o Implantable defibrillator: ! # mortality Drug treatment of Torsade de Pointes: • Often associated with prolongation of the QT interval • Causes of QT prolongation: o Electrolyte disturbances: ! Hypokalaemia 76 www.5 – 3.garrypettet. give warfarin for at least 3 weeks before and at least 4 weeks after o Control ventricular rate: ! Digoxin ! If ventricular rate still too fast: • "-blocker (can return patient to sinus rhythm) o Chemical cardioversion: ! Amiodarone or ! Flecainide (if haemodynamically stable) or ! "-blocker Chronic: o Control ventricular rate: ! Digoxin ! If rate still too fast consider: • (Cautiously) $ digoxin dose • "-blocker • Amiodarone o Anticoagulation: ! > 65 years: • Warfarin (INR 2.Copyright Dr Garry KJ Pettet 2005 .com .
g.Copyright Dr Garry KJ Pettet 2005 .garrypettet.2009 • ! Hypocalcaemia Congenital long QT syndromes Drugs: ! Class Ic and III anti-arrhythmics ! TCAs o Ischaemia Treatment: o IV MgSO4 o o Treatment of bradyarrhythmias: • Haemodynamically compromised: o Drugs: ! Atropine ± ! Isoprenaline / adrenaline o Pacing: ! External ! Temporary transvenous • Stable: o Withdraw any negatively chronotropic drugs (e.com 77 . "-blockers) o Exclude secondary causes: ! ACS ! Hypothyroidism o Assess need for permanent pacemaker Adenosine: • Indications: o Paroxysmal SVT o To aid diagnosis of broad complex SVTs • Mechanism of action: o Binds to adenosine (A1) receptors in the cardiac conduction system: ! Opens ACh-sensitive K+ channels o Slows conduction in the heart by prolonging the refractory period in the AVN / bundle of His • Adverse effects: o All are short-lived (half-life of 8 – 10secs) o Bronchospasm o Chest pain o Flushing o Severe bradycardia (rare) • Contraindications: o Asthma o 2nd or 3rd degree heart block (unless pacemaker in-situ) • Interactions: o Dipyridamole: ! Prolongs / enhances action of adenosine o Theophylline: ! Inhibits adenosine www.
"-adrenoceptors. Na+ and Ca2+ o Generally slows conduction through the heart • Pharmacokinetics: o Very long half-life: ! 10 – 100 days (average 36 days) o Requires a loading dose in life-threatening arrhythmias: ! Central vein (causes phlebitis in peripheral veins) o This means that drug interactions can occur long after amiodarone has been stopped • Adverse effects: o Common: ! Corneal microdeposits (reversible): • Can cause driver headlight dazzling at night ! Photosensitive rash o Less common: ! Thyroid dysfunction (hyper. this can be very refractory and may require cessation of amiodarone o Shortness of breath suggests development of pulmonary fibrosis • Contraindications: o Thyroid disease o Pregnancy o Iodine allergy (as amiodarone contains iodine) Interactions: o "-blockers / non-dihydropyridines (e.Copyright Dr Garry KJ Pettet 2005 . AV block and myocardial depression 78 • www.2009 Amiodarone: • Indications: o Paroxysmal: ! SVT ! Nodal tachycardia ! VT o Atrial flutter o AF o VF • Amiodarone is generally used when other drugs have been ineffective or are contraindicated • Mechanism of action: o Not fully understood o Blocks several channels: ! !-adrenoceptors. verapamil): ! $ risk bradycardia.com . diltiazem.g.garrypettet.or hypo-) ! Pulmonary fibrosis ! Grey skin colour ! Peripheral neuropathy ! Ataxia • Special notes: o Thyroid function must be checked before treatment and every 6 months: ! If hyperthyroidism develops.
2009 o o o o Digoxin: ! Amiodarone $ plasma levels of digoxin Class Ia drugs: ! $ QT interval Phenytoin: ! Amiodarone $ plasma levels of phenytoin Warfarin: ! Amiodarone $ plasma levels of warfarin Lidocaine (lignocaine): • Indications: o Ventricular arrhythmias (especially after MI): ! Stops VT and # risk of VF ! Does not # mortality when used prophylactically o Local anaesthesia • Mechanism of action: o Class Ib anti-arrhythmic agent o Not active orally (massive 1st-pass metabolism) o Blocks fast Na+ channels: ! Slows conduction in the heart (only ventricles) ! Inhibits AP propagation in nerve axons • Adverse effects: o Uncommon: ! Convulsions ! Drowsiness ! Bradycardia ! Cardiac arrest • Contraindications: o AV node block (all degrees) o Severe heart failure o Hypovolaemia • Interactions: o Cimetidine: ! $ plasma levels of lidocaine Flecainide: • Indications: o AVRT o WPW syndrome associated arrhythmias o Paroxysmal AF (chemical cardioversion) • Mechanism of action: o Class Ic anti-arrhythmic agent o Na+ channel blocker • Contraindications: 79 www.garrypettet.Copyright Dr Garry KJ Pettet 2005 .com .
com 80 .2009 o o Previous MI Haemodynamically significant valvular disease www.Copyright Dr Garry KJ Pettet 2005 .garrypettet.
e.Copyright Dr Garry KJ Pettet 2005 . grade II hypertension) • Treat if o >=140 / >=90 mmHg and (i.garrypettet.e. grade I hypertension) o Target organ damage or o CVS complications or o Diabetes or o CV event risk >=2%/year (>=20% at 10 years) Target blood pressure for patients on anti-hypertensive medication: 81 www.2009 Hypertension British hypertension society (BHS) classification of BP levels: • Optimal: o <120 / <80 mmHg • Normal: o <130 / <85 mmHg • High normal: o 130-139 / 85-89 mmHg • Hypertension: o Grade 1 (mild): ! 140-159 / 90-99 mmHg o Grade 2 (moderate): ! >160 – 179 / 100-109 mmHg o Grade 3 (severe): ! >=180 / >=110 mmHg o Isolated systolic: ! Systolic BP is more important than diastolic ! Grade 1: • 140-159 / <90 mmHg ! Grade 2: • >=160 / <90 mmHg Complications of hypertension: • Cerebral: o Encephalopathy o Haemorrhage o Thromboembolism o TIA • Other: o MI (hypertension accounts for 25% of MIs) o Heart failure o Dissecting aneurysm o Renovascular disease o Peripheral vascular disease When to treat patients with anti-hypertensive agents: • Definitely treat: o >=160 / >=100 mmHg (i.com .
com 82 .garrypettet.Copyright Dr Garry KJ Pettet 2005 .2009 • • • There is evidence for these systolic values but the diastolic is arbitrary Patients with diabetes. renal impairment or CVS disease: o <=130 / <=80 mmHg Other patients: o <=140 / <=85 mmHg The BHS ABCD approach to the treatment of hypertension: • Key: o ACE inhibitor o Beta blocker o Calcium channel blocker o Diuretic (thiazide) • Step 1: o Young (<55 yrs) and non-black: ! A (or B*) o Older (>55 yrs) or black: ! C or D • Step 2: o A (or B*) + C or D • Step 3: o A (or B*) + C + D • Step 4 (resistant hypertension): o Add either: ! !-blocker ! Spironolactone • *"-blockers will probably be removed from this algorithm as they may induce new onset diabetes mellitus www.
com .Copyright Dr Garry KJ Pettet 2005 . pseudomonas. anaerobes): o Aminoglycoside IV and o 3rd generation cephalosporin IV ± o Anti-pseudomonal penicillin IV • Aspiration: o Cefuroxime IV and o Metronidazole IV Treating meningitis: • Immediate treatment: o Outside hospital: ! Benzylpenicillin 1.2009 Antibiotic therapy Below are empirical treatments only – the correct antibiotic will depend upon sensitivities determined by bacteriological culture Treating pneumonia: • Community acquired: o Mild (streptococcus.garrypettet.2g IV/IM o Inside hospital: ! Cefotaxime 2g IV • Subsequent treatment: o Depends on sensitivities o Generally cefotaxime o Benzylpenicillin and rifampicin for meningococcal meningitis • Contacts – eradicate carriage: o Rifampicin (2 days) o Ciprofloxacin (single dose) Treating tuberculosis: • Initial phase (8 weeks on 3–4 drugs): 83 www. mycoplasma): ! Amoxicillin po ± ! Erythromycin po (if penicillin sensitive or atypicals) o Severe (same bugs as for mild): ! Co-amoxiclav IV or ! Cefuroxime IV and ! Erythromycin IV o Atypical: ! Legionella: • Clarithromycin ± rifampicin ! Chlamydia: • Tetracycline ! Pneumocystis carinii: • Co-trimoxazole • Hospital acquired (Gram (–ve). haemophilus.
depends on site): o Rifampicin o Isoniazid ± o Ethambutol Give pyridoxine throughout treatment (prevents isoniazid neuropathy) Treating septicaemia – source unknown: • Take blood cultures first! • Anti-pseudomonal penicillin (e.Copyright Dr Garry KJ Pettet 2005 .2009 • • o Rifampicin o Isoniazid o Pyrazinamide o Ethambutol (if isoniazid resistance is possible) Continuation phase (4–10 months on 2–3 drugs.garrypettet. but a good start would be: o Benzylpenicillin and 84 www.g. ticarcillin) and • Cefuroxime IV or • Gentamicin IV Treating Neutropenic sepsis: • Take blood cultures first! • First-line: o Piperacillin + Gentamicin • Second-line: o Ceftazidime + vancomycin • Third-line: o Add amphotericin B Treating a UTI: • Depends on sensitivities • Cystitis: o Mild: ! Trimethoprim o More severe: ! Co-amoxiclav ! Ciprofloxacin • Acute pyelonephritis: o Cefuroxime Treating MRSA infection: • Vancomycin or • Teicoplanin Treating clostridium difficile: • Metronidazole po or • Vancomycin po Treating cellulitis: • Depends on the organism.com .
2009 o Flucloxacillin Prophylactic antibiotics and surgery: • Single bolus as good as prolonged therapy: o Metronidazole IV and o Cefuroxime IV Helicobacter pylori eradication therapy: • One PPI and two antibiotics for two weeks • Usual combination (but there are many): o Omeprazole o Clarithromycin o Amoxicillin (or metronidazole) • Resistance to metronidazole is common www.Copyright Dr Garry KJ Pettet 2005 .garrypettet.com 85 .
2009 Antibiotics Antibiotics that inhibit cell wall synthesis: • "-lactams: o Penicillins o Cephalosporins • Glycopeptides: o Vancomycin o Teicoplanin • Carbapenems: o Imipenem • Monobactams: o Aztreonam Antibiotics that inhibit protein synthesis: • 30S ribosome: o Aminoglycosides: ! Gentamicin ! Amikacin o Tetracyclines: ! Tetracycline ! Doxycycline • 50S ribosome: o Macrolides: ! Erythromycin ! Clarithromycin o Chloramphenicol o Fusidic acid Antibiotics that inhibit nucleic acid synthesis: • Quinolones: o Ciprofloxacin • Metronidazole • Trimethoprim • Rifampicin • Sulphonamides Antibiotics that do not accumulate in renal impairment: • Chloramphenicol • Co-trimoxazole • Doxycycline • Isoniazid • Macrolides • Quinolones • Rifampicin Penicillins: • Are all active against Gram +ve bugs (some against Gram –ve bugs) 86 www.com .garrypettet.Copyright Dr Garry KJ Pettet 2005 .
2009 • • • • • • A common mechanism of resistance is the production of an enzyme ("lactamase) that degrades the drug Penicillin: o Benzylpenicillin (penicillin G): ! Parenteral (is destroyed by gastric acids) o Phenoxymethylpenicillin (penicillin V): ! Oral (but poor bioavailability) ! Used for prophylaxis in: • Splenectomy patients • Sickle cell anaemia patients o Indications: ! Pneumococcus ! Streptococcus ! Meningococcus ! Leptospiral infections Broad-spectrum (activity against some Gram –ve bugs as well): o Amoxicillin (oral or parenteral) o Indications: ! (As for penicillin) ! Escherichia coli ! Haemophilus influenzae (resistance is increasing ~15%) ! Salmonella "-lactamase resistant: o Flucloxacillin: ! Indications: • "-lactamase-producing staphylococci o Co-amoxiclav (Augmentin): ! Amoxicillin + ! Clavulanic acid ("-lactamase inhibitor) ! Indications: • Amoxicillin resistant URTIs and UTIs Anti-pseudomonal: o Ticarcillin o Pipericillin: ! Combined with Tazobactam (a "-lactamase inhibitor) as Tazocin Adverse effects: o Rash: ! Common to all penicillins ! Maculopapular rash in glandular fever if given amoxicillin o Nausea / vomiting o Uncommon: ! Anaphylactic shock ! Convulsions Contraindications: o Penicillin hypersensitivity Interactions: 87 • • www.garrypettet.Copyright Dr Garry KJ Pettet 2005 .com .
g. cefaclor) • Adverse effects: o Bleeding o Diarrhoea o Nausea / vomiting o Thrombophlebitis (parental cephalosporins) • Contraindications: o Hypersensitivity: ! There is also a 10% cross-reactivity with penicillins • Interactions: o Probenicid: ! Probenicid # excretion of the cephalosporins ! Allows for a # dose of cephalosporin to be used 88 www. cefalexin) o Second (e.g.garrypettet.2009 o o COC pill: ! Penicillins reduce the efficacy of the pill Probenicid: ! Probenicid # excretion of the penicillins ! Allows for a # dose of penicillin to be used or for prolonged high plasma levels to be attained Cephalosporins: • Have a similar range of activity to amoxicillin but are more "lactamase stable • Are 3 “generations” of parenteral cephalosporins: o As the generations progress. the cephalosporins become more effective against Gram –ve bugs o First generation have pretty much been superseded o Second: ! Cefuroxime: • Similar spectrum to amoxicillin o Third: ! All are a common cause of C.com . difficile diarrhoea ! Cefotaxime: • Important drug in the treatment of meningitis ! Ceftazidime: • Pseudomonas and others ! Ceftriaxone: • Long-half life (once daily administration) • Effective in serious infections: o Pneumonia o Septicaemia • Are 2 “generations” of orally active cephalosporins: o Both have similar spectrums of action: ! URTIs ! Refractory cystitis ! Otitis media o First (e.Copyright Dr Garry KJ Pettet 2005 .
does not need to be given with cilastatin • Adverse effects: o Nausea / vomiting / diarrhoea (3–4% of patients) o Cross-reactivity with "-lactam antibiotics o Seizures (imipenem >> meropenem) Aminoglycosides: • E. vancomycin.com .g.Copyright Dr Garry KJ Pettet 2005 .g. imipenem. teicoplanin • Active against aerobic and anaerobic Gram +ve bacteria • Vancomycin (oral or IV): o Indications: ! IV: • Infective endocarditis • MRSA ! • Oral: • Clostridium difficile (pseudomembranous colitis) • • • Teicoplanin: o Indications (IV or IM): ! Used for serious Gram +ve infections IV Vancomycin requires therapeutic drug monitoring Adverse effects: o Ototoxicity (tinnitus and deafness) o Nephrotoxicity (less so with teicoplanin) o Neutropenia Interactions: o Increased risk of ototoxicity with: ! Loop diuretics o Increased risk of nephrotoxicity with: ! Aminoglycosides ! Cyclosporin Carbapenems: • E. meropenem • Incredibly broad spectrum: o Active against both Gram +ve and –ve bacteria o "-lactamase stable o Is effective against MRSA and anaerobes o Best single agent choice for nosocomial infection • Imipenem: o Rapidly degraded by renal dipeptidase o Must be given in conjunction with cilastatin (a dipeptidase inhibitor) • Meropenem: o Similar to imipenem but is stable to renal dipeptidase.2009 Glycopeptides: • E. streptomycin • Active against many Gram –ve and some Gram +ve bacteria 89 www.g. amikacin.garrypettet. Gentamicin.
Copyright Dr Garry KJ Pettet 2005 .com 90 .g. neostigmine): ! Aminoglycosides antagonise the effects of these drugs Notes: o Neomycin is very poorly absorbed: ! Often used dermatologically or as part of bowel prep o Tobramycin: ! Can be inhaled (good in CF patients) ! Can precipitate acute airway obstruction Tetracyclines: • E.2009 • • • • • • • Indications: o Second line treatment for severe Gram –ve infection: ! Infective endocarditis ! Septicaemia ! Acute pyelonephritis o Topical: ! Eye ! Ear o Streptomycin is reserved for resistant tuberculosis Mechanism of action: o Bactericidal o Inhibit bacterial protein synthesis by binding to the 30S ribosome Pharmacokinetics: o Inactive orally (must be given IV / topically) o Excreted unchanged by the kidneys: ! Use with caution in renal impairment (adjust dose) o Therapeutic drug monitoring is required: ! Peak plasma levels should be measured (~1 hour after administration) Adverse effects: o Nephrotoxicity (renal tubular damage) o Ototoxicity (damage to CN VIII): ! “Deaf and dizzy” ! Can be irreversible Contraindications: o Myasthenia gravis: ! Aminoglycosides can impair neuromuscular transmission by inhibiting Ca 2+ -influx into nerve terminal and preventing release of ACh o Pregnancy Interactions: o Drugs potentiating the nephrotoxicity of aminoglycosides: ! Cyclosporin ! Loop diuretics: • Also potentiate ototoxicity o Anticholinesterases (e. tetracycline.g.garrypettet. doxycycline • Indications: www.
g. erythromycin.garrypettet. clarithromycin • Indications: o Erythromycin: www.2009 • • • Good for some intracellular organisms (as they penetrate macrophages): ! Chlamydia (STD) # doxycycline ! Rickettsia (Q-fever) ! Borrelia burgdorferi (Lyme disease) o Acne o Anthrax (doxycycline) Pharmacokinetics: o Were the first orally-active broad-spectrum antibiotics (can be given IV) o Bacteriostatic o Absorption from gut is variable .com 91 .# by: ! Ca2+ (milk) ! Mg2+ (antacids) ! Iron preparations o Excreted unchanged in the urine (except doxycycline) Adverse effects: o Deposited in growing bones / teeth: ! Causes staining and (occasionally) dental hypoplasia ! Do not use in children <12 years or in pregnancy o Renal impairment (except doxycycline) Contraindications: o Renal impairment (except doxycycline) o Fusidic acid: • Potent narrow-spectrum anti-staphylococcal antibiotic • Always used in combination to prevent resistance • Indications: o Infections caused by penicillin-resistant staphylococci o Especially: ! Osteomyelitis (well concentrated in bone) ! Staphylococcal endocarditis o Can be used topically • Adverse effects: o Reversible jaundice o Acute renal failure (monitor renal function) o Liver impairment (monitor LFTs) Macrolides: • E.Copyright Dr Garry KJ Pettet 2005 .
chlamydia.g. staphylococci. ofloxacin • Active against many Gram –ve and some Gram +ve bacteria: o Campylobacter o Escherichia coli o Pseudomonas o Salmonella • Indications: o UTI o Salmonella infection o Cystic fibrosis lung infections o Gonorrhoea o Tuberculosis (3rd-line drug) o Anthrax • Pharmacokinetics: o Ciprofloxacin has a near 100% bioavailability when taken orally • Adverse effects: o GI disturbance o Tendon damage (including rupture) o Seizures (lowers seizure threshold) • Cautions: o Epilepsy o Myasthenia gravis o History of tendon damage Interactions: 92 • www.g.Copyright Dr Garry KJ Pettet 2005 .2009 • • • Active against Gram +ve bacteria (e. influenzae) ! Part of helicobacter pylori eradication therapy Do not cross the blood-brain-barrier (no good for meningitis) Adverse effects: o Erythromycin causes nausea / vomiting / diarrhoea: ! Is an agonist at the motilin receptor in the gut o Phlebitis Interactions: o Inhibit cytochrome P450: ! $ levels of warfarin. streptococci) and the atypicals (e.com . legionella) ! A good “respiratory” antibiotic ! A substitute for penicillin in those with hypersensitivity o Clarithromycin: ! More potent than erythromycin (except H. ciprofloxacin.garrypettet.g. theophylline. cyclosporin A (and many others) o Digoxin: ! $ plasma levels of digoxin o Terfenadine (non-sedating antihistamine): ! $ risk of arrhythmias ! Quinolones: • E. mycoplasma.
garrypettet. cyclosporin A Metronidazole: • Indications: o Anaerobes o Protozoal infections: ! Entamoeba histolytica ! Giardia lamblia ! Trichomonas vaginalis o Part of helicobacter eradication therapy o Pseudomembranous colitis (C. theophylline. difficile) • Pharmacokinetics: o Oral.Copyright Dr Garry KJ Pettet 2005 .com . IV or rectal o Clinical / laboratory monitoring if treatment > 10 days • Adverse effects: o GI disturbances (uncommon and well tolerated) • Cautions: o Hepatic impairment • Interactions: o Disulfiram (Antabuse)-like reaction with alcohol: ! Flushing ! Hypotension ! Abdominal pain o Phenytoin: ! $ plasma levels of phenytoin o Warfarin: ! $ plasma levels of warfarin Rifampicin: • Indications: o Tuberculosis o Leprosy o Meningitis contact prophylaxis o MRSA • Adverse effects: o Deranged LFTs (usually mild but can be serious) o Stains secretions pink / orange: ! Saliva ! Tears ! Urine • Contraindications: o Jaundice • Interactions: o Potent cytochrome P450 inducer (many reactions): ! # efficacy of: • Carbamazepine • COC pill • Corticosteroids 93 www.2009 o Inhibits cytochrome P450 (many interactions): ! $ levels of warfarin.
phenytoin): ! Isoniazid $ plasma levels of these drugs Pyrazinamide: • Indications: o Tuberculosis • Pharmacokinetics: o Good CSF penetration (good in TB meningitis) • Adverse effects: o Hepatocellular toxicity • Contraindications: o Gout (avoid in acute attack) o Hepatic impairment o Porphyria Ethambutol: • Indications: o Tuberculosis (if isoniazid resistance is suspected) • Adverse effects: o Visual disturbances (reversible if drug stopped early): ! Caused by a retorbulbar neuritis ! Not too much of a problem with only 8 weeks of therapy • Contraindications: o Renal impairment ($ risk of visual damage) www.garrypettet.com 94 .2009 • • Phenytoin Warfarin Isoniazid: • Indications: o Tuberculosis • Adverse effects: o Peripheral neuropathy (more likely in): ! Alcoholism ! Chronic renal failure ! Diabetics ! HIV ! Malnutrition ! Can be prevented by pyridoxine (vitamin B6) o Hepatitis o Psychosis • Contraindications: o Hepatic impairment • Interactions: o Anticonvulsants (carbamazepine.Copyright Dr Garry KJ Pettet 2005 .
Copyright Dr Garry KJ Pettet 2005 . add a sulphonylurea o If not controlled on 2 drugs or intolerant consider adding: ! A glitazone ! Acarbose o Insulin if poor glycaemic control with oral agents: ! 50% of pts will require insulin within 6 years of diagnosis What • • • • • • to check at a diabetic’s annual review: Blood glucose record BP HbA1c Lipids Renal function Urine (protein / glucose) Treatment of diabetic ketoacidosis (DKA): • Only occurs in type I diabetes • IV fluids: o Patients may be 5–10L fluid deplete o Use 0.2009 Diabetes Treatment of diabetes: • Both types: o Diet: ! # weight (as this # insulin resistance) ! # simple sugars ! $ complex carbohydrates ! $ fibre intake o Address associated risk factors: ! Hyperlipidaemia ! Hypertension (<=130 / <=80 mmHg) ! Smoking • Type I: o All require insulin • Type II: o BMI < 25: ! Sulphonyurea o BMI > 25: ! Meformin (a biguanide) o If not controlled on a sulphonylurea./ pH o K+ (Initially plasma levels $ .9% saline (first bag usually ran in stat) • Monitor (initially hourly): o Creatinine (to look for pre-renal failure) o Glucose o HCO3.masks body wide K+ depletion) • Insulin: o Aim for a glucose fall of 5mmol/h 95 www.com .garrypettet. add metformin o If not controlled on metformin.
200–300mls 10% dextrose): ! high concentrations (e. alcoholics) • Once conscious: o Give the patient a meal • When to admit: o If patient is hypoglycaemia following oral anti-diabetics (as they can be very long-acting) Sulphonylureas: • E. glicazide (short-acting).garrypettet.g.g.com . infection) LMWH (to prevent thrombosis) until mobile Treatment of hyperglycaemic hyper-osmotic non-ketotic (HHONK) coma • Only occurs in type II diabetes • No acidosis (as ketosis is suppressed by endogenous insulin) • IV fluids • Insulin (small doses): o Wait until 1 hour after fluids (may not be needed) • Full heparin anticoagulation Treatment of hypoglycaemia: • If able to take oral treatment: o Lucozade (or other high sugar drink / sweet) • Else: o 20–30mg dextrose IV (e.0) consider bicarbonate: o Severe acidosis can impair insulin binding to its receptor o Comes in 50ml bottles (8. tolbutamide (very short-acting).g. glibenclamide (once daily) • Mechanism of action: o Are insulin secretagogues (thus require some functional "cells) o Reduce the K+ permeability of "-cells by blocking ATP-sensitive K+ channels: ! Causes depolarisation and Ca2+ entry ! Thus causing insulin secretion • Pharmacokinetics: o All bind strongly to albumin (several drug interactions) • Adverse effects: 96 www.g.2009 • • • • o Initial bolus of soluble insulin then insulin infusion Potassium replacement (monitor plasma levels): o Has been lost due to the diuresis o Don’t give more than 20mmols/L in each bag If acidosis severe (pH <7.4% = 1mg / ml) Identify the cause of the DKA (e. 50%) can be irritative and can even cause stroke!) o Glucagon 1mg IV/IM: ! Almost as fast as IV dextrose ! Doesn’t work when given repeatedly or if given to patients with no or poor glycogen reserves (e.g.Copyright Dr Garry KJ Pettet 2005 .
Copyright Dr Garry KJ Pettet 2005 - 2009
Weight gain (largely due to $ appetite) Hypoglycaemia (can be severe / fatal): ! Admit (as the hypoglycaemia can persist for up to 24 hrs) ! Much greater risk than with metformin o GI disturbances (~3% of patients) o Bone marrow suppression (rare) Cautions: o Elderly ± renal impairment: ! $$ risk of hypoglycaemia (mainly glibenclamide) o Breast-feeding Interactions: o Drugs potentiating the hypoglycaemic effect: ! Sulphonamides (including co-trimoxazole) ! Chloramphenicol o o
Metformin: • Usually given twice daily • A biguanide (the only available one!) • Mechanism of action: o Is an insulin-sensitizer o # gluconeogenesis o $ peripheral utilization of insulin o # LDL / VLDL • Does not cause hypoglycaemia • Adverse effects: o GI disturbances: ! Start at ~1g / daily ! Nausea / anorexia / vomiting / diarrhoea o Lactic acidosis (uncommon): ! Caused by a build-up of pyruvate o # absorption of vitamin B12 • Contraindications: o Conditions predisposing to metformin-induced lactic acidosis: ! Mild renal impairment ! Severe hepatic impairment ! Severe heart failure o Pregnancy / breast-feeding • Interactions: o Alcohol: ! $ risk of lactic acidosis
Glitazones (thiazolidinediones): • E.g. pioglitazone, rosiglitazone • Indications: o Type II diabetes:
Copyright Dr Garry KJ Pettet 2005 - 2009
Patients who cannot tolerate (or there are contraindications to) combination therapy with metformin and a sulphonylurea ! In such cases, the glitazone should replace whichever drug in the combination is poorly tolerated / contraindicated Mechanism of action: o Interact with a nuclear receptor (peroxisome proliferatoractivator receptor gamma " PPAR-') o PPAR-' regulates genes involved in lipid metabolism and insulin action o Reduce insulin resistance o # circulating insulin relative to plasma glucose but do not # glucose levels to normal Adverse effects: o Hepatotoxicity: ! Monitor LFTs before and during treatment o Weight gain o Anaemia (uncommon) Contraindications: o Hepatic impairment o Combination with insulin (risk of heart failure) !
Acarbose: • Mechanism of action: o Intestinal !-glucosidase inhibitor o Delays the digestion of starch and sucrose o Is taken with meals and lowers the post-prandial increase in blood glucose (~1-2mmol/L) • Adverse effects: o Abdominal pain / bloating o Flatulence • Contraindications: o IBD o History of abdominal surgery o Pregnancy Insulin: • N.B. normal individuals require ~60U of endogenous insulin daily • Indications: o All T1DM o T2DM where control / symptoms / complications poor o Hyperkalaemia (with glucose) • Pharmacokinetics: o Physical state: ! Short-acting soluble insulins (rapid onset): • E.g. Actrapid, insulin lispro, insulin asparte • Inject 15–30 mins before meals
Copyright Dr Garry KJ Pettet 2005 - 2009
• Onset in 30–60 mins • Maximum effect 2–4 hours • Duration up to 8 hours ! Intermediate-acting (isophane insulins): • Are insulin with protamine preparations • E.g. insulatard ! Long-acting: • Either insulin zinc suspensions (e.g. ultratard) or synthetics (e.g. insulin glargine) ! Mixed-insulins: • E.g. mixtard o Human insulin absorbed faster than porcine / bovine insulin o Porcine / bovine insulin may cause less hypoglycaemia o Factors affecting absorption: ! Temperature ! Exercise Insulin effects: o Adipose tissue: ! $ lipoprotein lipase activity: • # TGs ! $ GLUT-4 activity: • $ glucose storage as fat ! # lipolysis: o Liver: ! # glycogenolysis ! # gluconeogenesis ! Inhibition of ketogenesis o Muscle: ! # proteolysis ! $ GLUT-4 activity: • # plasma glucose levels Insulin regimes: o Twice daily mixed insulins: ! Possibly better for children or older T2DM o Basal bolus (qds) regime: ! More “physiological” ! Involves more injections ! Best regimen for # diabetic complications Problems with Actrapid (short-acting human insulin): o Needs to be given 15 minutes before meals o Can cause a late post-prandial hypoglycaemia: ! Leads to post-prandial hyperglycaemia (as patients don’t give enough as they fear the hypoglycaemia) Problems with insulin glargine (long-acting human insulin analogue): o Nocturnal hypoglycaemia (can be dangerous) o Uniform action (not physiological) Adverse effects: o Hypoglycaemia: ! 30% of T1DM ever (10%/year, 3% frequent episodes)
Copyright Dr Garry KJ Pettet 2005 - 2009
! Sweating ! Tachycardia ! Tremor ! Aggression ! Confusion ! Coma Fat hypertrophy / atrophy at injection site (rotate site to avoid this) Weight gain: ! As blood [glucose] is # you get hungry!
Copyright Dr Garry KJ Pettet 2005 - 2009
Classification of epilepsy: • Generalised: o Implies bilateral abnormal electrical activity in the brain with bilateral motor manifestations o Consciousness is impaired o Types: ! Tonic-clonic (grand-mal) ! Absence (petit-mal) ! Myoclonic • Partial: o A localised seizure that may be either: ! Simple (without loss of consciousness): • Jacksonian seizure ! Complex (with loss of awareness) o May progress to a generalised seizure Management of status epilepticus: • Remember 25% of status turns out to be pseudostatus • ABC (need to maintain airway) • Oxygen • If alcoholism / malnutrition give thiamine • If hypoglycaemic give glucose • Stop the seizure: o Lorazapam (slow IV bolus) if fails o Phenytoin (IV infusion) if fails o Phenobarbital IV if fails o Anaesthetise with thiopentone / propofol Drug treatment of epilepsy (NICE recommendations): • Generalised seizures: o First-line (all): ! Valproate o Second-line (tonic-clonic): ! Carbamazepine ! Phenytoin o Second-line (absence): ! Ethosuximide o Second-line (myoclonic): ! Ethosuximide ! Lamotrigine • Partial seizures: o First-line: ! Carbamazepine ! Valproate o Second-line: ! Lamotrigine
garrypettet.com 102 .2009 o ! Gabapentin ! Vigabatrin Third-line: ! Phenytoin Carbamazepine: • Indications: o Partial seizures (first-line) o Tonic-clonic seizures (second-line) o Trigeminal neuralgia o Bipolar disorder • Mechanism of action: o Related to the tri-cyclic antidepressants o Induces a use-dependent block of neuronal Na+ channels • Pharmacokinetics: o Has an active metabolite (produced in the liver) o t! of 10–20 hours o Is an enzyme inducer (even of it’s own metabolism) o Requires therapeutic drug monitoring • Adverse effects: o Ataxia o Nausea o Neutropenia o Sedation o SIADH o Teratogenic: ! Foetal neural tube defects • Contraindications: o AV conduction abnormalities (unless paced) o History of bone marrow depression o Porphyria • Interactions (many as is an enzyme inducer): o Carbamazepine # the efficacy of: ! COC pill ! Corticosteroids ! Cyclosporin ! Phenytoin ! Warfarin o Drugs that $ the level of carbamazepine: ! Cimetidine ! Erythromycin Phenytoin: • Indications: www.Copyright Dr Garry KJ Pettet 2005 .
Copyright Dr Garry KJ Pettet 2005 . valproate.g. the rate of inactivation does not $ in proportion to the plasma concentration ! This means that the t! $ as the dose is $ o ~90% protein bound: ! Some drugs (e.com . salicyclates) inhibit this binding competitively ! This $ the free [phenytoin] but also $ the hepatic clearance of phenytoin ! The net result is unpredictable o Is a potent enzyme inducer o Once daily dosage (should be nocte) o Requires therapeutic drug monitoring Adverse effects: o Ataxia o Sedation o Acne o Folate deficiency o Gum hypertrophy o Hirsuitism o Lymphadenopathy o Osteomalacia (vitamin D resistance) o Photosensitivity Cautions: o Hepatic impairment (# dose) # common o Pregnancy: ! Cleft palate Interactions (many): o Phenytoin # the efficacy of: ! COC pill ! Rifampicin ! Warfarin o Drugs that $ the level of phenytoin: ! Aspirin ! Cimetidine o Sodium valproate: • Indications: o All types of epilepsy (first-line) 103 www.garrypettet.2009 • • • • • All types of epilepsy (except absence seizures) but not first-line o Status epilepticus o Trigeminal neuralgia Mechanism of action: o Related to the barbiturates o Induces a use-dependent block of neuronal Na+ channels Pharmacokinetics: o t! of 20–60 hours o Has a saturable metabolism (zero-order kinetics): ! This means that over the therapeutic plasma concentration range.
2009 • • • • • Mechanism of action: o Not fully understood o Causes a significant $ in brain [GABA] Pharmacokinetics: o t! of 8–15 hours o Metabolised by the liver but not an enzyme inducer (may be an enzyme inhibitor) Adverse effects (fewer severe effects than most anticonvulsants): o Hepatotoxicity: ! Need to monitor LFTs o Teratogenicity: ! Neural tube defects ! Probably the safest anticonvulsant to use in pregnancy o Thinning / curling of the hair o Thrombocytopenia o Tremor o Sedation o Weight gain Contraindications: o Severe liver disease Interactions: o Drugs that # the efficacy of valproate: ! Neuroleptics ! Tri-cyclic antidepressants Phenobarbital: • Indications: o All types of epilepsy (except absence seizures) but not first-line o Status epilepticus • Mechanism of action: o Is a barbiturate o Binds to the GABA receptor and enhances actions of GABA • Pharmacokinetics: o Well absorbed o 50% protein bound o t! 36–120 hours o Enzyme inducer • Adverse effects: o Sedation with impairment of intellectual and motor performance o Ataxia o Osteomalacia o Folate deficiency • Cautions: o Elderly o Respiratory depression o Impaired hepatic / renal function 104 www.garrypettet.Copyright Dr Garry KJ Pettet 2005 .com .
2009 • Interactions (many more than shown below): o Phenobarbital # the efficacy of: ! COC pill ! Warfarin Vigabatrin: • Indications: o Epilepsy (usually second.or third-line) • Mechanism of action: o Was the first “designer” drug in the field of epilepsy o Is a irreversible GABA-transaminase inhibitor: ! $ [GABA] in the CSF • Pharmacokinetics: o t! 5 hours (although duration of action is long) o Is not an enzyme inducer • Adverse effects: o Depression o Psychotic disturbances o Visual field defects (~30% of patients) • Contraindications: o Those with visual field defects Lamotrigine: • Indications: o Can be used as monotherapy of: ! Generalised seizures (especially absence seizures) ! Partial seizures • Pharmacokinetics: o t! 15–70 hours • Adverse effects: o Rashes (very common): ! Can be as severe as Stevens-Johnson syndrome o Drowsiness o Tremor • Interactions: o Valproate: ! Valproate $ the plasma levels of lamotrigine Primidone: • Is a pro-drug of phenobarbital • ? an anticonvulsant in it’s own right • Adverse effects: o As for phenobarbital Ethosuximide: • Indications: o Absence seizures (second-line) • Pharmacokinetics: o t! of 30–70 hours 105 www.garrypettet.Copyright Dr Garry KJ Pettet 2005 .com .
garrypettet.2009 • o Is not an enzyme inducer Adverse effects: o Nausea / anorexia o Sedation o Ataxia o Hypersensitivity (rare) Gabapentin: • Indications: o Adjunctive treatment of partial seizures o Neuropathic pain o It’s role is likely to increase in the future • Pharmacokinetics: o t! of 5–7 hours o Not metabolised o Few (if any) interactions • Adverse effects: o Ataxia o Drowsiness www.Copyright Dr Garry KJ Pettet 2005 .com 106 .
metoprolol o High doses often needed • Amitriptylline: o Unrelated to it’s antidepressant effect • Sodium valproate: o Refractory migraines Treatment of migraine: • Simple analgesics: o E. sumatriptan o Can be given oral / sc / intranasally o Is a (relatively) selective vasoconstrictor o ~70% efficacy: ! Best if taken at onset to abort the migraine o Adverse effects: ! Dizziness ! Flushing o Avoid: ! In patients with IHD or uncontrolled hypertension: • Can cause angina-like pain (discontinue) ! With SSRIs and MAOIs • Ergotamine: o Rarely used now 107 www.g. atenolol.g.g.com .Copyright Dr Garry KJ Pettet 2005 .g.2009 Migraine Prophylaxis against migraine: • Avoid precipitating factors (if possible): o Foods (mainly tyramine containing food) o Irregular meals / sleeping patterns o Alcohol o “Weekend” migraines are probably caused by caffeine withdrawal • 5-HT antagonists: o E. paracetamol / aspirin / NSAIDs o Give with metoclopramide: ! Anti-emetic and $ gastric emptying (thus $ absorption of the analgesic) o Must be given early in an attack • 5-HT1D agonists: o E.garrypettet. pizotifen o Methysergide: ! Only prescribed by those experience in its use ! Good for cluster headaches ! Fibrotic side effects: • Cardiac fibrosis • Pulmonary fibrosis • Retroperitoneal fibrosis • "-blockers: o E. propranolol.
Copyright Dr Garry KJ Pettet 2005 .com 108 .garrypettet.2009 o o Primarily a vasoconstrictor Adverse effects: ! Nausea / vomiting ! Peripheral /coronary vasoconstriction www.
Copyright Dr Garry KJ Pettet 2005 .000/person/year o Adverse effects: ! ‘Flu-like symptoms ! Depression • Glatiramer: o May prevent relapsing as for IFN-" but does not alter the longterm prognosis Symptomatic treatment of MS: • Spasticity / painful spasms: o Baclofen: ! Inhibits nerve transmission at the spinal level ! Adverse effects: • Sedation • Hypotonia • Urinary disturbance ! Serious side effects can occur on abrupt withdrawal: • Convulsions • Hyperthermia • Psychiatric reactions o Dantrolene: ! Inhibits muscle contraction: • Prevents Ca2+ release from sarcoplasmic reticulum ! Adverse effects: • Aggravates weakness • Hepatotoxic • Detrusor instability: o Anticholinergics (e. oxybutynin.2009 Multiple sclerosis Drug treatment of an acute relapse of MS: • IV methylprednisolone: o High dose o Short course (3–5 days) o Does not alter the long-term prognosis • No other approaches have shown any benefit Prevention of relapse in MS: • Interferon-"1 (IFN-"1a and IFN-"1b): o Given SC / IM o Trials have shown a 30%# in relapses (only in relapsing / remitting disease) o Probably does not alter the natural history o Expensive: ! ~£10. TCAs) • Paroxysmal pain: o Anticonvulsants / TCAs www.garrypettet.g.com 109 .
pergolide o Used as an alternative or adjunct to L-dopa • Amantadine: o Useful in mild / moderate PD o May have a use in late disease with marked dyskinesia • Anticholinergics: o E. selegiline o Used as an adjunct to L-dopa to allow a # in dose: ! Can also # dose-related response fluctuations • Catechol – O – methyl transferase (COMT) inhibitors: o E. thus slow titration is essential • Mechanism of action: 110 www.Copyright Dr Garry KJ Pettet 2005 .com .g. lisuride. bromocriptine.2009 Parkinson’s disease Features of Parkinson’s disease: • Bradykinesia • Rigidity (“lead-pipe”) • Tremor (4–7 Hz. entacapone o May be useful in # end-of-dose fluctuations with L-dopa Levodopa: • An example of a prodrug • Must be combined with a peripheral dopa-decarboxylase inhibitor: o E. apomorphine.g. benserazide o Prevents L-dopa metabolism in the periphery o Do not cross the blood-brain barrier (BBB) o Thus # dose (by about 10 fold) o # adverse effects • Pharmacokinetics: o t! of 2 hours o There is a large individual variation in kinetics. carbidopa. “pill-rolling”) • Festinant gait • Loss of arm swinging • Monotonous speech • Loss of facial expression • Micrographia Drug treatment of Parkinson’s disease (PD): • Treatment should not be started before it is necessary because of delayed unwanted effects • Levodopa (L-dopa): o First-line therapy • Direct dopamine agonists: o E.g. benzhexol o Most useful in mild PD with tremor in younger patients o Also good for controlling dribbling • Monoamine oxidase B inhibitors (MAO-BIs): o E.g.garrypettet.g.
g.garrypettet.Copyright Dr Garry KJ Pettet 2005 .com . ~80% show improvement in rigidity and hypokinesia and ~20% are restored to near-normal function (for a period) Adverse effects: o Short-term: ! Nausea / vomiting: • Treat with domperidone (dopamine antagonist) ! GI disturbances ! Postural hypotension ! Cardiac dysrhythmias ! Haemolytic anaemia (rarely) o Long-term: ! Neuropsychiatric syndromes: • Delirium • Hallucinations (patient maintains insight) • Psychosis • Treatment: o Dose # o Atypical neuroleptics (e.2009 • • • Is a pro-drug of dopamine (Dopamine is not used as it cannot cross the BBB) L-dopa crosses the BBB and is rapidly converted to dopamine by dopa-decarboxylase in the brain o This dopamine replaces the deficiency in the basal ganglia With L-dopa. clozapine) ! Response fluctuations: • Akinesia: o End-of-dose • Dyskinesia: o Peak dose o Onset / end-of-dose • Unpredictable on-off responses (“yo-yo”-ing) • Treatment: o Careful regulation of plasma L-dopa levels o Use modified-release preparations o Try: ! COMT inhibitor ! MAO-BI ! Dopamine agonist ! Loss of response: • Usually within 2–5 years • ~50% are back to pre-treatment status after 5 yrs • Treatment: o Try dopamine agonist Contraindications: o Closed angle glaucoma o o o • Interactions: o Non-selective MAOIs: 111 www.
com .garrypettet.Copyright Dr Garry KJ Pettet 2005 . cabergoline. ropinirole o Side-effects are less than the older agents • Indications: o Can be used as an alternative to L-dopa but are usually used as adjuncts • Pharmacology: o Duration of action: ! Pergolide = cabergoline > bromocriptine > lisuride o Potency: ! Pergolide = lisuride > cabergoline > bromocriptine • Are less effective than L-dopa but are associated with fewer late unwanted dyskinetic effects • Adverse effects: o Nausea / vomiting o Hypotension Amantadine: • Mechanism of action: o Unknown 112 www.2009 o o ! Risk of hyperthermia syndrome with concomitant use ! Withdraw MAOIs 2 weeks before starting L-dopa Anti-hypertensives: ! Enhanced hypotensive effect Neuroleptics: ! Neuroleptics antagonise the action of L-dopa (and viceversa) Apomorphine: • PD indications: o Advanced disease with “on-off” periods with L-dopa • Pharmacokinetics: o Must be given parenterally (SC) • Mechanism of action: o Very potent dopamine D1 and D2 agonist • Adverse effects: o Profound nausea / vomiting o As for L-dopa • Contraindications: o Respiratory / CNS depression o Neuropsychiatric problems / dementia Dopamine agonists: • Older compounds (ergot derivatives): o Bromocriptine. pergolide • Recent compounds (synthetic): o Pramipexole. lisuride.
selegiline • Indications: o May allow L-dopa dose # o # end-of-dose deteriorations in advanced PD o Can be used alone to delay need for L-dopa for a few months • Adverse effects (reasonably well tolerated): o No “cheese reaction” (does not affect MAO-A) o Potentiates L-dopa related symptoms o Insomnia Catechol-O-methyl transferase (COMT) inhibitors: • E.g.Copyright Dr Garry KJ Pettet 2005 . procyclidine • Until L-dopa was discovered. anti-muscarinic agents were the only available treatment for PD • Mechanism of action: o As the nigrostriatal neurones progressively degenerate in PD. benzhexol.2009 • • o May cause release of dopamine o May be a weak anticholinergic Is less effective than L-dopa or even bromocriptine but it’s use may be revived for late onset dyskinesia Adverse effects: o Dizziness o Insomnia o Livedo reticularis o Peripheral oedema Anticholinergics: • E.g.g. entacapone • Mechanism of action: o Prolongs the action of a single dose of L-dopa 113 www. the release of (inhibitory) dopamine # and the excitatory cholinergic interneurones in the striatum become relatively overactive o Blocking these mACh receptors “resets” this balance o Only really reduce the tremor of PD (little effect on rigidity and Bradykinesia) • Use is declining rapidly (especially in the elderly) largely due to their unwanted effects on memory • Adverse effects: o CNS: ! Confusion ! Hallucinations ! Memory impairment o Other: ! Blurred vision ! Dry mouth ! Postural hypotension ! Constipation Monoamine oxidase B inhibitors (MAO-BIs): • E.garrypettet.com .
garrypettet.com 114 .Copyright Dr Garry KJ Pettet 2005 .2009 • Has no anti-PD activity when used alone but # the “off” time in late disease when used with L-dopa Adverse effects: o GI disturbances o Dyskinesias o Urine may be coloured reddish-brown o www.
2009 Drug-induced movement disorders The most commonly implicated drugs in this section are the antipsychotics (but also more common drugs such as metoclopramide) To be • • • • • covered: Acute dystonias Akathisia Parkinsonism Tardive dyskinesia Neuroleptic malignant syndrome Acute dystonias: • Dystonia is a syndrome of sustained muscle contractions that produce twisting and repetitive movements or abnormal postures • Presentation: o Most common in young males o Occurs within hours / days of starting the implicated drug o Usually oculogyric: ! Spasm of the extra-ocular muscles. forcing the eyes into upward or lateral gaze • Treatment: o IV anticholinergics (e.garrypettet.com . procyclidine) o ? continue oral anticholinergics for ~48 hours Akathisia: • This is a restless. repetitive and irresistible need to move • Can culminate in suicide • Occurs within days or months of starting the implicated drug • Equal sex incidence • May persist even after drug is stopped • Treatment: o Often ineffective o May respond to: ! Amantadine ! Anticholinergics ! "-blockers Parkinsonism: • Bradykinesia and rigidity but little tremor 115 www.Copyright Dr Garry KJ Pettet 2005 .g.
Copyright Dr Garry KJ Pettet 2005 . face. lips.com 116 .garrypettet.2009 • • • Affects up to 20% of patients on antipsychotics Presentation: o Usually in first few months of starting the drug o More common in the elderly Treatment: o Withdraw / # dose of drug if possible o Anticholinergics / Amantadine may be effective: ! Do not use L-dopa o May persist even after drug is stopped Tardive dyskinesia (TD): • Are involuntary movements of the tongue. sulpiride o A change of neuroleptic may help Malignant hyperthermia syndrome: • Is a rare idiosyncratic drug reaction that is unpredictable • Commonly implicated drugs: o Antipsychotics o Suxamethonium • Presentation: o Often a young male o Extreme rigidity o Hyperthermia o Fluctuating conscious level • There is a very high mortality if the syndrome goes unrecognised • Treatment: o Stop the causative drug o Dantrolene: ! Stops Ca2+ release in muscle ! Thus stopping the excessive muscle contractions www. trunk and extremities • Presentation: o Occurs after many months / years of using the drug o Affects up to ~20% of patients o More common in women and the elderly • Treatment: o Some neuroleptics are less likely to cause TD: ! Clozapine. risperidone.
g.com .garrypettet. the test should be preceded by a bolus of saline to act as a control Drug treatment of myasthenia gravis (MG): • Oral anticholinesterases: o Provide symptomatic improvement (complete relief is rare) • Corticosteroids: o Lead to a rapid improvement in most patients o Can produce total remission o High doses are usually needed (60mg on alternate days) • Immunosuppressants: o E. azathioprine.g. pyridostigmine • Indications: o Myasthenia gravis (oral) o Reversal of non-depolarising muscle relaxants (IV) • Mechanism of action: o Inhibit acetylcholinesterase. cyclophosphamide.Copyright Dr Garry KJ Pettet 2005 . neostigmine. cyclosporin o Lead to an improvement in most patients o Are steroid-sparing agents o More effective in older patients • Thymectomy: o Improves prognosis (especially in women <40 years with positive AChR antibodies and a history of <10 years) o Must always remove a thymoma if present o Complete remission is rare • Plasmapheresis: o Useful during exacerbations o Effects may last up to 3 months Anticholinesterases: • E.2009 Myasthenia gravis The Tensilon (edrophonium) test: • Give edrophonium IV as a bolus dose • Positive test: o Improvement of weakness occurs within seconds and the response lasts for 2–3 minutes • To be certain. thus $ the concentration of ACh in the synaptic cleft o Myasthenia gravis: ! The $ concentration of ACh has an $ probability of binding to a receptor at the neuromuscular junction o Reversal of muscle relaxants: ! The $ concentration of ACh overcomes the competitive blockade of the muscle relaxant • Adverse effects: o Abdominal cramps 117 www.
com 118 .Copyright Dr Garry KJ Pettet 2005 .2009 • o Bradycardia o Hypersalivation o Nausea / vomiting o Sweating Interactions: o Aminoglycosides: ! # the action of anticholinesterases www.garrypettet.
2009 Diuretics Loop diuretics: • E.Copyright Dr Garry KJ Pettet 2005 .g.com . drawing yet more water into the lumen o Also possess venodilator properties that are independent of their diuretic effect • Adverse effects: o Hypokalaemia o Hypocalcaemia o Hypomagnesaemia o Hyperuricaemia (can cause gout) o Deafness (high doses – effects on the endolymph) o Postural hypotension • Contraindications: o Renal failure with anuria • Interactions: o Aminoglycosides: ! $ risk of ototoxicity and nephrotoxicity o Digoxin: ! Hypokalaemia caused by furosemide $ risk of digoxin toxicity o Lithium: ! # excretion of lithium .$ plasma levels Thiazide diuretics: • E.garrypettet.g. metolazone • Indications: o Hypertension o Heart failure • Mechanism of action: o Moderately powerful diuretics (metolazone > bendrofluazide) o # reabsorption of Na+ in the distal tubule o The $ Na+ load in the distal tubule stimulates Na+ exchange with K+ and H+ ions thus $ their excretion and tending towards hypokalaemia and a metabolic alkalosis • Adverse effects: 119 www.pump o This section has a high capacity for absorbing NaCl and so loop diuretics produce the most profound diuresis o The $ Na+ that reaches the distal tubule also leads to an osmotic effect. bendrofluazide. furosemide • Indications: o Acute pulmonary oedema o Chronic heart failure o Oliguria secondary to acute renal failure • Mechanism of action: o Inhibit NaCl reabsorption in the thick segment of the ascending loop of Henle: ! Inhibit the Na+/K+/2Cl.
com .$ plasma levels o Potassium salts ($ risk of hyperkalaemia) Other potassium-sparing diuretics: 120 www.Copyright Dr Garry KJ Pettet 2005 .$ plasma levels Spironolactone (a potassium-sparing diuretic): • Indications: o Chronic heart failure (shown to # mortality) o Refractory hypertension (BHS step 4) o Ascites / oedema caused by cirrhosis o Conn’s syndrome (primary hyperaldosteronism) o Potassium conservation with thiazide and loop diuretics • Mechanism of action: o Is a competitive aldosterone antagonist o Aldosterone causes Na+ reabsorption and K+ excretion in the distal tubule o Inhibition of this action leads to a mild diuresis and retention of K+ o It is a weak diuretic because only 2% of the total Na+ reabsorption is under aldosterone control • Adverse effects: o Hyperkalaemia o Gynaecomastia o Impotence • Contraindications: o Hyperkalaemia o Addison’s disease • Interactions: o $ risk of hyperkalaemia: ! ACE inhibitors / AII receptor antagonists ! NSAIDs o Lithium: ! # excretion of lithium .2009 • • o Hypokalaemia o Hyponatraemia o Hyperglycaemia o Hypercalcaemia o Hyperlipidaemia o Hyperuricaemia o Postural hypotension o Impotence Contraindications: o Severe hepatic / renal impairment o Gout Interactions: o Digoxin: ! Hypokalaemia caused by thiazides $ risk of digoxin toxicity o Lithium: ! # excretion of lithium .garrypettet.
com 121 .garrypettet. mannitol • Indications: o Cerebral oedema • Mechanism of action: o Mannitol is a compound that is filtered by the kidneys but is not reabsorbed o Is given in amount such that it significantly contributes to plasma osmolarity o The $ plasma osmolarity (by compounds which cannot cross the blood-brain barrier) leads to extraction of water from the brain • Adverse effects: o Chills o Fever • Contraindications: o Congestive cardiac failure o Pulmonary oedema www.Copyright Dr Garry KJ Pettet 2005 .g. triamterene Indications: o Potassium conservation with thiazide and loop diuretics Mechanism of action: o Block Na+ channels in the distal tubule o $ Na+ excretion (thus causing a diuresis) and # K+ excretion Adverse effects: o Hyperkalaemia Contraindications: o Renal impairment Interactions: o $ risk of hyperkalaemia: ! ACE inhibitors / AII receptor antagonists ! NSAIDs o Lithium: ! # excretion of lithium .2009 • • • • • • E.$ plasma levels o Potassium salts ($ risk of hyperkalaemia) Osmotic diuretics: • E.g. amiloride.
garrypettet.2009 Muscle relaxants Types of muscle relaxants: • Depolarizing: o Suxamethonium • Non-depolarizing (competitive): o Can be reversed with an anticholinesterase (unlike suxamethonium) o Pancuronium: ! Long-duration of action ! Atropine-like effects o Vecuronium: ! No cardiovascular effects ! Short duration of action o Atracurium: ! Decomposes spontaneously in plasma: ! Does not depend on liver / kidneys for excretion o Rocuronium: ! Rapid onset (almost as fast as Suxamethonium) Suxamethonium: • Pharmacokinetics: o Is 2 ACh molecules linked by their acetyl groups o Rapid onset (1–1.Copyright Dr Garry KJ Pettet 2005 .com . the muscle fibres are activated causing twitching (fasciculation) • Adverse effects: o Muscle aches (caused by the fasciculation) o Prolonged block: ! ~1 in 2000 people have a deficiency of plasma pseudocholinesterase and paralysis may last several hours o Bradycardia o K+ release (from muscle) o Malignant hyperthermia: ! Very high mortality (~65%) ! Treated with dantrolene • Contraindications: o Family history of malignant hyperthermia o Hyperkalaemia • Interactions: o Drugs $ action of Suxamethonium (many): 122 www.5 minutes) o Very short duration of action (3–7 minutes): ! Metabolised by plasma pseudocholinesterase • Mechanism of action: o Suxamethonium diffuses slowly to the motor endplate and persist for long enough to cause loss of electrical excitability o Before paralysis occurs.
garrypettet. atracurium. pancuronium. rocuronium • Mechanism of action: o Do not cross the BBB or the placenta o Block the nicotinic ACh receptor at the motor endplate.2009 ! ! ! Aminoglycosides Metoclopramide Verapamil Non-depolarizing muscle relaxants: • E.Copyright Dr Garry KJ Pettet 2005 .com 123 .g. vecuronium. thus inhibiting muscle contraction • Adverse effects: o These vary between the various drugs (see above) o Hypotension o Anaphylactoid reactions www.
g. erythromycin) o Cytotoxic agents o Digoxin o Opioids • Vestibular disease (e.2009 Anti-emetics Causes of nausea and vomiting: • Drugs: o Antibiotics (e. seasickness) • Migraine • Abdominal disease • Pregnancy Physiology of nausea: • Emesis is coordinated by the vomiting centre (medulla oblongata) • An important input to the vomiting centre is the chemoreceptor trigger zone (CTZ) in the area postrema: o The CTZ is not protected by the BBB. metoclopramide. labyrinthitis) • Provocative movement (e.g.g. therefore circulating toxins/drugs can stimulate it o Possesses the following receptors: ! Dopamine (D2) ! Serotonin (5HT3) • The vomiting centre also receives cholinergic (muscarinic) and histamine input • Thus the following drug classes are helpful anti-emetics: o D2 receptor antagonists o 5-HT3 receptor antagonists o Anti-muscarinic agents o Antihistamines (H1) • Dexamethasone is a useful anti-emetic following cancer chemotherapy • Vomiting is easier to prevent than it is to stop D2 receptor antagonist anti-emetics: • E.Copyright Dr Garry KJ Pettet 2005 .g.garrypettet.g. analgesics in migraine with vomiting) • Adverse effects: 124 www. domperidone • Indications: o Nausea and vomiting due to: ! Abdominal disease ! Drugs (especially opioids) ! Migraine ! Post-operative nausea / vomiting • Mechanism of action: o Blocks D2 receptors in the CTZ o Prokinetic actions on the gut ($ absorption of many drugs): ! Can be an advantage (e.com .
g.2009 • • • o Acute dystonia (especially if age <20 years and female) o Hyperprolactinaemia Domperidone does not readily cross the BBB and is much less likely to cause central reactions (e.Copyright Dr Garry KJ Pettet 2005 .com . cinnarizine.garrypettet. ondansetron. hyoscine • Indications: o Prophylaxis against motion sickness • Adverse effects: o Blurred vision o Dry mouth o Drowsiness • Contraindications: o Prostatic enlargement o Glaucoma o Myasthenia gravis o Paralytic ileus • Interactions: o Alcohol: ! Sedative effects of hyoscine are enhanced by alcohol Antihistamine anti-emetics: • E. granisetron • Indications: o Nausea and vomiting due to: ! Cytotoxic agents ! Radiotherapy ! Post-operative nausea / vomiting • Adverse effects: o Headache o Constipation Anti-muscarinic anti-emetics: • E.g.g. cyclizine • Indications: o Nausea and vomiting due to: 125 www. dystonic reactions) Contraindications: o GI obstruction / perforation / haemorrhage o Recent (3–4 days) GI surgery Interactions: o NSAIDs: ! $ absorption of NSAIDs $ their beneficial (and toxic) effects 5-HT3 antagonist anti-emetics: • E.g.
garrypettet. e.2009 • • ! Vestibular disease ! Drugs Adverse effects: o Drowsiness o Anti-muscarinic effects.Copyright Dr Garry KJ Pettet 2005 .: ! Blurred vision ! Dry mouth Contraindications: o Prostatic enlargement o Glaucoma o Urinary retention www.com 126 .g.
2009 The eye Maintenance of intraocular pressure (IOP): • The IOP is determined by aqueous humour volume • Production: o Aqueous humour is produced by the highly vascularised processes of the ciliary body o The ciliary epithelial cells (which contain ATPase and carbonic anhydrase) absorb Na+ from the stroma and transport it to the intercellular clefts (which open on the aqueous humour side) o The hyperosmolality in the clefts leads to water flow from the stroma.garrypettet. producing a continuous flow of aqueous o The ciliary epithelium is also leaky and ~30% of aqueous is formed by ultrafiltration • Drainage: o Pupil " trabecular meshwork " canal of Schlemm " episcleral veins Treatment of acute narrow-angle glaucoma: • This must be treated quickly to prevent permanent retinal damage • # aqueous production: o Acetazolamide IV stat • $ aqueous outflow: o Pilocarpine eye drops stats o Mannitol IV stat: ! To draw water out of the eye • Prevent recurrence: o Surgery (Peripheral iridotomy) Drug treatment of chronic open-angle glaucoma: • All of the following treatments are given topically (eye drops) • # aqueous production: o "-blockers o !-agonists o Carbonic anhydrase inhibitors • $ aqueous outflow: o Muscarinic agonists Age-related macular degeneration (AMD): • Most common cause of blindness in the UK • New blood vessels form under the retina and leakage of fluid and blood from the vascular complexes causes severe loss of vision within a few years • Treatment (relatively new): o Verteporfin (photodynamic therapy): 127 www.Copyright Dr Garry KJ Pettet 2005 .com .
phenylephrine • # IOP by vasoconstriction of the ciliary body afferent blood vessels • Interestingly.Copyright Dr Garry KJ Pettet 2005 .g.g. timolol • Drugs of choice in chronic open-angle glaucoma • Mechanism of action: o Block "2 receptors on the ciliary processes and # aqueous secretion o May also block "-receptors on afferent blood vessels to the ciliary processes (this vasoconstriction # ultrafiltration) • Adverse effects (may be absorbed systemically): o Bradycardia o Bronchospasm • Contraindications: o Asthma o Heart block o Heart failure !-agonists in glaucoma: • E. dorzolamide (topical) • Inhibition of carbonic anhydrase prevents HCO3. which releases free radicals that destroy the new vessels Mydriatic drugs: • Muscarinic antagonists: o Also cause cycloplegia (paralysis of the ciliary muscle) o Tropicamide o Cyclopentolate • !-agonists: o Do not affect the pupillary light reflex or accommodation o Phenylephrine "-blockers and glaucoma: • E.and Na+ transport are linked. adrenaline.com .garrypettet.formation • Since HCO3. !-antagonists and "-agonists also # IOP: o $ aqueous outflow rather than #production o Dilatation of the aqueous / episcleral veins Carbonic anhydrase inhibitors: • E.g. Acetazolamide (IV / IM / oral). this leads to a # in aqueous formation • Dorzolamide can be used alone in those in whom "-blockers are contraindicated • Dorzolamide is a sulphonamide and systemic side effects can occur: o Rashes o Bronchospasm 128 www.2009 ! ! Is a light-sensitive dye that is given IV and is taken up by vascular endothelium A laser is then applied to the eye and this activates the dye.
garrypettet.g. pilocarpine • # IOP by contracting the ciliary muscle • This pulls the scleral spur and results in the trabecular meshwork being stretched and separated • The fluid pathways are opened up and aqueous outflow is increased • Adverse effects: o Miosis: ! Causes near-sightedness (blurred distance vision) ! Brow ache ! Headache ! Poor night vision www.com 129 .2009 Muscarinic agonists: • E.Copyright Dr Garry KJ Pettet 2005 .
and post-synaptic ! Inhibit adenylate cyclase and # cAMP • Dopaminergic pathways: o Mesolimbic / mesocortical: ! Concerned with mood and emotional stability ! Ventral tegmental area: • Ventral striatum and the frontal cortex o Nigrostriatal: ! Concerned with movement ! Substantia nigra and the dorsal striatum • Neuroleptics block D2 receptors: o Explains why they cause movement disorders as a side effect Clinical classification of neuroleptics: • Typical: o Produce extrapyramidal symptoms (EPS) • Atypical: o So-called because they have a low incidence of EPS o However.com 130 .2009 Antipsychotics (neuroleptics) The dopamine hypothesis of psychosis: • Psychotic symptoms result from $ dopamine neurotransmission • Dopamine receptors: o D1-like: ! D1 and D5 ! Are post-synaptic ! Stimulate adenylate cyclase and $ cAMP o D2-like: ! D2. all apart from clozapine can cause EPS at high doses Chemical classification of neuroleptics: • Typical: o Phenothiazines: ! Propylamines (chlorpromazine): • Sedation ++ • Anticholinergic ++ • EPS ++ ! Piperidines (thioridazine): • Sedation ++ • Anticholinergic ++ • EPS + • Can cause torsade de pointes ! Piperazines (fluphenazine): • Sedation + • Anticholinergic + • EPS +++ o Thioxanthines (flupenthixole): ! Sedation + www. D3 and D4 ! Are both pre.Copyright Dr Garry KJ Pettet 2005 .garrypettet.
Copyright Dr Garry KJ Pettet 2005 .2009 • ! Anticholinergic + ! EPS ++ o Butyrophenones (haloperidol): ! Sedation ! Anticholinergic ! EPS +++ Atypical: o “True”: ! Clozapine: • Sedation ++ • Anticholinergic + • EPS o “Apparent”: ! Sulpiride: • Sedation + • Anticholinergic – • EPS + ! Risperidone: • Sedation ++ • Anticholinergic + • EPS + General effects of the neuroleptics: • Early (hours): o Desired: ! Sedation (histamine / !-receptor blockade) ! Tranquilisation (dopamine blockade) o Unwanted: ! Acute dystonic reactions • Medium (days–weeks): o Desired: ! Suppression of: • Delusions • Disordered thinking • Hallucinations o Unwanted: ! Akathisia ! Parkinsonism • Late (months–years): o Desired: ! Prevention of relapse o Unwanted: ! Tardive dyskinesia • Any time: o Neuroleptic malignant syndrome Chlorpromazine: • Indications: o Psychotic disorders (e.garrypettet.com .g. schizophrenia / mania) o Labyrinthine disorders / vertigo 131 www.
2009 • • o Nausea / vomiting o Chronic hiccups Adverse effects: o Common: ! Sedation ! Anticholinergic effects: • Blurred vision • Dry mouth • Postural hypotension • Constipation • Urinary retention ! Extrapyramidal effects: • Acute dystonia • Akathisia • Parkinsonism • Tardive dyskinesia ! Hyperprolactinaemia: • Amenorrhoea • Galactorrhoea • Impotence o Uncommon: ! Neuroleptic malignant syndrome ! Agranulocytosis ! Cholestatic jaundice Interactions: o ACE inhibitors: ! Can cause severe hypotension Haloperidol: • Indications: o Psychosis o Motor tics • Adverse effects: o Common: ! Extrapyramidal effects: • Acute dystonia • Akathisia • Parkinsonism ! Postural hypotension o Uncommon: ! Convulsions ! Neuroleptic malignant syndrome ! Tardive dyskinesia ! Weight loss • Interactions: o Amiodarone: ! $ risk of ventricular arrhythmias o Carbamazepine: ! # plasma levels of haloperidol (metabolism accelerated) 132 www.garrypettet.com .Copyright Dr Garry KJ Pettet 2005 .
g.garrypettet.Copyright Dr Garry KJ Pettet 2005 .com 133 .2009 o Fluoxetine: ! $ plasma levels of haloperidol Clozapine: • Regarded by many as the only “true” atypical neuroleptic: o EPS is not evident even at high doses o Effective in patients refractory to other neuroleptics o Can treat the negative symptoms of schizophrenia • Mechanism of action: o Blocks D4 and 5-HT2 receptors o Weak blockade of striatal D2 receptors • Adverse effects: o Agranulocytosis (requires regular blood monitoring) o Myocarditis / cardiomyopathy o Ileus • Contraindications: o Severe cardiac disorders o History of neutropenia / agranulocytosis • Interactions: o Avoid concomitant use with drugs that have a high risk of causing agranulocytosis (e. carbimazole) www.
antihypertensives " postural hypotension o "-receptors (# density) • Brain: o $ sensitivity to anxiolytics and hypnotics (may lead to confusion) • Heart (failing): o # perfusion of liver / kidneys " # function of these organs Two groups of drugs in the elderly cause 2/3 of all adverse drug reactions: • Drugs acting on the: • Brain: o Antidepressants o Anti-Parkinson’s drugs o Hypnotics • Circulation: o Antihypertensives o Digoxin o Diuretics Compliance issues in the elderly: • Living alone / unsupervised 134 www.g.garrypettet.Copyright Dr Garry KJ Pettet 2005 .2009 Drugs in the elderly. young or pregnant Pharmacokinetics in the elderly: • Distribution: o # body water: ! Thus water soluble drugs have a # volume of distribution (Vd) ! Thus $ [water soluble drugs] o $ body fat: ! Lipid soluble drugs have an $ Vd ! Thus # [fat soluble drugs] o # plasma albumin: ! # drug protein binding ! Thus $ levels of drugs that usually bind to protein o # weight (no longer a 70kg man!): ! Thus standard dose will lead to $ [drug] • Metabolism: o # oxidation o # first-pass metabolism o # induction of liver enzymes o Warfarin is more effective • Excretion: o # GFR o # tubular secretion Altered end-organ sensitivity in the elderly: • Autonomic nervous system: o Defective compensatory mechanisms: ! E.com .
g.Copyright Dr Garry KJ Pettet 2005 . methotrexate) • Tetracyclines • Thalidomide • Warfarin Drugs to avoid in later pregnancy: • Aspirin: o Haemorrhage o Kernicterus • Aminoglycosides: o CN VIII damage • Anti-thyroid drugs (e.com 135 .g. chloramphenicol " grey baby syndrome • Excretion: o # GFR: ! The neonate has 30% of adult GFR and 20% of adult tubular secretion ! This $ to 50% at 1 week of age ! $ to 100% at 6 months of age Drugs with adverse effects on foetal development: • ACE inhibitors • Alcohol • Androgens • Anticonvulsants • Folate antagonists (e. carbimazole): o Goitre o Hypothyroidism • Benzodiazepines: o “Floppy baby” syndrome • Chloramphenicol: o Grey baby syndrome www.garrypettet.g.2009 • • • Confusion because of change in tablet shape / colour Impaired vision Arthritic hands Pharmacokinetics in neonates: • Absorption: o # gastric motility o Variable peripheral perfusion (care with IM injections) • Distribution: o Blood brain barrier is immature o $ body water: ! Thus # [water soluble drugs] o # body fat: ! Thus $ [fat soluble drugs] o Protein binding low (adult levels at 1 year of age) • Metabolism: o # P450 activity o # conjugation: ! E.
Copyright Dr Garry KJ Pettet 2005 .com 136 .2009 • • Warfarin: o Haemorrhage Sulphonylureas: o Kernicterus www.garrypettet.
Copyright Dr Garry KJ Pettet 2005 .com .2009 Cytotoxic chemotherapy Classification of anti-cancer drugs: • Alkylating agents: o Cyclophosphamide o Chlorambucil o Cisplatin o Dacarbazine o Ifosfamide o Mitomycin C • Anti-metabolites: o Folate antagonists: ! Methotrexate o Pyrimidine analogues: ! 5-Fluorouracil (5-FU) ! Cytarabine (cytosine arabinoside) ! Gemcitabine o Purine analogues: ! Azathioprine • Cytotoxic antibiotics: o Anthracyclines: ! Doxorubicin (adriamycin) o Bleomycin • Plant derivatives: o Taxanes: ! Paclitaxel o Vinca alkaloids: ! Vincristine ! Vinblastine • Epipodophyllotoxins: o Etoposide • Hormonal: o Antagonists: ! Anti-androgens: • Cyproterone ! Anti-oestrogens: • Tamoxifen o Corticosteroids o GnRH analogues: ! Goserelin o Somatostatin analogues: ! Octreotide • Miscellaneous compounds: o Hydroxyurea Some example chemotherapy regimens: • BEP: o Bleomycin 137 www.garrypettet.
2009 • • • o Etoposide o Cisplatinum o Testicular teratoma CHOP: o Cyclophosphamide o Hydroxydaunomycin (doxorubicin) o Oncovin (vincristine) o Prednisolone o Radical treatment of non-Hodgkin’s lymphoma (NHL) ABVD: o Adriamycin (doxorubicin) o Bleomycin o Vinblastine o Dacarbazine o Hodgkin’s lymphoma FEC: o 5-Fluorouracil o Etoposide o Cyclophosphamide o Breast cancer General adverse effects of cytotoxic agents: • Nausea / vomiting patient’s biggest concern • Alopecia • Oral / intestinal ulceration • Diarrhoea • Bone marrow suppression: o Anaemia physician’s biggest concern o Leucopenia o Thrombocytopenia • Teratogenicity • Carcinogenesis Emesis-risk: • High risk: o Treat with granisetron + dexamethasone + domperidone) o Cisplatinum (high dose) o Etoposide (high dose) o Dacarbazine o Ifosfamide • Moderate risk: o Cisplatinum (low dose) o Cyclophosphamide o Doxorubicin o Methotrexate (high dose) • Low risk: o Treat with domperidone ± dexamethasone o Bleomycin o Methotrexate (low dose) 138 www.Copyright Dr Garry KJ Pettet 2005 .com .garrypettet.
garrypettet. ifosfamide.g. rheumatoid arthritis) ! Nephritic syndrome ! Vasculitis o Adverse effects (in addition to the general ones above): ! Haemorrhagic cystitis: • Due to the metabolite acrolein • Can be ameliorated by: o $ fluid intake o Mesna (a sulphydryl donor) ! Infertility in men: • Long-term use • May be irreversible • Cisplatin: o A platinum containing alkylating agent o Revolutionised the treatment of tumours of the testes / ovary o Adverse effects: ! Nephrotoxicity ! Very severe nausea / vomiting ! Peripheral neuropathy ! Ototoxicity ! Anaphylactoid reactions Pyrimidine analogues: • E.g.e. 5-FU. chlorambucil. gemcitabine • 5-FU: 139 www.com .g. dacarbazine. during S phase with a block at G2) o Results in apoptotic cell death • Cyclophosphamide: o Indications: ! Malignancy ! Autoimmune disease (e.g. mitomycin • Mechanism of action: o Readily form covalent bonds with the bases in DNA o Prevent cell division by cross-linking the two strands of the double helix o Their main action occurs during replication (i. cisplatin. cyclophosphamide. SLE. granisetron) + o Dexamethasone • Delayed: o Domperidone / metoclopramide o Dexamethasone Alkylating agents: • E. cytarabine.Copyright Dr Garry KJ Pettet 2005 .2009 o o Mitomycin Vincristine Prevention of nausea / vomiting: • Acute: o 5-HT3 antagonist (e.
SLE) o Prevention of transplant rejection o Steroid-sparing agent • Mechanism of action: o 6-MP is converted to a “fraudulent” nucleotide o Is incorporated into and interferes with replicating DNA o Also impairs the de novo pathway of purine synthesis • Adverse effects: o Nausea / vomiting o Bone marrow suppression o Alopecia o Jaundice • Interactions: o Allopurinol: ! Allopurinol inhibits the metabolism of azathioprine. doxorubicin • Mechanism of action: o Inserts itself between base pairs (intercalation): ! Alters the topography of DNA ! Causes unwinding of DNA o Causes topoisomerase II-associated DNA strand breaks o Causes free-radical formation: ! Responsible for cardiac toxicity (as the heart cannot inactivate them due to a lack of catalase activity) • Adverse effects: o Cardiac toxicity: ! Acute Myocarditis / pericarditis 140 www. azathioprine (a pro-drug of 6-MP) • Indications: o Autoimmune diseases (e.g.g.g. 6-mercaptopurine (6-MP).2009 • • Mechanism of action: ! Interferes with thymidylate synthetase (essential for the production of thymidylic acid) ! Impairs DNA synthesis (but not RNA or protein synthesis) Cytarabine: o Mechanism of action: ! Incorporated into DNA and RNA ! Inhibits DNA replication and (to a lesser extent) DNA repair Gemcitabine: o An analogue of cytarabine o Has fewer unwanted effects: ! ‘Flu-like symptoms ! Mild myelotoxicity o Purine analogues: • E. rheumatoid arthritis. thus $ it’s toxicity Cytotoxic antibiotics: • E.com .Copyright Dr Garry KJ Pettet 2005 .garrypettet.
g. paclitaxel (taxol) • Derived from Yew tree bark • Mechanism of action: o Stabilise cell microtubules (in effect “freezing” them) o Prevents spindle formation in mitotic cells and causing cell cycle arrest in metaphase • Adverse effects: o Bone marrow suppression o Hypersensitivity: ! Must pre-treat the patient with: • Antihistamines • Corticosteroids o Neurotoxicity Vinca • • • alkaloids: E.2009 ! Late onset cardiac failure: • 5% of patients after high dose therapy Taxanes: • E.garrypettet.com .g.Copyright Dr Garry KJ Pettet 2005 . vincristine. vinblastine Extracts of the periwinkle plant Mechanism of action: o Bind to tubulin and inhibit it’s polymerisation into microtubules o This prevents spindle formation o Leads to cell cycle arrest in metaphase • Adverse effects: o Relatively non-toxic o Neurotoxicity: ! Paraesthesia ! Neuromuscular abnormalities o Fatal if given intrathecally Hydroxyurea: • Indications: o Malignancy o Sickle cell anaemia ($ production of fetal Hb) • Mechanism of action: o A urea analogue o Inhibits ribonucleotide reductase o Interferes with the conversion of ribonucleotides to deoxyribonucleotides Anti-malarials Main signs / symptoms of malaria: • ‘Flu-like symptoms: o Headache o Malaise o Myalgia 141 www.
vivax): ! Improves liver clearance of the parasite Prophylaxis against malaria: • Avoid getting bitten if possible • High risk of P.Copyright Dr Garry KJ Pettet 2005 .com .garrypettet. Falciparum: o Quinine and o Tetracycline or doxycycline or clindamycin o Alternatives: ! Malarone or ! Fansidar • Non-falciparum: o Chloroquine ± o Primaquine (if P.2009 • • • • • Fever ± chills Anaemia Jaundice Hepatosplenomegaly No lymphadenopathy / rash Poor prognostic signs: • Young (< 3 years) • Pregnant • Hyperparisitaemia (> 5% of RBCs) • CNS: o Fits o Coma • Renal: o Blackwater fever (haemoglobinuria) o Oliguria o Acure renal failure • Hypoglycaemia (< 2.falciparum: o Chloroquine and proguanil Quinine: • Adverse effects: o Tinnitus o Nausea Chloroquine: • Adverse effects: o Retinopathy 142 www.falciparum: o Mefloquine o Malarone o Doxycycline • No / low risk of P.ovale / P.2 mmol/L) • Acidosis ($ [lactate]) Treatment of malaria: • If species unknown or mixed infection then treat as for falciparum • P.
2009 o Psychosis Fansidar: • Adverse effects: o Stevens-Johnson syndrome o Blood dyscrasias o Deranged LFTs Primaquine: • Adverse effects: o Haemolytic anaemia (G6PD-deficiency) o Methaemoglobinaemia Mefloquine: • Adverse effects: o Severe psychiatric reactions: ! More common in young women with a previous history of psychiatric illness • Has a long t! (needs to be started 2–3 weeks before travelling) www.garrypettet.Copyright Dr Garry KJ Pettet 2005 .com 143 .
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