Pharmacokinetics:Metabolism

The majority of phase I and phase II reactions take place in the liver) Usually both phase I and II reactions ↓↓ lipid solubility Drug metabolism usually involves two types of biochemical reactions

1. Phase I reactions Oxidatio n, reduction, hydrolysis Products more active and potentially toxic) Mainly performed by the P450 enzymes Some drugs are metabolised by specific enzymes Alcohol dehydrogenase and xanthine oxidase.

2. Phase II reactions Conjugation Products are typically inactive & excreted in urine or bile. Glucuronyl , acetyl, methyl, sulphate and other groups are typically involved

First-pass metabolism 'first-order' "Elimination kinetics" "Rate of drug elimination is proportional to drug concentration" Helpful to reduce the drug Conc. To therapeutic level. As a consequence much larger doses are need orally than if given by other routes. Ex

1. aspirin2. isosorbide dinitrate3. glyceryl trinitrate4. lignocaine5. propranolol6. verapamil7. isoprenaline8. testosterone9. hydrocortisone

Zero-order kinetics = Saturation Pharmacokinetics "Rate of excretion is constant despite changes in plasma concentration (due to saturation of the metabolic process) ↑↑Risk of toxicity

1. Alcohol people may fail a breathalyser test in the morning if they have been drinking the night befor2. heparin3. Phenytoin (long half life needs monitoring)4. Salicylates

Acetylator status 50% of the UK population are deficient in hepatic N-acetyltransferase (affect toxcisity of the drug) Drugs affected by acetylator status

1. Isoniazid Men, unusually, less likely to develop isoniazid hepatotoxicity. Concurrent use of Rifampicin and Pyrazinamide is also a risk factor isoniazid hepatotoxicity.

2. Sulfasalazine3. Procainamide4. Hydralazine5. Dapsone

P450 enzyme systemInduction usually requires prolonged exposure to the inducing drug, as opposed to P450 inhibitors, where effects are often seen rapidly

(++++) P450 (- - - -) P450 system1. Anti- Biotic Rifampicin2. Anti fungal Griseofulvin3. Antiepileptics  Phenytoin, Carbamazepine4. Anti- Seizure Barbiturates "phenobarbitone"5. St John's Wort6. Chronic alcohol intake

1. Antibiotics Ciprofloxacin, Erythromycin, Isoniazid2. Anti- Fungal imidazoles (ketoconazole, fluconazole)3. Anti- Viral ritonavir4. Anti- Epileptic Na + valproate 5. Anti- Depressant SSRIs: fluoxetine, sertraline6. Anti- Acid Cimetidine,omeprazol

7. Smoking (affects CYP1A2(↓↓ Amynophylin effect smokers require more aminophylline)

7. Anti- Arrhythmic Amiodarone8. Anti- Gout allopurinol9. acute alcohol intake10. quinupristin11. Grapefruit juice ( interact with Simvastatin )

DRESS syndrome Unexpected, severe reaction to medication W several organs are commonly affected (Skin, Liver, Kidneys, Lungs and Heart). Not all organs at any one time.  reaction occurs 2-8 weeks after commencing the offending drug Feature

1. Morbilliform skin rash in 80%, often exfoliative dermatitis,2. Vesicles and bullae may be seen. 3. Erythroderma 10% of cases, Mucosal involvement in 25% and facial swelling in 30%. 4. ↑↑ Fever and inflammation of ≥ 1 organs. 5. Systematic symptoms which can include

Haematological abnormalities Eosinophilia (30% > 2.0 * 109 /L) ↑/↓ WBCs, ↓↓(Platelet & Hb), Atypical lymphocytes)Enlarged lymph nodes (75%)Mild kidney disease 10% (interstitial nephritis is common, renal failure is rare)CVS myocarditis, pericarditis,liver enlargement, hepatitis and rarely hepatic necrosis with liver failure (abnormal liver function " 70-90% ↑↑transaminases),lung disease (pneumonitis, pleuritis, pneumonia),CNS meningitis and encephalitis,GIT in"Severe cases" (acute colitis and pancreatitis can occur)Endocrine abnormalities Thyroiditis and D.M. 

Diagnosis Difficult to determine the exact drug causing the hypersensitivity as first exposure may have started 8 weeks prior. Common drugs

1. Allopurinol,

2. Anti-epileptics3. Antibiotics4. Immunosuppresants5. HIV treatment6. NSAIDS. 

Suspected diagnosis Triad of [Extensive Skin rash + ↑↑ fever + Organ involvement] supported by eosinophilia and ↑↑liver function RegiSCAR has proposed a diagnostic criteria at least 3 of the following: 

1. Hospitalisation2. Reaction suspected to be drug related3. Acute skin rash4. Fever about 38ºC5. Enlarged lymph nodes at two sites6. Involvement of ≥ 1 internal organ7. Blood count abnormalities such as low platelets, raised eosinophils or abnormal lymphocyte count.

Skin biopsy "confirm the diagnosis" [inflammatory infiltrate (eosinophils), Extravasated erythrocytes and Oedema]. Regular blood tests including FBC, clotting, liver and renal function, CK, viral screen, glucose and thyroid function tests should be taken. Investigations looking for complications should be undertaken including ECG, CXR, echocardiogram, and urinalysis. 

Treatment1. All possible medications stopped and supportive care started. 2. Rash

Antihistamines , topical steroids and emollients. Systemic steroids severe cases [Exfoliative dermatitis / Pneumonitis / hepatitis] Regularly checked and secondary infections treated with antibiotics

3. Careful fluid balance is necessary and clinicians should be aware of the patients nutritional status.4. Occasionally immunosuppressants, IV immunoglobulin and plasmapheresis may be started. 5. Potential culprit drugs should not be restarted again.

6. The mortality is around 8%. DDSteven Johnson's syndrome (SJS) and toxic epidermal necrolysis (TEN) skin disorders with drug reactions (limited to the skin and not ↑↑LFTs. SJS would typically present with mucosal involvement, whilst TEN causes desquamating skin lesions.

Carbon monoxide poisoningCO ↑↑affinity for Hb O2. Total Hb is normal(Not affect plasma O2), but active sites get occupied by CO ↓↓Hb saturation Hypoxia. CO has a high affinity left-shift of the oxygen dissociation (early plateau).There are approximately 50 per year deaths from accidental carbon monoxide. A pulse Oximeter normal oxygen saturation (ABG is required to check for plasma O2)Questions may hint at badly maintained housing e.g. student houses.

Features of carbon monoxide toxicity 1. Headach e 90% of cases2. Nausea and Vomiting, Vertigo 50%3. Confusion, subjective weakness : 30%4. Severe toxicity

'pink' skin and mucosae , Hyperpyrexia Arrhythmias Extrapyramidal features Coma, death

Investigations1. Pulse oximetry may be falsely high due to similarities between oxyhaemoglobin and carboxyhaemoglobin venous or arterial blood gas2. Typical carboxyhaemoglobin levels

< 3% non-smokers (Normal) < 10% smokers Heavy smokers may have a carboxyhaemoglobin concentration of 10-15% 10 - 30% symptomatic (headache, vomiting)

> 30% Severe toxicity3. ECG is a useful supplementary investgation to look for cardiac ischaemia

Management 100% high-flow oxygen via a non-rebreather mask

1. ↓↓ the half-life of Carboxyhemoglobin (COHb)2. Administered as soon as possible, (minimum 6 h )3. target O2 saturations are 100%4. Treatment is continued until all symptoms have resolved , rather than monitoring CO levels

Hyperbaric oxygen Some evidence long-term outcomes may be better than standard oxygen therapy for more severe cases (levels > 25%) Other indication for hyperbaric oxygen

1. Loss of Consciousness at any point. 2. Neurological signs other than headache.3. Myocardial ischaemia or arrhythmia 4. Pregnancy

Cyanide poisoning Used in (Insecticides, Photograph development and the production of certain metals Fires involving the burning of plastics.  Cyanide (- -) Mitochondrial cytochrome c oxidase Enz cessation of electron transfer chain histotoxic hypoxia (cells unable to create ATP. 

Presentation1. 'classical' features: brick-red skin, smell of bitter almonds2. Acute

Hypoxia Hypotension Headache, confusion

3. Chronic Ataxia Peripheral neuropathy

Dermatitis4. Presentation with normal O2 saturations ↑↑ pO2 and flushing (or 'brick red' skin) DD. From CO poisoning

Management1. supportive measures: 100% oxygen2. Definitive IV  Hydroxocobalamin also combination of

Amyl nitrite (inhaled) S odium nitrite (IV), Na thiosulfate (IV)

Mercury poisoningThe commonest cause of mercury poisoning is ingestion via foodstuffs- in particular fish and whale. Features

1. Paraesthesia2. Visual field defects3. Hearing loss (Sensorineurl) 4. irritability5. Renal tubular acidosis

Organophosphate insecticide poisoningOrganophosphate poisoning inhibit   acetylcholinesterase upregulation (++) of nicotinic and muscarinic cholinergic neurotransmission. In warfare, Sarin gas   is a highly toxic synthetic organophosphorus compound that has similar effects.

Features (accumulation of acetylcholine Parasympathetic ) "mnemonic = SLUD" 1. Salivation2. Lacrimation3. Urination4. Defecation/diarrhoea5. Bronchorrhea6. CVS Hypotension, Bradycardia7. Small pupils, Muscle fasciculation, Muscle weakness

Management1. Atropine2. the role of pralidoxime is still unclear - meta-analyses to date have failed to show any clear benefit

Antibiotics: gross mechanism of action(- -) cell wall formation (- -) protein synthesis (- -) DNA Damages DNA (- -) Folic Acid (- -) RNA1. (- -) peptidoglycan cross linking

Penicillins Cephalosporins  Carbopenems

2. peptidoglycan synthesis: Glycopeptides  Vancomycin Teicoplanin > duration of

action/ OD after loading dose.

by acting on the Ribosome1. 50Ssubunit

Macrolides Chloramphenicol Clindamycin Linezolid Streptogrammins

2. 30S subunit Aminoglycosides Tetracycline

Quinolones  Ciprofloxacin

Metronidazole 1. sulphonamides2. trimethoprim

R ifampicin

Penicillin allergy Allergy to penicillin is common (allergy may be intolerance/side-effects (diarrhoea) or coincidental rash (amoxicillin in patients with infectious mononucleosis). Urticarial rash or itching make it ↑↑ likely IgE mediated allergy.  Around 0.5-6.5% of patients who are allergic to penicillin are also allergy to cephalosporins. (↑↑ 1 st generation , ↓↓ 2 nd & 3 rd generations) History of immediate hypersensitivity to penicillin should not receive a cephalosporin. If a cephalosporin is essential (No alternative antibacterial)

Used with caution Should be avoided Cefixime Cefaclor

Cefotaxime Cefuroxime Ceftazidime Ceftriaxone

Cefadroxil Cefalexin Cefradine Ceftaroline Fosamil

Types of penicillin:1. Phenoxymethylpenicillin2. Benzylpenicillin3. Flucloxacillin4. Amoxicillin5. Ampicillin6. Co-amoxiclav (Augmentin)7. Co-fluampicil (Magnapen)8. Piperacillin + Tazobactam (Tazocin)9. Ticarcillin + Clavulanic acid (Timentin)

Macrolides Erythromycin 1st macrolide used clinically newer examples Clarithromycin and Azithromycin. Act by (- -) bacterial protein synthesis by blocking translocation (Bacteriostatic in nature, but also depends on dose and type of organism). Mechanism of resistance Post-transcriptional Methylation of the 23S bacterial ribosomal RNA Erythromycin used in gastroparesis as it has prokinetic properties (↑↑Gastric emptying )

Adverse effects1. GIT "Common" Nausea is less common with clarithromycin than erythromycin2. Cholestatic jaundice risk ↓↓ if erythromycin stearate is used3. (- -) P450 4. Azithromycin is associated with hearing loss and tinnitus

Common interactions1. Statins stopped W Macrolides (significantly ↑↑↑risk of myopathy and rhabdomyolysis)

(- -) cytochrome P450 isoenzyme CYP3A4 (Metabolises statins).2. potentially interact with amiodarone, warfarin

QuinolonesWorks by (- -) DNA synthesis and are bactericidal in nature. Examples include:

1. ciprofloxacin2. levofloxacin

Mechanism of action (- -) topoisomerase II (DNA gyrase) and topoisomerase IV

Mechanism of resistanceMutations to DNA gyrase, (efflux pumps ↓↓ intracellular quinolone concentration)

Adverse effects1. ↓↓ seizure threshold in patients with epilepsy2. Tendon damage (including rupture) - ↑↑↑ risk W steroids (treatment being 8 days before problems occur)3. Cartilage damage (animal models generally avoided (but not necessarily contraindicated) in children4. lengthens QT interval

Contraindications1. Pregnancy or breastfeeding2. G6PD

Gentamicin Aminoglycoside antibiotic poorly lipid-soluble therefore given parentally (Infective endocarditis) or topically (Otitis externa).

Adverse effects1. Ototoxicity

due to auditory or vestibular nerve damage irreversible

2. Nephrotoxicity accumulates in renal failure the toxicity is 2ry to acute tubular necrosis (direct damage to the renal tubules) concomitant use of furosemide ↑↑risk ↓↓ doses and ↑↑monitoring is required

Contraindications Myasthenia gravisDosing

1. significant ototoxic and nephrotoxic potential monitor plasma concentrations2. Measurement Both peak (1 hour after administration) and trough levels (just before the next dose)

if the trough (pre-dose) level is high ↑↑ interval between the doses if the peak (post-dose) level is high ↓↓ dose

Tuberculosis: drug side-effects and mechanism of actionRifampicin Isoniazid Pyrazinamide Ethambutol inhibits RNA synthesis

(- -) bacterial DNA dependent RNA polymerase prevent transcription of DNA into mRNA

1. (++) P450 2. Hepatotoxicity3. Orange secretions 4. flu-like symptoms

(- -) mycolic acid synthesis

1. peripheral neuropathys add pyridoxine (Vitamin B6)

2. (- -)P4503. Hepatotoxicity4. Agranulocytosis

Converted by pyrazinamidase into pyrazinoic (- -) fatty acid synthase (FAS) I

1. Hepatotoxicity1. Uric acid  gout2. Arthralgia, myalgia

(- -) arabinosyl transferase Enz (polymerizes arabinose into arabinan)

Optic neuritischeck visual acuity before & during treatment

Dose adjusting in renal impairment

Alcohol - problem drinkingS/E

1. Excessive alcohol develop Polyurea ↓↓Ca ++ -dependent secretion of (ADH ) by blocking channels in neurohypophyseal nerve terminal.2. Nausea associated with hangovers vagal stimulation to the Vomiting Centre . 3. severe episode of alcohol may experience tremors ↑↑ glutamate production by neurones to "compensate for the previous inhibition by ethanol".

ManagementNutritional supportAlcoholic patients should receive oral thiamine if their 'diet may be deficient'

Drugs used1. Acute withdrawal Benzodiazepines. 2. Promotes abstinence Disulfram

Alcohol intake S evere reaction due to (- -) acetaldehyde dehydrogenase . Even small amounts of alcohol (Perfumes, Foods, Mouthwashes) can produce severe symptoms. CI/ IHD and psychosis

3. ↓↓↓ Craving Acamprosate A weak antagonist of NMDA receptors , improves abstinence

Ethylene glycol toxicitya type of alcohol used as a Coolant OR Antifreeze. Features of toxicity are divided into 3 stages:

1. Stage 1 : symptoms similar to alcohol intoxication Confusion, Slurred speech, Dizziness2. Stage 2 :   metabolic acidosis + high anion gap and high osmolar gap + Also tachycardia + hypertension3. Stage 3: AKI

Management has changed in recent times1. Fomepizol e, (Inhibitor of alcohol dehydrogenase now used first-line in preference to ethanol

2. Ethanol (Traditionally used ) Compete with Ethylene Glycol for the enzyme Alcohol dehydrogenaseThis ↓↓↓ Toxic metabolites (glyceraldehydes and glycolic acid) responsible for the haemodynamic/metabolic features of poisoning

3. Haemodialysis refractory cases (Metaboloic acidosis)

DD. Methanol poisoning similar fashion, but with visual disturbance and occasionally blindness. Treated with Fomepizole.

Methanol poisoning Methanol poisoning effects (Alcohol "Intoxication, Nausea" + Specific visual problems (blindness, Macular edema) 2ry to accumulation of formic acid. The actual pathophysiology of visual loss is not understood but thought caused by a form of optic neuropathy (Accumulation of metabolites in the nerv) Metabolic Acidosis W ↑↑ anion gap

Management1. Fomepizole (competitive inhibitor of alcohol dehydrogenase) or Ethanol2. Haemodialysis

Paracetamol overdose: management Potentially toxic dose of Paracetamol (>75mg/kg ) Complications of overdose

1. Hepatotoxicity (Metabolic pathways) The liver normally conjugates paracetamol with glucuronic acid/sulphate.

Overdose conjugation system saturated Oxidation by P450 mixed function Oxidases ↑↑Toxic metabolite (N-acetyl-B-benzoquinone imine "NAPQI" Normally glutathione acts as a defence mechanism by conjugating with the toxin (Non-toxic mercapturic acid). If glutathione stores run-out, the toxin forms covalent bonds with cell proteins, denaturing them and leading to cell death. This occurs not only in hepatocytes but also in the renal tubules N-acetyl cysteine is a precursor of glutathione  ↑↑ hepatic glutathione production (Replenish Glutathione)

Factors ↑↑ risk of hepatotoxicity Treated on lower threshold (↑↑Toxic metabolites) liver enzyme-inducing Drugs (rifampicin, phenytoin, carbamazepine, St John's Wort) History of chronic alcohol excess Malnourished patients (Anorexia nervosa) or not eaten for a few days, due to depletion of glutathione.

Factors not ↑↑ risk of hepatotoxicity Acute alcohol intake and may actually be protective (- -) CYP2E1, preventing oxidising paracetamol to the toxic metabolite

2. Delayed nephrotoxicity especially in significant overdose Follow up ↑↑ KFTs

Treatment Within 1 hour "minority" activated charcoal ↓↓ absorption of the drug. Acetylcysteine should be given if:

1. Staggered overdose or Doubt over the time of ingestion, (regardless of the plasma paracetamol concentration)2. Concentration ≥ single treatment line (100 mg/L at 4 hours) and (15 mg/L at 15 hours), (regardless of risk factors of hepatotoxicity)

Acetylcysteine infused over 1 hour ↓↓adverse effects.  Commonly causes an anaphylactoid reaction (non-IgE mediated mast cell release).  Treatment stopping the infusion, then restarting at a slower rate.

Criteria for liver transplantation (paracetamol liver failure)1. Arterial pH < 7.3, 24 hours after ingestion2. OR all of the following:

PT > 100 seconds

Creatinine > 300 µmol/l

Grade III or IV encephalopathy

Acute intermittent porphyria: drugsAD defect in Porphobilinogen deaminase, (enzyme involved in the biosynthesis of haem. It characteristically presents with abdominal and neuropsychiatric symptoms in 20-40 year olds. ↑↑females (5:1)

Drugs which may precipitate attack Drugs considered safe to use1. alcohol2. Barbiturates3. Benzodiazepines4. Halothane5.  Thiopental Na6. Oral contraceptive pill7. sulphonamides

1. Aspirin2. Beta-blockers3. codeine4. morphine5. chlorpromazine6. metformin7. paracetamol8. penicillin

Adrenoceptor agonistsAlpha-1 agonists

1. vasoconstriction (Skin, kidney , mucous membrane)2. relaxation of GI smooth muscle3. Salivary secretion4. Hepatic glycogenolysis5. Phenylephrine

Alpha-2 agonists clonidine

Beta-1 agonists dobutamine

Beta-2 agonists salbutamol

Beta-3 agonists being developed, may have a role in preventing obesity (stimulation causes lipolysis)

Alpha antagonists alpha-1 Doxazosin (Treatment of hypertension and benign prostatic hypertrophy

alpha-1a Tamsulosin - acts mainly on urogenital tract

alpha-2 yohimbine non-selective phenoxybenzamin e (previously used in peripheral arterial disease)

Beta antagonists   Beta-1 Atenolol Beta-2 Phentolamine. Non-selective Propranolol

Mixed alpha and beta antagonists Carvedilol Labetalol

AdrenalineSympathomimetic amine with both alpha and beta adrenergic stimulating properties. Indications

1. anaphylaxis 0.5ml 1:1,000 IM2. cardiac arrest 1ml of 1:1000 IV (10ml 1:10,000 IV)

Management of accidental injection local infiltration of phentolamine

short acting alpha blocker, It is normally used mainly to control blood pressure during surgical resection of phaeochromocytoma

Background responsible for the fight or flight response released by the adrenal glands acts on α 1 and 2, β 1 and 2 receptors acts on β 2 receptors in skeletal muscle vessels-causing vasodilation increases cardiac output and total peripheral resistance causes vasoconstriction in the skin and kidneys causing a narrow pulse pressure

Actions on α adrenergic receptors:  (- -) insulin secretion by the pancreas stimulates glycogenolysis in the liver and muscle stimulates glycolysis in muscle

Actions onβ adrenergic receptors: stimulates glucagon secretion in the pancreas stimulates ACTH stimulates lipolysis by adipose tissue

Induces Hyperglycemia, Hyperlactatemia and Hypokalaemia. insulin secretion is suppressed by alpha adrenergic stimulation Hyperglycemia by ↑↑ hepatic glycogenolysis and gluconeogenesis. In skeletal muscle, epinephrine ↑↑ glycolysis and glycogenolysis ↑↑ lactate (serves as a substrate for hepatic neoglucogenesis (Cori cycle). There is also a marked increase in oxygen consumption. Epinephrine also increases lipolysis and decreases muscular proteolysis.

Dopamine receptor agonistsIndications

1. Parkinson's disease delay treatment until the onset of disabling symptoms

elderly, L-dopa is sometimes used as an initial treatment

2. Prolactinoma/Galactorrhoea3. Acromegaly4. Cyclical breast disease

Overview Ex: Bromocriptine, Ropinirole, Cabergoline, Apomorphine Ergot-derived dopamine receptor agonists (Bromocriptine, Cabergoline, Pergolide "valvular dysfunction ")  pulmonary, retroperitoneal and cardiac fibrosis. ESR, Creatinine and chest x-ray (Prior to treatment and closely monitored)

Adverse effects1. Nausea/Vomiting (++) brain Vomiting Centre2. Postural hypotension3. Hallucinations4. Daytime somnolence

Drugs which act on serotonin receptors Drugs act via modulation of the serotonin ( 5-HT ) system. It should be noted that 5-HT receptor agonists are used in the acute treatment of migraine whilst 5-HT receptor antagonists are used in prophylaxis.

Agonists Antagonists1. Sumatriptan acute treatment of migraine2. Ergotamine partial agonist of 5-HT1 receptors

1. Pizotifen prophylaxis of migraine attacks. 2. Methysergide rarely used due to the risk of retroperitoneal fibrosis3. Cyproheptadine control diarrhoea in patients with carcinoid syndrome4. Ondansetron antiemetic

Serotonin syndromeCauses

Monoamine oxidase inhibitors SSRIs

St John's Wort, often taken over the counter for depression, can interact with SSRIs to cause serotonin syndrome The combination of two or more serotonergic medications greatly increases the risk

Ecstasy amphetamines

Features Neuromuscular excitation (Hyperreflexia, myoclonus, rigidity Spasticity) autonomic nervous system excitation (hyperthermia) altered mental state Dilated pupil.

Management supportive including IV fluids Benzodiazepines Severe cases serotonin antagonists (Cyproheptadine and Chlorpromazine)

St John's Wort Effective as tricyclic antidepressants in the treatment of mild-moderate depression

Mechanism similar SSRIs + noradrenaline uptake inhibition) Should not be prescribed because of uncertainty about appropriate doses, variation of preparations, and potential serious interactions with other drugs'

Adverse effects 1. S/Es in trials similar to placebo2. Serotonin syndrome3. (++) P450 system, ↓ levels of drugs (Warfarin, Ciclosporin, COCP)

Octreotide Long-acting analogue of somatostatin (from D cells of pancreas (- -) GH, Glucagon and Insulin). Uses

1. acute treatment of variceal haemorrhage2. Acromegaly3. Carcinoid syndrome"1st line", Also Cyprohiptadine can be used.4. VIPomas5. refractory diarrhoea6. Prophylaxis Prevent complications following Pancreatic Surgery

Adverse effects Gallstones & Billiary Colic (2ry to biliary stasis)

Antiarrhythmic s The Vaughan Williams classification

Class Examples Mechanism of action NotesIa 1. Quinidine

2. Procainamide3. Disopyramide

Block sodium channels ↑↑AP duration

Quinidine toxicity cinchonism (headache, tinnitus, thrombocytopaenia) Procainamide drug-induced lupus

Ib 1. Lidocaine Block sodium channels

Class Examples Mechanism of action Notes2. Mexiletine3. Tocainide

↓↓ AP duration

Ic 1. F lecainide2. Encainide3. Propafenone

Block sodium channels No effect on AP duration

II 1. Propranolol2. Atenolol3. Bisoprolol4. Metoprolol

Beta-adrenoceptor antagonists

III 1. Amiodarone2. Sotalol3. Ibutilide4. Bretylium

Block potassium channels

IV 1. Verapamil 2. Diltiazem

Calcium channel blockers

Flecainide 1c Ant arrhythmic ↓↓conduction of the action potential by acting as a potent   Na channel blocker (specifically the Nav1.5 Na channels).

This may be reflected by ↑↑ QRS complex and ↑↑PR interval. Indications1. AF 2. SVT W\ Accessory pathway ( WPW )

Contraindications   1. Post MI ↑↑Mortality 2. Structural heart disease (Heart Failure)3. sinus node dysfunction 2nd-degree or greater AV block

4. Atrial Flutter

Adverse effects1. -Ve Inotropic2. Bradycardia3. Proarrhythmic4. Oral Paraesthesia5. Visual disturbances

Procainamide works in a similar way to flecainide but instead induces a rapid blocking of the batrachotoxin activated sodium channels rapidly

Beta-blockersIndications

1. angina2. post-myocardial infarction3. heart failure certain beta-blockers improve both symptoms and mortality4. arrhythmias rate-control drug of choice in atrial fibrillation5. Hypertension6. Thyrotoxicosis7. Migraine prophylaxis8. Anxiety

Examples Atenolol Propranolol: one of the first beta-blockers to be developed. Lipid soluble therefore crosses the blood-brain barrier

Side-effects1. bronchospasm2. cold peripheries

3. fatigue4. Sleep disturbances, including nightmares5. erectile dysfunction

Contraindications1. uncontrolled heart failure2. asthma3. sick sinus syndrome4. concurrent verapamil use: may precipitate severe bradycardia

Beta-blocker overdos e Features

1. Bradycardia2. Hypotension3. Heart failure4. Syncope

Management1. Bradycardic atropine2. Resistant cases Glucagon (+ Ve inotropic action on the heart and ↓↓ renal vascular resistance. 3. Cardiac pacing reserved for patients unresponsive to pharmacological therapy4. Haemodialysis is not effective in beta-blocker overdose

AmiodaroneClass III antiarrhythmic block K channels ↓ repolarisation prolongs the action potential. other actions blocking Na channels ( class I effect)

(Atrial, nodal and ventricular tachycardias) Very long half-life (20-100 days). → loading doses are frequently used Given into central veins (causes thrombophlebitis) Proarrhythmic ↑↑QT interval Coexistent hypokalaemia significantly increases this risk.

interacts with (p450 inhibitors) Decreases metabolism of warfarin TFT, LFT, U&E(K check), CXR prior to treatment TFT, LFT every 6 months

Adverse effects of amiodarone use1. thyroid dysfunction both hypothyroidism   and   hyper-thyroidism 2. Corneal deposits3. Pulmonary fibrosis/pneumonitis4. liver fibrosis/hepatitis5. peripheral neuropathy, myopathy6. photosensitivity7. 'slate-grey' appearance8. Thrombophlebitis and injection site reactions9. Bradycardia10. ↑↑ QT interval

Amiodarone and the thyroid gland1 in 6 patients taking amiodarone thyroid dysfunction

1. Amiodarone-induced hypothyroidism Due to ↑↑ iodine content of amiodarone "Wolff-Chaikoff effect" (↑↑Iodine ↓↓Thyroxin) Tyroxine replacemen t + Amiodarone may be continued if this is desirable VT

2. Amiodarone-induced Thyrotoxicosis AIT type 1 AIT type 2

Pathophysiology ↑↑↑ iodine-induced thyroid hormone synthesis Amiodarone-related destructive thyroiditisGoitre Present AbsentManagement Carbimazole or K+ perchlorate CorticosteroidsUnlike in AIH, amiodarone should be stopped if possible in patients who develop AIT

Calcium channel blockers Management of CVS disease. Voltage-gated calcium channels are present in (Myocytes, cells of the conduction system and vascular smooth muscle cells).

Examples Indications & notes Side-effects and cautionsVerapamil Angina, hypertension, arrhythmias 

Highly negatively inotropicShould not be given with beta-blockers as may cause heart block

Heart failurehypotension, Bradycardic, dyspepsia (relax lower oesophageal sphincter)flushing constipation

Diltiazem Angina, hypertension Less negatively inotropic but caution W C heart failure or are taking beta-blockers

Hypotension,bradycardia,heart failure, ankle swelling

Nifedipine, amlodipine, felodipine (dihydropyridines)

Hypertension, angina, Raynaud'sAffects the peripheral vascular smooth muscle > myocardium (Not worsening of heart failure)

Flushing, headache, ankle swelling

Atropineantagonist of the muscarinic acetylcholine receptor.treatment of organophosphate poisoningtachycardia, mydriasis

AdenosineTerminate SVT. ↑ by Bupivicaine and dipyridamole  (antiplatelet agent) and ↓by theophyllines.

Mechanism of actioncauses transient heart block in the AVN, agonist of A1 receptor in the AVN, which ↓ adenylyl cyclase ↓ cAMP hyperpolarization by ↑ outward K flux.

short half-life (8-10 sec) infused via a large cannula 

Adverse effectschest pain, bronchospasm avoided in asthmatics , transient flushing, enhance conduction down accessory pathways (e.g. WPW syndrome)

Phosphodiesterase type V inhibitors PDE5 inhibitors cause V.D through an   increase in cGMP   smooth muscle relaxation in blood vessels supplying the corpus cavernosum Used in the treatment of erectile dysfunction & pulmonary hypertension. Examples

1. Sildenafil (Viagra) - this was the first phosphodiesterase type V inhibitor2. Tadalafil (Cialis)3. Vardenafil (Levitra)

Contraindications1. patients taking nitrates and related drugs such as nicorandil2. Doxazosin avoiding alpha-blockers for 4 hours after sildenafil3. Hypotension4. Recent   stroke  or MI (waiting 6 months)

Side-effects visual disturbances (blue discolouration, non-arteritic anterior ischaemic neuropathy Nasal congestion Flushing GIT S/E Headache

Nicorandila vasodilatory drug used to treat angina.

It is a potassium-channel activator with vasodilatation is through activation of guanylyl cyclase ↑↑ cGMP.

Adverse effects headache flushing anal ulceration

Contraindications left ventricular failure

Blood Thinners

Adenosine diphosphate (ADP) receptor inhibitors Clopidogrel

Prasugrel

Ticagrelor

Ticlopidine

Mechanism (ADP) is platelet activation factors, +++ by G-coupled receptors P2Y1 and P2Y12 sustained platelet aggregation and stabilization of the plaque. ADP receptor.

inhibitors drugs blocks P2Y12 receptor.

ACS undergoing PCI Aspirin (75-100mg daily) + prasugrel (10mg daily), ticagrelor (90mg twice daily), or clopidogrel (75mg daily, if prasugrel or ticagrelor are not suitable) for 12 months, with aspirin alone thereafter

S/Eticagrelor may cause dyspnoea due to the ↓ clearance of adenosine

Interactions and contraindications Clopidogrel and proton pump inhibitors, particularly omeprazole and esomeprazole Prasugrel absolute contraindications prior stroke or TIA, high risk of bleeding, and hypersensitivity

Ticagrelor contraindicated in a high risk of bleeding, history of intracranial haemorrhage, and hepatic dysfunction. caution in those with acute asthma or COPD, higher rates of dyspnoea.  if his clinical condition allows you are able to wait 3–4 days to observe the patient and understand whether the dyspnoea is transient or more longer lasting

Mechanism block effects of angiotensin II at the AT1 receptor ↓ progression of renal disease in patients with diabetic nephropathy losartan ↓↓ CVA and IHD mortality in hypertensive patients

Aspirin Irreversable block cyclooxygenase-

1 and 2 (responsible for prostaglandin, prostacyclin and thromboxane synthesis).

(- -) Thromboxane A2 (V.C & platlet adhesion) in platelets ↓↓ ability of platelets to aggregate

Recently aspirin is not licensed for routine primary prevention. first-line for patients with IHD DD.( clopidogrel first-line ischaemic stroke and PAD) Dental practice not to stop Aspirin

Diagnosis 1st line 2nd lineACS(medically) ASA (lifelong) & ticagrelor (1Y) If aspirin CI→ clopidogrel (lifelong)

PCI ASA (lifelong) & prasurgrel or ticagrelor (1 y) If aspirin CI →clopidogrel (lifelong)TIA ASA (lifelong) Aspirin (lifelong) & dipyridamole (lifelong)

Ischemic stroke Clopidogrel (lifelong) Aspirin (lifelong) & dipyridamole (lifelong)

PAD Clopidogrel (lifelong) Asprin (lifelong)

Potentiates1. Oral hypoglycaemics2. warfarin3. steroids

CI children < 16 (risk of   Reye's syndrome ). An exception is Kawasaki disease (benefits outweigh the risks.

Selective COX 2 inhibitors (NSAID) directly targets Cyclooxygenase-2 ↓↓ inflammation and pain, (No GIT ulcer, ↑↑Platelet aggregation ↑↑ CVS risk )

Salicylate overdose A key concept salicylate overdose mixed respiratory alkalosis and metabolic acidosis. Early (++) "Respiratory Centre" respiratory alkalosis  Later (Direct acid effects salicylates + acute renal failure)  acidosis. In children metabolic acidosis tends to predominate. Features

1. Hyperventilation (centrally stimulates respiration)2. Tinnitus3. Lethargy, Sweating4. Pyrexia

Salicylate causes uncoupling of oxidative phosphorylation ↓↓ ATP production, ↑↑(O2 consumption and CO2) and heat production

5. nausea/vomiting6. Dysregulation of glucose hyperglycaemia and hypoglycaemia7. seizures8. coma

Treatment1. General

ABC

Charcoal first-line in patients who have ingested the drug within one hou r 2. urinary alkalinization (IV sodium bicarbonate - enhances elimination of aspirin in the urine3. Haemodialysis "Indications'

Serum concentration > 700mg/L Metabolic acidosis resistant to treatment Acute renal failure Pulmonary oedema Seizures Coma

Heparin heparin Generally activate antithrombin III, 2 main types :

1. Unfractionated heparin forms a complex (--) thrombin, factors Xa, IXa, XIa and XIIa. 2. LMWH only ↑↑↑ action of antithrombin III on factor Xa

Adverse effects 1. Bleeding2. Thrombocytopenia - see below3. Osteoporosis and an increased risk of fractures4. ↑↑ K+ caused by (- -) aldosterone secretion

Standard heparin Low molecular weight heparin (LMWH)Administration IV S.CDuration Short LongSide-effects 1. Bleeding

2. Heparin-induced thrombocytopaenia (HIT)3. Osteoporosis

1. Bleeding2. Lower risk of HIT and osteoporosis with LMWH

Monitoring (APTT) Anti-Factor Xa (routine monitoring is not required)Notes Useful in ↑↑ risk of bleeding (terminated rapidly standard management of VTE treatment

Standard heparin Low molecular weight heparin (LMWH) Also useful in renal failure prophylaxis ACS

Heparin-induced thrombocytopaenia (HIT)1. After 5-10 days of treatment2. Immune mediated - antibodies against complexes of platelet factor 4 (PF4) and heparin (++) platelet activation by cross-linking FcγIIA receptors3. Prothrombotic condition Thrombosis and skin allergy4. > 50% ↓↓ platelets5. Treatment alternative anticoagulants Lepirudin and Danaparoid

Dipyridamole antiplatelet mainly used in combination with aspirin after an ischaemic stroke or TIA. Non-↓↓ phosphodiesterase, (normally break down cAMP), but particularly active against PDE5 (like sildenafil) and PDE6 ↑↑ platelet cAMP ↓↓intracellular Ca +

levels ↓↓ cellular uptake of adenosine  ↑↑ adenosine effect (Exogenous use of adenosine (ttt SVT) CI in patients on dipyridamole for this reason.  inhibition of thromboxane synthase

Anti- LipidDrugs Mechanism of action Adverse effects

Statins HMG Co-A reductase (- -) Myositis, ↑↑ LFTsNicotinic Acid (H + ) ↓↓ Hepatic VLDL Secretion Flushing, Myositis

FibRates Agonist of PPAR-alpha ++ lipoprotein lipase expression Myositis, Pruritus, CholestasisCholectyramine ↓↓ bile acid reabsorption in small intestine

Up regulating the amount of cholesterol that is converted to bile acidGI side-effects

Ezetimibe ↓↓Cholesterol absorption in the small intestine HeadacheNicotinic acid (niacin)

Treatment of patients with hyperlipidaemia limited by side-effects. ↑↑ HDL levels. ↓↓ Cholesterol and triglyceride concentrations

Adverse effects1. Flushing: mediated by prostaglandins2. Myositis Not to be used W Statin 3. ↓↓ glucose tolerance

Allopurinol Prevention of gout works by inhibiting xanthine oxidase.

1. should not be started until 2 weeks after an acute attack has settled (Symptoms settle)2. initial dose 100 mg od, every few weeks to aim for a serum uric acid of < 300 µmol/l3. NSAID or colchicine cover should be used when starting allopurinol

Indications for allopurinol1. Recurrent attacks started if a second attack, or further attacks occur within 1 year'2. Tophi 3. Renal disease4. uric acid Renal stones5. Prophylaxis

Cytotoxics prevent tumer lysis syndrome (lymphoma) Diuretics

6. Patients with Lesch-Nyhan syndrome often take allopurinol for life

Adverse effectsmost significant are dermatological stop allopurinol immediately if they develop a rash:

1. Severe cutaneous adverse reaction (SCAR)2. Drug reaction with eosinophilia and systemic symptoms (DRESS)

Patients at a high risk of severe cutaneous adverse reaction should be screened for the HLA-B 5801 allele. Diuretic use Ethnicity (Thai Chinese, Korean descent) Chronic kidney disease.

3. Stevens-Johnson syndrome

Interactions1. Azathioprine

metabolised to active compound 6-mercaptopurine Xanthine oxidase responsible for the oxidation of 6-mercaptopurine to 6-thiouric acid Allopurinol ↑↑6-mercaptopurine Much ↓↓ dose (25%) must if the combination cannot be avoided

2. Cyclophosphamide Allopurinol ↓↓ renal clearance may cause marrow toxicity

3. Theophylline allopurinol causes ↑↑plasma concentration of theophylline by inhibiting its breakdown

Botulinum toxinlicensed indications:

1. Cosmetic2. Blepharospasm3. Hemifacial spasm (UMNL Not Bells palsy )4. Focal spasticity cerebral palsy patients, hand and wrist disability associated with stroke5. Spasmodic torticollis6. Severe hyperhidrosis of the axillae7. Achalasia patient is not suitable for surgical intervention (for example in some elderly patients)

Caustic substance ingestionThe majority of cases are accidental exposures to household products: these are usually of little clinical consequence. Conversely, significant morbidity can occur when the substance is consumed in larger quantities with the intention of deliberate self-harm. Types of substance (vital to obtain bottle/label if possible)

Strong alkali Strong acid Oxidising agents Na + Hydroxide , K + Hydroxide (Dishwasher cleaner, industrial cleaners) Liquefactive necrosis (↑↑oesophageal injury)

Hydrochloric Acid , Nitric Acid car batteries, WC cleaner Coagulative necrosis (↑↑ gastric injury)

Hydrogen peroxid e, Na + hypochlorite Household bleac h

Acute management  (general principles, local guidance on timing of endoscopy and PPI may vary)

ABCDE approach (caution to airway swelling and compromise, look for peri-oral oedema) Urgent upper GI surgical referral

if signs of perforation present (surgical emphysema, mediastinal widening on chest x-ray) deally within 12 hours (sometimes 24 hours dependent on local guidance). IF wait until after the initial insult recovered avoid endoscopy between days 5 and 15 post ingestion (oesophageal strength is at its lowest) Symptomatic ingestion (drooling, vomiting, dysphagia, odynophagia, chest pain) urgent assessment with upper GI endoscopy to assess the

degree of ulceration (Zargar classification). Extensive injury on endoscopy prompt consideration of urgent surgical exploration.

↑↑ dose IV PPI Avoid nasogastric tube potential re-exposure of the upper GI tract to the substance. Avoid neutralisation of ingested substance (with milk) exothermic reaction will release heat and may cause further injury Oral fluid and observation then discharge in asymptomatic patients (No odynophagia)

Complications1. Acute

Upper GI ulceration, perforation Upper airway injury and compromise Aspiration pneumonitis Infection Electrolyte disturbance (hypocalcaemia in hydrofluoric acid ingestion)

2. Chronic

Strictures, fistulae, gastric outlet obstruction Upper GI carcinoma (1000-3000 fold)

combined oral contraceptive pill Advantages Disadvantages1. highly effective (failure rate < 1 per 100 woman years)2. doesn't interfere with sex3. contraceptive effects reversible upon stopping4. Periods regular, lighter and less painful5. ↓↓ovarian cysts, benign breast disease, acne vulgaris6. ↓↓ risk (Ovarian, Endometrial Cancer  (last for decades after cessation7. ↓↓colorectal cancer8. Protect against PID

1. forget to take it2. No protection against STI3. ↑↑↑ VTE 4. ↑↑↑ Breast and cervical cancer5. ↑↑↑stroke and IHD (especially in smokers)6. Temporary (Headache, Nausea, Breast tenderness) 7. Weight gain (Controversial)

Contraindications according to a four point scale, as detailed below:1. UKMEC 1 No restriction for the use of the contraceptive method2. UKMEC 2 advantages > disadvantages3. UKMEC 3 disadvantages > advantages4. UKMEC 4 unacceptable health risk

UKMEC 3 conditions UKMEC 4 conditions 1. > 35 years + smoking (< 15 /day)2. BMI > 35 kg/m^2*3. "1st degree relatives < 45 years" + thromboembolic disease 4. Controlled HTN5. Carrier gene mutations associated with breast cancer

(BRCA1/BRCA2)6. current gallbladder disease7. Immobility (wheel chair use)

1. > 35 years + smoking (>15 /day)2. migraine with aura3. history of thromboembolic diseas e OR thrombogenic mutation4. History of stroke OR IHD 5. uncontrolled hypertension6. Current breast cancer7. Breast feeding < 6 weeks post-partum8. Cervical cancer is not a contraindication to use . 

(COCP small increase in cervical cancer risk after 5 years & ↑↑2-fold risk after 10 years.

9. Major surgery with prolonged immobilisation

Diabetes mellitus diagnosed > 20 years ago is classified as UKMEC 3 or 4 depending on severity breast feeding 6 weeks - 6 months postpartum was changed from UKMEC 3 → 2 Weight Gain is not ↑↑ supported

Concurrent antibiotic use1. Antibiotics may interfere

Affect enterohepatic circulation of oestrogen make pills ineffective antibiotics might ↓↓absorption of the pill 'extra- precautions'/ barrier methods for the duration of antibiotic treatment and for 7 days afterwards

2. precautions should still be taken with enzyme inducing antibiotics (Rifampicin and Rifaximin)

Switching combined oral contraceptive pills Contradictory advice.

pill free interval does not need to be omitted missing the pill free interval if the progesterone changes. (more recommended)

Progestogen only pill: advantages/disadvantagesAdvantages Disadvantages

1. ↑↑↑ effective (failure rate = 1 per 100 woman years)

2. doesn't interfere with sex3. Reversible upon stopping4. can be used whilst breast-feeding5. Used when COCP pill is CI

Smokers > 35 Ys History of VTE

1. Irregular periods May not have periods , Irregular OR Light periods.(Most common)

This is the most common S/E2. Doesn't protect against STI3. ↑↑ Incidence of functional ovarian cysts . 4. Common S/E

Breast tenderness weight gain

Acne Headaches

These symptoms generally subside after the first few months

Tamoxifen Selective oEstrogen Receptor Modulator (SERM)  oestrogen receptor antagonist and partial agonist. It is used in the management of oestrogen receptor positive breast cancer. Adverse effects

1. Menstrual disturbance vaginal bleeding, amenorrhoea2. Hot flushes - 3% of patients stop taking tamoxifen due to climacteric side-effects3. VTE4. Endometrial cancer5. Osteoporosis

Tamoxifen is typically used for 5 years following removal of the tumour. Raloxifene is a pure oestrogen receptor antagonist, and carries a lower risk of endometrial cancer

TeratogensDrug/condition Effect

ACE inhibitors Renal dysgenesis Craniofacial abnormalities

1. Carbamazepine2. Valproate

Neural tube defects Craniofacial abnormalities

Warfarin Craniofacial abnormalities1. Cocaine2. Smoking

IUGR Preterm labour

Aminoglycosides OtotoxicityChloramphenicol 'Grey baby' syndrome

Drug/condition EffectTetracyclines Discoloured teethDiethylstilbesterol Vaginal clear cell adenocarcinoma

Lithium Ebstein's anomaly (atrialized right ventricle)Thalidomide Limb reduction defectsMaternal diabetes mellitus 1. Macrosomia

2. Neural tube defects3. Caudal regression syndrome4. Polyhydramnios5. Preterm labour

Digoxin Cardiac glycoside rate control (AF) + positive inotropic properties improving symptoms (but not mortality) in patients with heart failure.

↓↓ conduction AV node slows the ventricular rate in atrial fibrillation and flutter ↑↑ cardiac muscle contraction (- -) Na + /K + ATPase pump on the same site as potassium Hypokalaemia ↑↑ inhibitory effects Cause short QT interval Also (++) vagus nerve digoxin has a narrow therapeutic index

Monitoring & Toxicity 1. digoxin level is not monitored routinely, except in suspected toxicity (within 8 to 12 hours of the last dose)2. Plasma concentration alone does not determine digoxin toxicity (Might occur within the therapeutic range). 3. likelihood of toxicity (↑↑ progressively from 1.5 to 3 mcg/l.)

Features1. generally unwell, lethargy, nausea & vomiting, anorexia, confusion, yellow-green vision2. Arrhythmias (AV block, bradycardia)3. Gynaecomastia

Precipitating factors1. Classically: Hypokalaemia

Hypokalaemia → digoxin more easily bind to the ATPase pump → increased inhibitory effects2. ↑↑ age3. Renal failure4. Myocardial ischaemia5. ↑↑ (Ca, Na, H) Hypercalcaemia, Hypernatraemia, Acidosis6. ↓↓Mg++ 7. ↓↓ Abumin8. ↓ ↓Temperature 9. ↓↓ Thyroid10. Drugs

Anti-arrhythmic  Amiodarone, Quinidine, Verapamil, Diltiazem Spironolactone (competes for secretion in distal convoluted tubule therefore reduce excretion) Thiazides and Loop diuretics (Hypokalaemia) Ciclosporin.

Management1. Digibind2. correct arrhythmias3. monitor potassium

Dieuritics ACE inhibitors

first-line treatment in younger patients with hypertension, heart failure, less effective Afro-Caribbean patients, diabetic nephropathy and have a role in the secondary prevention of ischaemic heart disease.Mechanism of action:

inhibit the conversion angiotensin I to angiotensin II

ACE inhibitors are activated by phase 1 metabolism in the liver

Side-effects: Cough around 15% up to a year after starting treatment increased bradykinin levels angioedema: may occur up to a year after starting treatment

hyperkalaemia

first-dose hypotension: more common in patients taking diuretics (Giddy = Syncope)Cautions and contraindications

pregnancy and breastfeeding - avoid renovascular - significant renal impairment undiagnosed bilateral renal artery stenosis

AS - may result in hypotension

hereditary of idiopathic angioedema

specialist advice ACE inhibitors in patients with K >= 5.0 mmol/LInteractions

Hypotension high-dose diuretic therapy > 80 mg of furosemide a day)Monitoring

U/E initially and after increasing the dose

a rise in the creatinine and K may be after starting, acceptable ↑ in creatinine, up to 30%, ↓ GFR of up to 25%   from baseline and an ↑ in K up to 5.5 mmol/l*.

K> 6mmol/L should prompt cessation of ACE I in a patient with CKD (1st step)

Angiotensin II receptor blockerssituations where patients have not tolerated an ACEI, due to cough. candesartan, losartan, irbesartan

S/E hypotension and hyperkalaemia . used with caution in patients with renovascular disease.

Hypomagnesaemia Cause of low magnesium

1. Alcohol2. Drugs

Diuretics Loop or Thiazide Proton pump inhibitors "Omeprazole" when with Loop or Thiazide diuretics but are Not independently associated with hypomagnesaemia.

3. Diarrhoea4. Conditions causing diarrhea Crohn's, ulcerative colitis5. Total Parenteral nutrition Refeeding Syndrome. 6. ↓↓ (K+, Ca++) Causes resistance for correction 7. Metabolic disorders Gitleman's and Bartter's

Features may be similar to hypocalcaemia:1. Paraesthesia2. Tetany3. Seizures4. Arrhythmias5. ↓↓ PTH secretion → hypocalcaemia6. ECG features similar to those of Hypokalaemia (QT prolongation.)7. ↑↑ Digoxin Toxicity

Treatment1. < 0.4 mmol/l

IV 40 mmol of Mg++ sulphate over 24 hours

2. > 0.4 mmol/l

oral magnesium salts (10-20 mmol orally per day) Diarrhoea can occur with oral magnesium salts  Magnesium salts can be given as "Laxatives".

Other uses (Torsade de Pointes), acute asthma and prevention/treatment of seizures in pre-eclampsia.Lithium toxicity

Lithium is a mood stabilising most commonly prophylactically in bipolar disorder but also as an adjunct in refractory depression. It has a very narrow therapeutic range (0.4-1.0 mmol/L) and a long half-life excreted primarily by the kidneys. Lithium Toxicity generally occurs following concentrations > 1.5 mmol/L  Precipitated by:

1. Renal failure2. Dehydration3. Drugs:

Diuretics (Especially Thiazides" loop diuretics are safer) ACE inhibitors/ARBS

(Both should not be commenced in hypertensive patient on Lithium) NSAIDs Metronidazole.

Features of toxicity1. Coarse tremor (a fine tremor is seen in therapeutic levels)2. Coma3. Acute confusion4. Hyperreflexia5. Seizure

Management1. Mild-moderate toxicity (Apathy and Restlessness) volume resuscitation with normal saline2. Haemodialysis Severe toxicity

Level > 2 mmol/L Neurological symptoms (Seizures, Confusion) Renal failure.

3. Na+ bicarbonate is sometimes used ↑↑ alkalinity of the urine (++) lithium excretion

Tricyclic overdoseAmitryptiline and Dosulepin (dothiepin) are particularly dangerous in overdose. Features

1. Early features relate to anticholinergic properties Dry mouth Dilated pupils Blurred vision . Agitation Sinus tachycardia

2. Features of severe poisoning include: Arrhythmias Seizures Metabolic acidosis Coma

3. ECG changes include : widening of QRS

Widening of QRS > 100ms ↑↑risk of seizures QRS > 160ms is ventricular arrhythmias.

sinus tachycardia prolongation of QT interval

Management1. 50 gm of charcoal if within one hour of ingestion.2. IV bicarbonate

1st-line therapy (50 ml of 8.4%) if

pH < 7.1

QRS > 100 ms

Arrhythmias

Hypotension

3. Other drugs for arrhythmias class 1a (Quinidine) and class Ic (Flecainide) are CI ↑↑ depolarisation class III drugs (Amiodarone) avoided (↑↑QT interval) Response to lignocaine is variable.

4. IV lipid emulsion increasingly used to bind free drug and reduce toxicity (Also Verapamil, BB)5. Dialysis is ineffective in removing tricyclics

Oculogyric crisisA dystonic reaction  form of extrapyramidal disorder to certain drugs or medical conditions. Features

1. Restlessness, Agitation2. involuntary upward deviation of the eyes

Causes Antipsychotics Dopaminergic medications (classically Metoclopramide and Haloperidol) Post encephalitic Parkinson's disease

Management IV Anti-Muscarinic

1. Benztropine 2. Procyclidine3. diphenhydramine

Cocaine Alkaloid derived from the coca plant (recreational stimulant) (XX) the uptake (Dopamine, Noradrenaline and Serotonin) Cardiovascular effects

1. Myocardial infarction2. hypertension3. Aortic dissection4. both tachycardia and bradycardia may occur5. QRS widening and QT prolongation.

Neurological effects1. seizures2. Mydriasis3. Hypertonia, hyperreflexia

Psychiatric effects1. agitation2. psychosis3. hallucinations

Others1. ischaemic colitis following cocaine ingestion. (abdominal pain or rectal bleeding)2. Hyperthermia3. Metabolic acidosis4. Rhabdomyolysis

Management of cocaine toxicity Benzodiazepines generally first-line for most cocaine-related problems Chest pain  (Benzodiazepines + Glyceryl trinitrate). (MI 1ry PCI) Hypertension (benzodiazepines + sodium nitroprusside)

Beta-blockers in cocaine-induced CVS "controversial" risk of unopposed alpha coronary spasm) If a reasonable alternative in an exam choose it

Ecstasy poisoning (MDMA, 3,4-Methylenedioxymethamphetamine) Clinical features

1. CNS agitation, anxiety, confusion, ataxia2. CVS tachycardia, hypertension3. ↓↓↓ Na4. ↑↑ Temperature5. Rhabdomyolysis

Management supportive Dantrolene may be used for hyperthermia if simple measures fail

Novel psychoactive substancesMedical term Recreational drugs (MDMA and Cannabis). Termed as 'Legal Highs'/ "M-CAT"

Stimulants Cannabinoids Hallucinogenic Depressant Other substances Similar to MDMA, Amphetamines ↑↑Serotonin, Dopamine Noradrenaline,

'high' and euphoria

Common Ex 1. "Mephedrone " ('bath salts','M-CAT'.'meow meow').Cathinone similar to khat, a plant in

East Africa2. Benzylpiperazine

('Exodus', 'Legal X', 'Legal E')

"Synthetic Cannabinoid receptor agonists" Referred to as 'spice'

Sprayed on to herbal mixtures smoked.

liquid ( inhaled using e-cigarettes

S/E like cannabis

Dissociatives and Psychedelics

1. Dissociatives similar to ketamine (sense of not being connected to the physical body or time.

Ex: Methoxetamine ('mexxy')

2. Psychedelics Similar

Opioid ORBenzodiazepine-based

1. Pill or a powder2. Similar to the original drug

& S/E are similar3. benzodiazepine NPS

↑↑ longer half-life

1. Gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL) 'G', 'Geebs' or 'Liquid Ecstasy'

Respiratory ↓↓ When taken with other respiratory ↓↓(

alcohol) can be potentially life threatening

2. Nitrous oxide: 'Hippie crack'

Swallowed as a pill/powder ('bombing') or snorted

S/E similar to MDMA/cocaine.risk of serotonin syndrome

effect to LSD although may also be a stimulant

immunosuppressant drugs1. Myco ph enolate mofeti l

(- -) Inosine Monophosphate Dehydrogenase (needed for purine synthesis)

as T and B cells are particularly dependent on this pathway it can reduce proliferation of immune cells  Used in organ transplantation and autoimmune conditions.

2. Azathioprin e is metabolised to the active compound mercaptopurine, a purine analogue that inhibits (Purine) DNA synthesis. Methotrexate is an antimetabolite which inhibits dihydrofolate reductaseCyclosporine + tacrolimus: inhibit calcineurin thus decreasing IL-2

3. Cyclosporin e ↓↓Calcinurin (Phosphatase ++ T-cell) by binding to Cyclophilin forming a complex & ↓↓ IL-2 release ↓↓ proliferation of T cells.(Like Tacrolimus) 'virtually non-myelotoxic'. S/E (↑↑↑ fluid, BP, K+, hair, gums, glucose)

1. Nephrotoxicity Fluconazole (- -) metabolism of ciclosporin (↑↑Ciclosporin Nephrotoxicity).2. Hepatotoxicity3. fluid retention HTN

4. hyperlipidaemia5. ↑↑↑K 6. Hypertrichosis ( ↑↑Hair)7. gingival hyperplasia 8. Tremor9. impaired glucose tolerance10. ↑↑ susceptibility to severe infection

Indications1. Organ transplantation2. rheumatoid arthritis3. psoriasis (has a direct effect on keratinocytes as well as modulating T cell function)4. Ulcerative colitis5. pure red cell aplasia

4. Tacrolimu s Tacrolimus is a macrolide used as an immunosuppressant to prevent transplant rejection. It has a very similar action to ciclosporin:

↓↓proliferation of T cells by reducing IL-2 release binds to FKBP protein forming a complex (- -) calcineurin (a phosphotase (++) various transcription factors in T cells) More potent than ciclosporin incidence of organ rejection is less. Nephrotoxicity and impaired glucose tolerance is more common

4. Methotrexate Antimetabolite that   inhibits Dihydrofolate reductase (Enzyme essential for the synthesis of purines and pyrimidines) preventing the reduction of dihydrofolic acid to tetrahydrofolic acid.It is considered an 'important' drug as whilst it can be very effective careful prescribing and close monitoring is essential. Indications

1. inflammatory arthritis, especially rheumatoid arthritis2. psoriasis

3. some chemotherapy acute lymphoblastic leukaemiaAdverse effects

1. Mucositis2. Myelosuppression3. Pneumonitis4. Pulmonary fibrosis5. Liver fibrosis

Pregnancy Avoided for at least   6 months after treatment has stopped Men using methotrexate need to use effective contraception for at least   6 months   after treatment

Prescribing methotrexate High potential for patient harm taken weekly, rather than daily FBC, U&E and LFTs need to be regularly monitored before starting treatment and repeated weekly until therapy stabilized monitored folic acid 5mg once weekly taken > 24 hours after methotrexate dose Starting dose 7.5 mg weekly only one strength prescribed (usually 2.5 mg)

Interactions avoid prescribing trimethoprim OR Co-trimoxazole concurrently - ↑↑↑ risk of marrow Aplasia ↑↑ - dose   Aspirin  ↑↑ risk of methotrexate toxicity secondary to reduced excretion

Methotrexate toxicityTreatment of choice is folinic acid

Hydroxychloroquine is used in the management of rheumatoid arthritis and systemic/discoid lupus erythematosus. It is pharmacologically very similar to chloroquine which is used to treat certain types of malaria.

Adverse effects bull's eye retinopathy - may result in severe and permanent visual losso recent data suggest that retinopathy caused by hydroxychloroquine is more common than previously thought and the most recent RCOphth guidelines

(March 2018) suggest colour retinal photography and spectral domain optical coherence tomography scanning of the maculao baseline ophthalmological examination and annual screening is generally recommened

A contrast to many drugs used in rheumatology, hydroxychloroquine may be used if needed in pregnant women.

Monitoring

the BNF advises: 'Ask patient about visual symptoms and monitor visual acuity annually using the standard reading chart'

Azathioprine is metabolised to the active compound mercaptopurine, a purine analogue that inhibits purine synthesis. A thiopurine methyltransferase (TPMT) test may be needed to look for individuals prone to azathioprine toxicity.

Adverse effects include

bone marrow depression nausea/vomiting pancreatitis increased risk of non-melanoma skin cancer

A significant interaction may occur with allopurinol and hence lower doses of azathioprine should be used.

Azathioprine is generally considered safe to use in pregnancy.

Tumour necrosis factor (TNF) pro-inflammatory cytokine with multiple roles in the immune systemTNF is secreted mainly by macrophages and has a number of effects on the immune system, acting mainly in a paracrine fashion:

1. activates macrophages and neutrophils2. acts as costimulator for T cell activation3. key mediator of bodies response to Gram negative septicaemia4. similar properties to IL-15. anti-tumour effect (e.g. phospholipase activation)

TNF-alpha binds to both the p55 and p75 receptor. These receptors can induce apoptosis. It also cause activation of NFkBEndothelial effects include increase expression of selectins and increased production of platelet activating factor, IL-1 and prostaglandinsTNF promotes the proliferation of fibroblasts and their production of protease and collagenase. It is thought fragments of receptors act as binding points in serum

Systemic effects include pyrexia, increased acute phase proteins and disordered metabolism leading to cachexia

TNF is important in the pathogenesis of rheumatoid arthritis - TNF blockers (e.g. infliximab, etanercept) are now licensed for treatment of severe rheumatoid

TNF blockers1. infliximab: monoclonal antibody, IV administration2. etanercept: fusion protein that mimics the inhibitory effects of naturally occurring soluble TNF receptors, subcutaneous administration3. adalimumab: monoclonal antibody, subcutaneous administration4. adverse effects of TNF blockers include reactivation of latent tuberculosis and demyelination

Monoclonal antibodiesManufactured by "Somatic cell hybridization Technique" fusion of myeloma cells with spleen cells from a mouse "immunized with the desired antigen". The fused cells are termed a "Hybridoma" act as a 'factory' for producing monoclonal Abs. The main limitation mouse antibodies are immunogenic formation of human anti-mouse antibodies (HAMAs) This is overcomed by combining the Variable region from the mouse body + Constan t region from human antibody .

Uses1. Medical imaging when combined with a radioisotope2. Identification of cell surface markers in biopsied tissue3. Diagnosis of viral infections

Example Mechanism of action Uses

(anti-TNF) Infliximab 1. Rheumatoid arthritis 2. Crohn's

TNF alpha antagonist Etanercept T.B and viral hepatitis should be ruled out prior to starting therapy Psoriasisanti-IL17 Brodalumab completed registration for psoriasis reserved however for patients who fail to

control on other interventionsAnti- IL6 Toclizumab Rheumatoid arthritis

OKT3 (anti-CD3) Muromonab-CD3 1. prevent organ rejection

(anti-CD20)Twenty Rituximab 1. Non-Hodgkin's lymphoma 2. Rheumatoid arthritis

(anti-CD52) Alemtuzumab Chronic lymphocyticleukaemia

"Programmed Cell Death" inhibitor (PD-1) Nivolumab

PD-1 receptors (on the surface of T cells) cancer cell express the PD-L1 protein antibodies block this receptor & disable T cells.

The PD-1 inhibitors block this receptor, leaving T- cells to remain active and alert other immune cells (Macrophages to the cancer)

Cytotoxic T-lymphocyte associated protein4 (CTLA-4)

Ipilimumab down-regulates T cell responses by cancer Blocking this with inhibitors (++) immune system against cancer. 

Nivolumab + Ipilimumab Undergoing trials Solid malignancies lung,oesophageal& head and neck Prolonged therapy Hypophysitis and Hypothyroidism (Conistipation,..

3. Stage 4 Metastatic Melanoma 4. Lymphoma .

"Epidermal growth factor receptor antagonist"(EGFR)

(HER1) "Human epidermal growth factor" antagonist

1. Cetuximab2. Erlotinib

(Tarceva)

Oncogenic (++) Tyrosine kinases autophosphorylates the receptor Cancer cell growth.

1. Metastatic colorectal cancer.2. SQ. cell cancers. 3. head and neck cancer

(HER2/neu receptor antagonist):

Trastuzumab (Herceptin)

2 main cancers overexpress HER2 Breast 30% & gastric adenocarcinoma 20% Acts on tyrosine kinase receptors anti-tumour effects by binding to HER2

receptor stopping the activation of tyrosine kinases

1. Metastatic breast cancer2. Trastuzumab + cisplatin +

capecitabine OR 5-fluorouracil for HER2 +Ve metastatic stomach adenocarcinoma

HER3 Overexpression of HER3 (Breast Ovarian, Colorectal, SQ cell carcinoma) (++) tyrosine kinase receptors

"Vascular Endothelial Growth factor inhibitors" (VEGF)

Bevacizumab(B Blood)

Acts on tyrosine kinase receptors   Inhibits VEGF receptors (which stimulates angiogenesis)

Colorectal cancer

Platelet-Derived Growth Factor Receptor (PDGFR)

1. Imatinib2. Dasatinib

Acts on tyrosine kinase receptors Treatment of leukaemias

glycoprotein IIb/IIIa receptor antagonist

Abciximab Prevention of ischaemic event in patients undergoing PCI

ALK-1 inhibitors Crizotinib Acts on anaplastic lymphoma kinase (a tyrosine kinase).

Trastuzumab (Herceptin) (- -) HER2/neu receptors Stop (++) Tyrosine Kinases. Two main cancers which overexpress HER2 include breast 30% and gastric adenocarcinoma 20% Trastuzumab + cisplatin + capecitabine or 5-fluorouracil HER2 positive metastatic adenocarcinoma of the stomach.  It is used mainly in metastatic breast cancer although some patients with early disease are now also given trastuzumab. Adverse effects

1. Flu-like symptoms and diarrhoea are common2. Cardiotoxicity more common when Anthracyclines also used. (Echo before starting treatment)

Immunoglobulins: therapeutics formed from large pool of donors (5,000) IgG molecules with a subclass distribution similar to that of normal blood Half-life of 3 weeks

Uses of IV immunoglobulins 1. 1ry and 2ry Immunodeficiency2. ↓↓ serum IgG levels following haematopoietic stem cell transplant for malignancy3. Idiopathic thrombocytopenic purpura4. Myasthenia gravis5. Guillain-Barre syndrome6. chronic inflammatory demyelinating polyradiculopathy7. Kawasaki disease8. Toxic Epidermal Necrolysis9. Dermatomyositis10. Pneumonitis induced by CMV following transplantation

Metformin A biguanide used type 2 D.M. it does not cause hypoglycaemia and weight gain USES

1. 1st-line D.M, particularly (overweight).2. Polycystic ovarian syndrome 3. Non-alcoholic fatty liver disease

Mechanism of action1. (++) AMP-activated protein kinase (AMPK)

Major cellular regulator of lipid and glucose metabolism (++) (glucose uptake, fatty acid oxidation, insulin sensitivity)/ (- -)gluconeogenesis.2. ↑↑ insulin sensitivity3. ↓↓ hepatic gluconeogenesis4. may ↓↓gastrointestinal absorption of carbohydrates

Adverse effects 1. GIT "5 %Common" (nausea, anorexia, Diarrhoea, Bloating) intolerable in 20%2. ↓↓ Vit B12 absorption - rarely a clinical problem3. Lactic Acidosis* with severe liver disease or   renal failure

Contraindications1. Chronic kidney disease

Reviewed if Creatinine is > 130 µmol/l (or eGFR < 45 ml/min) Stopped if the creatinine is > 150 µmol/l (or eGFR < 30 ml/min)

2. ↑↑ Tissue hypoxia (Recent MI, Sepsis, AKI and severe dehydration) May cause Lactic Acidosis Metabolic Acidosis W ↑↑Anion gap

3. Iodine-containing x-ray contrast media (Angiography, CA, IV Pyelography (IVP) ↑↑ renal impairment due to contrast nephropathy Discontinued on the day of the procedure and for 48 hours thereafter

4. Alcohol abuse is a relative contraindicationStarting Metformin

1. Metformin should be titrated up slowly to ↓↓incidence GIT side-effects 500mg od with food for 14 days (at least 1 week) then 500mg bd for 14 days then review.

2. Unacceptable side-effects (GIT) Modified-release metformin (evening) should be considered started at 500mg once per day ↑↑ 10-15 days on the basis of blood glucose measurements Up to 2 g daily of the standard-release may start with the same daily dose of metformin modified-release.

Motion sicknessMotion sickness nausea and vomiting occurs when ↑↑discrepancy between visually perceived movement and the vestibular systems sense of movement

Management ( Hyoscine > Cyclizine > Promethazine)1. Hyoscine (Transdermal patch) most effective treatment (Use is limited due to S/E)2. Non-sedating antihistamines (Cyclizine or Cinnarizine) in preference to sedating preparation (Promethazine).

Finasteride

Finasteride is 5 alpha-reductase inhibitor (enzyme metabolises testosterone into dihydrotestosterone. Indications1. Benign prostatic hyperplasia2. male-pattern baldness

Adverse effects1. Impotence2. Ejaculation disorders3. ↓↓ libido4. Gynaecomastia and Breast tenderness5. Finasteride causes decreased levels of serum prostate-specific antigen

Quinine toxicity (cinchonism)known "Cinchonism" remarkably toxic drug (not so readily acknowledged). It is used as an antimalarial and prophylactic against leg cramps.

FeaturesShort term fatal

1. Cardiac arrhythmia Common finding blockade of Na channel↑↑ QRS and k channel QT intervals VT or VF causing death. 

2. Flash pulmonary oedema hypoxia and necessitating positive pressure ventilation.3. Hypoglycaemia "Common finding" (++) pancreatic insulin secretion and this should be corrected rapidly if present. 4. Classical hallmarks (CNS) Tinnitus, Visual blurring

DD. difficult to distinguish from aspirin poisoning measurement of serum salicylate levels. permanent neural damage , if the patient survives. 

5. Flushed and dry skin and Abdominal pain.6. Metabolic Acidosis 

Long-term fatal. 1. Incipient renal failure

Management 2. largely supportive with fluids, inotropes and bicarbonate as needed 3. Positive pressure ventilation for pulmonary oedema.

Drug causes of Agranulocytosis1. Antithyroid drugs Carbimazole, Propylthiouracil2. Antipsychotics atypical antipsychotics (CLOZAPINE)3. Antidepressant Mirtazapine4. Antiepileptics  Carbamazepine, Valproate5. Antibiotics Penicillin,   Chloramphenicol, Co-trimoxazole

6. Cytotoxic drugs Methotrexate7. Drug-induced impaired glucose tolerance

Drugs cause impaired glucose tolerance:1. Thiazides , furosemide (less common)2. Steroids3. Tacrolimus,   Ciclosporin 4. Interferon-alpha5. Nicotinic acid6. Antipsychotic7. Beta-blockers   cause a slight impairment of glucose tolerance used with caution in diabetics as they can interfere with the

metabolic and autonomic responses to hypoglycaemia

Drug-induced thrombocytopenia (probable immune-mediated)

1. Heparin2. Antibiotics Penicillins, Sulphonamides, Rifampicin3. Anticonvulsants Carbamazepine, Valproate4. Quinine5. Abciximab6. NSAIDs (enhance platlet aggregation )7. Diuretics: Furosemide

G6PD Drugs Absolute CI High risk Small risk No theoretical riskQuinolones

Ciprofloxacin Norfloxacin

1. Primaquine2. Sulfonamides3. Methylene blue

Chloroquine 1. Trimethoprim 2. Ibuprofen3. sodium valproate

Moxifloxacin) 4. Dapsone 5. Doxorubicin

Drug causes of urticaria1. Aspirin (common)2. NSAIDs3. Penicillins  Most common antibiotic (Doxycycline might cause but less common)4. Opiates

Drug-induced urinary retention1. Tricyclic Antidepressants Amitryptiline (has also anti- cholinergic effect)2. Anticholinergics3. Opioids4. NSAIDs5. Disopyramide

Drugs causing lung fibrosisPatient might presented W chronic cough & dyspnea + fine inspiratory crackles , FEV1/FVC ratio >70%.

1. Amiodarone2. Nitrofurantoin3. Penicillamine4. Cytotoxic agents Busulphan, Bleomycin, Cyclophosphamide5. Anti-rheumatoid drugs  Methotrexate, Sulfasalazine6. Ergot-derived dopamine receptor agonists (bromocriptine, cabergoline, pergolide)

Drugs causing ocular problemsCataracts Corneal Opacities Optic neuritis Retinopathy

1. Steroids 1. Amiodarone2. Indomethacin

1. Amiodarone2. Ethambutol3. Metronidazole

1. Chloroquine (hydroxychloroquine).2. Quinine3. Vigabatrin.

Sildenafil c an cause both blue discolouration and non-arteritic anterior ischaemic neuropathy

Drugs causing photosensitivity A maculopapular erythematous rash on the forearms and face and anterior chest W sun exposure typical of a photosensitivity rash

1. Thiazides 2. Anti-biotics Tetracyclines, Sulphonamides, Ciprofloxacin3. Anti –arrhythmic Amiodarone4. Anti- glycemic sulphonylureas5. NSAIDs Piroxicam6. Psoralens

Toxin TreatmentParacetamol activated charcoal if < 1 hour ago

N-acetylcysteine (NAC) liver transplantation

Salicylate Urinary alkalinization is now rarely used CI Cerebral and pulmonary oedema (most units now proceeding straight to haemodialysis severe poisoning)

haemodialysisOpioid/opiates NaloxoneBenzodiazepines Flumazenil (Risk of seizures with flumazenil only used with severe or iatrogenic overdoses).

The majority supportive care only TricyclicAntidepressants

IV bicarbonate  ↓↓ seizures and arrhythmias in "severe toxicity" Arrhythmias

1. Correction of acidosis is the first line2. Class 1a (Quinidine) and class Ic antiarrhythmics (Flecainide) are contraindicated prolong depolarisation.

Toxin Treatment3. Class III drugs (Amiodarone) avoided prolong the QT interval. 4. Response to lignocaine is variable

Dialysis is ineffective in removing tricyclicsLithium Mild-moderate toxicity volume resuscitation with normal saline

Haemodialysis  severe toxicity Na+ bicarbonate sometimes used ↑↑ alkalinity of the urine it promotes lithium excretion

Warfarin Vitamin K, prothrombin complexHeparin Protamine sulphateBeta-blockers if bradycardic then atropine

in resistant cases glucagon may be usedEthylene glycol ethanol has been used for many years

works by competing with ethylene glycol for the enzyme alcohol dehydrogenase this limits the formation of toxic metabolites (e.g. Glycoaldehyde and glycolic acid) which are responsible for the

haemodynamic/metabolic features of poisoning fomepizole , an inhibitor of alcohol dehydrogenase, is now used first-line in preference to ethanol Haemodialysis also has a role in refractory cases

Methanol poisoning fomepizole or ethanol haemodialysis

Organophosphate insecticides

Atropine the role of pralidoxime is still unclear - meta-analyses to date have failed to show any clear benefit

Digoxin Digoxin-specific antibody fragmentsIron Desferrioxamine a chelating agent Lead Dimercaprol, calcium edetateCarbon monoxide 100% oxygen

hyperbaric oxygenCyanide Hydroxocobalamin; also combination of amyl nitrite, sodium nitrite, and sodium thiosulfate

Therapeutic drug monitoringPhenytoin Ciclosporin Digoxin LithiumNot monitored routinely immediately before dose (checked if)1. adjustment of phenytoin dose2. suspected toxicity3. detection of non-adherence to medication

immediately before dose at least 6 hrs post-dose range = 0.4 - 1.0 mmol/l take 12 hrs post-dose

Haemodialysis in overdoseDrugs cleared with haemodialysis " BLAST" Drugs cannot be cleared with haemodialysis "BBDDT"

1. Barbiturate2. Lithium3. Alcohol (inc methanol, ethylene glycol)4. Salicylates5. Theophyllines (charcoal haemoperfusion is preferable)

1. beta-blockers2. benzodiazepines3. tricyclics4. digoxin5. dextropropoxyphene (Co-proxamol)

Prescribing in patients with heart failureThe following medications may exacerbate heart failure:

1. ThiazolidinedionesPioglitazone is contraindicated as it causes fluid retention

2. Verapamilnegative inotropic effect

3. NSAIDs/glucocorticoidsshould be used with caution as they cause fluid retentionlow-dose aspirin is an exception - many patients will have coexistent CVS disease and the benefits of taking aspirin easily outweigh the risks

4. Class I antiarrhythmicsFlecainide (negative inotropic and proarrhythmic effect)

Prescribing in patients with renal failureavoid in renal failure Accumulate in CKD "Dose adjustment" Relatively safe "according degree CKD"

1. AntibioticsTetracyclineNitrofurantoin

2. NSAIDs3. Lithium4. Metformin

1. Most antibioticsPenicillinsCephalosporinsVancomycin GentamicinStreptomycin

2. Digoxin3. Atenolol4. Methotrexate5. Sulphonylureas6. Furosemide7. Opioids

Oxycodone safer opioid moderate to end-stage renal failure metabolised in the liverMorphine metabolites accumulate in renal failure 

1. AntibioticsErythromycin Rifampicin

2. Diazepam3. Warfarin

Diabetes drugs:Side effectDrug Side-effect

Metformin GIT side-effects Lactic acidosis

Sulfonylureas Chlorpropamide

Hypoglycaemic episodes ↑↑ appetite and weight gain SIADH Liver dysfunction (cholestatic)

Glitazones Weight gain

Drug Side-effect Fluid retention (CI : Heart failure) Liver dysfunction Fractures

Gliptins PancreatitisPrescribing in pregnant patients

Very few drugs are known to be completely safe in pregnancy. If given history of absence/ Non-effective contraception treated as pregnant

Antibiotics1. Tetracyclines2. Aminoglycosides3. Sulphonamides4. Trimethoprim5. Quinolones (Avoid due to arthropathy in some animal studies)

Other drugs1. ACE inhibitors, ARBs2. Statins3. Warfarin4. Sulfonylureas5. Metformin

Sometimes used in pregnancy many diabetic women are converted to insulin for the duration of the pregnancy to try and maximise control and minimise complications

6. Retinoids (including topical)7. Cytotoxic agents

The majority of antiepileptics (Valproate, Carbamazepine and Phenytoin) are known to be potentially harmful. The decision to stop such treatments however is difficult as uncontrolled epilepsy is also a risk