Pharmacokinetics: - 1 File Download



Pharmacokinetics:Metabolism The majority of phase I and phase II reactions take place in the liver)Usually both phase I and II reactions ↓↓ lipid solubilityDrug metabolism usually involves two types of biochemical reactions Phase I reactions Oxidation, reduction, hydrolysisProducts more active and potentially toxic)Mainly performed by the P450 enzymes Some drugs are metabolised by specific enzymes Alcohol dehydrogenase and xanthine oxidase. Phase II reactions Conjugation Products are typically inactive & excreted in urine or bile.Glucuronyl, acetyl, methyl, sulphate and other groups are typically involvedFirst-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. Exaspirinisosorbide dinitrateglyceryl trinitratelignocainepropranololverapamilisoprenalinetestosteronehydrocortisoneZero-order kinetics = Saturation Pharmacokinetics"Rate of excretion is constant despite changes in plasma concentration (due to saturation of the metabolic process) ↑↑Risk of toxicity Alcohol people may fail a breathalyser test in the morning if they have been drinking the night beforheparinPhenytoin (long half life needs monitoring)SalicylatesAcetylator status50% of the UK population are deficient in hepatic N-acetyltransferase (affect toxcisity of the drug)Drugs affected by acetylator statusIsoniazidMen, unusually, less likely to develop isoniazid hepatotoxicity.Concurrent use of Rifampicin and Pyrazinamide is also a risk factor isoniazid hepatotoxicity.SulfasalazineProcainamideHydralazineDapsoneP450 enzyme systemInduction usually requires prolonged exposure to the inducing drug, as opposed to P450 inhibitors, where effects are often seen rapidly(++++) P450(- - - -) P450 systemAnti- Biotic RifampicinAnti fungal GriseofulvinAntiepileptics ?Phenytoin,?CarbamazepineAnti- Seizure Barbiturates "phenobarbitone"St John's WortChronic alcohol intakeSmoking?(affects CYP1A2(↓↓ Amynophylin effect smokers require more aminophylline)Antibiotics Ciprofloxacin,?Erythromycin, IsoniazidAnti- Fungal imidazoles (ketoconazole, fluconazole)Anti- Viral ritonavirAnti- Epileptic Na+ valproateAnti- Depressant SSRIs:?fluoxetine,?sertralineAnti- Acid Cimetidine,omeprazolAnti- Arrhythmic AmiodaroneAnti- Gout allopurinolacute alcohol intakequinupristinGrapefruit juice (interact with Simvastatin)DRESS syndromeUnexpected, 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 drugFeature Morbilliform?skin rash in 80%, often exfoliative dermatitis,Vesicles and bullae may be seen. Erythroderma 10% of cases, Mucosal involvement in 25% and facial swelling in 30%. ↑↑ Fever and inflammation of ≥ 1 organs. 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.?DiagnosisDifficult to determine the exact drug causing the hypersensitivity as first exposure may have started 8 weeks mon drugs Allopurinol, Anti-epilepticsAntibioticsImmunosuppresantsHIV treatment 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:?HospitalisationReaction suspected to be drug relatedAcute skin rashFever about 38?CEnlarged lymph nodes at two sitesInvolvement of ≥ 1 internal organBlood 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 betaken. Investigations looking for complications should be undertaken including ECG, CXR, echocardiogram, and urinalysis.?TreatmentAll possible medications stopped and supportive care started. Rash Antihistamines, topical steroids and emollients.Systemic steroids severe cases [Exfoliative dermatitis / Pneumonitis / hepatitis]Regularly checked and secondary infections treated with antibioticsCareful fluid balance is necessary and clinicians should be aware of the patients nutritional status.Occasionally immunosuppressants, IV immunoglobulin and plasmapheresis may be started. Potential culprit drugs should not be restarted again. 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?Headache 90% of casesNausea and Vomiting, Vertigo 50%Confusion, subjective weakness : 30%Severe toxicity'pink' skin and mucosae, Hyperpyrexia ArrhythmiasExtrapyramidal features Coma, deathInvestigationsPulse oximetry may be falsely high due to similarities between oxyhaemoglobin and carboxyhaemoglobin venous or arterial blood gasTypical 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 toxicityECG is a useful supplementary investgation to look for cardiac ischaemiaManagement100% high-flow oxygen via a non-rebreather mask↓↓ the half-life of Carboxyhemoglobin (COHb)Administered as soon as possible, (minimum 6 h )target O2 saturations are 100%Treatment is continued until all symptoms have resolved, rather than monitoring CO levelsHyperbaric oxygenSome evidence long-term outcomes may be better than standard oxygen therapy for more severe cases (levels > 25%)Other indication for hyperbaric oxygenLoss of Consciousness at any point. Neurological signs other than headache.Myocardial ischaemia or arrhythmia Pregnancy Cyanide poisoningUsed 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.?Presentation'classical' features: brick-red skin, smell of bitter almondsAcuteHypoxiaHypotensionHeadache, confusionChronicAtaxiaPeripheral neuropathyDermatitisPresentation with normal O2 saturations ↑↑ pO2 and flushing (or 'brick red' skin) DD. From CO poisoningManagementsupportive measures: 100% oxygenDefinitive IV ?Hydroxocobalamin?also?combination of Amyl nitrite (inhaled)Sodium nitrite (IV), Na thiosulfate (IV)Mercury poisoningThe commonest cause of mercury poisoning is ingestion via foodstuffs- in particular fish and whale.?FeaturesParaesthesiaVisual field defectsHearing loss (Sensorineurl) irritabilityRenal tubular acidosisOrganophosphate 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"?SalivationLacrimationUrinationDefecation/diarrhoeaBronchorrheaCVS Hypotension,?BradycardiaSmall pupils, Muscle fasciculation, Muscle weaknessManagementAtropinethe role of pralidoxime is still unclear - meta-analyses to date have failed to show any clear benefitAntibiotics: gross mechanism of action(- -) cell wall formation(- -) protein synthesis(- -) DNADamages DNA(- -) Folic Acid(- -) RNA(- -) peptidoglycan cross linkingPenicillinsCephalosporins?Carbopenemspeptidoglycan synthesis:?Glycopeptides?VancomycinTeicoplanin > duration of action/ OD after loading dose. by acting on the Ribosome50SsubunitMacrolidesChloramphenicolClindamycinLinezolidStreptogrammins30S subunitAminoglycosidesTetracyclineQuinolones?CiprofloxacinMetronidazole sulphonamidestrimethoprimRifampicinPenicillin allergyAllergy 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. (↑↑ 1st generation, ↓↓ 2nd & 3rd generations) History of immediate hypersensitivity to penicillin should not receive a cephalosporin. If a cephalosporin is essential (No alternative antibacterial) Used with cautionShould be avoidedCefiximeCefotaximeCefuroximeCeftazidimeCeftriaxoneCefaclorCefadroxilCefalexinCefradineCeftaroline FosamilTypes of penicillin:PhenoxymethylpenicillinBenzylpenicillinFlucloxacillinAmoxicillinAmpicillinCo-amoxiclav (Augmentin)Co-fluampicil (Magnapen)Piperacillin + Tazobactam (Tazocin)Ticarcillin + Clavulanic acid (Timentin)MacrolidesErythromycin 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 RNAErythromycin used in gastroparesis as it has prokinetic properties (↑↑Gastric emptying)Adverse effectsGIT "Common" Nausea is less common with clarithromycin than erythromycinCholestatic jaundice risk ↓↓ if erythromycin stearate is used(- -) P450?Azithromycin is associated with hearing loss and tinnitusCommon interactionsStatins stopped W Macrolides (significantly ↑↑↑risk of myopathy and rhabdomyolysis) (- -) cytochrome P450 isoenzyme CYP3A4 (Metabolises statins).potentially interact with amiodarone, warfarinQuinolonesWorks by (- -) DNA synthesis and are bactericidal in nature. Examples include:ciprofloxacinlevofloxacinMechanism of action (- -) topoisomerase II (DNA gyrase) and topoisomerase IVMechanism of resistanceMutations to DNA gyrase, (efflux pumps ↓↓ intracellular quinolone concentration)Adverse effects↓↓ seizure threshold?in patients with epilepsyTendon damage?(including rupture) - ↑↑↑ risk W steroids (treatment being 8 days before problems occur)Cartilage damage?(animal models generally avoided (but not necessarily contraindicated) in childrenlengthens QT intervalContraindicationsPregnancy or?breastfeedingG6PDGentamicin Aminoglycoside antibiotic poorly lipid-soluble therefore given parentally (Infective endocarditis) or topically (Otitis externa).Adverse effectsOtotoxicitydue to auditory or vestibular nerve damageirreversibleNephrotoxicityaccumulates in renal failurethe toxicity is 2ry to?acute tubular necrosis (direct damage to the renal tubules)concomitant use of?furosemide ↑↑risk↓↓ doses and ↑↑monitoring is requiredContraindications Myasthenia gravisDosingsignificant ototoxic and nephrotoxic potential monitor plasma concentrationsMeasurement 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 actionRifampicinIsoniazidPyrazinamideEthambutolinhibits RNA synthesis (- -) bacterial DNA dependent RNA polymerase prevent transcription of DNA into mRNA(++) P450 HepatotoxicityOrange secretionsflu-like symptoms(- -) mycolic acid synthesisperipheral neuropathysadd pyridoxine (Vitamin B6)(- -)P450HepatotoxicityAgranulocytosisConverted by pyrazinamidase into pyrazinoic (- -) fatty acid synthase (FAS) IHepatotoxicityUric acid ?goutArthralgia, myalgia(- -) arabinosyl transferase Enz (polymerizes arabinose into arabinan)Optic neuritischeck visual acuity before & during treatmentDose adjusting in renal impairmentAlcohol - problem drinkingS/EExcessive alcohol develop Polyurea ↓↓Ca++ -dependent secretion of (ADH) by blocking channels in neurohypophyseal nerve terminal.Nausea associated with hangovers vagal stimulation to the Vomiting Centre . 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 usedAcute withdrawal Benzodiazepines. Promotes abstinence DisulframAlcohol intake Severe reaction due to (- -) acetaldehyde dehydrogenase. Even small amounts of alcohol (Perfumes, Foods, Mouthwashes) can produce severe symptoms. CI/ IHD and psychosis↓↓↓ Craving AcamprosateA 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:Stage 1: symptoms similar to alcohol intoxication Confusion, Slurred speech, DizzinessStage 2:?metabolic acidosis + high anion gap and high osmolar gap + Also tachycardia + hypertensionStage 3: AKIManagement has changed in recent timesFomepizole, (Inhibitor of alcohol dehydrogenase now used first-line in preference to ethanolEthanol (Traditionally used ) Compete with Ethylene Glycol for the enzyme Alcohol dehydrogenaseThis ↓↓↓ Toxic metabolites (glyceraldehydes and glycolic acid) responsible for the haemodynamic/metabolic features of poisoningHaemodialysis refractory cases (Metaboloic acidosis)DD. Methanol poisoning similar fashion, but with visual disturbance and occasionally blindness. Treated with Fomepizole.Methanol poisoningMethanol 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 gapManagementFomepizole (competitive inhibitor of alcohol dehydrogenase)?or EthanolHaemodialysisParacetamol overdose: managementPotentially toxic dose of Paracetamol (>75mg/kg)Complications of overdose 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 tubulesN-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 excessMalnourished 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 metaboliteDelayed nephrotoxicity especially in significant overdose Follow up ↑↑ KFTsTreatment Within 1 hour "minority" activated charcoal ↓↓ absorption of the drug.Acetylcysteine should be given if:Staggered overdose or Doubt over the time of ingestion, (regardless of the plasma paracetamol concentration)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)Arterial pH < 7.3, 24 hours after ingestionOR all of the following:PT > 100 secondsCreatinine > 300 ?mol/lGrade III or IV encephalopathyAcute 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 attackDrugs considered safe to usealcoholBarbituratesBenzodiazepinesHalothane?Thiopental?NaOral contraceptive pillsulphonamidesAspirinBeta-blockerscodeinemorphinechlorpromazinemetforminparacetamolpenicillinAdrenoceptor agonistsAlpha-1 agonistsvasoconstriction (Skin, kidney , mucous membrane)relaxation of GI smooth muscleSalivary secretionHepatic glycogenolysisPhenylephrineAlpha-2 agonistsclonidineBeta-1 agonistsdobutamineBeta-2 agonistssalbutamolBeta-3 agonistsbeing developed, may have a role in preventing obesity (stimulation causes lipolysis)Alpha antagonistsalpha-1 Doxazosin (Treatment of hypertension and benign prostatic hypertrophyalpha-1a Tamsulosin - acts mainly on urogenital tractalpha-2 yohimbinenon-selective phenoxybenzamine (previously used in peripheral arterial disease)Beta antagonists?Beta-1 AtenololBeta-2 Phentolamine.Non-selective PropranololMixed alpha and beta antagonists Carvedilol Labetalol AdrenalineSympathomimetic amine with both alpha and beta adrenergic stimulating properties. Indicationsanaphylaxis 0.5ml 1:1,000 IMcardiac arrest 1ml of 1:1000 IV (10ml 1:10,000 IV)Management of accidental injectionlocal infiltration of phentolamine short acting alpha blocker, It is normally used mainly to control blood pressure during surgical resection of phaeochromocytomaBackgroundresponsible for the fight or flight responsereleased by the adrenal glandsacts on α 1 and 2, β 1 and 2 receptorsacts on β 2 receptors in skeletal muscle vessels-causing vasodilationincreases cardiac output and total peripheral resistancecauses vasoconstriction in the skin and kidneys causing a?narrow pulse pressureActions on α adrenergic receptors:?(- -) insulin secretion by the pancreasstimulates glycogenolysis in the liver and musclestimulates glycolysis in muscleActions onβ adrenergic receptors:stimulates glucagon secretion in the pancreasstimulates ACTHstimulates lipolysis by adipose tissueInduces 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 agonistsIndicationsParkinson's diseasedelay treatment until the onset of disabling symptomselderly, L-dopa is sometimes used as an initial treatmentProlactinoma/GalactorrhoeaAcromegalyCyclical breast diseaseOverviewEx: Bromocriptine, Ropinirole, Cabergoline, ApomorphineErgot-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 effectsNausea/Vomiting (++) brain Vomiting CentrePostural hypotensionHallucinationsDaytime somnolenceDrugs 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.AgonistsAntagonistsSumatriptan acute treatment of migraineErgotamine partial agonist of 5-HT1 receptorsPizotifen prophylaxis of migraine attacks. Methysergide rarely used due to the risk of retroperitoneal fibrosisCyproheptadine control diarrhoea in patients with carcinoid syndromeOndansetron antiemeticSerotonin syndromeCausesMonoamine oxidase inhibitorsSSRIsSt John's Wort, often taken over the counter for depression, can interact with SSRIs to cause serotonin syndromeThe combination of two or more serotonergic medications greatly increases the riskEcstasyamphetaminesFeaturesNeuromuscular excitation (Hyperreflexia, myoclonus, rigidity Spasticity)autonomic nervous system excitation (hyperthermia)altered mental stateDilated pupil.Managementsupportive including IV fluidsBenzodiazepinesSevere cases serotonin antagonists (Cyproheptadine?and Chlorpromazine)St John's WortEffective as tricyclic antidepressants in the treatment of mild-moderate depressionMechanism 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?S/Es in trials similar to placeboSerotonin syndrome(++) P450 system, ↓ levels of drugs (Warfarin, Ciclosporin, COCP) OctreotideLong-acting analogue of somatostatin (from D cells of pancreas (- -) GH, Glucagon and Insulin). Usesacute treatment of variceal haemorrhageAcromegalyCarcinoid syndrome"1st line", Also Cyprohiptadine can be omasrefractory diarrhoeaProphylaxis Prevent complications following Pancreatic SurgeryAdverse effectsGallstones & Billiary Colic (2ry to biliary stasis)AntiarrhythmicsThe Vaughan Williams classification ClassExamplesMechanism of actionNotesIaQuinidineProcainamideDisopyramideBlock sodium channels↑↑AP durationQuinidine toxicity cinchonism (headache, tinnitus, thrombocytopaenia)Procainamide drug-induced lupusIbLidocaineMexiletineTocainideBlock sodium channels↓↓ AP durationIcFlecainideEncainidePropafenoneBlock sodium channelsNo effect on AP durationIIPropranololAtenololBisoprololMetoprololBeta-adrenoceptor antagonistsIIIAmiodaroneSotalolIbutilideBretyliumBlock potassium channelsIVVerapamil?DiltiazemCalcium channel blockersFlecainide1c 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. IndicationsAFSVT W\ Accessory pathway (WPW)Contraindications?Post MI ↑↑Mortality Structural heart disease (Heart Failure)sinus node dysfunction 2nd-degree or greater AV blockAtrial FlutterAdverse effects-Ve InotropicBradycardiaProarrhythmicOral ParaesthesiaVisual disturbancesProcainamide works in a similar way to flecainide but instead induces a rapid blocking of the batrachotoxin activated sodium channels rapidlyBeta-blockersIndicationsanginapost-myocardial infarctionheart failure certain beta-blockers improve both symptoms and mortalityarrhythmias rate-control drug of choice in atrial fibrillationHypertensionThyrotoxicosisMigraine prophylaxisAnxietyExamplesAtenololPropranolol: one of the first beta-blockers to be developed. Lipid soluble therefore crosses the blood-brain barrierSide-effectsbronchospasmcold peripheriesfatigueSleep disturbances, including nightmareserectile dysfunctionContraindicationsuncontrolled heart failureasthmasick sinus syndromeconcurrent verapamil use: may precipitate severe bradycardiaBeta-blocker overdoseFeaturesBradycardiaHypotensionHeart failureSyncopeManagementBradycardic atropineResistant cases Glucagon (+ Ve inotropic action on the heart and ↓↓ renal vascular resistance. Cardiac pacing reserved for patients unresponsive to pharmacological therapyHaemodialysis is not effective in beta-blocker overdoseAmiodaroneClass 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 usedGiven into central veins (causes?thrombophlebitis)Proarrhythmic ↑↑QT interval Coexistent hypokalaemia significantly increases this risk.interacts with (p450 inhibitors) Decreases metabolism of warfarinTFT, LFT, U&E(K check), CXR prior to treatment TFT, LFT every 6 monthsAdverse effects of amiodarone usethyroid dysfunction both?hypothyroidism?and?hyper-thyroidismCorneal depositsPulmonary fibrosis/pneumonitisliver fibrosis/hepatitisperipheral neuropathy, myopathyphotosensitivity'slate-grey' appearanceThrombophlebitis and injection site reactionsBradycardia↑↑ QT intervalAmiodarone and the thyroid gland1 in 6 patients taking amiodarone thyroid dysfunctionAmiodarone-induced hypothyroidismDue to ↑↑ iodine content of amiodarone "Wolff-Chaikoff effect" (↑↑Iodine ↓↓Thyroxin) Tyroxine replacement + Amiodarone may be continued if this is desirable VT Amiodarone-induced ThyrotoxicosisAIT type 1AIT type 2Pathophysiology↑↑↑ iodine-induced thyroid hormone synthesisAmiodarone-related destructive thyroiditisGoitrePresentAbsentManagementCarbimazole or K+ perchlorateCorticosteroidsUnlike in AIH, amiodarone should be stopped if possible in patients who develop AITCalcium channel blockers Management of CVS disease. Voltage-gated calcium channels are present in (Myocytes, cells of the conduction system and vascular smooth muscle cells). ExamplesIndications & notesSide-effects and cautionsVerapamilAngina, hypertension, arrhythmias?Highly negatively inotropicShould not be given with beta-blockers as may cause?heart blockHeart failurehypotension,?Bradycardic,?dyspepsia (relax lower oesophageal sphincter)flushing constipationDiltiazemAngina, hypertension?Less negatively inotropic but?caution?W C heart failure or are taking beta-blockersHypotension,bradycardia,heart failure,?ankle swellingNifedipine, amlodipine, felodipine?(dihydropyridines)Hypertension, angina, Raynaud'sAffects the peripheral vascular smooth muscle > myocardium (Not worsening of heart failure)Flushing,?headache,?ankle swellingAtropineantagonist of the muscarinic acetylcholine receptor.treatment of organophosphate poisoningtachycardia, mydriasisAdenosineTerminate?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 inhibitorsPDE5 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. ExamplesSildenafil (Viagra) - this was the first?phosphodiesterase type V inhibitorTadalafil (Cialis)Vardenafil (Levitra)Contraindicationspatients taking nitrates and related drugs such as nicorandilDoxazosin avoiding alpha-blockers for 4 hours after sildenafilHypotensionRecent?stroke?or?MI?(waiting 6 months)Side-effectsvisual disturbances (blue discolouration,?non-arteritic anterior ischaemic neuropathyNasal congestionFlushingGIT S/EHeadacheNicorandila vasodilatory drug used to treat angina. It is a?potassium-channel activator with vasodilatation is through?activation of guanylyl cyclase ↑↑ cGMP.Adverse effectsheadacheflushinganal ulcerationContraindicationsleft ventricular failureBlood ThinnersAdenosine diphosphate (ADP) receptor inhibitorsClopidogrelPrasugrelTicagrelorTiclopidineMechanism (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 thereafterS/Eticagrelor may cause dyspnoea due to the ↓ clearance of adenosineInteractions and contraindicationsClopidogrel and proton pump inhibitors, particularly omeprazole and esomeprazolePrasugrel 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 lastingMechanism block effects of angiotensin II at the AT1 receptor↓ progression of renal disease in patients with diabetic nephropathylosartan ↓↓ CVA and IHD mortality in hypertensive patientsDiagnosis1st line2nd lineACS(medically)ASA (lifelong) & ticagrelor (1Y)If aspirin CI→ clopidogrel (lifelong)PCIASA (lifelong) & prasurgrel or ticagrelor (1 y)If aspirin CI →clopidogrel (lifelong)TIAASA (lifelong)Aspirin (lifelong) & dipyridamole (lifelong)Ischemic strokeClopidogrel (lifelong)Aspirin (lifelong) & dipyridamole (lifelong)PADClopidogrel (lifelong)Asprin (lifelong)AspirinIrreversable 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 PotentiatesOral hypoglycaemicswarfarinsteroidsCI 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 overdoseA 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.FeaturesHyperventilation (centrally stimulates respiration)TinnitusLethargy, Sweating PyrexiaSalicylate causes uncoupling of oxidative phosphorylation ↓↓ ATP production, ↑↑(O2 consumption and CO2) and heat productionnausea/vomitingDysregulation of glucose hyperglycaemia and hypoglycaemiaseizurescomaTreatmentGeneral ABCCharcoal first-line in patients who have ingested the drug within one hoururinary alkalinization (IV sodium bicarbonate - enhances elimination of aspirin in the urineHaemodialysis "Indications'Serum concentration > 700mg/LMetabolic acidosis resistant to treatmentAcute renal failurePulmonary oedemaSeizuresComaHeparinheparin Generally activate antithrombin III, 2 main types :Unfractionated heparin forms a complex (--) thrombin, factors Xa, IXa, XIa and XIIa. LMWH only ↑↑↑ action of antithrombin III on factor XaAdverse effects BleedingThrombocytopenia?- see belowOsteoporosis?and an?increased risk of fractures↑↑ K+ caused by (- -) aldosterone secretionStandard heparinLow molecular weight heparin (LMWH)AdministrationIVS.CDuration ShortLongSide-effectsBleedingHeparin-induced thrombocytopaenia (HIT)OsteoporosisBleedingLower risk of HIT and osteoporosis with LMWHMonitoring (APTT)Anti-Factor Xa (routine monitoring is not required)NotesUseful in ↑↑ risk of bleeding (terminated rapidlyAlso useful in?renal failurestandard management of VTE treatmentprophylaxis ACSHeparin-induced thrombocytopaenia (HIT)After 5-10 days of treatmentImmune mediated -?antibodies against complexes of platelet factor 4 (PF4) and heparin (++) platelet activation by cross-linking FcγIIA receptorsProthrombotic condition Thrombosis and skin allergy> 50% ↓↓ platelets Treatment alternative anticoagulants Lepirudin and DanaparoidDipyridamole 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 synthaseAnti- LipidDrugsMechanism of actionAdverse effectsStatinsHMG Co-A reductase (- -)Myositis, ↑↑ LFTsNicotinic Acid (H+)↓↓ Hepatic VLDL SecretionFlushing, MyositisFibRatesAgonist of PPAR-alpha ++ lipoprotein lipase expressionMyositis, Pruritus, CholestasisCholectyramine↓↓ bile acid reabsorption in small intestineUp regulating the amount of cholesterol that is converted to bile acidGI side-effectsEzetimibe↓↓Cholesterol absorption in the small intestineHeadacheNicotinic acid (niacin)Treatment of patients with hyperlipidaemia limited by side-effects.↑↑ HDL levels.↓↓ Cholesterol and triglyceride concentrations Adverse effectsFlushing: mediated by?prostaglandinsMyositis Not to be used W Statin ↓↓ glucose toleranceAllopurinol Prevention of gout works by inhibiting?xanthine oxidase.should not be started until?2 weeks?after an acute attack has settled (Symptoms settle)initial dose 100 mg od, every few weeks to aim for a serum uric acid of < 300 ?mol/lNSAID or colchicine cover should be used when starting allopurinolIndications for allopurinolRecurrent attacks started if a second attack, or further attacks occur within 1 year'TophiRenal diseaseuric acid Renal stonesProphylaxis Cytotoxics prevent tumer lysis syndrome (lymphoma) DiureticsPatients with Lesch-Nyhan syndrome often take allopurinol for lifeAdverse effectsmost significant are dermatological stop allopurinol immediately if they develop a rash:Severe cutaneous adverse reaction (SCAR)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 useEthnicity (Thai Chinese, Korean descent)Chronic kidney disease.Stevens-Johnson syndromeInteractionsAzathioprinemetabolised to active compound 6-mercaptopurineXanthine oxidase responsible for the oxidation of 6-mercaptopurine to 6-thiouric acidAllopurinol ↑↑6-mercaptopurineMuch ↓↓ dose (25%) must if the combination cannot be avoidedCyclophosphamideAllopurinol ↓↓ renal clearance may cause marrow toxicityTheophyllineallopurinol causes ↑↑plasma concentration of theophylline by inhibiting its breakdownBotulinum toxinlicensed indications:CosmeticBlepharospasmHemifacial spasm (UMNL Not Bells palsy )Focal spasticity cerebral palsy patients, hand and wrist disability associated with strokeSpasmodic torticollisSevere hyperhidrosis of the axillaeAchalasia 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 alkaliStrong acidOxidising agentsNa+ Hydroxide, K+ Hydroxide (Dishwasher cleaner, industrial cleaners) Liquefactive necrosis (↑↑oesophageal injury)Hydrochloric Acid, Nitric Acid car batteries, WC cleaner Coagulative necrosis (↑↑ gastric injury)Hydrogen peroxide, Na+ hypochlorite Household bleachAcute 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 referralif 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 PPIAvoid 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)ComplicationsAcuteUpper GI ulceration, perforationUpper airway injury and compromiseAspiration pneumonitisInfectionElectrolyte disturbance (hypocalcaemia in hydrofluoric acid ingestion)ChronicStrictures, fistulae, gastric outlet obstructionUpper GI carcinoma (1000-3000 fold)combined oral contraceptive pill Advantages Disadvantageshighly effective (failure rate < 1 per 100 woman years)doesn't interfere with sexcontraceptive effects reversible upon stoppingPeriods regular, lighter and less painful↓↓ovarian cysts, benign breast disease, acne vulgaris↓↓ risk (Ovarian, Endometrial Cancer ?(last for decades?after cessation↓↓colorectal cancerProtect against PIDforget to take itNo protection against STI↑↑↑ VTE↑↑↑ Breast and cervical cancer↑↑↑stroke and IHD (especially in smokers)Temporary (Headache, Nausea, Breast tenderness) Weight gain (Controversial)Contraindications according to a four point scale, as detailed below:UKMEC 1 No restriction for the use of the contraceptive methodUKMEC 2 advantages > disadvantagesUKMEC 3 disadvantages > advantagesUKMEC 4 unacceptable health riskUKMEC 3 conditions UKMEC 4 conditions > 35 years + smoking (< 15 /day)BMI > 35 kg/m^2*"1st degree relatives < 45 years" + thromboembolic disease Controlled HTNCarrier gene mutations associated with breast cancer (BRCA1/BRCA2)current gallbladder diseaseImmobility (wheel chair use)> 35 years + smoking (>15 /day)migraine with aurahistory of thromboembolic disease OR thrombogenic mutationHistory of stroke OR IHDuncontrolled hypertensionCurrent breast cancerBreast feeding < 6 weeks post-partumCervical cancer is not a contraindication to use.?(COCP small increase in cervical cancer risk after 5 years & ↑↑2-fold risk after 10 years. Major surgery with prolonged immobilisationDiabetes mellitus diagnosed > 20 years ago is classified as UKMEC 3 or 4 depending on severitybreast feeding 6 weeks - 6 months postpartum?was changed from UKMEC 3 → 2Weight Gain is not ↑↑ supported Concurrent antibiotic useAntibiotics may interfereAffect 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 afterwardsprecautions should still be taken with enzyme inducing antibiotics (Rifampicin and Rifaximin)Switching combined oral contraceptive pillsContradictory 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/disadvantagesAdvantagesDisadvantages↑↑↑ effective (failure rate = 1 per 100 woman years)doesn't interfere with sexReversible upon stoppingcan be used whilst breast-feedingUsed when COCP pill is CI Smokers > 35 Ys History of VTEIrregular periodsMay not have periods, Irregular OR Light periods.(Most common)This is the most common S/EDoesn't protect against STI↑↑ Incidence of functional ovarian mon S/E Breast tendernessweight gainAcneHeadachesThese symptoms generally subside after the first few monthsTamoxifenSelective oEstrogen Receptor Modulator (SERM)? oestrogen receptor antagonist and partial agonist. It is used in the management of oestrogen receptor positive breast cancer. Adverse effectsMenstrual disturbance vaginal bleeding, amenorrhoeaHot?flushes?- 3% of patients stop taking tamoxifen due to climacteric side-effectsVTEEndometrial cancerOsteoporosisTamoxifen 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 cancerTeratogensDrug/conditionEffectACE inhibitorsRenal dysgenesisCraniofacial abnormalitiesCarbamazepineValproateNeural tube defectsCraniofacial abnormalitiesWarfarinCraniofacial abnormalitiesCocaineSmokingIUGRPreterm labourAminoglycosidesOtotoxicityChloramphenicol'Grey baby' syndromeTetracyclinesDiscoloured teethDiethylstilbesterol Vaginal clear cell adenocarcinomaLithium Ebstein's anomaly (atrialized right ventricle)Thalidomide Limb reduction defectsMaternal diabetes mellitusMacrosomiaNeural tube defectsCaudal regression syndromePolyhydramniosPreterm labourDigoxin 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 nervedigoxin has a narrow therapeutic indexMonitoring & Toxicity digoxin level is not monitored routinely, except in suspected toxicity (within 8 to 12 hours of the last dose)Plasma concentration alone does not determine digoxin toxicity (Might occur within the therapeutic range). likelihood of toxicity (↑↑ progressively from 1.5 to 3 mcg/l.)Featuresgenerally unwell, lethargy, nausea & vomiting,?anorexia,?confusion,?yellow-green visionArrhythmias (AV block,?bradycardia)GynaecomastiaPrecipitating factorsClassically:?HypokalaemiaHypokalaemia → digoxin more easily bind to the ATPase pump → increased inhibitory effects↑↑ ageRenal failureMyocardial ischaemia↑↑ (Ca, Na, H) Hypercalcaemia, Hypernatraemia, Acidosis↓↓Mg++ ↓↓ Abumin↓ ↓Temperature ↓↓ ThyroidDrugsAnti-arrhythmic ?Amiodarone,?Quinidine,?Verapamil,?DiltiazemSpironolactone?(competes for secretion in distal convoluted tubule therefore reduce excretion)Thiazides?and?Loop diuretics (Hypokalaemia) Ciclosporin.ManagementDigibindcorrect arrhythmiasmonitor potassiumDieuritics 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 IIACE inhibitors are activated by phase 1 metabolism in the liverSide-effects:Cough around 15% up to a year after starting treatment?increased bradykinin levelsangioedema: may occur up to a year after starting treatmenthyperkalaemiafirst-dose hypotension: more common in patients taking diuretics (Giddy = Syncope)Cautions and contraindicationspregnancy?and breastfeeding - avoidrenovascular?- significant renal impairment undiagnosed bilateral renal artery stenosisAS?- may result in hypotensionhereditary of idiopathic angioedemaspecialist advice ACE inhibitors in patients with K >= 5.0 mmol/LInteractionsHypotension high-dose diuretic therapy > 80 mg of furosemide a day)MonitoringU/E initially and after increasing the dosea 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, irbesartanS/E hypotension and hyperkalaemia. used with caution in patients with renovascular disease. Hypomagnesaemia Cause of low magnesiumAlcoholDrugs Diuretics Loop or ThiazideProton pump inhibitors"Omeprazole" when with Loop or Thiazide diuretics but are Not independently associated with hypomagnesaemia.DiarrhoeaConditions causing diarrhea Crohn's, ulcerative colitisTotal Parenteral nutrition Refeeding Syndrome. ↓↓ (K+, Ca++) Causes resistance for correction Metabolic disorders Gitleman's and Bartter'sFeatures may be?similar to hypocalcaemia:ParaesthesiaTetanySeizuresArrhythmias↓↓ PTH secretion → hypocalcaemiaECG features similar to those of Hypokalaemia (QT prolongation.)↑↑ Digoxin ToxicityTreatment< 0.4 mmol/l IV 40 mmol of Mg++ sulphate over 24 hours> 0.4 mmol/loral 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 toxicityLithium 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:Renal failureDehydrationDrugs:Diuretics (Especially?Thiazides" loop diuretics are safer)ACE inhibitors/ARBS(Both should not be commenced in hypertensive patient on Lithium)NSAIDsMetronidazole.Features of toxicityCoarse tremor (a fine tremor is seen in therapeutic levels)ComaAcute confusionHyperreflexiaSeizureManagementMild-moderate toxicity (Apathy and Restlessness) volume resuscitation with normal salineHaemodialysis Severe toxicity Level > 2 mmol/LNeurological symptoms (Seizures, Confusion) Renal failure. Na+ bicarbonate is sometimes used ↑↑ alkalinity of the urine (++) lithium excretionTricyclic overdoseAmitryptiline and Dosulepin (dothiepin) are particularly dangerous in overdose. FeaturesEarly features relate to anticholinergic propertiesDry mouth Dilated pupilsBlurred vision.AgitationSinus tachycardiaFeatures of severe poisoning include:ArrhythmiasSeizuresMetabolic acidosisComaECG changes include:widening of QRSWidening of QRS > 100ms ↑↑risk of seizures QRS > 160ms is ventricular arrhythmias.sinus tachycardiaprolongation of QT intervalManagement50 gm of charcoal if within one hour of ingestion.IV bicarbonate1st-line therapy (50 ml of 8.4%) ifpH < 7.1QRS > 100 msArrhythmiasHypotensionOther drugs for arrhythmiasclass 1a (Quinidine) and class Ic (Flecainide) are CI ↑↑ depolarisationclass III drugs (Amiodarone) avoided (↑↑QT interval)Response to lignocaine is variable.IV lipid emulsion increasingly used to bind free drug and reduce toxicity (Also Verapamil, BB)Dialysis is ineffective in removing tricyclicsOculogyric crisisA dystonic reaction ?form of extrapyramidal disorder to certain drugs or medical conditions. FeaturesRestlessness, Agitationinvoluntary upward deviation of the eyesCausesAntipsychoticsDopaminergic medications (classically Metoclopramide and Haloperidol)Post encephalitic Parkinson's diseaseManagementIV?Anti-MuscarinicBenztropine ProcyclidinediphenhydramineCocaineAlkaloid derived from the coca plant (recreational stimulant) (XX) the uptake (Dopamine, Noradrenaline and Serotonin)Cardiovascular effectsMyocardial infarctionhypertensionAortic dissectionboth tachycardia and bradycardia may occurQRS widening and QT prolongation.Neurological effectsseizuresMydriasisHypertonia, hyperreflexiaPsychiatric effectsagitationpsychosishallucinationsOthersischaemic colitis?following cocaine ingestion. (abdominal pain or rectal bleeding)HyperthermiaMetabolic acidosisRhabdomyolysisManagement of cocaine toxicityBenzodiazepines generally first-line for most cocaine-related problemsChest 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 itEcstasy poisoning (MDMA, 3,4-Methylenedioxymethamphetamine) Clinical featuresCNS agitation, anxiety, confusion, ataxiaCVS tachycardia, hypertension↓↓↓ Na↑↑ TemperatureRhabdomyolysisManagementsupportiveDantrolene may be used for hyperthermia if simple measures failNovel psychoactive substancesMedical term Recreational drugs (MDMA and Cannabis). Termed as 'Legal Highs'/ "M-CAT" StimulantsCannabinoidsHallucinogenicDepressantOther substancesSimilar to MDMA, Amphetamines ↑↑Serotonin, Dopamine Noradrenaline, 'high' and euphoriaCommon Ex "Mephedrone" ('bath salts','M-CAT'.'meow meow').Cathinone similar to khat, a plant in East AfricaBenzylpiperazine('Exodus', 'Legal X', 'Legal E')Swallowed as a pill/powder ('bombing') or snortedS/Esimilar to MDMA/cocaine.risk of serotonin syndrome"Synthetic Cannabinoid receptor agonists"Referred to as 'spice'Sprayed on to herbal mixtures smoked.liquid ( inhaled using e-cigarettesS/E like cannabisDissociatives and PsychedelicsDissociatives similar to ketamine (sense of not being connected to the physical body or time.Ex: Methoxetamine ('mexxy')Psychedelics Similar effect to LSD although may also be a stimulantOpioid ORBenzodiazepine-basedPill or a powderSimilar to the original drug & S/E are similarbenzodiazepine NPS ↑↑ longer half-lifeGamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL) 'G', 'Geebs' or 'Liquid Ecstasy'Respiratory ↓↓When taken with other respiratory ↓↓( alcohol)can be potentially life threateningNitrous oxide: 'Hippie crack'immunosuppressant drugsMycophenolate mofetil(- -) 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.Azathioprine 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-2Cyclosporine↓↓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)Nephrotoxicity Fluconazole (- -) metabolism of ciclosporin (↑↑Ciclosporin Nephrotoxicity).Hepatotoxicityfluid retention HTNhyperlipidaemia↑↑↑KHypertrichosis ( ↑↑Hair)gingival hyperplasiaTremorimpaired glucose tolerance↑↑ susceptibility to severe infectionIndicationsOrgan transplantationrheumatoid arthritispsoriasis (has a direct effect on keratinocytes as well as modulating T cell function)Ulcerative colitispure red cell aplasiaTacrolimusTacrolimus 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 releasebinds 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 commonMethotrexateAntimetabolite 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. Indicationsinflammatory arthritis, especially?rheumatoid arthritispsoriasissome chemotherapy acute lymphoblastic leukaemiaAdverse effectsMucositisMyelosuppressionPneumonitisPulmonary fibrosisLiver fibrosisPregnancyAvoided for at least?6 months?after treatment has stoppedMen using methotrexate need to use effective contraception for at least?6 months?after treatmentPrescribing methotrexate High potential for patient harm taken weekly, rather than dailyFBC, 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 doseStarting dose 7.5 mg weekly only one strength prescribed (usually 2.5 mg)Interactionsavoid prescribing?trimethoprim?OR Co-trimoxazole?concurrently - ↑↑↑ risk of marrow Aplasia↑↑ - dose?Aspirin ?↑↑ risk of methotrexate toxicity secondary to reduced excretionMethotrexate toxicityTreatment of choice is?folinic acidHydroxychloroquine 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 effectsbull's eye retinopathy - may result in severe and permanent visual lossrecent 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 maculabaseline ophthalmological examination?and annual screening is generally recommenedA contrast to many drugs used in rheumatology, hydroxychloroquine may be used if needed in pregnant women.Monitoringthe 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 includebone marrow depressionnausea/vomitingpancreatitisincreased risk of non-melanoma skin cancerA 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:activates macrophages and neutrophilsacts as costimulator for T cell activationkey mediator of bodies response to Gram negative septicaemiasimilar properties to IL-1anti-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 serumSystemic effects include pyrexia, increased acute phase proteins and disordered metabolism leading to cachexiaTNF is important in the pathogenesis of rheumatoid arthritis - TNF blockers (e.g. infliximab, etanercept) are now licensed for treatment of severe rheumatoidTNF blockersinfliximab: monoclonal antibody, IV administrationetanercept: fusion protein that mimics the inhibitory effects of naturally occurring soluble TNF receptors, subcutaneous administrationadalimumab: monoclonal antibody, subcutaneous administrationadverse effects of TNF blockers include reactivation of latent tuberculosis and demyelinationMonoclonal 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 + Constant region from human antibody.UsesMedical imaging when combined with a radioisotopeIdentification of cell surface markers in biopsied tissueDiagnosis of viral infectionsExample Mechanism of actionUses (anti-TNF)InfliximabRheumatoid arthritis Crohn'sTNF alpha antagonistEtanerceptT.B and viral hepatitis should be ruled out prior to starting therapyPsoriasisanti-IL17Brodalumabcompleted registration for psoriasis reserved however for patients who fail to control on other interventionsAnti- IL6Toclizumab Rheumatoid arthritisOKT3 (anti-CD3) Muromonab-CD3prevent organ rejection(anti-CD20)Twenty RituximabNon-Hodgkin's lymphoma Rheumatoid arthritis(anti-CD52)AlemtuzumabChronic lymphocyticleukaemia "Programmed Cell Death" inhibitor (PD-1) NivolumabPD-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)Ipilimumabdown-regulates T cell responses by cancer Blocking this with inhibitors (++) immune system against cancer.?Nivolumab + IpilimumabUndergoing trials Solid malignancies lung,oesophageal& head and neck Prolonged therapy Hypophysitis and Hypothyroidism (Conistipation,..Stage 4 Metastatic MelanomaLymphoma."Epidermal growth factor receptor antagonist"(EGFR)(HER1) "Human epidermal growth factor" antagonistCetuximabErlotinib (Tarceva)Oncogenic (++) Tyrosine kinases autophosphorylates the receptor Cancer cell growth.Metastatic colorectal cancer.SQ. cell cancers. 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 kinasesMetastatic breast cancerTrastuzumab + cisplatin + capecitabine OR 5-fluorouracil for HER2 +Ve metastatic stomach adenocarcinoma HER3Overexpression 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 cancerPlatelet-Derived Growth Factor Receptor (PDGFR)ImatinibDasatinibActs on tyrosine kinase receptorsTreatment of leukaemiasglycoprotein IIb/IIIa receptor antagonistAbciximabPrevention of ischaemic event in patients undergoing PCIALK-1 inhibitorsCrizotinibActs 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 effectsFlu-like symptoms and diarrhoea are commonCardiotoxicity more common when Anthracyclines also used. (Echo before starting treatment)Immunoglobulins: therapeuticsformed from large pool of donors (5,000) IgG molecules with a subclass distribution similar to that of normal bloodHalf-life of 3 weeksUses of IV immunoglobulins 1ry and 2ry Immunodeficiency↓↓ serum IgG levels following haematopoietic stem cell transplant for malignancyIdiopathic thrombocytopenic purpuraMyasthenia gravisGuillain-Barre syndromechronic inflammatory demyelinating polyradiculopathyKawasaki diseaseToxic Epidermal NecrolysisDermatomyositisPneumonitis induced by CMV following transplantationMetforminA biguanide used type 2 D.M. it does not cause hypoglycaemia and weight gain USES1st-line D.M, particularly (overweight).Polycystic ovarian syndrome Non-alcoholic fatty liver diseaseMechanism of action(++) AMP-activated protein kinase (AMPK)Major cellular regulator of lipid and glucose metabolism (++) (glucose uptake, fatty acid oxidation, insulin sensitivity)/ (- -)gluconeogenesis.?↑↑ insulin sensitivity↓↓ hepatic gluconeogenesismay ↓↓gastrointestinal absorption of carbohydratesAdverse effects?GIT "5 %Common"?(nausea, anorexia, Diarrhoea, Bloating) intolerable in 20%↓↓ Vit B12 absorption?- rarely a clinical problemLactic Acidosis* with severe liver disease or?renal failureContraindicationsChronic kidney disease Reviewed if Creatinine is > 130 ?mol/l (or eGFR < 45 ml/min)Stopped if the creatinine is > 150 ?mol/l (or?eGFR < 30 ml/min)↑↑ Tissue hypoxia (Recent MI, Sepsis, AKI and severe dehydration)May cause Lactic AcidosisMetabolic Acidosis W ↑↑Anion gap Iodine-containing x-ray contrast media (Angiography, CA, IV Pyelography (IVP)↑↑ renal impairment due to contrast nephropathyDiscontinued on the day of the procedure and for 48 hours thereafterAlcohol abuse is a relative contraindicationStarting MetforminMetformin should be?titrated up slowly?to ↓↓incidence GIT side-effects500mg od with food for 14 days (at least 1 week) then 500mg bd for 14 days then review.Unacceptable side-effects (GIT) Modified-release metformin (evening) should be consideredstarted at 500mg once per day ↑↑ 10-15 days on the basis of blood glucose measurementsUp 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 movementManagement ( Hyoscine > Cyclizine > Promethazine)Hyoscine (Transdermal patch) most effective treatment (Use is limited due to S/E)Non-sedating antihistamines (Cyclizine or Cinnarizine) in preference to sedating preparation (Promethazine). FinasterideFinasteride is 5 alpha-reductase inhibitor (enzyme metabolises testosterone into dihydrotestosterone. IndicationsBenign prostatic hyperplasiamale-pattern baldnessAdverse effectsImpotenceEjaculation disorders↓↓ libidoGynaecomastia and Breast tendernessFinasteride causes decreased levels of serum prostate-specific antigenQuinine 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 Cardiac arrhythmia Common finding blockade of Na channel↑↑ QRS and k channel QT intervals VT or VF causing death.?Flash pulmonary oedema hypoxia and necessitating positive pressure ventilation.Hypoglycaemia?"Common finding" (++) pancreatic insulin secretion and this should be corrected rapidly if present. Classical hallmarks (CNS) Tinnitus, Visual blurringDD. difficult to distinguish from aspirin poisoning measurement of serum salicylate levels.permanent neural damage, if the patient survives.?Flushed and dry skin and Abdominal pain.Metabolic Acidosis?Long-term fatal.?Incipient renal failureManagement largely supportive with fluids, inotropes and bicarbonate as needed Positive pressure ventilation for pulmonary oedema.Drug causes of AgranulocytosisAntithyroid drugs Carbimazole, PropylthiouracilAntipsychotics atypical antipsychotics (CLOZAPINE)Antidepressant MirtazapineAntiepileptics ?Carbamazepine, ValproateAntibiotics Penicillin,?Chloramphenicol, Co-trimoxazoleCytotoxic drugs MethotrexateDrug-induced impaired glucose toleranceDrugs cause impaired glucose tolerance:Thiazides,?furosemide?(less common)SteroidsTacrolimus,?CiclosporinInterferon-alphaNicotinic acidAntipsychoticBeta-blockers?cause a slight impairment of glucose tolerance used with caution in diabetics as they can?interfere with the metabolic and autonomic responses to hypoglycaemiaDrug-induced thrombocytopenia (probable immune-mediated)HeparinAntibiotics Penicillins, Sulphonamides, RifampicinAnticonvulsants Carbamazepine, ValproateQuinineAbciximabNSAIDs (enhance platlet aggregation )Diuretics: FurosemideG6PD Drugs Absolute CIHigh riskSmall riskNo theoretical riskQuinolones CiprofloxacinNorfloxacin Moxifloxacin)PrimaquineSulfonamidesMethylene blueDapsone DoxorubicinChloroquine Trimethoprim Ibuprofensodium valproate Drug causes of urticariaAspirin (common)NSAIDsPenicillins ?Most common antibiotic (Doxycycline might cause but less common)OpiatesDrug-induced urinary retentionTricyclic Antidepressants Amitryptiline (has also anti- cholinergic effect)AnticholinergicsOpioidsNSAIDsDisopyramideDrugs causing lung fibrosisPatient might presented W chronic cough & dyspnea + fine inspiratory crackles , FEV1/FVC ratio >70%.AmiodaroneNitrofurantoinPenicillamineCytotoxic agents Busulphan,?Bleomycin, CyclophosphamideAnti-rheumatoid drugs ?Methotrexate,?SulfasalazineErgot-derived dopamine receptor agonists (bromocriptine, cabergoline, pergolide)Drugs causing ocular problemsCataractsCorneal OpacitiesOptic neuritisRetinopathySteroidsAmiodaroneIndomethacinAmiodaroneEthambutolMetronidazoleChloroquine (hydroxychloroquine). QuinineVigabatrin.Sildenafil can cause both blue discolouration and non-arteritic anterior ischaemic neuropathyDrugs causing photosensitivityA maculopapular erythematous rash on the forearms and face and anterior chest W sun exposure typical of a photosensitivity rashThiazidesAnti-biotics Tetracyclines, Sulphonamides, CiprofloxacinAnti –arrhythmic AmiodaroneAnti- glycemic sulphonylureasNSAIDs PiroxicamPsoralensToxinTreatmentParacetamolactivated charcoal if < 1 hour agoN-acetylcysteine (NAC)liver transplantationSalicylateUrinary alkalinization is now rarely used CI Cerebral and pulmonary oedema (most units now proceeding straight to haemodialysis severe poisoning)haemodialysisOpioid/opiatesNaloxoneBenzodiazepinesFlumazenil (Risk of seizures with flumazenil only used with severe or iatrogenic overdoses).The majority supportive care only TricyclicAntidepressantsIV bicarbonate? ↓↓ seizures and arrhythmias in "severe toxicity"ArrhythmiasCorrection of acidosis is the first lineClass 1a (Quinidine) and class Ic antiarrhythmics (Flecainide) are contraindicated prolong depolarisation. Class III drugs (Amiodarone) avoided prolong the QT interval. Response to lignocaine is variable Dialysis is ineffective in removing tricyclicsLithiumMild-moderate toxicity volume resuscitation with normal salineHaemodialysis? severe toxicityNa+ bicarbonate sometimes used ↑↑ alkalinity of the urine it promotes lithium excretionWarfarinVitamin K, prothrombin complexHeparinProtamine sulphateBeta-blockersif bradycardic then?atropinein resistant cases?glucagon?may be usedEthylene glycolethanol?has been used for many yearsworks by competing with ethylene glycol for the enzyme alcohol dehydrogenasethis limits the formation of toxic metabolites (e.g. Glycoaldehyde and glycolic acid) which are responsible for the haemodynamic/metabolic features of poisoningfomepizole, an inhibitor of alcohol dehydrogenase, is now used first-line in preference to ethanolHaemodialysis?also has a role in refractory casesMethanol poisoningfomepizole or ethanolhaemodialysisOrganophosphate insecticidesAtropinethe role of pralidoxime is still unclear - meta-analyses to date have failed to show any clear benefitDigoxinDigoxin-specific antibody fragmentsIronDesferrioxamine a chelating agentLeadDimercaprol, calcium edetateCarbon monoxide100% oxygenhyperbaric oxygenCyanideHydroxocobalamin; also combination of?amyl nitrite, sodium nitrite, and sodium thiosulfateTherapeutic drug monitoringPhenytoinCiclosporinDigoxinLithiumNot monitored routinely immediately before dose?(checked if)adjustment of phenytoin dosesuspected toxicitydetection of non-adherence to medication immediately before doseat least 6 hrs post-doserange = 0.4 - 1.0 mmol/ltake 12 hrs post-doseHaemodialysis in overdoseDrugs cleared with haemodialysis " BLAST"Drugs cannot be cleared with haemodialysis "BBDDT"BarbiturateLithiumAlcohol (inc methanol, ethylene glycol)SalicylatesTheophyllines (charcoal haemoperfusion is preferable)beta-blockersbenzodiazepinestricyclicsdigoxindextropropoxyphene (Co-proxamol)Prescribing in patients with heart failureThe following medications may exacerbate heart failure:ThiazolidinedionesPioglitazone is contraindicated as it causes fluid retentionVerapamilnegative inotropic effectNSAIDs/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 risksClass I antiarrhythmicsFlecainide (negative inotropic and proarrhythmic effect)Prescribing in patients with renal failureavoid in renal failureAccumulate in CKD "Dose adjustment"Relatively safe "according degree CKD" AntibioticsTetracyclineNitrofurantoinNSAIDsLithiumMetforminMost antibioticsPenicillinsCephalosporinsVancomycin GentamicinStreptomycinDigoxinAtenololMethotrexateSulphonylureasFurosemideOpioids Oxycodone safer opioid moderate to end-stage renal failure metabolised in the liverMorphine metabolites accumulate in renal failure?AntibioticsErythromycin RifampicinDiazepamWarfarinDiabetes drugs:Side effectDrugSide-effectMetforminGIT side-effectsLactic acidosisSulfonylureasChlorpropamideHypoglycaemic episodes↑↑ appetite and weight gainSIADHLiver dysfunction (cholestatic)GlitazonesWeight gainFluid retention (CI : Heart failure)Liver dysfunctionFracturesGliptinsPancreatitisPrescribing in pregnant patientsVery few drugs are known to be completely safe in pregnancy. If given history of absence/ Non-effective contraception treated as pregnant AntibioticsTetracyclinesAminoglycosidesSulphonamidesTrimethoprimQuinolones (Avoid due to arthropathy in some animal studies)Other drugsACE inhibitors, ARBsStatinsWarfarinSulfonylureasMetformin Sometimes used in pregnancy many diabetic women are converted to insulin for the duration of the pregnancy to try and maximise control and minimise complicationsRetinoids (including topical)Cytotoxic agentsThe 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 ................
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