Pharmacopoeia ICU Flashcards

Question

ENOXAPARIN (LMWH) / ANTICOAGULANT

Answer 1

Consisting of smaller fragments of heparin, LMWH is prepared from unfractionated heparin by controlled enzymatic or chemical depolymerization. The mean molecular weight of LMWH is 5000, one-third the mean molecular weight of unfractionated heparin. It has similar indications to unfractionated heparin. PHARMACEUTICAL ASPECTS Usually given SC, but can be given IV for a more rapid response. PHARMACODYNAMICS Like heparin, LMWH exerts its anticoagulant activity by activating antithrombin. With a mean molecular weight of 5000, which corresponds to about 17 saccharide units, at least half of the pentasaccharide-containing chains of LMWH are too short to bridge thrombin to antithrombin. Consequently, LMWH catalyzes factor Xa inhibition by antithrombin more than thrombin inhibition PHARMACOKINETICS ABSORPTION bioavailabilty 90% after SC injection (more than heparin) routes of administration SC (occasionaly IV) doses 1mg/kg BD therapeutic, 20 or 40mg OD Prophylactic onset / duration Antifactor Xa activity: ~12 hours DISTRIBUTION volume of distribution 4.3 L (based on antifactor Xa activity) protien binding Does not bind to heparin binding proteins METABOLISM mechanism Hepatic, to lower molecular weight fragments (little activity) ELIMINATION half life 2-4 times longer than standard heparin, independent of dose; excretion Urine (40% of dose; 10% as active fragments) MAJOR ISSUES OR SIDE EFFECTS Unlike heparin, enoxaparin is excreted renally and as such it requires dose adjustment in the setting of renal impairment. It has an improved side eect prole however with signicantly less thrombocytopaenia and osteoporosis, enabling long term treatment.

Answer 2

Erythromycin is the parent drug of the macrolides, but newer drugs such as clarythromicin and roxithromycin are also available. They have a similar range of activity to penicillins and may be used as an alternative in patients with allergy. They cover most gram positive organisms, Neisseria and haemophilis, with activity against gram positive and gram negative aneorobes. They may also be used as a prokinetic in critical care. PHARMACEUTICAL ASPECTS Available in both oral and IV PHARMACODYNAMIC ASPECTS Macrolides are baceteridal or bacteriostatic bepending on plasma concentration. They halt bacterial protien synthesis by binding to the 50S ribosomal subunit. PHARMACOKINETIC ASPECTS ABSORPTION bioavailabilty 18% to 45% routes of administration PO/IV doses up to 4g per day in divided doses onset / duration 2-4 hrs to peak, food dependent DISTRIBUTION volume of distribution protien binding 73% to 81% lipid solubility minimal CSF penetration some improve ment with inammed meninges METABOLISM mechanism Demethylation primarily via hepatic CYP3A4 ELIMINATION half life 1.5-2 hours excretion Primarily feces; urine (2% to 15% as unchanged drug) MAJOR ISSUES OR SIDE EFFECTS Nausea, vomitting and diarrhoea occur especially following IV delivery due to the prokinetic eect. Associated with a prolonged QT with attendant risk of arryth mias. Actions of warfarin, theophylline and digoxin may all be increased with coadministration of macrolides.

Answer 3

Is a cardioselective beta blocker with rapid onset and oset. It is used for the short term management tachycardia and hypertension in a monitored patient and for SVT termination. It has no intrinsic sympathomimetic activity or membrane stabilising properties. PHARMACEUTICAL ASPECTS It is only available as an IV formulation. It is presented as a clear liquid usually at a concentration of 10mg/ml. PHARMACODYNAMIC ASPECTS Beta blockage leads to decreased Gs activity in receptor associated organs and associated decrease in adenylyl cyclase and intracellular Ca2+. It produces decreases in heart rate and cardiac output and myocardial oxygen consumption. PHARMACOKINETIC ASPECTS ABSORPTION bioavailabilty Only available as IV therefore 100% routes of admin IV dose In 10mg increments titrate to eect DISTRIBUTION volume of distrib 3.5 L/Kg protien binding 60% to albumin lipid solubility is high so it crosses the BBB METABOLISM neither hepatic or renal! by red blood cell esterases to a mostly inactive metabolite ELIMINATION half life 10 minutes excretetion In urine MAJOR ISSUES OR SIDE EFFECTS Care should be taken when used in conjuction with opiods and halothane and in patients with obstructive airway disease. Use with Ca Channel blockers may result in complete heart block. It is an irritant to veins and may lead to tissue necrosis with extravasation

Answer 4

Fentanyl is a synthetic phenylpiperidine derivative with a rapid onset of action. It is a μ receptor agonist and as such it shares morphines eects. It’s main dierences are due to it’s lipid solubility, rapid redistribution and prolonged context sensitive half time. PHARMACEUTICAL ASPECTS Fentanyl is presented as a colourless solution for injection containing 50 mcg/ml, as transdermal patches (25mcg-100mcg per hour) and as lozenges. PHARMACODYNAMIC ASPECTS It has the same mode of action and generally similar eects to morphine although it is less likely to precipitate histamine release. PHARMACOKINETIC ASPECTS ABSORPTION bioavailabilty 50-70% when taken buccal/sublingual route routes of administration IM, IV, buccal, topical doses Bolus: 1-2 mcg/kg or 25-100 mcg/dose; continuous infusion rate: 1-2 mcg/kg/hour or 25-200 mcg/hour onset I.M.: 7-8 mins; I.V immediate; Transdermal 6 hours duration I.M.: 1-2 hours; I.V.: 0.5-1 hour; Transdermal 12 hrs DISTRIBUTION volume of distribution 4-6 L/kg protien binding 80% to 85% lipid solubility Highly lipophilic (600 times morphine) pKa 8.4 (10% ionised) METABOLISM mechanism Hepatic, primarily via CYP3A4 ELIMINATION half life I.V.: 2-4 hours, prolonged context sensitive half time excretion Urine 75% MAJOR ISSUES OR SIDE EFFECTS The side effect profile is similar to morphine. Differences are due to the lipid solubility. Unlike morphine it does not cause delayed respiratory depression because it rapidly diuses into and out of the CSF. Because of the raised context sensitive half time prolonged infusion may lead to increased duration of action and subsequent side eects.

Answer 5

Flecainide is a fluorinated derivative of procainamide. Flecainide is used in the prophylaxis and treatment of paroxysmal atrial brillation or utter, SVT and serious ventricular arrhythmias not responsive to other therapies including DC shock. PHARMACEUTICAL ASPECTS It is presented as an IV presentation in 10mg/ml or in an oral preparation in 50 or 100mg tablets. Concentration monitoring aims for a therapeutic range of 0.-0.9 mg/L PHARMACODYNAMIC ASPECTS Flecainide prevents the fast sodium f;ux into cardiac tissue and prolongs phase 0 of the action potential. It has no eect on the action potential duration or the refractory period. Its eects are more pronounced in the conduction pathways. It has moderate negative inotropic eects. PHARMACOKINETIC ASPECTS ABSORPTION bioavailabilty rapidly absorbed, 90% bioavailability routes of administration IV/ PO doses IV 2mg/Kg over 10 minutes, PO 50-100mg BD DISTRIBUTION volume of distribution 6-10kg/L protien binding 50% METABOLISM mechanism hepatic with active metabolites ELIMINATION half life 7-22 hours, increased with congestive heart failure or renal dysfunction; End-stage renal disease: excretion Urine (80% to 90%, 10% to 50% as unchanged drug and metabolites) MAJOR ISSUES OR SIDE EFFECTS Dizziness, parathesia and headaches complicate use. The major drawback of ecainide however is the proarrhythmogenic aspects, especially in the setting of LV dysfunction or recent MI. has signicant pharmacokinetic interactions with many other drugs, including digoxin, propranolol and amiodarone.

Answer 6

Flucloxacillin is a semi synthetic penicillin which has a narrow spectrum but is useful for treating staphlococci which are resistant to benpen due to beta-lactamase activity. It is well absorbed from the gut but is given IV if the infection is serious. It should not be used if the organism is sensitive to benpen as benpen is more bacteriocidal. PHARMACEUTICAL ASPECTS May be given orally or parenterally. It is marketed under several trade names in Australia including Flopen. It is available in tablet form or powder for reconstitution. PHARMACODYNAMIC ASPECTS Beta-lactam antibiotics inhibit the growth of sensitive bacteria by inactivating enzymes located in the bacterial cell membrane, which are involved in the third stage of cell wall synthesis. It is during this stage that linear strands of peptidoglycan are cross-linked, beta lactams prevent this linking occuring. PHARMACOKINETIC ASPECTS ABSORPTION bioavailabilty 50–70% routes of administration PO, IV or IM doses Usually given QID or TDS in up to 2g/day DISTRIBUTION volume of distribution ~0.28 L/kg protien binding up to 95% lipid solubility penetration into CSF occurs with inamed meninges only METABOLISM mechanism Hepatic with active metabolites ELIMINATION half life 0.75–1 hours, prolonged in anuria/renal impair excretion Urine (50-65% as unchanged drug) MAJOR ISSUES OR SIDE EFFECTS Up to 10% of the population have allergies to penicillins. Due to the high percentage excreted renally unchanged dose adjustment is required in low urine output states. Severe cholestatic hepatitis has been reported idiosyncratically.

Answer 7

Flumazenil is an imidazobenzodizepine. It is a competitive antagonist at benzodiazepine and is used for the reversal of BDZ sedation used for anaesthesia. It may be used for BDZ overdose or intoxication but it is rarely indicated for this use due to the associated risks of precipitating a withdrawal syndrome. PHARMACEUTICAL ASPECTS It is available in injectable form, 0.1mg/ml in 5ml vials. PHARMACODYNAMICS Competes with benzodiazepines at GABAA receptors and reduces the potentiation eect of BDZ at this receptors. Flumazenil does not antagonize the CNS eect of drugs aecting GABA-ergic neurons by means other than the benzodiazepine receptor (such as ethanol, barbiturates, general anesthetics) and does not reverse the eects of opioids. PHARMACOKINETICS ABSORPTION bioavailabilty 100% routes of administration IV doses 0.1-0.3mg initially, titrate to eect up to 2mg onset / duration 1-3 mins / ~1 hour (nb may wear o prior to metabolism of the BDZ thus a return to sedation is a concern). DISTRIBUTION volume of distribution Initial Vd: 0.5 L/kg protien binding 40% to 50% METABOLISM mechanism Hepatic; dependent upon hepatic blood ow (therefore prolonged in liver failure) ELIMINATION half life biphasic, initial 10 mins, terminal 40-80mins excretion urine MAJOR ISSUES OR SIDE EFFECTS Side eects include nausea and vomitting. It may precipitate anxiety and agitation. Major concern is precipitating a withdrawal syndrome in a BDZ dependent patient, therefore caution should be exercised when considering its use.

Answer 8

Frusemide is an organis ion that enter the tubular lumen primarily through secretion into the proximal tubule. Frusemide is a carboxylic acid derivative and represents the most potent diuretic available, are responsible for an 25% increase in the excretion of sodium ltered load. It is used in severe heart failure to reduce peripheral and pulmonary oedema. It may also be used in chronci and acute renal failure. PHARMACEUTICAL ASPECTS It is available as both a tablet form in 20 and 40mg quantities and for IV injection PHARMACODYNAMIC ASPECTS Frusemide acts in the thick ascending limb of the loop of Henle where it inhibits Na+ reabsorption by blocking the Na+.K+.2Cl- symporter located in the apical membrane of these cells and causing a signicant diuresis. It produces arteriolar vasodilation which reduces TPR. Preload is also reduced ahead of any diuresis. In contrast to thiazides there is a decrease in renal blood ow. The main electrolyte disturbances are hypokalaemia, hyponatraemia, hypomagnesmaemia and a hypochloraemic alkalosis. PHARMACOKINETIC ASPECTS ABSORPTION bioavailabilty Orally - 50% (20mg PO = 10mg IV) routes of administration PO, IV, SL, IM doses ranging from 10-20mg stat to 2-3g grams per day onset Diuresis: Oral, S.L: 30-60 minutes; I.V.: ~5 minutes duration Oral, S.L.: 6-8 hours; I.V.: 2 hours DISTRIBUTION protien binding 91% to 99%; primarily to albumin METABOLISM mechanism Minimally hepatic ELIMINATION half life Normal renal function: 0.5-2 hours; End-stage renal disease: 9 hours excretion Urine (Oral: 50%, I.V.: 80% as unchanged drug) MAJOR ISSUES OR SIDE EFFECTS It may cause ototoxicity, especially if delivered in high doses rapidly, this is compounded by impaired renal function and the use of aminoglycosides. Electrolyte disturbances as liste above, often given with potassium replacement or potassium sparing drugs.

Answer 9

Glyceryl trinitrate (also known as nitrogylcerin) is an organic nitrate similar to isosorbide mononitrate and isosorbide dinitrate. It is used for the treatment of stable angina and acute pulmonary oedema. PRESENTATION It is presented in tablets for sublingual administration, in transdermal patches and as a clear liquid with a concentration of 5mg/ml. The injectable form comes in a glass vial due to GTN being absorbed into some plastics. PHARMACODYNAMICS The mode of action is the same for the inorganic nitrates although GTN must rst combine with Thio containing compound to produce NO. . NO activates guanylyl cyclase in smooth muscles which in tern increases cGMP leading to a reduction in intracellular calcium and vasodilation. Venous dilation is greater than arterial dilation and the benets in angina are believed to be related to decreased myocardial oxygen demand. In the CNS vasodilation increases ICP and causes headache. There is also relaxation of the sphincter of Oddi in the gut. PHARMACOKINETICS ABSORPTION bioavailabilty Rapidly absorbed from the sublingual mucosa and enters the circulation via the SVC. Also absorbed in the gut but rst pass metabolism means a bioavailabity is as low as 5% routes of administration SL, IV, Topically doses 400-800mcg SL, 5mg Top, 5-80mcg min uptitrated IV onset / duration SL 1-3 mins / 25 mins. IV immediate/ 5mins DISTRIBUTION volume of distribution ~3 L/kg protien binding 60% METABOLISM mechanism Hepatic to via thiols into NO products ELIMINATION half life 1-4 minutes excretion Urine (as inactive metabolites) Headache is a common side eect due to raised ICP from cerebral venodilation. MAJOR ISSUES OR SIDE EFFECTS There is rapid tolerance possibly due to thiol depletion and breaks are required for chronic administration such as transdermal delivery. A rare side eect is development of methaemoglobin.

Answer 10

Heparin is an anionic, mucoploysaccaride, organic acid containing many sulphide residues. It occurs naturally in the liver and mast cell granules and has a variable molecular weight of 5000 - 25000 Daltons. It is used for the treatment and prevention of VTE, ACS, and in haemodylasis and ECMO. PRESENTATION It is derived from porcine mucosal cells rich in mast cells. It is available only in injectable form (SC or IV) and is described in terms of international units not weight due to its variable potencies. PHARMACODYNAMICS Heparin acts as an anticoagulant by activating antithrombin and accelerating the rate at which antithrombin inhibits clotting enzymes, particularly thrombin and factor Xa. Once bound to antithrombin, heparin induces a conformational change in the reactive center loop of antithrombin that renders it more readily accessible to its target proteases. PHARMACOKINETICS ABSORPTION bioavailabilty reduced SC due to endothelial binding routes of administration IV / SC doses 5000U SC BD prophylaxis, 5000U IV then infusion therapeutic doses (titrate to eect) onset / duration I.V.: Immediate; SC: ~20-30 minutes DISTRIBUTION protien binding very high lipid solubility low, does not cross BBB or placenta METABOLISM mechanism Hepatic by heparinases ELIMINATION half life variable half life - rapidly binds endothelial cells resulting in a short half life at low doses (30mins), as dose increases half time is prolonged (up ot 150mins) excretion urine MAJOR ISSUES OR SIDE EFFECTS Associated with bleeding, thrombocytopaenia (associated with heparin induced thrombocytopaenia syndrome HITS) and osteoporosis (if delievered for greater than a month). It can cause a transient trasaminitis. In the event of bleeding, protamine will bind heparin (1mg per 100U) thus reduce further haemorrhage.

Answer 11

Hydralazine is a direct vasodilator whose mechanism of action is poorly understood. It is sometimes used IV in the treatment of hypertensive emergencies, and in the management of severe HTN associated with pregnancy. PRESENTATION It is available in oral forms 25-50mg and as a 20mg powder for reconstitution and injection. It should not be reconstituted with 5% dextrose because this degrades the drug quickly. PHARMACODYNAMICS Diffrent textbooks identify dierent mechanisms for this drug which indicate the poor understanding. It is poosible that hydralazine activates guanylyl cyclase, increasing cAMP and decreasing Ca, causing vasodilation. NO may play a role. IP3 may be a second messenger involved. The eects are arteriole vasodilation with preserved venous tone, and minimal eect on epicardial vasculature. There is a reex increase in HR, CO and activation of the RAAS leading to peripheral oedema. PHARMACOKINETICS ABSORPTION bioavailabilty well absorbed but high rst pass metabolism leading to a bioavailability of 30% routes of administration oral or IV doses 25-100mg BD PO, 5-10mg over 20mins, titrated onset / duration 15mins / up to 4 days possibly due to avid smooth muscle binding (Hemmings) DISTRIBUTION protien binding 85% to 90% METABOLISM mechanism N-acetylated in the bowel and/or the liver ELIMINATION half life is greatly dependent on genetically acetylation rates, ranging from 1 hour to 8 hours excretion MAJOR ISSUES OR SIDE EFFECTS The activation of the RAAS and the increase in HR and Co make this drug less ecacious. Because of this reason it is often given in combination with a thiazide or betablocker. Long term use is associated with lupus like syndrome Christopher Andersen 2012

Answer 12

HYDROCHLOROTHIAZIDE / THIAZIDE DIURETIC PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Thiazides are chemically related to the sulphonamides and are widely used in the treatment of heart failure and hypertension, often in combination with another class of drug. Like the loop diuretics organic anions. They are also mostly bound to plasma protiens, and they gain access to the tubule via secretion in the proximal tubule. Is available in orange scored tablets of 25mg or in a range of dierent combination medications with other antihypertensives. HCT acts to inhibit Na+ reabsorption in the early portion of the distal tubule by blocking the Na+.Cl- symporter in the apical membrane of these cells. Naturesis occurs with thiazide diuretics is 5-10% of the ltered load. They achieve their antihypertensive eect by a reduction in TPR and decrease plasma volume, these eects are achieved at a low dose. They reduce renal blood ow and may cause a reduction in GFR. Like frusemide they cause hypo -kalaemia, natraemia, chlorameic acidosis, and magneseamia. Unlike frusemide they may cause a hypercalcaemia secondary to decreased excretion. Reduced glyconeogensis and insulin may lead to increased BSL. ABSORPTION bioavailabilty ~50% to 80% routes of administration PO doses 12.5-200mg daily onset / duration Diuresis: ~2 hours / 6-12 hours DISTRIBUTION volume of distribution 3.6-7.8 L/kg protien binding 68% METABOLISM mechanism Not metabolized ELIMINATION half life 5.6-14.8 hours excretion Urine (as unchanged drug) One of the main issues is potassium derangement in addition to the other metabolic disturbances listed above. There are a range of indiosyncratic blood dyscrasias. Rash and photsensitivity may occur. Interactions may prolong the action of non depolarising muscle relaxants. NSAIDs antagonise their action.

Answer 13

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Ibuprofen is a proprionic acid non steroidal anti inammatory drug. It has mild anti inammatory and analgesic eects but has the best saftey prole of the commonly used NSAIDs. It is normally presented as 200mg tablets, although it may be prepared in some formulations in combination with codiene. Reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, which results in decreased formation of prostaglandin precursors; has antipyretic, analgesic, and anti-inammatory properties ABSORPTION bioavailabilty Rapid (85%) routes of administration oral doses 400mg TDS onset / duration 30-60 minutes / 4-6 hours DISTRIBUTION volume of distribution Vd: 6.35 L protien binding 90% to 99% (may displace highly protien bound drugs such as warfarin altering their pharmacody namic properties. pKa 4.5 weak acid (mostly non ionised and therefore absorbed via the gut and small bowel METABOLISM mechanism Hepatic via oxidation ELIMINATION half life 2-3 hours excretion Urine (primarily as metabolites; 1% unchanged) Selective COX-2 inhibitors are associated with an increased risk of thromboembolic events, however all NSAIDs, irrespective of their selectivity can worsen cardiovas cular disease. NSAIDs may worsen renal function by impairing the action of PGE2 and causing vasoconstriction. Much of the concern with NSAIDs relates to their increased risk of gastrointestinal events such as ulceration and GORD. COX-2 selectivity reduces this morbidity but has not shown a mortality benet, possibly due to the drugs causing delayed healing of ulcers. Lastly, ibuprofen may reduce the beneficial aspects of antiplatelet action caused by low dose aspirin.

Answer 14

Isoprenaline is a synthetic catcholamine which used primarily for its beta agonist properties. In Australia it is indicated in heart block, unstable bradycardia and as an adjunct in cardiogenic, septic of hypovolaemic shock. It is available in injectable form only, in concentrations of 200mcg/mL, in 1 and 5ml vials. Its eects are via agonism of the beta1 and 2 receptors. As such it increases heart rate and inotropy (beta1), and tends to maintain systolic BP but decreases diastolic BP due to decreased peripheral resistance. (beta2). It is a potent bronchodilator but tends to worsen V/Q matching (it was previously used for this purpose in the UK but was withdrawn due to increased mortality). It has stimulant eects on the CNS. It increases splanchic and renal perfusion due to vasodilation (beta2). ABSORPTION bioavailabilty 100% routes of administration IV doses 20mcg bolus or 0.5-10mcg/minute titrated onset / duration IV immediate / 10-15 minutes DISTRIBUTION protien binding 65% protien bound METABOLISM mechanism Via conjugation in many tissues including hepatic and pulmonary ELIMINATION half life 2.5-5 minutes excretion Urine (primarily as sulfate conjugates) It is contraindicated in tachycardia, and may worsen ischaemia due to increased myocardial oxygen demand. It may cause hypoxia due to a worsening of V/Q matching. Tachyphlaxis may occur in prolonged use.

Answer 15

Ketamine is a phencyclidine (remember the street drug name PCP) derivative that produces dissociative anesthesia, which resembles a cataleptic state in which the eyes remain open with a slow nystagmic gaze. It also produces profound analgesia at subanaesthetic doses and modulates central sensitization, hyperalgesia and opioid tolerance. Ketamine is presented as a racemic mixture or as the single S (+) enantiomer which is 2-3 times as potent, more quickly metabolised and has less severe side-effects than as the R (-) enantiomer. It is soluble in water forming an acidic solution pH 3.5-5.5. It comes in liquid solution, 100mg/mL in 2mL vials. Ketamine binds noncompetitively to the phencyclidine recognition site on N-methyl-D-aspartate (NMDA) receptors. Unlike propofol and etomidate, ketamine has only weak actions at GABAA receptors. Cardio- It stimulates the SNS by increasing adrenaline and norad, this masks its mild myocardial depressant effects. Resp- The RR is often increased and it causes bronchodilation. CNS - The dissociation is between the limbic and thalmocortical regions. EEG shows alpha waves replaced by theta and beta waves. CBF and ICP are increased. ABSORPTION bioavailabilty Oral: 16%; Intranasal: 50% routes of administration IV, PO, IN doses 1-4.5mg/kg for induction, 1-2mg/kg of analgesia onset / duration 30 seconds / 5-10 minutes DISTRIBUTION volume of distribution 3 L/kg protein binding minimal 35% lipid solubility high lipid solubility, crosses BBB rapidly pKa METABOLISM mechanism Hepatic via hydroxylation and N-demethylation active metabolite norketamine 33% relative potency ELIMINATION half life Alpha: 10-15 minutes; Beta: 2.5 hours excretion Primarily urine The main concerns with the use of ketamine are the emergence delirium which may occur as the patient comes out of anaethesia. Cardiovascular effects may cause issues. Should be used with caution in patients at risk of elevated ICP.

Answer 16

Labetalol is, as the name suggests an alpha 1 blocker and a non selective beta blocker. It is used in the setting of an acute hypertenisve crisis. Labetalol is available as a 50-400mg tablets and as a colourless solution containing 5mg/ml. It is a racemic solution with four stereoisomers present in equal proportions. The SR isomer is likely responsible for the alpha blocking eects and the RR isomer for the betablockade. Beta blockage leads to decreased G s activity in receptor associated organs and associated decrease in adenylyl cyclase and intracellular Ca2+. It produces decreases in heart rate and cardiac output and myocardial oxygen consumption. Alpha blockage leads to decrease G q activation and subsequent decrease in IP3 and intracellular Ca2+ and subsequent peripheral vasodilation. ABSORPTION bioavailabilty complete absorption but high rst pass metabolism results in bioavailability 25% routes of administration IV and oral doses IV in 20mg pushes, oral for HTN 100-400mg BD DISTRIBUTION volume of distribution 3-16 L/kg protien binding 50% lipid solubility moderately lipid soluble, can enter CNS METABOLISM mechanism Hepatic, primarily via glucuronide conjugation ELIMINATION half life 6-8 hours excretion Urine (60% as glucuronide conjugates,

Answer 17

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Is a relatively new agent with dual actions of selectively inhibiting phsophodiester ase and increasing cardiac myoctye sensitivity to calcium. It is currently used in the short term management of severe acute heart failure. It is available in IV form only 2.5mg/mL in 5 and 10ml vials. Levosimendan appears to increase myolament calcium sensitivity by binding to cardiac troponin C in a calcium-dependent manner. Levosimendan also leads to vasodilation through the opening of ATP-sensitive potassium channels. By these inotropic and vasodilatory actions, levosimendan increases cardiac output without increasing myocardial oxygen demand. Levosimendan also has a selective phosphodiesterase (PDE)-III inhibitory action that may contribute to the inotropic eect of this compound under certain experimental conditions. It has been reported that levosimendan may act preferentially as a Ca2+ sensitizer at lower concentrations, whereas at higher concentrations its action as a PDE-III inhibitor becomes more prominent ABSORPTION bioavailabilty 100% routes of administration IV doses loading dose of 12 to 24 mcg/kg over 10 minutes then continuous infusion of 0.05-0.2 mcg/kg/min onset / duration DISTRIBUTION volume of distribution limited pharmacokinetic data METABOLISM mechanism complete metabolism to inactive metabolites ELIMINATION half life 1 hour excretion unknown The interferrence with potassium channels causes an increase in the QTc which is believed to result in increased risk of arrhythmias. Caution should be exercised in paitents with renal or hepatic impairment.

Answer 18

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Lignocaine is an amide local anaesthetic with has class IB antiarrhythmic proper ties. The blocking of sodium channels reduces nerve propagation in the PNS (and CNS) and in cardiac tissue it is used to treat ventricular arrhythmias. It has also been used for the treatment of cerebral gas embolism although this is contraversial. It is presented in 1% or 2% solutions (10-20mg/ml) for IM or IV injection. It is often delivered as a continuos infusion reaching steady state in around 7 hours. It may also be presented as an oral solution “xylocaine viscous” Lidocaine blocks Na+ channels in cardiac muscle cells, as well as in motor and sensory nerve bres. The rate of rise of phase 0 of the action potential is reduced in cardiac myocytes and the action potential period is decreased. In pacemaker cells phase 4 is prolonged due to an increased threshold potential which reduced automaticity. ABSORPTION routes of administration SC, IV, IM and via ETT doses 75–100 mg, followed by a constant infusion 2mg/min max dose 3mg/kg or 7mg/kg with adrenaline onset / duration 45-90 seconds / 10-20 minutes DISTRIBUTION volume of distribution 1.1-2.1 L/kg altered in CHF and liver protien binding (duration) 60% to 80% lipid solubility (potency) high crosses blood-brain barrier pKa (onset of action) 7.9 METABOLISM mechanism 90% hepatic; active metabolites monoethylg lycinexylidide (MEGX) and glycinexylidide (GX) can accumulate and may cause CNS toxicity ELIMINATION half life Biphasic: Prolonged with CHF, liver disease, shock, ARF/CRF; Initial: 7-30 minutes; Terminal: 2 hours excretion Urine (ects. Greater than 5 leads to CNS eects including confusion, sedation, agitation and parathesia. Greater than 20 leads to AV block, unresponsive hypotension and eventually death. See local anaesthetics page.

Answer 19

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Lisonpril is an active drug that is not metabolised and is excreted directly into urine. It is a competitive ACE inhibitor that is used for management of hyperten sion, LV dysfunction post myocardial infarction and in the setting of heart failure. It’s use has been shown to decrease progression of heart failure (disease modify ing). It is an oral formulation presented as white tablets in dosage ranging from 5mg to 20mg tablets. Cardiovascular - Competitive inhibition of angiotensin coverting enzyme leads to decreased angiotensin II production and its eects. TPR and Afterload is decreased to a greater extent than preload, and this may result in improved CO in heart failure patients. HR is usually unchanged and baroreceptor reexes also unchanged. Renal- the impairment of AngII means that the body is less able to respond to a drop in renal perfusion and this may precipitate failure. Metabolic - Accumulation of K+ may occur due to decreased aldosterone. ABSORPTION bioavailabilty absorbed variably with bioavailabilty of 30% routes of administration oral doses commenced at 6.25mg TDS and uptitrated potency highly potent DISTRIBUTION protien binding 25% protien bound METABOLISM mechanism not metabolised ELIMINATION half life 12 hours excretion urine unchanged A dry cough may occur especially in patients with pre-exisiting lung disease. Caution should be exercised in patients on potassium sparing medications. NSAIDs may precipitate renal failure.

Answer 20

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Losartan is a substituted imidazole compound which selectively blocks AT2 receptors throughout the body. It is presented in 50mg tablets. Unlike many of the other durgs in this class it does not come as a combination medication with a thiazide (although this combina tion is available overseas). Eects are broadly similar to ACE inhibitors. The blocking of AT2 receptors reduces the action of angiotensin II. Notably as ACE is not inhibited, there is not increased levels of bradykinin, hence there is less cough associated with ARBs and possibly less vasodilation and peripheral oedema attributed to bradykinin levels. ABSORPTION bioavailabilty well absorbed from the gut but extensive rst pass metabolism leads to bioavilability of 25% to 33%, routes of administration oral doses 50-100mg daily onset/duration 6 hours, prolonged action due to metabolite DISTRIBUTION volume of distribution 34L protien binding high lipid solubility low, does not cross BBB METABOLISM mechanism Hepatic (14%) via CYP2C9 and 3A4 to active metabolite, E-3174 (40 times more potent than losartan) ELIMINATION half life 1.5-2 hours E-3174 6-9 hours excretion Urine (4% as unchanged drug, 6% as active Contraindicated like ACE inhibitors in bilateral renal artery stenosis, and pregnancy. Caution in sodium depleted patients similar to ACE inhibitors.

Answer 21

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS is the fourth most common cation in the body (after Na+, K+ and Ca2+), and approximately 35–40% is present in cardiac and skeletal muscle. It is used in the setting of arrhythmias for termination of VF/torsades as per ALS protocols and in the treatment of digitalis toxicity. Other uses include pre-eclampsia and eclampsia and magnesium replacement. O label use in acute severe asthma. [See syllabus notes for more Mg information] It is presented in a number of forms including magnesium oxide, magnesium chloride and magnesium sulfate. All three are used for replacement therapy but only magnesium sulfate is used for eclampsia and arrhythmias. Magnesium sulfate is presented as a liquid with a concentration of 0.5mg/ml in 5 of 10ml vials. The mechanism of action is unknown but may reect an eect on the inward current, possibly a Ca2+ current, responsible for the triggered upstroke arising from EADs. Magnesium ions are bound to cellular ATP, and act as a cofactor for Na+/K+ ATPase, so that intracellular concentrations of Mg2+ may aect Na+ and K+ transfer. It has benet even in magnesium replete patients. ABSORPTION bioavailabilty 100% when administered IV routes of administration IV or PO doses 1-2g IV over 15 mins for torsades de pointes onset / duration immediate onset / duration 30 mins DISTRIBUTION protien binding 30% bound to albumin METABOLISM mechanism bound to bone or excreted unprocessed in urine ELIMINATION half life not known excretion Urine (as magnesium) Care should be taken when delivering IV: ECG monitoring, vital signs, deep tendon reexes; magnesium concentrations if frequent or prolonged dosing required particularly in patients with renal dysfunction, calcium, and potassium concentra tions. Contraindicated in myasthenia gravis and care to be taken in renal failure.

Answer 22

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Mannitol is the only osmotic diuretic in current use, and in contrast to other agents it commonly produces a moderate increase in blood pressure after administration. It is a polyhydric alcohol with a molecular weight of about 200, and is usually synthesized by reduction of the monosaccharide mannose. It is more commonly used to cause acute reductions in intracranial pressure or introccular pressure. It is also used to test for airway hyperresponsiveness. Mannitol is available in 100g in either 1000ml or 500ml (10% or 20%) solutions for injection. It crystallises at low temperatures, especially the 20% solution but will redissolve it heated up. As the name suggests it acts as an osmotic agent. It increased the plasma osmolality and draws water out of the CSF and vitreous body. Osmotics like mannitol are freely ltered at the glomerulus but are poorly reabsorbed. Because the proximal tubule is involved in the reabsorption of 60-70% of the ltered load this is the most important site of action. ABSORPTION bioavailabilty 100% routes of administration IV doses 1-2g/kg IV onset / Diuresis: Injection: 1-3 hours; Reduction in intracra nial pressure: ~15-30 minutes duration Reduction in intracranial pressure: 1.5-6 hours DISTRIBUTION volume of distribution 34.3 L; remains conned to extracellular space generally doesn’t cross BBB METABOLISM mechanism Minimally hepatic to glycogen ELIMINATION half life Terminal: 4.7 hours excretion Urine (~55% to 87% as unchanged drug) Usually rare and idosyncratic. It may cause symptoms of pulmonary hypertension.

Answer 23

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Meropenem like the other carbepenems are beta lactams that contain a fused beta-lactam rung and a ve member ring system that diers from penicillins because it is unsaturated and contains a carbon atom instead of a sulphur atom. It has a broader spectrum of action than other beta lactams. Unlike the other carbepenems Meropenems do not require coadministration with cilastatin because it is not degrade by renal dipeptidase. Is presented as white crystals for reconstitution. It comes in doses of 500mg or 1g and is very expensive ($1000 per gram). Inhibits bacterial cell wall synthesis by binding to several of the penicillin-binding proteins, which in turn inhibit the nal transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis; bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested ABSORPTION bioavailabilty IV only 100% doses 500mg-1g TDS onset / duration peak at 1hr DISTRIBUTION volume of distribution ~0.3 L/kg protien binding ~2% lipid solubility crosses the BBB with CSF conc = plasma METABOLISM mechanism Patrially metabolised Hepatic; ELIMINATION half life 1-1.5 hours (renal impairment increases signif.) excretion Urine (~70% as unchanged drug) May cause injection site irritation. May cause seizures similar to Benpen but only in susceptible patients. Caution in renal patients due to large amount excreted unchanged. Should not be used concurrenly with probenecid. Can cause confusion.

Answer 24

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Metaraminol is a synthetic nocatecholamine with both direct and indirect sympathomimetic actions. It acts mainly via alpha1/2 adrenoceptors to cause vasoconstriction but also has some minor beta activity. It is used in the short term correction of blood pressure in the settng of regional anaesthesia and o label for short term BP correction. Available as a clear solution 10mg/mL in one mL vials and usually diluted to 10mg in 10ml or 20ml Its main actions are through increased total peripheral resistance. There may be a transient bradycardia due to baroreceptor feedback upon intiation of the infusion. Pulmonary vascular resistance is also increased. There may be an increased coronary artery ow by an indirect mechanism (stimulates NA release). ABSORPTION bioavailabilty 100% routes of administration IV only doses given in 0.1-0.2mg boluses titrated to BP onset / duration immediate / up to 20 minutes DISTRIBUTION volume of distribution limited date on pharmacokinetics METABOLISM mechanism Hepatic ELIMINATION half life Short excretion Unknown Caution should be exercisd in patients with pulmonary hypertension. It may cause

Answer 25

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Methyldopa is a centrally acting antihypertensive agent that exerts its antihyper tensive action via an active metabolite. Methyldopa’s signicant adverse eects currently limit its use in the U.S. to treatment of hypertension in pregnancy, where it has a record for safety. It is available as an oral formulation in Australia in 250mg tablets. Its metabolite produces a clonidine like alpha2 agonist eect in cardiovascular control centres that results in reduced sympathetic outow. The metabolite also acts as a false neurotransmitter reducing peripheral SNS eects by reducing noradrenaline synthesis. It is primarily used to dpress overall SNS activity (HR, BP and TPR) but can also cause sedation, psychosis and depression. ABSORPTION bioavailabilty absorded by an amino acid transporter (% ?) routes of administration oral doses 125-250mg BD titrated onset of action 3-6 hours, duration 24 hours (this is becuase of the prolonged process in substituting for noradrenaline in peripheral sites) DISTRIBUTION protien binding

Answer 26

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Is a relatively seletive beta blocker with no intrinsic sympathomimetic activity. Early use of metoprolol in haemodynamically stable myocardial infarction reduces infarct size and incidence of VF. It is used for rate control in atrial brillation and may be used to treat hypertension. Is available in oral form as an immediate release or sustained release in increments of 25mg. It is also available as an IV formulation usually 1mg/ml Beta blockage leads to decreased G s activity in receptor associated organs and associated decrease in adenylyl cyclase and intracellular Ca2+. It produces decreases in heart rate and cardiac output and myocardial oxygen consumption. Whilst it does have some beta 2 action it has little or no eect on these receptors at doses less than 100mg. ABSORPTION bioavailabilty Absoption is rapid and complete, however there is extenisve rst pass metabolism bioavailability = 50% routes of admin PO or IV dose Orally in 12.5mg increments, IV in 1-2mg boluses DISTRIBUTION volume of distrib 5.5 L/Kg protien binding 10-20% to albumin lipid solubility is high so it crosses the BBB METABOLISM hepatic or renal Extensively hepatic via CYP2D6 ELIMINATION half life 3-8hours excretetion In urine 5-10% unchanged Rapid withdrawal should be avoided as it may precipitate tachycardia, hyperten sion and/or ischaemia. Care should be taken when used in conjuction with opiods and halothane and in patients with obstructive airway disease. Use with Ca Channel blockers may result in complete heart block

Answer 27

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Midazolam is a water-soluble benzodiazepine with an imidazole ring in its structure that accounts for its stability in aqueous solutions and its rapid metabolism. Compared with diazepam, midazolam is two to three times as potent. As with other benzodiazepines, the amnestic eects of midazolam are more potent than its sedative eects. It also has anticonvulsant properties. Midazolam is presented as a clear solution at a pH of 3.5. At this pH is almost completely ionised and therefore water soluble. Since its pKa is 6.5 it is 89% un-ionised at physiological pH and can therefore cross lipid membranes. Benzodiazepines appear to produce all their pharmacologic eects by facilitating the actions of gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the CNS. Benzodiazepines do not activate GABAA receptors but rather enhance the anity of the receptors for GABA. As a result of this drug-induced increased anity of GABA receptors for the inhibitory neurotrans mitter, an enhanced opening of chloride gating channels results in increased chloride conductance, thus producing hyperpolarization of the postsynaptic cell membrane ABSORPTION bioavailabilty IV 100%, PO 45% routes of administration IV, PO, IN, IM doses 2-2.5mg initially then 1mg boluses to eect onset / duration 1-5 minutes / 2 hours DISTRIBUTION volume of distribution 0.8-2.5 L/kg protien binding 95% lipid solubility see above (high at physiological pH) pKa 6.5 METABOLISM mechanism Extensively hepatic via CYP3A4 active metab ELIMINATION half life 1-4 hours; prolonged with cirrhosis, congestive heart failure, obesity, and elderly excretion Urine (as glucuronide conjugated metabolites) It uses the same cytochrome as alfentanil and if used together the eects may be prolonged. Main issues are from overdosage and excessive sedation and depression of respiratory drive.

Answer 28

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Milrinone is a selective phosphodiesterase inhibitor in cardiac and vascular tissue, resulting in vasodilation and inotropic eects with little chronotropic activity. It is used is severe refractory heart failure for short periods of time and in low cardiac output states such as post cardiac surgery. It is presented as a yellow solution containing 1mg/mL and may be stored at room temperature. It requires dilution before use and should not be given in the same line as sodium bicarbonate or frusemide. Phosphodiesterase is an intracellular enzyme which breaks down cAMP by hydrolysis. Inhibitors therefore lead to an increase in intracellular cAMP. Peripher ally this is manifested as arterial and venodilation and in the myocytes this manifests as increased contractility and therefore inotropy. ABSORPTION bioavailabilty 100% routes of administration IV doses onset / duration 5-15 minutes DISTRIBUTION volume of distribution 0.32-0.45 L/kg protien binding plasma: ~70% METABOLISM mechanism Hepatic (12%) ELIMINATION half life Normal renal function: ~2.5 hours excretion Urine (85% as unchanged drug) Milrinone may precipitate or worsen SVT and VT therefore continuos cardiac monitoring is required. They have been shown to worsen outcome in acute on chronic heart failure. They cause hypotension secondary to peripheral vasodila tion. As the drug is excreted in urine unchanged dose adjustment is required in patients with renal failure.

Answer 29

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Minoxidil is a direct vasodilator whose mechanism of action is poorly understood. It is described by Goodman as a potassium channel actiivator but this is contradicted in other texts. It is used primarily in sever refractory hypertension in combination with other antihypertensives. It is available in 10mg tablets Similar to hydralazine in that dierent textbooks identify dierent mechanisms for this drug which indicate the poor understanding. The eects are arteriole vasodilation with preserved venous tone, and minimal eect on epicardial vasculature. There is a reex increase in HR, CO and activation of the RAAS leading to peripheral oedema. Interestingly it is associated with increased hair production and is used topically to treat baldness. ABSORPTION bioavailabilty up to 90% routes of administration oral doses 10-40mg PO daily onset / duration ~30 minutes / up to 5 days due to avid smooth muscle binding DISTRIBUTION protien binding None METABOLISM mechanism Hepatic primarily via glucuronidation ELIMINATION half life 4 hours excretion Urine (12% as unchanged drug) The activation of the RAAS and the increase in HR and CO make this drug less ecacious. Because of this reason it is almost always given in combination with a thiazide or betablocker. It is contraindicated in phaechromocytoma and may precipitate pericardial eusion and worsen angina.

Answer 30

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Is a naturally occuring phenanthrene derivative. Along with codiene and thebain it is isolated from opium an extract of the poppy plant Papaver Somniferum. Its primary use is for analgesia, it is particularly eective when treating visceral pain (so-called slow pain). It may also be used as an adjunct in the treatment of acute pulmonary oedema and rarely as an anti-tussive agent or for diarrhoea in oncology. Morphine is available in a range of formulations, either as a clear liquid for injection, orally in both immediate (liquid or tablet) and sustained release forms (MS Contin). Binds primarily to G-Protien coupled μ-opioid receptors which increases andenylyl cyclase and agonises their action. This has generally an inhibitory action, modulating the pain response to produce analgesia, causing dyphoria or euphoria, confusion and psychomimetic eects, depressing respiratory drive and cough reexes, decreasing gut motility, causing reduced small bowel secretions and CBD spasm, causing urinary retention, decreasing TPR and depressing baroreceptor drive leading to postural hypotension, causing skin ushing and pruritis secondary to histamine release. Excitatory action causes miosis (parasymp) ABSORPTION bioavailabilty 30% routes of administration oral, SC, IM, SL, IV, intrathecal doses titrated to eect, may increase x100 with tolerance onset / duration Oral ~30 minutes; I.V.: 5-10 minutes DISTRIBUTION volume of distribution 3-4 L/kg protien binding 30% to 35% lipid solubility low compared to other opioids pKa 8.0 (25% ionised at pH 7.4) METABOLISM mechanism Metabolised to morphine-3-glucuronide (70%) and morphine-6-glucuronide (10%) by gut wall and liver . M6G is 10-20 times potent, may accumulate in renal failure ELIMINATION half life 2-4 hours excretion urine and faeces Signicant issues with dependence and addiction. Patients develop tolerance therefore requiring increasing doses. Signicant side eects as above. If used intrathecally may develop delayed respiratory depression (rostral migration).

Answer 31

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Naloxone is a pure opioid competitive antagonist and will reverse eects at μ, δ, and κ receptors although its anity is greatest for μ receptors. It is used to reverse the deleterious eects of opioid administration. Naloxone is usually presented in a 1ml vial containing 400mcg. It is also available as a minijet with the same dose but an increased volume (2 or 5ml). Naloxone competitively antagonises the opioid receptors, reversing the eects of narcotics by displacing them from the receptor. Has minimal intrinsic activity. ABSORPTION bioavailabilty 100% (IV) poorly absorbed orally routes of administration IV / ETT/Intranasal doses usually 400mcg bolus onset / duration ~2 minutes / ~30-120 minutes DISTRIBUTION volume of distribution not known protien binding 30% METABOLISM mechanism Hepatic glucuronidation to naloxone-3- glucuronide ELIMINATION half life 0.5-1.5 hours (nb may be less than exogenous opioid, therefore patient may become resedated when eect wears o. excretion Urine (as metabolites) May precipitate SNS activity producing hypertension, tachycardia and pulmonary odema, Slow administration reduces risk of nausea & vomiting, Crosses placenta and may precipitate withdrawal in opioid dependent neonate

Answer 32

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Neostigmine is a quaternary amine. It is utilised for its indirect cholinomimetic properties which result from the inhibition of cholinesterase and therefore the reduced breakdown of acetylcholine. Clinically its most frequent use is to reverse the eects of nonpolarising neuromuscular blockers. Other indications include the treatment of myasthenia gravis. In Australia is only available in parenteral formulations although overseas is also available in tablet form. When given for reversal of NMBD it is usually coadminis tered with an anticholinergic such as glycopyrrolate or atropine to reduce its eects at muscarinic receptors. Inhibits destruction of acetylcholine by acetylcholinesterase which facilitates transmission of impulses across myoneural junction. The prolongs ACh actions at the synaptic cleft. Cardiovascular eects include bradycardia (vagal potentiation), bronchospasm especially in asthmatics, increased salivation, and intestinal motility (which may manifest as abdominal cramping). ABSORPTION bioavailabilty IV 100% (poorly absorbed orally) routes of administration IV (PO in the USA) doses 50mcg/kg to reverse NMBD onset / duration 1-5 mins / 1-2 hours DISTRIBUTION volume of distribution low volume of distribution protien binding minimally protien bound lipid solubility likely low due to ionised quartenary amine METABOLISM mechanism Hepatic only partial ELIMINATION half life 30 mins - 2hrs, prolonged in renal disease excretion urine (55% unchanged) May lead to a cholinergic crisis with increased cholinergic eects such as increased sweating, involuntary defacation and urination, miosis, nystagmus, bradycardia, hypotension, increased muscle weakness, CNS eects including agitation, seizures and coma, respiratory depression and ultimately death.

Answer 33

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Nicorandil is a potassium channel activator which also has a nitrate moiety and it is used in the treatment of stabel angina It is available in oral form only with 10 and 20mg tablets. Nicorandil activates KATP channels, causing hyperpolarization and relaxation of vascular smooth muscle. These eects are sugmented by its nitrate moiety which is metabolised to nitric oxide which stimulates guanylyl cyclase, decreasing cAMP and causing vasodilation. ABSORPTION bioavailabilty absorption is >90% and minimal rst past metabolism gives a bioavailability >80% routes of administration oral doses 5-20mg BD onset / duration 30mins / up to 12 hrs DISTRIBUTION volume of distribution 1L/kg protien binding 25% METABOLISM mechanism Hepatic metabolism by denitration ELIMINATION half life 1 hr excretion In urine as inactive metabolites One of the major side eects is headaches although these usually improve with continued use.

Answer 34

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Nifedipine, is the prototypical dihydropyridine and has primarily arterial vasodila tory eects with little eect on electrical conduction in the heart. Other dihydro pyridines including—amlodipine, felodipine, nicardipine, share many of the cardiovascular eects of nifedipine. It is used primarily for hypertension and angina and in the setting of preterm labour. Is available in sustained and immediate release oral formulations, 10-60mg Nifedipine selectively dilates arterial resistance vessels. The decrease in arterial blood pressure elicits sympathetic reexes, with resulting tachycardia and positive inotropy. Thus, arteriolar resistance and blood pressure are lowered, contractility and segmental ventricular function are improved, and heart rate and cardiac output are modestly increased. ABSORPTION bioavailabilty Well absorbed moderate rst pass metabo lism leading to bioavailability of 60% routes of administration oral doses 10-20mg BD onset / duration ~20 minutes / not stated DISTRIBUTION protien binding ~90% lipid solubility moderately low, minimal BBB (nimodipine is an analogue with higher solubility and is used in cerebral vasospasm) METABOLISM mechanism Hepatic via CYP3A4 to inactive metabolites ELIMINATION half life 2-5 hours (prolonged in liver failure) excretion Urine (60% to 80% as inactive metabolites); feces It should not be used for acute blood pressure reduction in hypertensive emergencies. Peripheral oedema is a common side eect, 2-3 weeks post initiation of therapy. Other side eects are related to its vasodilating properties and include ushing, vertigo, headaches, hypotension and parathesias. There is a risk of coronary vasospasm with acute withdrawal.

Answer 35

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Sodium nitroprusside is an inorganic complex that acts as a prodrug. It consists of ve CN groups and one NO group attached a iron molecule covalently bonded to sodium. SNP is only available in injectable form. It is unstable and must be stored out of light and not in alkaline conditions or it rapidly degrades. The nitroso group (−N = O−) in sodium nitroprusside reacts with sulphydryl groups (–SH) in vascular smooth muscle, forming nitric oxide and nitrosothiol derivatives. Both these metabolites stimulate guanylate cyclase, increasing cGMP levels and producing generalized relaxation of vascular smooth muscle. Consequently, sodium nitroprusside produces both arterial and venular dilatation. ABSORPTION bioavailabilty 100% (IV only) doses 10-200mcg/min uptitrated to eect onset / duration onset ect 2 minutes, and the eect disappears within 3 minutes after the infusion is stopped METABOLISM mechanism Nitroprusside is converted to cyanide ions in the bloodstream; decomposes to prussic acid which in the presence of sulfur donor is converted to thiocyanate (hepatic and renal rhodanase systems) ELIMINATION half life Parent drug: ects are from excessive hypotension and include nausea, vomitting, abdominal pain, and postural hypotension. Abrupt withdrawal may lead to a rebound hypertension. Longer term there is signicant risk of cyanide accumulation and associated toxicity and impaired oxidative phosphorylation.

Answer 36

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Is a naturally occuring catecholamine that is released by mammalian postgangli onic sympathetic nerves. NA constitutes 10–20% of the catecholamine content of human adrenal medulla. It is used extensively in a critical care setting for mainte nence of haemodynamic parameters via increase in total peripheral resistance. It is presented in an injectable solution only, usually 1mg/mL in 2 mL vials and should be diluted in either 5% dextrose or 0.9% sodium chloride. It should be adminstered via central line due to risk of extravasation associated necrosis. Its eects are mediated mainly via stimulation of the alpha1 receptors but also through beta receptors. Systemically administered NA causes peripheral vasoconstriction, increases systolic and diastolic BP and may cause a reex bradycardia. CO may fall and myocardial oxygen usuage is increased. Renal and hepatic ow fall due to vasoconstriction. ABSORPTION bioavailabilty 100% routes of administration IV Only doses 8-12 mcg / minute uptitrated to eect onset / duration immediate / 1-2 minutes DISTRIBUTION lipid solubility doesn’t cross the BBB METABOLISM mechanism Via catechol-o-methyltransferase (COMT) and monoamine oxidase (MAO) Up to 25% is taken up as the drug passes through the lungs ELIMINATION half life 2 minutes excretion Urine (84% to 96% as inactive metabolites) Excessive doses cause severe hypertension. Reduced blood ow to organs such as kidney and intestines is a constant danger with the use of NE.

Answer 37

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Is a semi-synthetic thebaine derivative, which has primarily μ receptor activity but also has some weak κ and δ receptor activity. Presented as white tablets in either immediate release or sustained release formulations. Is presented in combination with paracetamol in US formulations. Mainly through mu receptor actions but he weak K action may cause some of the negative eects (dysphoria, psychomimetic). ABSORPTION bioavailabilty 60% to 87% routes of administration PO doses 20mg oxycodone oral = 10mg morphine IV onset / duration 10-15 minutes / 3-6 hours DISTRIBUTION volume of distribution 2.6 L/kg protien binding ~45% lipid solubility crosses BBB so high METABOLISM mechanism CYP3A family metabolism to noroxycodone and via CYP2D6 to oxymorphone (active), both of which are subsequently conjugated ELIMINATION half life 2-4 hrs excretion urine Interindividual variability in metabolism. Other standard opioid side eects.

Answer 38

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Paracetamol is a para-aminophenol which is sometimes classied as a NSAID but as it has little peripheral anti-inammatory properties this may be eroneous. It is used for its antipyretic and analgesic properties. Available as a tablet or capsule usually in dosage of 500mg. Also available as a solution for titration of dose in the paediatric population and as an IV prepara tion. It is generally accepted that it has little eect on peripheral COX-1 or COX-2, although it inhibits central COX-3 (a COX-1 subtype). Consequently, it prevents the enhanced synthesis of prostaglandin E2 in the hypothalamus during pyrexia, and thus reduces elevated body temperature. It has similar eects to aspirin on non-specic pain. Paracetamol is also synergistic with opioid medications, reducing the overall opioid requirement by 20-30%. ABSORPTION bioavailabilty Primarily absorbed in small intestine, 80% routes of administration PO, PR, IV doses 1g QID or 15mg/kg QID in pts ect prole and is suitable for use in pregnancy and paediatric populations. Overdosage leads to both hepato and renal toxicity, plasma levels should be plotted on a nomogram and consideration of eNAC infusion commenced as appropriate. ALT is a marker of damage.

Answer 39

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Phenoxybenzamine is a long acting non selective alpha blocker. It has a high anity for alpha1 adrensoceptors. It is used in the treatment of phaeochromocy toma. It is presented a capsules containing 10mg and as a clear faintly straw coloured solution for IV injection containing 100mg/2ml. Importantly it forms covalent bonds with alpha-adrenoceptors, so that the eects of single doses can last for at least several days. The restoration of normal responsiveness to alpha-adrenoceptor agonists is dependent on the synthesis of new receptors. It causes peripheral vasodilation, relaxes the urethra and increases opening of the bladder ABSORPTION bioavailabilty is 20-30% in oral form routes of administration oral or IV doses 10-20mg BD, uptitrate to control BP DISTRIBUTION volume of distribution not known protien binding not known lipid solubility not known METABOLISM mechanism not known ELIMINATION half life IV is 24 hours excretion not known Orthostatic hypotension, syncope and vertigo as per other alpha blockers.

Answer 40

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Phenytoin is a sodium channel blocking anticonvulsant for status epilepticus, partial or tonic clonic seizures but not absence seizures. Which is also used as a treatment for trigeminal neuralgia and cardiac arrythmias in the setting of TCA overdose. Phenytoin poorly water soluble, but may be presented as fosphenytoin which is soluble and suitable for IV preparations. The mechanism of action is dependent on the ability to bind to and stabilise inactivated sodium channels. This prevents the further generation of action potentials that are central to seizure activity. It may also reduce Ca entry into cells blocking neurotransmitter release and enhancing the action of GABA. ABSORPTION bioavailabilty 90% when given orally. routes of administration PO and IV doses 5-20 mg/kg (plasma levels required aim 10-20mg/L) onset / duration 30mins-1hr / variable DISTRIBUTION volume of distribution 0.6-0.7 L/kg protien binding >90% and may have increased free plasma levels (and eects) when there is competition for binding. METABOLISM mechanism hepatic, hydroxylation and gluconoridation. Becomes zero order at higher concentrations ELIMINATION half life 6-24 hours depending on concentration excretion Urine (ects include cardiac arrythmias, hirsutism in females, gingival hyperplasia, SIADH. It can induce hepatic enzymes and eect the metabolism of other drugs including warfarin. It is teratogenic. There is signicant interpatient variability due to genetic predisposition to slow hydroxylation in 10% of population.

Answer 41

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Prazosin is a highly selective alpha1 blocker that is used for the treatment of essential hypertension, congestive heart failure, raynaud’s and benign prostatic hypertrophy. Prazosin is presented as 0.5 - 2mg tablets. Alpha blockage leads to decrease G q activation and subsequent decrease in IP3 and intracellular Ca2+ . Cardiovascular eects include peripheral arterial and venous vasodilation and subsequent decrease in TPR but little or no reex tachycardia (diastole decreases the most). Urinary eects include bladder trigone and sphincter muscle relaxation which is useful in BPH (Tamulosin is also an alpha1 blocker). CNS - syncope and headaches may occur due to rapid BP decrease. ABSORPTION bioavailabilty 43% to 82% due to rst pass metabolism routes of administration oral doses commenced at 0.5mg TDS then uptitrated DISTRIBUTION volume of distribution 0.5 L/kg protien binding 92% to 97% METABOLISM mechanism Extensively hepatic by demethylation and conjugation with some active metabolites ELIMINATION half life 2-3 hours excretion Mostly faeces, (6% to 10% as unchanged drug) May precipitate orthostatic hypotension, syncope or vertigo. It blunts the compensatory vasoconstriction in spinal and epidural anaesthesia and may cause profound hypotension. Dryness of mouth is also a side-eect.

Answer 42

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Is the prototypical Vaughan Williams Class IA antiarrhythmic which has been superseeded by newer agents and is not currently available in Australia. It was previously used in the treatment of ventricular and atrial arrhythmias. It is presented in oral and parenteral formulations for IV or IM uses. Other drugs with group 1A actions include quinidine and disopyramide. These drugs aect both atrial and ventricular arrhythmias. They block INa, and therefore slow conduction velocity in the atria, Purkinje bers, and ventricular cells. At high doses they also slow AV conduction. The reduction in ventricular conduction results in increased QRS duration in the ECG. In addition, the 1A drugs block IK and slow repolarization. Therefore, they increase AP duration and the eective refractory period (ERP) in addition to slowing conduction velocity and ectopic pacemakers. The increase in AP duration generates an increase in QT interval. ABSORPTION bioavailabilty not stated but likely high as PO = IV doses routes of administration IV, IM, PO doses 50mg day in divided doses onset / duration I.M. 10-30 minutes DISTRIBUTION volume of distribution 2 L/kg protien binding 15% to 20% METABOLISM mechanism Hepatic via acetylation to produce N-acetyl procainamide (NAPA) (active metabolite) ELIMINATION half life 2.5-5.0 excretion mainly eliminated unchanged in urine Procainamide is proarrhythmogenic secondary to its QT prolongation and may precipitate torsdaes de pointes. If given IV it can cause hypotension. Chronic use is associated with development of anti nuclear antibodies and a lupus-like syndrome

Answer 43

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS ABSORPTION bioavailabilty - lipid soluble and well absorbed but has a high 1st pass metabolism leading to a bioavailability of 30% routes of administration - oral or IV doses PO up to 320mg, IV 0.5mg - 10mg titrated to eect DISTRIBUTION volume of distribution 4 litres/kg in adults protien binding 90% protien bound in adults lipid solubility high lipid solubility METABOLISM Hepatic via CYP2D6, and CYP1A2 to 4-hydroxypropranolol (active) and inactive compounds ELIMINATION half life 3-6 hours exceretion most metabolites are excreted in urine Propanolol is a non-selective Beta Blocker with no intrinsic sympathomimetic activity. It is used to treat hypertension, angina, essential tremor, haemodynami cally stable oesophaegeal varacies and as migraine prophylaxis. It is the treatment of choice in thyrotoxicosis as it treats the eects and prevents conversion of T4 to T3. Is a racemic mixture with the S-isomer conferring most eects, and the R-isomer stopping T4 to T3 conversion. It is presented in both oral and IV forms. The oral formulations may be enterically coated to ensure sustained release and range in dose from 60-160mg. Immediate release oral preparations range in dose from 10-80mg. IV formulations are signicantly smaller due to extensive rst pass metabolism and it is usually in 20mg/5ml preparations. Beta blockage leads to decreased G s activity in receptor associated organs and associated decrease in adenylyl cyclase and intracellular Ca2+. It produces decreases in heart rate and cardiac output and myocardial oxygen consumption. Rapid withdrawal should be avoided as it may precipitate tachycardia, hyperten sion and/or ischaemia. Care should be taken when used in conjuction with opiods and halothane and in patients with obstructive airway disease.

Answer 44

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Propofol (2,6-di-isopropyl phenol) is a chemically inert phenolic derivative with anaesthetic properties. It is used for the induction and maintenence of general anaesthesia. Although propofol is almost insoluble in water at pH 7.0, forming a colourless or pale straw-coloured liquid, it is highly lipid soluble. It is presented as a 1% preparation and appears a a white opaque liquid-water emulsion containing soya bean oil or puried egg phosphatide. It is a weak organic acid with a pKa of 11 and is therefore almost entirely un-ionised at physiological pH. Propofol produces general anaesthesia by selective modulation of the activity of th GABA A receptor. The site of action is quite distinct from the modulatory site for barbiturates and benzodiazepines, and GABA itself. There is a rapid loss of consciousness due to rapid distribution across the BBB. It causes dose dependent respiratory depression and may cause apnoea. Often causes a signicant drop in BP due to decreased TPR, but without a reex tachycardia (this appears to be infusion rate dependent). It is not emetogenic and may have antiemetic properties. ABSORPTION bioavailability 100% routes of administration IV doses 2-2.5mg/kg induction, 5mcg/kg/min uptitrated in ICU onset / duration 30 seconds / 3-10 minutes DISTRIBUTION volume of distribution 2-10 L/kg; after a 10-day infusion, Vd approaches 60 L/kg; decreased in the elderly protien binding 97% to 99% lipid solubility is very high pKa 11 METABOLISM mechanism Hepatic to water-soluble sulfate and glucuron ide conjugates (~50%) ELIMINATION half life Biphasic: Initial 40 min; Terminal 4-7 hrs (up to 60hrs) excretion Urine (~88% as metabolites, 40% as glucuronide) It causes haemodynamic instability during induction. May be painful on injection. It may cause propofol infusion syndrome in patients on prolonged infusions (eg ICU pts) characterised by metabolic acidosis, myocardial failure and ultimately death. Monitor for lipaemia in prolonged infusion. Christopher Andersen 2012

Answer 45

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Ramipril is a prodrug requiring hepatic activation to ramiprilat. Ramiprilat is a competitive ACE inhibitor that is used for management of hypertension, LV dysfunction post myocardial infarction and in the setting of heart failure. It’s use has been shown to decrease progression of heart failure (disease modifying). It is an oral formulation presented as tablets or capsules in dosage ranging from 1.25mg to 10mg. Cardiovascular - Competitive inhibition of angiotensin coverting enzyme leads to decreased angiotensin II production and its eects. TPR and Afterload is decreased to a greater extent than preload, and this may result in improved CO in heart failure patients. HR is usually unchanged and baroreceptor reexes also unchanged. Renal- the impairment of AngII means that the body is less able to respond to a drop in renal perfusion and this may precipitate failure. Metabolic - Accumulation of K+ may occur due to decreased aldosterone. ABSORPTION bioavailabilty 50–60% is absorbed, bioavailability 30% routes of administration oral doses commenced at 2.5 mg Daily and uptitrated potency potent DISTRIBUTION protien binding 75% protien bound METABOLISM mechanism Hepatic to the active form, ramiprilat ELIMINATION half life triphasic elimination prole of the active metabolite ramiprilat with T1/2 1-2 hrs, 13-17hrs and >50hrs. excretion Urine (60%) and feces (40%) as parent drug and metabolites A dry cough may occur especially in patients with pre-exisiting lung disease. Caution should be exercised in patients on potassium sparing medications. NSAIDs may precipitate renal failure.

Answer 46

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS NOTABLE ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Is a synthetic phenylpiperdine derivative of fentanil with a unique metabolism. It is a pure μ receptor agonist therefore shares many of its actions with morphine and the related compounds. It is used during aneasthesia for its potent (but short lived) analgesic properties, most commonly during larygoscopy. It is presented as a white crystalline powder for reconstitution. Pure mu receptor agonist. ABSORPTION bioavailabilty 100% routes of administration IV doses similar potency to fentanyl, 1mcg/kg as a bolus onset / duration 1-3 minutes DISTRIBUTION volume of distribution 0.1 L/kg; increased in children protien binding ~70% (primarily alpha1 acid glycoprotein) lipid solubility around 1/10 of fentanyl, but x 50 morphine pKa 7.1 METABOLISM mechanism Rapid via blood and tissue esterases ELIMINATION half life Terminal: 10-20 minutes; eective: 3-10 minutes excretion Urine Bradycardia, hypotension, muscle rigidity, May contribute to hyperalgesia following prolonged infusion. The most important aspect to the pharmacology of remifentanil is the rapid metabolism due to plasma and tissue esterases. The benet of this is that it can be used in patients with liver/renal disease, and dierent age, sex, body habitus without signicant dose modicication. It is also not context sensitive.

Answer 47

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Sodium valproate (or valproic acid) has multiple putative mechanisms and is used for the rst line treatment of epilepsy (including tonic-clonic, partial and absence), and as a second line agent with respect to trigeminal neuralgia, migraine and bipolar disorder. It is avilable in enteric coated tablets or an IV form. It should not be injected IM as it may cause necrosis. Proposed mechanisms of action suggested for valproate include prolongation of sodium channels recovery phase, blocking of T-calcium channels and decreased breakdown of GABA. This leads to an increased seizure threshold, and reduction in action potential propagation. ABSORPTION bioavailabilty ~90% relative to I.V. dose routes of administration oral IV doses 15-30mg/kg divided doses daily up titrated onset / duration 1-4hrs DISTRIBUTION protien binding 80% to 90% lipid solubility high (but carrier mediated transport to the CSF may also occur) METABOLISM mechanism Extensively hepatic via glucuronide conjuga tion and mitochondrial beta-oxidation (some active metab) ELIMINATION half life ~15 hours excretion Urine (30% to 50% as glucuronide conjugate, 3% as unchanged drug) Nausea, cramping and vomitting occur in up to 16% of patients. A major concern is idiosyncratic fulminant liver failure. Monitoring of hepatic function however does not reduce the incidence of this. Monitoring of plasma concentrations may be required to monitor toxicity, but is poorly correlated to therapeutic eect.

Answer 48

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS As the name suggests, sotalol is a beta blocker but it also has class III eects and is often categorised in this class. It is used for the prevention of SVT and in the treatment of ventricular tachyarrhythmias. Sotalol is a racemic mixture of d- and l-sotalol; both isomers have similar Class III antiarrhythmic eects while the l-isomer is responsible for virtually all of the beta-blocking activity. It is presented in 80 or 160mg tablets or as a clear liquid with 10mg/ml Sotalol is a nonselective b adrenergic receptor antagonist that also prolongs cardiac action potentials by inhibiting delayed rectier and possibly other K+ currents. As a result the ventricular rate is slowed and there is a prolonged QT interval. ABSORPTION bioavailabilty well absorbed and up to 95% bioavailability routes of administration IV or PO doses 80-160mg PO or 50-100mg IV over 20 mins onset / duration IV ~5-10 minutes, PO 1-2 hours duration: 8-16 hours DISTRIBUTION volume of distribution 1.2-2.4 L/kg protien binding None METABOLISM mechanism None ELIMINATION half life 12 hours excretion Urine as unchanged drug The class III eect on the QT interval predisposes patients to degenerating in torsades de pointes (with a risk of 2% in pts with sustained VF/VT). This risk is increased in electrolyte imbalance. It may precipitate heart failure. Other side eects include bronchospasm, visual disturbances and sexual dysfunction.

Answer 49

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Spionolactone is a competitive aldosterone antagonist and a weak androgen receptor antagonist. It is used to treat primary hyperaldosteronism (Conn’s Disease) and secondary hyperaldosteronism associated oedema (such as heart failure and liver cirrhosis). The androgen blocking mechanism is utiised in women with hirsutism but causes side eects in men including gynaecomastia. Presented as 25-100mg tablets. Competes with aldosterone for receptor sites in the distal renal tubules, increasing sodium chloride and water excretion while conserving potassium and hydrogen ions. Blocks androgen receptors sites weakly. ABSORPTION bioavailabilty incompletely absorbed routes of administration oral doses 25-200mg daily onset / duration 3-4 hours / up to 3 days DISTRIBUTION volume of distribution protien binding 91% to 98% lipid solubility METABOLISM mechanism Hepatic to multiple metabolites, including active metabolites canrenone and 7-alpha-spirolactone ELIMINATION half life Spironolactone: 1-2hrs metabolites up to 24hrs excretion Urine and feces As this medication is potassium sparing, elevated potassium is a signicant risk and should be monitored. It is often given in combination with a loop diuretic for this reason. The andogren blocking aspects mean gynaecomastia and galactorrhea are a problem for men taking spirolonactone and it is not suitable in pregnancy.

Answer 50

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Tramadol is a cyclohexanol derivative. It is a racemic mixture, with each enantiomer producing specic actions. Tramadol is presented as immediate release, 12 hour release and 24 hour release tablets. Tramadol has agonist properties at all opioid receptors but particularly at μ receptors. At equi-analgesic doses it produces less respiratory depression and constipation. In other aspects it is similar to morphine. It also inhibits the reuptake of noradrenaline and serotonin. ABSORPTION bioavailabilty 75% routes of administration oral doses has 1/5th potency of morphine, 50-100mg q4-6hr onset / duration ~1 hour / 9 hours (immediate release) DISTRIBUTION volume of distribution 2.5-3 L/kg protien binding ~20% lipid solubility crosses BBB METABOLISM mechanism Extensively hepatic via demethylation , glucuronidation, and sulfation; active metabolite formed by CYP2D6 (M1; O-desmethyl tramadol) ELIMINATION half life Tramadol: ~6-8 hours; Active metabolite: 7-9 hours; prolonged in elderly, hepatic or renal impairment excretion Urine (30% unchanged drug; 60% as metabolites) Caution should be exercised when used in combination with SSRIs or MAO inhibitors as it may precipitate a serotonin syndrome. As noted above it causes less respiratory depression and constipation, but these remain signicant side eects especially in combination with other agents. Patients decient in CYP2D6 may have a decreased analgesic eect.

Answer 51

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Thiopental is 5-ethyl-5`-(1-methylbutyl)-2-thiobarbituric acid and is the sulphur analogue of pentobarbital. It is a short-acting barbiturate with sedative, hypnotic, and anticonvulsant properties. Apart from induction it is also used in status epilepticus. The sodium salt is a pale yellowish-white powder with a bitter taste and an garlic-like odour. It readily dissolves in deionized water producing an alkaline solution due to its ionized sulphur atom (S−), which has strongly basic properties and attracts H+. Once reconstituted it is stable for ~ one week. Thiopental and other barbiturates mainly act by increasing the duration of GABA-dependent chloride channel opening. Barbiturates depress the sensory cortex, decrease motor activity, alter cerebellar function, and produce drowsiness, sedation, and hypnosis. In high doses, maximally reduces brain O2 consumption and exhibits anticonvulsant activity; barbiturates produce dose-dependent respiratory depression. ABSORPTION bioavailabilty 100% routes of administration IV doses 3-5mg/kg as induction dose onset / duration I.V.: 30-60 seconds / 5-30 minutes DISTRIBUTION volume of distribution ~1.6 L/kg protien binding 72% to 86% lipid solubility high lipid solubility pKa 7.6 METABOLISM mechanism Hepatic, primarily to inactive metabolites, when given as an infusion may develop zero order kinetics due to enzyme saturation ELIMINATION half life 3-11.5 hours excretion renal, reduce dose by one quarter when CrCl ex tachycardia. Respiratory depression is dose dependent. Decreased CBF, ICP, and brain O2 consumption. Severe anaphylaxis in 1 in 20000. May precipitate acute porphyria.

Answer 52

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Tiroban binds to the glycoprotien IIb/IIIa receptor on the surface of platelets. It has a similar action to the monoclonal antibody abciximab. It is used in patients with non stable angina and NSTEMI in high risk patients. It is presented for injection in 0.25mg/ml in 50ml vials. Its trade name is aggrastat. It is usually given with low dose aspirin and heparin infusion. All markers of coagulation should be checked within six hours of commencing treatment, and then daily. Tiroban and abciximab act by inhibiting the platelet glycoprotien IIb/IIIa receptor and as such they block the nal common pathway of platelet aggregation. They do not block platelet adhesion, secretion of platelet products, inammatory eects or thrombin activation. ABSORPTION bioavailabilty routes of administration doses onset / duration more rapid oset than abciximab and other agents. DISTRIBUTION volume of distribution protien binding METABOLISM mechanism ELIMINATION half life excretion 65% renal and 25% faecal clearance Requires dose adjustment in renal failure with creatinine clearance ects relate to haemorrhage, although spontaneous haemorrhage is uncommon. Reversal is problematic and platelet infusion is recommended if there is uncontrolled bleeding.

Answer 53

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Vancomycin is a tricyclic glycopeptide antibiotic produced by streptococcus orientalis. It possesses a broad spectrum of activity against gram positive bacteria including MRSA. Recommended to be stored at 2-8 degrees. Available as a clear solution. It may cause vessel irritation when infused peripherally and it is recommended that it is given slowly as a result. Monitoring is required to ensure adequate dosing. Vancomycin exerts its action by inhibiting the formation of the peptidoglycan polymers of the bacterial cell wall. Unlike penicillins, which act mainly to prevent the cross-linking of peptidoglycans which gives the cell wall its strength, "vancomycin" prevents the transfer and addition of the muramylpentapeptide building blocks that make up the peptidoglycan molecule itself. ABSORPTION bioavailabilty Oral: Poor; I.M.: Erratic; Intraperitoneal: ~38% routes of administration IV doses 500mg-1g QID is the usual dose onset / duration DISTRIBUTION volume of distribution Vd: 0.4-1 L/kg; Distributes widely in body tissue and uids, except for CSF, improved CSF penetration with inamed meninges protien binding ~50% METABOLISM mechanism Little or no metabolism ELIMINATION half life Biphasic half life, prolonged in renal fail. excretion via kidneys unchanged May cause hypersensitivity reactions including anaphylaxis. Rapid infusion is associated with red-man syndrome. Ototoxicity which appears to be related to dose is a concern. Nephrotoxicity has declined with improved formulations.

Answer 54

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Vasopressin a naturally occuring peptide released from the posterior pituitary also known as anti diuretic hormone. It is available in two forms for theraputic use, desmopressin (DDAVP) and vasopressin. It is used in diabetes insipidis, control of bleeding in patients with VwB disease and mild haemophilia and o label as a catecholamine sparing drug in the the setting of mild to moderate septic shock. It is measured in international units and comes in a vial with 20 units per mL requiring dilution for eective delivery. It cannot be given orally as it is inactivated by trypsin. Vasopressin receptors are GCPR that exist in three main forms, V1a, V1b and V2. V1a receptors are found in multiple places including vascular smooth muscle and platelets are responsible for the vasopressor actions and platelet aggregation. V2 receptors are found renal collecting duct and ascending limb. and are responsible for ADH actions. ABSORPTION bioavailabilty 100% IV routes of administration IV (o label), IM, SC, IN doses I.V.: 0.01-0.04 units/minute for the treatment of septic shock. onset / duration rapid / 2-8 hrs if given IN DISTRIBUTION volume of distribution limited data METABOLISM mechanism hepatic and renal ELIMINATION half life if given intranasally 4 hours excretion Urine (5% unchanged) Causes hyponatraemia with water retention avoid in CHF. May cause severe vasoconstriction and necrosis (not to be given peripherally). Doses above 0.04 units/min may cause arrhythmias or asystole. Actions on GI smooth muscle cause abdominal cramping, nausea and diarrhoea.

Answer 55

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Verapamil is a synthetic derivative of papaverine that is supplied as a racemic mixture. It is the levoisomer of verapamil which is specic for slow calcium channels. It is used to control hypertension, treat angina,and in arrythmias such as SVT to slow conduction through the SA and AV nodes. It is available as immediate and sustained release oral formulations in doses ranging from 40-240mg. It may come in combination with the ACE inhibitor trandolapril. It is also available as an IV formulation with a concentration of 2.5mg/ml (2ml vial). The levoisomer causes main eects (arterial vasodilation). Verapamil slows conduction through the AV and SA node to a greater extent then other Ca channel blockers. The dextroisomer of verapamil is devoid of activity at slow calcium channels and instead acts on fast sodium channels, accounting for the local anesthetic eects of verapamil (1.6 times as potent as procaine). ABSORPTION bioavailabilty Well absorbed by high rst pass metabolism leading to bioavailability of 20% to 35% routes of administration oral or IV doses onset / duration 1-2 hours / 6-8 hours (for oral intake) DISTRIBUTION volume of distribution 3.89 L/kg protien binding ~90% METABOLISM mechanism Hepatic via multiple CYP isoenzymes , one active metabolite with 20% activity ELIMINATION half life 3-7 hours excretion Urine (70% as metabolites, 3% to 4% as unchanged drug); feces (16%) in patients without congestive heart failure, ventricular performance is not impaired and actually may improve, especially if ischemia limits performance. In contrast, in patients with congestive heart failure, intravenous verapamil can cause a marked decrease in contractility and left ventricular function. It should be avaioded in pts with WPW.

Answer 56

PHARMACEUTICAL ASPECTS PHARMACODYNAMIC ASPECTS PHARMACOKINETIC ASPECTS MAJOR ISSUES OR SIDE EFFECTS Warfarin is a water soluble coumarin derivative and is used for the prophylaxis of systemic thrombo embolism in patients with AF, valvular heart disease and in the prevention of VTE and PE. Warfarin is a racemic mixture of two enantiomers R and S with the biological eects more prominent in the S isomer. It is presented as oral tablets in a range of dosages and requires careful titration according to INR in all patients. Warfarin inhibits vitamin K epoxide reductase (VKOR), thereby blocking the γ-carboxylation process of clotting factors II, VII, IX and X and the anticlotting Protien C and S. This results in the synthesis of vitamin K–dependent clotting proteins that are only partially γ-carboxylated. Warfarin acts as an anticoagulant because these partially γ- carboxylated proteins have reduced or absent biologic activity. The onset of action of warfarin is delayed until the newly synthesized clotting factors with reduced activity gradually replace their fully active counter parts. ABSORPTION bioavailabilty oral, rapid complete routes of administration oral doses titrate to PT/INR onset / duration 24-72 hrs / Full therapeutic eect: 5-7 days DISTRIBUTION volume of distribution 0.12 L/kg protien binding 99% METABOLISM mechanism Hepatic, primarily via CYP2C9 two common variants in this cytochome lead to increased warfarin eect (therefore decreased dosing requirement) ELIMINATION half life 20-60 hours; Mean: 40 hours excretion Urine (92%, primarily as metabolites) The main side eect of warfarin is bleeding. In the setting of uncrontrolled haemorrhage vitamin K may be given along with FFP in accordance with the INR. Other side eects include idosyncratic skin necrosis. There are extensive interac tions with other meds, diet and protien binding. May cause a prothrombotic state during initiation due to Protien C ad S being blocked rst.

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