Antihypertensive agents

NC Hwang 2008

Classification According to site of action

According to mechanism of action

According to usage during anaesthesia

DIURETIC AGENTS hypertension control with diuretic-based pharmacotherapy results in better prevention of heart failure than pressure reduction with other drugs through depletion of body sodium stored, reduction of blood volume + vasodilatation depletion of body sodium stores and reduction in blood volume sodium contributes to vascular resistance by increasing vessel stiffness and neural reactivity, possibly related to increased sodium-calcium exchange with a resultant increase in intracellular calcium initially, reduced blood volume, reduced cardiac output, increased peripheral vascular resistance after 6-8 weeks, cardiac output returns to normal, peripheral resistance declines direct vasodilating effects with vasodilatation, cardiac output is maintained or increased indapamide, a non-thiazide sulfonamide diuretic has both diuretic and vasodilator activities amiloride, inhibits smooth muscle responses to contractile stimuli, probably though effects on transmembrane and intracellular calcium movement that are independent of its action on sodium excretion selection of diuretics thiazide mild to moderate hypertension loop diuretics (frusemide) severe hypertension, when multiple drugs with sodiumretaining properties are used in renal insufficiency, when GFR is < 30-40ml/min blood pressure response continues to increase as dose increases

Antihypertensive agents
Thiazides emerged from synthesis of more potent carbonic anhydrase, prototype is hydrochlorothiazide all have an unsubstituted sulphonamide group main site of effect is at distal convoluted tubules where 10% of filtered NaCl is reabsorbed mechanism of action main effect inhibition of NaCl transport predominantly in the distal convoluted tubules by inhibition of Na+/Cl- symport (or transporter)

NC Hwang 2008

elimination degree of protein binding determines the contribution that filtration makes to tubular delivery of thiazides sulphonamides are organic acids and are secreted by the organic acid secretory system secretion inhibited by indomethacin and probenecid compete with the secretion of uric acid, uric acid secretory rate may be reduced with initial hyperuricaemia adverse effects hyponatraemia, hypochloraemia, reduced extracellular fluid hypokalaemia*, metabolic alkalosis, arrhythmia*, weakness, fatigability, parasthesia hypomagnesaemia hypercalcaemia hyperuricaemia*, gout hypertriglyceridaemia*, hypercholesterolaemia hyperglycaemia* hypersensitivity * associated with hydrochlorothiaxide > 25mg/day drug interactions quinidine (prolongation of QT interval leading to polymorphic ventricular tachycardia or torsade de pointes, due to hypokalaemia) thiazides diminish the effects of anticoagulants, uricosuric agents, sulphonylureas, insulin thiazides increase the effects of anaesthetics, diazoxides, digoxin, lithium, loop diuretics, vitamin D effect of thiazide diuretics decreased by as action depends partly on production of prostaglandin, effect can be inhibited by NSAIDs bile acid sequestrants (reduce reabsorption of thiazides), methanamines (alkalinization of urine) risk of hypokalaemia increased by amphotericin B and corticosteroids examples

other effects retention of carbonic anhydrase inhibitory activity - increased excretion of HCO3due to increased delivery of NaHCO3 to collecting tubule, increased luminal negative electrical potential - enhanced secretion of K+ and titratable acid (regulated by aldosterone) competition with the secretion of uric acid initial hyperuricaemia reduction of the normal lumen-positive potential derived from K+ recycling across the apical membrane of the DCT, Ca++ and Mg++ are not driven out of the lumen by electrical forces hypomagnesaemia lower intracellular Na+ enhances basolateral membrane Na+/Ca++ exchange increasing overall reabsorption of Ca++ in additon to active reabsorption of through apical membrane Ca++ channel at DCT (regulated by parathyroid hormone) rarely cause hypercalcemia but can unmask hypercalcemia due to other causes, e.g. hyperparathyroidism, carcinoma, sarcoidosis) facilitation of the opening of Ca++-dependent K+ channels in the pancreatic beta cells, causing hyperpolarization of these cells reducing glucose-evoked insulin secretion hyperglycaemia may be related to hypokalaemia as hyperglycaemia is partially reversible with correction of hypokalaemia short-term thiazide usage raises cholesterol, triglycerides, and LDL, long-term usage is not necessarily associated with significant alterations in lipid levels

Antihypertensive agents
Loop diuretics sulphonamide derivatives frusemide, bumetanide, torsemide phenoxyacetic acid derivative ethacrynic acid main site of effect is at ascending loop of Henle where 35% of filtered NaCl is reabsorbed mechanism of action main effect selective inhibition of Na+/K+/2Cl- transport system in the luminal membrane of the thick ascending limb of loop of Henle

NC Hwang 2008

adverse effects hyponatraemia, hypochloraemia, reduced extracellular fluid, hypercalcaemia may occur with severe dehydration hypophasphataemia hyperuricaemia, gout hypomagnesaemia hypocalcaemia hypokalaemia, metabolic alkalosis, arrhythmia (especially with digoxin), weakness, fatigability, parasthesia hyperglycaemia hypersensitivity ototoxicity increase plasma concentration of LDL cholesterol and triglycerides, while decreasing HDL cholesterol hypersensitivity autoimmune reaction, bone marrow depression photosensitivity gastrointestinal disturbances contraindications severe Na+ and volume depletion sensitive to other sulphonamides for sulphonamidebased diuretics hepatic cirrhosis decreased secretion of the drug, in part because of the high serum aldosterone concentrations leading to enhanced salt reabsorption at the collecting ducts drug interactions aminoglycosides (augmentation of ototoxicity) oral anticoagulant (increase activity) digoxin (potentiate digoxin-induced arrhythmias) increase plasma concentrations of lithium, propranolol sulphonylureas (hyperglycaemia) cisplatin (increased risk of diuretic-induced ototoxicity) NSAIDs (reduce diuretic response) probenecid (reduce transport into tubular lumen and hence diuretic response) thiazide diuretics (synergism of diuretic activity) examples

other effects inhibition of Na+ uptake inhibits cotransport of phosphate and other vital metabolites hypophosphataemia inhibition of Na+/K+/2Cl- cotransporter, reduction of the normal lumen-positive potential derived from K+ recycling, increase in Mg++ and Ca++ excretion hypomagnesaemia, hypocalcaemia weak inhibitor of carbonic anhydrase activity increased excretion of HCO3hypovolaemia associated enhanced uric acid reabsorption in proximal tubule hyperuricaemia increase urinary excretion of K+ and titratable acid due to increase delivery of Na+ to distal tubule inhibition of Cl- and Ca++ influx in pancreatic beta cells reduces insulin release; and inhibition of glucose transport in adipocytes glucose intolerance alterations in the electrolyte composition of endolymph occurs most frequently with rapid intravenous administration, less frequently with oral administration - ototoxicity higher incidence with ethacrynic acid lowers HDL sensitization to sulphonamide can result in autoimmune reaction thrombocytopenia

Antihypertensive agents
2 RECEPTOR AGONIST 2 receptors are located on presynaptic adrenergic neurons in the central nervous system, stimulation of which inhibits the release of noradrenaline

NC Hwang 2008

both methyldopa and clonidine bind more tightly to 2 than to 1 adrenoceptors 2 receptors found in nucleus tractus solitarius (NTS) of the medulla, nucleus coerulus 2 receptors are coupled to Go and Gi Go interacts with membrane bound phospholipase C and is coupled to voltage-gated Ca++ channel, reducing inward conductance of Ca++ activation of Gi gated K+ channels increases outward conductance of K+, hyperpolarisation of the neuronal cell; Gi also supports inhibition of adenylyl cyclase reduce sympathetic outflow from vasopressor centres in the brainstem but allow these centres to retain or even increase their sensitivity to baroreceptor control less risk of postural hypotension as no direct effect on peripheral sympathetic neurons clonidine also binds to imidazoline receptors in the rostral ventrolateral medulla (RVLM), which is considered the common pathway for sympathetic vasomotor outflow I1 (brain) and I2 (brain, kidney pancreas) I1 subgroup binding site for imidazoline drugs with antihypertensive effects may be a G protein-coupled receptor that utilises the IP3 and DAG as second messenger system I1 selectivity: moxonidine > rilmenidine > clonidine > dexmedetomidine > mivazerol less sedation and less dry mouth with moxonidine and rilmenidine

Antihypertensive agents
Methyldopa indicated for mild to moderately severe hypertension during pregnancy adverse effects sedation, persistent mental lassitude, impaired mental concentration, mental depression, nightmares vertigo extrapyramidal signs positive Coombs test (in 10-20% of patients undergoing therapy > 12 months) lactation associated with increased prolactin secretion can occur both in men and women mediated by inhibition action on dopaminergic mechanisms in the hypothalamus Clonidine other actions suppression of locus coeruleus sedation and sleep analgesic effects slight reduction of minute ventilation decrease intraocular pressure alter neuronal activity in the spinal cord - treatment of spasticity blocks adrenaline-induced platelet aggregation inhibit secretion of adrenocorticotropic hormone (ACTH) and cortisol inhibition of insulin release by direct effect on islets of Langerhans adverse effects dry mouth, sedation centrally-mediated, dose dependent mental depression treatable with tricyclic antidepressants rebound hypertension from withdrawal of the drug after prolonged use (hypertensive crisis) nervousness, tachycardia, headache, sweating after omitting one or two doses of the drug sexual dysfunction contact dermatitis with transdermal patch

NC Hwang 2008

Guanfacine and guanabenz both central acting 2 adrenergic receptor lower blood pressure by activation of brainstem receptors with resultant suppression of sympathetic activity pharmacokinetics both well absorbed after oral administration Vd 4-6 L/kg guanfacine 50% excreted unchanged in urine, 50% metabolized; t 12-24 hours guanabenz extensively metabolized by liver; t 4-6 hours dose adjustment in cirrhosis adverse effects similar to clonidine but less severe withdrawal syndrome may occur after abrupt discontinuation

Antihypertensive agents
GANGLION BLOCKING AGENTS drugs that block the nicotinic cholinoceptors on postganglionic neurons in both sympathetic and parasympathetic ganglia, e.g. trimethaphan camsylate no longer available clinically because of the toxicities related to their primary action adverse effects from sympathoplegia excessive orthostatic hypotension sexual dysfunction adverse effects from parasympathoplegia constipation, urinary retention precipitation of glaucoma, blurred vision dry mouth ADRENERGIC NEURON BLOCKING AGENTS these drugs lower blood pressure by preventing the normal physiologic release of noradrenaline from postganglionic sympathetic neurons, e.g. guanethidine, reserpine Guanethidine structure includes a highly basic nitrogen (guanidine group) that makes the drug too polar to enter the central nervous system this drug has no central nervous system effects mechanism of action depletion of noradrenaline stores guanethidine is transported across the sympathetic nerve membrane by the same mechanism that transports noradrenaline (uptake 1) once guanethidine has entered the nerve, it is concentrated in transmitter vesicles, where it replaces noradrenaline, causing a gradual depletion of noradrenaline stores in the nerve ending blocks excitation-secretion coupling by Ca++ local anaesthetic effect local blockade of membrane electrical activity may occur in nerve endings, inhibiting the release of noradrenaline

NC Hwang 2008

absorption after oral dose, bioavailability variable 3-50% distribution retention of the drug in nerve endings and uptake into other sites contribute to large volume of distribution and long t of 5 days with constant dosing, the onset of sympathoplegic is gradual, maximum effects in 1-2 weeks clearance 50% cleared by the kidney contraindication pheochromocytoma hypertensive crisis by release of catecholamine pharmacodynamic effects early in the course of therapy, hypotensive effects is associated with reduced cardiac output, due to bradycardia and relaxation of capacitance vessels, without consistent change in peripheral resistance with chronic therapy, peripheral resistance decreases sodium and water retention may be marked during guanethidine therapy adverse effects postural hypotension and hypotension following exercise severe reduction in blood pressure if dosages are excessively high, or increased too rapidly up-regulation of post-synaptic receptors after long-term therapy delayed or retrograde ejaculation (into the bladder) in men diarrhoea due to parasympathetic predominance drug interaction drugs that block the catecholamine uptake process (cocaine, tricyclic antidepressants) or displace amines from nerve terminals (amphetamine, tyramine, reserpine) block the effects of guanethidine concomitant TCA administration reduces antihypertensive effect of guanethidine; if dosage of guanethidine is increased for antihypertensive effect and TCA is then stopped, severe hypotension or cardiovascular collapse from unopposed action of guanethidine guanethidine increases sensitivity to hypertensive effects of exogenously administered sympathomimetic agents, from inhibition in neuronal uptake of such amines phenylpropanolamine, in commercial preparations for rhinitis, can produce hypertension in patients taking guanethidine

Antihypertensive agents
Reserpine an alkaloid extracted from the roots of Rauwolfia serpentina, for treating mild to moderate hypertension mechanism of action readily enters the brain irreversibly blocks uptake of biogenic amines into vesicles, probably by interfering with an uptake mechanism that depends on Mg++ and ATP; resulting in depletion of noradrenaline, dopamine, and serotonin in both central and peripheral neurons chromaffin granules of the adrenal medulla are also depleted of catecholamines effects entirely metabolised, but prolonged effects due to irreversible inactivation of the carriers in catecholamine storage granules central effects sympathetic reflexes remain largely intact, blood pressure is reduced in supine as well as in standing patients, and postural hypotension is mild depletion of cerebral amine stores - sedation, mental depression, and extrapyramidal effects

NC Hwang 2008

peripheral effects depletion of peripheral amines probably accounts for much of the antihypertensive effect of reserpine contraindication mental depression gastric ulceration adverse effects postural hypotension, less with low doses sedation. lassitude, nightmares severe mental depression with high dosages extrapyramidal effects resembling Parkinsons disease, due to dopamine depletion in the corpus striatum mild diarrhoea, gastrointestinal cramps, increase gastric acid secretion

1-ADRENOCEPTOR ANTAGONISTS mechansim of action reversible 1 receptor antagonists can dissociate from the receptors phentolamine, tolazoline, prazosin, labetalol duration of action largely dependent on the rate at which it dissociates from the receptor the clearance and half-life irreversible 1 receptor antagonists covalently bind to the receptors and do not dissociate from the receptors (e.g. phenoxybenzamine) effects of the drug may persist long after the drug has been cleared from the plasma restoration of tissue responsiveness after extensive -receptor blockade (e.g. by phenoxybenzamine) is dependent on the synthesis of new receptors, which may take several days

effects postural hypotension and reflex tachycardia postural hypotension due to blockade of 1 receptors in venous smooth muscle compensatory increase in blood volume with chronic use eye - myosis nasal mucosa - congestion and stuffiness inhibition of contraction of the trigone and sphincter muscles in the base of bladder and prostate resulting in incontinence indications pheochromocytoma hypertensive emergencies chronic hypertension retention of salt and water occurs if administered without a diuretic peripheral vascular disease treatment of clonidine withdrawal syndrome urinary obstruction prevention of dermal necrosis after inadvertent extravasation of -adrenergic agonist male sexual dysfunction direct intracavernous injection of phentolamine with papaverine

Antihypertensive agents
classes alkylating agent phenoxybenzamine imidazolines phentolamine, tolazoline piperazinyl quinazolines prazosin, terazosin, doxazosin, trimazosin indoles yohimbine, indoramin ergot derivatives ergotamine, dihydroergotamine Phenoxybenzamine a haloalkylamine mechanisms of action blocks both 1 and 2 adrenergic receptors forms a reactive ethyleneimonium intermediate that covalently binds to receptors, resulting in irreversible blockade long duration of action, 14-48 hours slight selectivity for 1 receptors, less so than prazosin inhibits presynaptic reuptake of released noradrenaline also blocks histamine (H1), acetylcholine, and serotonin receptors effects blocks catecholamine induced vasoconstriction causes significant fall in blood pressure when the sympathetic tone is high e.g. as a result of upright posture or because of hypovolaemia cardiac output may increase because of reflex effects and because of some blockade of presynaptic 2 receptors in cardiac sympathetic nerves indications pheochromocytoma benign prostatic obstruction pharmacokinetics low bioavailability after oral administration crosses BBB t probably 24 hours, but effect depends on rate of synthesis of receptors adverse effects postural hypotension tachycardia nasal stuffiness inhibition of ejaculation non specific central nervous system effects: fatigue, sedation, nausea urinary incontinence Phentolamine imidazoline derivative mechanisms of action competitive a receptor antagonist with similar affinity for 1 and 2 receptors, causing a reduction in peripheral resistance blocks serotonin receptors and K+ channels agonist at muscarinic and H1 and H2 receptors

NC Hwang 2008

tachycardia results from 2 causes baroreflex mechanism antagonism of presynaptic a2 receptors lead to enhanced release of noradrenaline from sympathetic nerves, noradrenaline then acts via unblocked adrenoceptors formulation oral phentolamine mesylate is rapidly absorbed and eliminated; peak plasma concentrations are achieved in 30-60 min, and the half-life approximates 5-7 h IV bolus or infusion adverse effects cardiac stimulation: tachycardia, arrhythmias, myocardial ischaemia gastrointestinal stimulation: diarrhoea and increased gastric acid production indications pheochromocytoma reduce extent of dermal necrosis after extravasation of agonist hypertensive crisis male sexual dysfunction Prazocin piperazinyl quinazoline selectivity for 1:2 receptor is 1000:1 blood pressure is reduced more in the upright than in the supine position receptor selectivity allows noradrenaline to exert unopposed negative feedback (on presynaptic 2 receptor) on its own release may partially explain the absence of reflex tachycardia with prazosin (cf phentolamine and phenoxybenzamine) potent inhibitor of cyclic nucleotide phosphodiesterase absorption 50-70% bioavailability after oral administration peak concentrations reached within 1-3 hours after oral dose distribution 95% tightly bound to 1-acid glycoprotein free fraction subject to change by diseases that modify the concentration of this protein clearance entirely metabolised t about 2-3 hours, although antihypertensive effect is longer, 4-6 hours plasma concentration increased in patients with congestive heart failure, due to reduced firstpass metabolism indications hypertension congestive heart failure benign prostatic hyperplasia adverse effects first dose phenomenon, dizziness palpitation headache lassitude development of antinuclear factor in serum

Antihypertensive agents
1-ADRENOCEPTOR ANTAGONISTS mechanism of antihypertensive action decrease in cardiac output negative inotropic and chronotropic effects adrenoceptor blockade at atrioventricular node inhibition of 1-mediated renin production and depression of the renin-angiotensin-aldosterone system inhibition of peripheral prejunctional adrenoceptors reducing sympathetic vasoconstrictor nerve activity may result in an initial rise in peripheral vascular resistance from unopposed receptormediated effects distinguishing properties reversible / irreversible binding to receptors full antagonists / partial agonists (intrinsic sympathomimetic activity, ISA) relative affinity for 1 and 2 receptors pharmacokinetic characteristics local anaesthetic membrane-stabilising effects (MSA) types pure antagonists occupancy of a beta receptor causes no activation of the receptor partial agonists (intrinsic sympathetic activity) cause partial activation of the receptor, but less than that caused by full agonists adrenaline and isoprenaline inverse agonists have the ability to inactivate active state receptors propranolol > carvedilol in producing negative chronotropic and inotropic effects selective 1 antagonists lipophilic antagonist

NC Hwang 2008

hydrophilic antagonist

non-selective antagonist

pharmacokinetic properties absorption most of the drugs in this class are well absorbed after oral administration peak concentrations occur 1-3 hours after ingestion sustained release preparations of propranolol and metoprolol are available bioavailability first pass effect, extensive for most, with low bioavailability except for betaxolol, penbutolol, pindolol, and sotalol interindividual variability hepatic extraction mechanism may become saturated distribution rapidly distributed and have large volumes of distribution propranolol and penbutolol are quite lipophilic and readily cross the blood brain barrier if highly protein bound, are not cleared significantly by haemodialysis clearance t of most receptor antagonists 2-5 hours, except esmolol, with t of 10 minutes propranolol and metoprolol are extensively metabolised in the liver atenolol , celiprolol, and pindolol are less completely metabolised nadolol is excreted unchanged in the urine (normally t up to 24 hours, prolonged in renal failure) clinical effect of these drugs are often prolonged well beyond the time predicted from half-life

Antihypertensive agents
other effects respiratory tract bronchoconstriction with increased airway resistance use of selective 1 receptor antagonists may be preferable when 2 receptor blockade is undesirable esmolol, acebutolol, metoprolol, bisoprolol, celiprolol, atenolol, betaxolol as specific 1 receptor antagonist without 2 activity is currently unavailable, therefore these drugs should generally be avoided in patients with asthma eye decrease aqueous humor production, reduce intraocular pressure, especially in glaucoma metabolic and endocrine function inhibit lipolysis inhibit glycogenolysis in the liver increased plasma concentration of VLDL and decreased concentrations of HDL cholesterol after chronic administration, LDL concentrations generally do not change these change are less likely to occur with blockers with intrinsic sympathomimetic activity (partial agonists: acebutolol, celiprolol, carteolol, pindolol, oxprenolol) intrinsic sympathetic activity drugs with retention of ISA (partial agonists) may be useful for patients who develop symptomatic bradycardia or bronchoconstriction with nonselective beta receptor antagonists acebutolol, celiprolol, carteolol, oxprenolol, pindolol membrane stabilizing action result from typical local anaesthetic blockade of sodium channels can be demonstrated in neurons, heart muscle, and skeletal muscle membrane acebutolol, betaxolol, labetalol, metoprolol, pindolol, propranolol, oxprenolol these drugs should not be applied topically to the eye adverse effects result of blockade in heart, vessels and bronchial tree occur in patients with reduced myocardial reserve, asthma, peripheral insufficiency, and diabetes discontinuing propranolol after prolonged use can precipitate withdrawal syndrome nervousness, tachycardia, increased intensity of angina, increased of blood pressure, withdrawal syndrome may involve upregulation or supersensitivity of adrenoceptors gastrointestinal effects diarrhoea, constipation, nausea, vomiting not attributed to beta receptor blockade insomnia, lassitude, mental depression, nightmares

NC Hwang 2008

metabolism increased plasma triglycerides, decreased HDL-cholesterol, which theoretically can contribute to atherogenesis contraindications bronchial asthma severe bradycardia decompensated NYHA functional class IV heart failure requiring intravenous inotropic support sick sinus syndrome (unless a permanent pacemaker is in place) second- or third-degree atrioventricular block cardiogenic shock severe liver impairment known hypersensitivity clinical applications depending on specific action of the drug: cardiovascular system hypertension ischaemic heart disease cardiac arrhythmias hypertrophic obstructive cardiomyopathy glaucoma hyperthyroidism neurologic diseases migraine tremors portal hypertension and bleeding from oesophageal varices Propranolol prototype 1 and 2 adrenoceptors blocking drug may block some serotonin receptors in the brain no detectable partial agonist action at receptors for treatment of mild to moderate hypertension, without postural hypotension in severe hypertension, propranolol is useful in preventing reflex tachycardia that often results from treatment with direct vasodilators resting bradycardia and a reduction in heart rate during exercise are indicators of beta-blocking effect pharmacokinetics absorption highly lipophilic, almost completely absorbed after oral administration oral doses subjected to extensive first-pass hepatic inactivation bioavailability has low and dose-dependent bioavailability distribution 90% of the drug in circulation is bound to plasma proteins, Vd of 4 L/kg metabolism extensively metabolized in liver, metabolites excreted in urine t of 4 hours one metabolite, 4-hydroxypropranolol has active receptor antagonist activity clearance may vary with hepatic blood flow and liver disease, and may change with administration of other drugs that affect hepatic metabolism

Antihypertensive agents
Metoprolol potency compared with propranolol equipotent at 1 adrenoceptors 50-100x less at 2 adrenoceptors relative cardioselectivity advantageous in treating hypertensive patients who suffer from asthma, diabetes or peripheral vascular disease, since 2 receptor activity is important in the liver (for glycogenolysis) and blood vessels (vasodilatation) *cardioselectivity is not complete, asthma may still be exacerbated by metoprolol Celiprolol 1 selective antagonist 2 receptor agonist may promote bronchodilation has weak vasodilator properties of uncertain mechanism efficacious in treating hypertension and angina Labetalol available a racemic mixture molecule has 2 centres of asymmetry: 2 pairs of chiral isomers (4 isomeric compounds) RR isomer is a potent nonselective blocker potency is less than that of propranolol has some intrinsic sympathomimetic activity at 2 receptor (may contribute to vasodilatation) SR isomer is a potent 1 blocker potency is less than that of phentolamine SS has some 1 blocking effect RS isomer devoid of and blocking effects : antagonism after oral dosing varies from 3:1 to 10:1 Carvedilol administered as racemic mixture, rapidly absorbed following oral administration both S and R isomers have approximately equal blocking potency S(-) isomer is nonselective adrenoceptor blocker isomers are stereoselectively metabolised in the liver, which means elimination half-lives may differ average 7-10 hours primarily metabolised by the liver, undergoes extensive first-pass metabolism 3 active metabolites but none of these appears to have beta-blocking activity <2% of given dose excreted unchanged in the urine other effects calcium channel blocking activity antioxidant properties inhibits generation of oxygen free radicals and prevents low-density lipoprotein oxidation, which in turn, reduces the uptake of LDL into the coronary vasculature adverse effects postural hypotension dizziness, fatigue diarrhoea (2.2%) bradycardia (2.1%) insomnia (1.6%) dyspnoea (1.4%) oedema (1.4%)

NC Hwang 2008

Bisoprolol antagonist at 1 and receptors possesses an asymmetric carbon-atom in its structure, and is provided as a racemic mixture S-enantiomer is responsible for most of the blocking activity Sotalol a nonselective receptor antagonist has marked class III antiarrhythmic effects, reflecting potassium channel blockade Esmolol ultra-short acting selective 1 receptor blocker 40:1 affinity for 1 receptor cardioselectivity benefits asthmatic patients structure contains ester linkage esterases in red blood cells rapidly metabolise esmolol to a metabolite with low affinity for receptors short half-life of 8 minutes useful in controlling supraventricular arrhythmias, perioperative hypertension, and myocardial ischaemia in acutely ill patients CALCIUM CHANNEL BLOCKERS mechanism of action inhibition of calcium influx into arterial smooth muscle cells, resulting in arteriolar dilatation and lowering of blood pressure classification according to structure, of calcium channel blockers with vasodilatory properties phenylalkylamines verapamil (not for treatment of hypertension) dihydropyridine amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine benzothiazepines diltiazem (not for treatment of hypertension) classification according to generations first generation agents (nifedipine, verapamil and diltiazem) second generation agents (subsequently developed dihydropyridine-derivatives) greater vascular selectivity, a longer duration of action and a small trough-to-peak variation in plasma concentrations.

Antihypertensive agents
mechanism of action all three types of selective calcium channel blockers interact with the 1 subunit of the L-type calcium channel, each binds to a different receptor site binding sites for all three chemical types of calcium channel blocker are present in many tissues, including myocardium, smooth muscle, skeletal muscle, and glandular tissue, however, the activity of each calcium channel blocker in a particular tissue varies drugs binding at the dihydropyridine site appear to increase the affinity of diltiazem for the benzothiazepine site, and vice versa haemodynamic differences among the agents may influence the choice of a particular agent dihydropyridines act preferentially on vascular smooth muscle, exerting potent peripheral vasodilating effects verapamil and diltiazem are less specific for peripheral vascular smooth muscle and more active in the myocardium and cardiac conductive tissues, for cardiac depressant effect and for inhibition of reflex sympathetic activity binding of the drug reduces the frequency of channel opening result in marked decrease in transmembrane calcium current smooth muscle relaxation reduction in cardiac contractility decrease in sinus node pacemaker rate decrease in atrioventricular node conduction velocity channel block can be partially reversed by elevating the concentration of calcium drugs that increase the transmembrane flux of calcium, such as sympathomimetics skeletal muscles are not depressed by calcium channel blockers because intracellular pools of calcium are utilised to support excitation-contraction coupling effect on smooth muscles vascular smooth muscle more sensitive to calcium channel blockers than bronchiolar, gastrointestinal and uterine smooth muscle arterioles are more sensitive than veins, orthostatic hypotension not a common adverse effect reducing peripheral resistance in patients with angina reduces left ventricular wall stress reduction of coronary arterial tone, prevents focal arterial spasm vascular selectivity nicardipine > amlodipine > nifedipine > verapamil

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nimodipine has a high affinity for cerebral blood vessels, reducing vasospasm after subarachnoid haemorrhage

effects on the heart ischaemia causes membrane depolarisation, calcium influx in ischaemic cells is increased elevated intracellular calcium accelerates the activity of several ATP-consuming enzymes, which further depletes the already marginal cellular ATP stores, making the heart even more susceptible to ischaemic damage calcium channel blockers reduce this ischaemic damage by reducing the incidence of arrhythmias and the ultimate size of the infarct reduction in cardiac contractility, cardiac output, and cardiac oxygen consumption nonspecific sympathetic antagonism is most marked with diltiazem, less with verapamil nifedipine does not appear to have this effect, thus reflex tachycardia to hypotension occurs frequently with nifedipine and less so with verapamil sodium channel blockade by bepridil, verapamil and diltiazem negligible effect by dihydropyridines potassium channel blockade by bepridil results in prolongation of cardiac repolarisation and a distinct risk of induction of arrhythmias verapamil and diltiazem block calcium-dependent action potential in slow response cells in the SA node and AV node, resulting in blocking of impulse generation in the nodes block AV node more selectively than do the dihydropyridines effective in treating supraventricular reentry tachycardia and decreasing ventricular response in atrial fibrillation or flutter nifedipine does not affect AV nodal conduction comparison of cardiovascular effects ranked from least prominent (0) to most prominent (5)

Antihypertensive agents
non cardiovascular effects minimally interfere with stimulus-secretion coupling in glands and nerve endings because of differences between calcium channels in different tissues verapamil inhibit insulin secretion in humans, but the dosage required are greater than those used in management of angina may interfere with platelet aggregation in vitro and prevent or attenuate the development of atheromatous lesions in animals verapamil blocks P170 glycoprotein which is responsible for transport of many foreign drugs out of cancer (and other) cells, this action is not stereospecific increased expression of the P170 multidrug transporter protein is associated with the development of resistance to chemotherapy in cancer cells verapamil partially reverses the resistance of cancer cells to many chemotherapeutic drugs adverse effects bradycardia atrioventricular block if combining verapamil or diltiazem with beta blocker congestive heart failure from negative inotropic effecte myocardial infarction if onset of hypotension is rapid cardiac arrest torsade de pointes bepridil prolongs cardiac action potential, contraindicated in patients with prolonged QT syndrome flushing, oedema, dizziness, nausea, and constipation indications angina only with slow release and long acting calcium channel blockers immediate-release short acting calcium channel blockers can increase the risk of myocardial infarction, therefore are contraindicated in non-Q infarction, diltiazem can reduce frequency of post-infarct angina hypertension but can worsen heart failure because of negative inotropic effect supraventricular tachyarrhythmias verapamil and diltiazem caution in digitalised patient, verapamil may increase plasma digoxin concentrations through pharmacokinetic interaction, (less consistent with diltiazem and nifedipine) hypertrophic cardiomyopathy migraine Raynauds phenomenon atherosclerosis contraindications vasodilator treatment in presence of heart failure all calcium channel blockers can worsen heart failure as a result of negative inotropic effect verapamil or diltiazem in combination with -blocker bepridil in the presence of arrhythmias bepridil prolongs cardiac action potential

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prompt-release, short acting nifedipine in the presence of myocardial infarction due to rapid onset of hypotension with this formulation and resulting sympathetic response pharmacokinetics

Verapamil onset of action: <1.5 minute IV, 30 minutes oral metabolism and excretion extensively metabolised by liver, dose reduction in patients with liver impairment 70% eliminated by kidney 15% by gastrointestinal tract indications angina, hypertension, arrhythmias (migraine, cardiomyopathy) adverse effects hypotension, myocardial depression, constipation, dependent oedema Nifedipine onset of action: 5-20 min after sublingual or oral route, less than 1 minute after intravenous administration metabolism and excretion: metabolised to an acid lactate 80% of the drug and metabolite excreted in urine indications angina, hypertension migraine, cardiomyopathy, Raynauds phenomenon adverse effects hypotension, dizziness, flushing, nausea, constipation, dependent oedema Nicardipine onset of action:20 minutes oral metabolism and excretion: extensively metabolised in liver indications angina hypertensive emergencies, intra- and postoperative hypertension adverse effects headache, oedema, dizziness, flushing precautions not compatible with sodium bicarbonate solution or Hartmann solution patients with renal or liver impairment, hypotension and glaucoma contraindications intracranial haemorrhage increased intracranial pressure pregnant or nursing woman

Antihypertensive agents
Amlodipine onset of action: 20 min metabolism and excretion: extensively metabolised indications angina, hypertension adverse effects headache, oedema, fatigue, nausea, flushing, dizziness contraindications known hypersensitivity to dihydropyridines, pregnancy, lactation Diltiazem onset of action: <3 minute IV, >30 minutes oral metabolism and excretion: extensively deacylated drug and metabolites excreted by gastrointestinal tract indications angina, hypertension (Raynauds phenomenon) adverse effects hypotension, myocardial depression, constipation, dependent oedema HYDRAZINE DERIVATIVES Hydralazine dilates arterioles but not veins mechanism of action interfering with the storage of catecholamines displaces catecholamines from secretory vesicles displaces vesicular Ca++ these effects occur within seconds independent of endothelium and is not related to guanylate cyclase activation absorption: well absorbed orally metabolism by acetylation (bimodal distribution of population) rapid acetylator - greater first-pass metabolism, lower bioavailability (25%), less antihypertensive benefit from a given dose than do slow acetylators t ranges from 2-4 hours duration of action due to avid binding to vascular tissue, vascular effects persist longer than do blood concentrations adverse effects headache nausea, anorexia palpitations sweating, flushing angina or ischaemic arrhythmias as a result of reflex tachycardia and sympathetic stimulation in patients with ischaemic heart disease lupus erythematosus-like syndrome slow acetylators prone to develop the syndrome (arthralgia, myalgia, skin rashes, and fever) reversible by discontinuation of hydralazine peripheral neuropathy drug fever

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NITRIC OXIDE INDUCERS / NITROSOVASODILATORS mechansim of action by intracellular release of nitric oxide nitric oxide binds to the haem complex of guanylate cyclase the resulting nitrosyl-haem activates this enzyme with increased production of cGMP and activation of cGMPdependent protein kinase this is followed by phosphorylation of target proteins and dephosphorylation of myosin light chain biological activity of nitric oxide is rapidly terminated due to avid binding to Hb

nitric oxide 1980: endothelium dependent vascular relaxation demonstrated and endothelial derived relaxation factor (EDRF) proposed 1986: Furchgott and Ignarro independently proposed NO as EDRF 1987: production of NO by endothelium was confirmed by Palmer et al. Sodium nitroprusside a nitrovasodilator having a structure a complex of iron, cyanide groups and a nitroso moiety mechanism of action dilates both arterioles and veins reducing both peripheral vascular resistance and venous return result of activation of guanylyl cyclase, either via release of nitric oxide or direct stimulation of the enzyme increasing cyclic GMP, which relaxes smooth muscle

Antihypertensive agents
metabolism 2 stages non-enzymatic pathway in the blood, nitroprusside is rapidly metabolised by uptake into red blood cells an electron is transferred from the (ferrous) Fe++ of HbO2 forming methaemoglobin with (ferric) Fe+++ the resulting nitroprusside molecule is unstable and releases all 5 CN1mg SNP releases 0.44mg CNenzymatic pathway cyanide in turn is metabolised by the mitochondrial enzyme rhodanase, in the presence of thiosulphate (sulphur donor), to thiocyanate 60-70% to thiocyanate rate limiting factor is availability of endogenous thiosulphate (sulphurdonor) thiocyanate is distributed in extracellular fluid and slowly eliminated by the kidney most normal adults can metabolise approximately 50 mg of SNP with existing sulphur stores factors reducing these stores malnutrition surgery diuretics cyanide radicals may accumulate and produce clinical toxicity when infusions exceed 2g/kg/min, or when suphur donors and methaemoglobin are exhausted CN- - metabolism

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delayed hypothyroidism thiocyanate inhibition of iodide uptake by the thyroid administration by intravenous infusion in aqueous solution is sensitive to UV light, should be made up fresh before use and the preparation shielded from light dosage range 0.5 g/kg/min to 10 g/kg/min as necessary to control blood pressure at the higher rate, if continued for more than an hour, may result in toxicity require intra-arterial monitoring of arterial blood pressure management of cyanide toxicity sodium nitrite (NaNO2) reduces HbO2 to methaemoglobin; methaemoglobin has very high affinity for CN- and will compete with cytochrome oxidase for CN-, thus administration of sodium nitrite 5 mg/kg (over 3-4 min) soon after cyanide exposure will regenerate active cytochrome the cyanhaemoglobin produced can be further detoxified by intravenous administration of a sulphur donor, sodium thiosulphate (Na2S2O3) 150 mg/kg (intravenously over 15 min) , resulting in the formation of thiocyanate ion (SCN-), a less toxic ion that is readily excreted hydroxocobalamin 5-10 mg (intravenously) can also be given to form the nontoxic cyanocobalamin Nitroglycerin mechanism of action denitrated by glutathione Stransferase, releasing free nitrite ion in smooth muscle cell a different enzymatic reaction releases nitric oxide NO nitric oxide or (S-nitrosothiol derivative) causes activation of guanylyl cyclase production of prostaglandin E or prostacyclin (PGI2) and membrane hyperpolarisation may be involved calcitonin gene-related peptide, widely distributed in cardiovascular tissues and release is regulated by NO and cGMP, causes vasodilatation pharmacokinetics absorption low bioavailability (10-20%) by oral route, due to high-capacity hepatic organic nitrate reductase that removes nitrate groups in a stepwise fashion from the parent molecule until the drug is inactivated sublingual, buccal, and transdermal route avoids first-pass effect, preferred for achieving therapeutic blood concentration rapidly total dose by this route is small and effect is of short duration metabolism unchanged nitrate compounds have t of 2-8 minutes partially denitrated metabolites have longer t, up to 3 hours four main metabolites, only dinitroglycerins have significant vasodilatory efficacy

adverse effects type II lactic acidosis tissue hypoxia from cytochrome oxidase inhibition following formation of cytochrome iron-CN- complex increase in the mixed venous PO2 arrhythmias excessive hypotension death methaemoglobinaemia methaemoglobin has low affinity for oxygen, leading to tissue hypoxia and death thiocyanate accumulation weakness, disorientation, psychosis, muscle spasms, convulsions with serum concentration greater than 10mg/dl

Antihypertensive agents
elimination excreted primarily as glucuronide derivatives of the denitrated metabolites via kidney effects on vascular smooth muscle all segments of the vascular system from aorta through large veins relax in response to nitroglycerin veins respond at lowest concentrations, arteries at slightly higher concentrations, concentration of SH receptors greater in veins arterioles and precapillary sphincters are dilated less than the large vessels, partly because of reflex response and partly because different vessels vary in their ability to release nitric oxide compensatory responses evoked by baroreceptors and hormonal mechanisms responding to decrease blood pressure in normal subjects, nitroglycerin transiently increases total coronary blood flow in patients with coronary artery disease, no increase in total coronary blood flow relief of angina probably the result of decreased myocardial oxygen consumption secondary to reduction in preload and blood pressure effects on other smooth muscle organs relaxation of smooth muscle of bronchi, gastrointestinal tract and genitourinary tract relaxation of the uterus with bolus doses of nitroglycerin 50 g effects on platelets nitric oxide released from nitroglycerin stimulates guanylyl cyclase in platelets increase in cGMP and decrease in calcium entry responsible for decrease in platelet aggregation effects on haemoglobin nitrite ion reacts with haemoglobin (containing ferrous iron) to produce methaemoglobin (containing ferric iron) methaemoglobin has low affinity for oxygen, large amounts of nitrite can result in pseudocyanosis, tissue hypoxia and death in an adult, the plasma concentration of nitrites even from large amounts of organic and inorganic nitrates will not cause significant methaemoglobinaemia, however in an infant, toxicity may result methaemoglobinaemia, if excessive, can be treated by giving methylene blue intravenously action of methylene blue depends on the availability of reduced nicotinamide adenine nucleotide phosphate (NADPH) within the red blood cells tolerance or tachyphylaxis following prolonged therapy with nitrates, long-acting oral or transdermal, intravenous infusions for more than a few hours without interruption adverse effects extension of therapeutic vasodilatation orthostatic hypotension tachycardia throbbing headache causes

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decreased tissue sulphydryl groups treat with sulphydryl-generating agent diminished release of NO from nitroglycerin may be partially reversed with thiolcontaining compounds like acetylcysteine decreased activation of guanylyl cyclase decreased release of endogenous CGRP may be partially reversed by Nacetylcysteine- or captorpil-induced release of CGRP sympathetic compensation increase in vascular tone retention of salt and water

POTASSIUM CHANNEL OPENERS Minoxidil mechanism of action metabolite minoxidil sulphate opens potassium channels in smooth muscle membrane involves ATP sensitive K+ channel this action stabilises the membrane at its resting potential and makes contraction less likely dilates arterioles but not veins indications replaces hydralazine when maximal doses of the latter are not effective in patients with renal failure and hypertension, who do not respond well to hydralazine pharmacokinetics absorption: well absorbed by gastrointestinal tract distribution not protein-bound duration of action may persist for over 24 hours metabolism primarily by conjugation in the liver minoxidil glucuronide and minoxidil sulphate t about 4 hours

Antihypertensive agents
adverse effects associated with reflex sympathetic stimulation sodium and fluid retention headache sweating hypertrichosis Diazoxide similar chemically to thiazide diuretics but lacks diuretic activity indications hypertensive emergencies hypoglycaemia secondary to insulinoma mechanism of action prevents smooth muscle contraction by opening potassium channels and stabilizing the membrane potential at the resting level involves ATP sensitive K+ channel distribution binds extensively to serum albumin and vascular tissue metabolism both metabolised and excreted unchanged t about 24 hours duration of action after a rapid injection, onset in 5 minutes, lasts for 4-12 hours adverse effects hypotension occurs after smaller doses in patients with chronic renal failure, due to reduced protein binding capacity greater if pretreated with -blockers to prevent reflex tachycardia and associated increase in cardiac output can result in stroke and myocardial infarction reflex sympathetic response angina, ischaemia, cardiac failure hyperglycaemia inhibits insulin release from pancreas, probably by opening potassium channels in beta cell membrane particularly in patients with renal insufficiency salt and water retention INHIBITORS OF RENIN-ANGIOTENSIN SYSTEM

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renin-angiotensin system renin release from renal cortex, stimulated by reduced renal arterial pressure or perfusion sympathetic output reduced sodium delivery increased sodium concentration at the distal renal tubule acts upon 2-globulin, to split off the inactive decapeptide angiotensin I angiotensin I may contribute to maintaining high vascular resistance in hypertensive states associated with high plasma renin activity renal artery stenosis intrinsic renal disease malignant hypertension essential hypertension also generated in a parallel system in the heart may be responsible for trophic changes such as cardiac hypertrophy (myocardial remodelling) converted primarily by endothelial angiotensin converting enzyme (ACE) in the lung, to the arterial vasoconstrictor octapeptide angiotensin II angiotensin II converted in the adrenal gland to angiotensin III angiotensin II and III both stimulate aldosterone release aldosterone causes sodium retnetion, potassium and magnesium loss, proinflammatory action, noradrenaline release, endothelial dysfunction and reduced vascular compliance angiotensin converting enzyme or peptidyl dipeptidase as ACE, converts angiotensin I to angiotensin II as plasma kininase, inactivates bradykinin, a potent vasodilator bradykinin works in part by stimulating the release of nitric oxide and prostacyclin inhibited by ACE inhibitor RENIN INHIBITOR Aliskiren octanamide, nonpeptide, low molecular weight, orally active designed through molecular modelling techniques potent specific inhibitor of renin plasma half life of 24h good water solubility and low lipophilicity resistant to biodegradation by peptidases in intestines, liver, and blood causes a dose dependent decrease in plasma renin activity, to effectively block the formation of both angiotensin I and II, and to decrease plasma and urine concentrations of aldosterone

Antihypertensive agents
ANGIOTENSIN CONVERTING ENZYME INHIBITORS mechanism of action inhibit angiotensin conversion, decreasing peripheral vascular resistance stimulating action on the kallikrein-kinin system, stimulating the release of nitric oxide and prostacyclin do not result in reflex sympathetic activation, may be due to downward setting of baroreceptors or to enhanced parasympathetic activity can be used safely in patients with ischaemic heart disease indications hypertension diminishing proteinuria and stabilising renal function in patients with diabetic nephropathy probably result from improved intrarenal haemodynamics, with decreased glomerular efferent arteriolar resistance and a resulting reduction of intraglomerular capillary pressure congestive heart failure preservation of left ventricular function in years following myocardial infarction, by reducing postinfarction myocardial remodelling adverse effects severe hypotension with hypovolaemic acute renal failure in the presence of bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney hyperkalaemia due to decreased aldosterone secretion dry cough mediated by bradykinin altered sense of taste allergic skin rashes drug fever (10% incidence) thrombocytopaenia, or pancytopaenia pancreatitis headache, light headed nausea, vomiting, stomach discomfort, abdominal pain, anorexia, diarrhoea contraindications 2nd and 3rd trimesters of pregnancy risk of foetal hypotension, anuria, renal failure, sometimes foetal malformations or death renal insufficiency drug interactions potassium supplements or potassium-sparing diuretics (spironolactone, triamterene) hyperkalaemia due to decreased aldosterone secretion diuretic antihypertensive agents excessive hypotension diuretics increases plasma renin activity other vasodilators (nitrates) enhanced hypotension

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nonsteroidal anti-inflammatory agents impair the hypotensive effects of ACE inhibitors by blocking bradykinin-mediated vasodilatation via the production of prostacyclin insulin or oral hypoglycaemic agents hypoglycaemia lithium ACEi accelerates reabsorption of lithium in renal tubules lithium toxicity (sleepiness, tremor) precautions patients who have severe hypertension are undergoing haemodialysis are undergoing diuretic therapy are on strict salt restriction engage in hazardous activity (dizziness) have to undergo surgery in the next 24 hours Captorpil pharmacokinetics absorption readily absorbed bioavailability about 70% after fasting, but decreased by 30-40% if taken with food distribution distributed to most tissues except central nervous system metabolism chiefly to disulphide conjugates with other sulphydryl-containing molecules t less than 3 hours excretion less than half of an oral dose is excreted unchanged in urine time course of ACEi concentrations and effects

Enalapril a prodrug that is converted by de-esterification to enalaprilat enalaprilat available for intravenous use, for hypertensive emergencies peak concentrations of enalaprilat occur 3-4 hours after dosing with enalapril excreted unchanged by kidneys, t of enalaprilat about 11 hours reduce dose in renal insufficiency

Antihypertensive agents
Lisinopril lysine derivative of enalaprilat absorption slow, peak blood concentrations at about 7 hours after a dose clearance excreted unchanged by kidneys, t about 12 hours reduce dose in renal insufficiency Imidapril a long-acting, non-sulphydryl ACE inhibitor used for treatment of hypertension, chronic congestive heart failure, acute myocardial infarction, and diabetic nephropathy is as potent as enalaprilat and about twice as potent as captopril causes a lower incidence of dry cough pharmacokinetics absorption well absorbed orally peak plasma concentration in 2 hours, t about 2 hours metabolism rapidly converted in the liver to its active metabolite imidaprilat. peak plasma concentration in 6-8 hours, t about 8 hours elimination imidapril and its metabolites are excreted chiefly in the urine reduce dose in renal insufficiency contraindications history of hypersensitivity history of angioedema due to another ACEi undergoing LDL apheresis using dextran cellulose sulphate dextran cellulose sulphate accelerates the production of kinin, and accumulation of bradykinin, resulting hypotension and shock undergoing haemodialysis with acrylonitrile methallyl sulphonate sodium membrane acrylonitrile methallyl sulphonate sodium accelerates the production of kinin, and accumulation of bradykinin pregnant women and women who may be pregnant ANGIOTENSIN II RECEPTOR (AT1) ANTAGONISTS, ARA/ARB mechanism of action block angiotensin type I (AT1) receptor more selective blocker of angiotensin effects than ACE inhibitors more complete block of the angiotensin action as there are other enzymes capable of generating angiotensin II no effect on bradykinin metabolism e.g. losartan, valsartan, candesartan, irbesartan, olmesartan

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Beneficial effects of ARA improvement of endothelial function prevention of development of atherosclerosis reduction of inflammatory response reduction of platelet aggregation prevention of vascular remodelling prevention of progression of left ventricular hypertrophy reduction of myocardial fibrosis prevention of cardiac systolic and diastolic dysfunction prevention of kidney dysfunction prevention of hypertension-related erectile dysfunction prevention of retinal hypertension or diabetic change prevention of cognitive impairment in the elderly hypertensive patient lowering of serum uric acid concentration Losartan pharmacokinetics absorption well absorbed orally metabolism undergoes substantial first pass metabolism with a bioavailability of approximately 33%. oxidation of the 5-hydroxymethyl group on the imidazole ring produces active 5-carboxylic acid metabolite that is responsible for most of angiotensin II antagonism t of losartan 2 hours; active metabolite 6-9 hours excretion 65% biliary excretion (losartan and its metabolite) 35% recovered in the urine adverse effects similar to those of ACE inhibitors, including the hazard during pregnancy