NC Hwang 2008

Antihypertensive agents

Classification DIURETIC AGENTS

•According to site of action
•According to mechanism of action
•According to usage during anaesthesia
•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 sodium-
retaining properties are used
•in renal insufficiency, when GFR is < 30-40ml/min
•blood pressure response continues to increase as dose
increases
 NC Hwang 2008
Antihypertensive agents
Thiazides •elimination
•emerged from synthesis of more potent carbonic •degree of protein binding determines the contribution
anhydrase, prototype is hydrochlorothiazide that filtration makes to tubular delivery of thiazides
•all have an unsubstituted sulphonamide group •sulphonamides are organic acids and are secreted by the
•main site of effect is at distal convoluted tubules where organic acid secretory system
10% of filtered NaCl is reabsorbed •secretion inhibited by indomethacin and
probenecid
•mechanism of action •compete with the secretion of uric acid, uric
•main effect acid secretory rate may be reduced with initial
•inhibition of NaCl transport predominantly in hyperuricaemia
the distal convoluted tubules by inhibition of
Na+/Cl- symport (or transporter) •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

•other effects •drug interactions

•retention of carbonic anhydrase inhibitory •quinidine (prolongation of QT interval leading to
activity - increased excretion of HCO3- polymorphic ventricular tachycardia or torsade de
•due to increased delivery of NaHCO3 to pointes, due to hypokalaemia)
collecting tubule, increased luminal negative •thiazides diminish the effects of
electrical potential - enhanced secretion of K+ •anticoagulants, uricosuric agents,
and titratable acid (regulated by aldosterone) sulphonylureas, insulin
•competition with the secretion of uric acid - •thiazides increase the effects of
initial hyperuricaemia •anaesthetics, diazoxides, digoxin, lithium, loop
•reduction of the normal lumen-positive diuretics, vitamin D
potential derived from K+ recycling across the •effect of thiazide diuretics decreased by
apical membrane of the DCT, Ca++ and Mg++ •as action depends partly on production of
are not driven out of the lumen by electrical prostaglandin, effect can be inhibited by
forces – hypomagnesaemia NSAIDs
•lower intracellular Na+ enhances basolateral •bile acid sequestrants (reduce reabsorption of
membrane Na+/Ca++ exchange increasing thiazides), methanamines (alkalinization of
overall reabsorption of Ca++ in additon to active urine)
reabsorption of through apical membrane Ca++ •risk of hypokalaemia increased by
channel at DCT (regulated by parathyroid •amphotericin B and corticosteroids
hormone)
•rarely cause hypercalcemia but can unmask •examples
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
•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 HCO3-
•hypovolaemia 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
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 sulphonamide-
based 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
 NC Hwang 2008
Antihypertensive agents
α2 RECEPTOR AGONIST
•α2 receptors are located on presynaptic adrenergic
neurons in the central nervous system, stimulation of
which inhibits the release of noradrenaline

•both methyldopa and clonidine bind more tightly to α2

than to α1 adrenoceptors
•α2 receptors found in nucleus tractus solitarius (NTS) of
the medulla, nucleus coerulus
•α2 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
 NC Hwang 2008
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 β 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
•Guanfacine and guanabenz
•both central acting α2 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; t½β 12-24 hours
•guanabenz extensively metabolized by liver;
t½β 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 t½β 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
α1-ADRENOCEPTOR ANTAGONISTS
•mechansim of action
•reversible α1 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 α1 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 α-receptor blockade (e.g. by
phenoxybenzamine) is dependent on the
synthesis of new receptors, which may take
several days
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 Parkinson’s
disease, due to dopamine depletion in the corpus
striatum
•mild diarrhoea, gastrointestinal cramps,
•increase gastric acid secretion
•effects
•postural hypotension and reflex tachycardia
•postural hypotension due to blockade of α1
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 α-adrenergic agonist
•male sexual dysfunction
•direct intracavernous injection of phentolamine
with papaverine
 NC Hwang 2008
Antihypertensive agents
•classes •tachycardia results from 2 causes
•alkylating agent •baroreflex mechanism
•phenoxybenzamine •antagonism of presynaptic a2 receptors lead to
•imidazolines enhanced release of noradrenaline from
•phentolamine, tolazoline sympathetic nerves, noradrenaline then acts via
•piperazinyl quinazolines unblocked β adrenoceptors
•prazosin, terazosin, doxazosin, trimazosin •formulation
•indoles •oral phentolamine mesylate is rapidly absorbed
•yohimbine, indoramin and eliminated; peak plasma concentrations are
•ergot derivatives achieved in 30-60 min, and the half-life
•ergotamine, dihydroergotamine approximates 5-7 h
•IV bolus or infusion
Phenoxybenzamine •adverse effects
•a haloalkylamine •cardiac stimulation: tachycardia, arrhythmias,
•mechanisms of action myocardial ischaemia
•blocks both α1 and α2 adrenergic receptors •gastrointestinal stimulation: diarrhoea and
•forms a reactive ethyleneimonium intermediate increased gastric acid production
that covalently binds to α receptors, resulting in •indications
irreversible blockade •pheochromocytoma
•long duration of action, 14-48 hours •reduce extent of dermal necrosis after
•slight selectivity for α1 receptors, less so than extravasation of α agonist
prazosin •hypertensive crisis
•inhibits presynaptic reuptake of released noradrenaline •male sexual dysfunction
•also blocks histamine (H1), acetylcholine, and serotonin
receptors Prazocin
•piperazinyl quinazoline
•effects •selectivity for α1:α2 receptor is 1000:1
•blocks catecholamine induced vasoconstriction •blood pressure is reduced more in the upright
•causes significant fall in blood pressure when the than in the supine position
sympathetic tone is high e.g. as a result of upright posture •receptor selectivity allows noradrenaline to
or because of hypovolaemia exert unopposed negative feedback (on
•cardiac output may increase because of reflex effects presynaptic α2 receptor) on its own release
and because of some blockade of presynaptic α2 •may partially explain the absence of
receptors in cardiac sympathetic nerves reflex tachycardia with prazosin (cf
phentolamine and phenoxybenzamine)
•indications •potent inhibitor of cyclic nucleotide phosphodiesterase
•pheochromocytoma •absorption
•benign prostatic obstruction •50-70% bioavailability after oral administration
•peak concentrations reached within 1-3 hours
•pharmacokinetics after oral dose
•low bioavailability after oral administration •distribution
•crosses BBB •95% tightly bound to α1-acid glycoprotein
•t½β probably 24 hours, but effect depends on rate of •free fraction subject to change by
synthesis of α receptors diseases that modify the concentration
of this protein
•adverse effects •clearance
•postural hypotension •entirely metabolised
•tachycardia •t½β about 2-3 hours, although antihypertensive
•nasal stuffiness effect is longer, 4-6 hours
•inhibition of ejaculation •plasma concentration increased in patients with
•non specific central nervous system effects: fatigue, congestive heart failure, due to reduced first-
sedation, nausea pass metabolism
•urinary incontinence •indications
•hypertension
Phentolamine •congestive heart failure
•imidazoline derivative •benign prostatic hyperplasia
•mechanisms of action •adverse effects
•competitive a receptor antagonist with similar affinity •first dose phenomenon, dizziness
for α1 and α2 receptors, causing a reduction in peripheral •palpitation
resistance •headache
•blocks serotonin receptors and K+ channels •lassitude
•agonist at muscarinic and H1 and H2 receptors •development of antinuclear factor in serum
 NC Hwang 2008
Antihypertensive agents
β1-ADRENOCEPTOR ANTAGONISTS •lipophilic β antagonist
•mechanism of antihypertensive action
•decrease in cardiac output
•negative inotropic and chronotropic effects
•adrenoceptor blockade at atrioventricular node
•inhibition of β1-mediated renin production and
depression of the renin-angiotensin-aldosterone system
•inhibition of peripheral prejunctional β adrenoceptors
reducing sympathetic vasoconstrictor nerve activity
•may result in an initial rise in peripheral
vascular resistance from unopposed α receptor-
mediated effects
•distinguishing properties
•reversible / irreversible binding to β receptors
•full antagonists / partial agonists (intrinsic
sympathomimetic activity, ISA)
•relative affinity for β1 and β2 receptors •hydrophilic β antagonist
•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 •pharmacokinetic properties
isoprenaline •absorption
•inverse agonists •most of the drugs in this class are well
•have the ability to inactivate active state absorbed after oral administration
receptors •peak concentrations occur 1-3 hours after
•propranolol > carvedilol in producing negative ingestion
chronotropic and inotropic effects •sustained release preparations of propranolol
and metoprolol are available
•selective β1 antagonists •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
•non-selective β antagonist and readily cross the blood brain barrier
•if highly protein bound, are not cleared
significantly by haemodialysis
•clearance
•t½ of most β receptor antagonists 2-5 hours,
except esmolol, with t½ 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 t½ up to 24 hours, prolonged in renal
failure)
•clinical effect of these drugs are often
prolonged well beyond the time predicted from
half-life
 NC Hwang 2008
Antihypertensive agents
•other effects •metabolism
•respiratory tract •increased plasma triglycerides, decreased
•bronchoconstriction with increased airway HDL-cholesterol, which theoretically can
resistance contribute to atherogenesis
•use of selective β1 receptor antagonists may be •contraindications
preferable when β2 receptor blockade is •bronchial asthma
undesirable •severe bradycardia
•esmolol, acebutolol, metoprolol, •decompensated NYHA functional class IV heart failure
bisoprolol, celiprolol, atenolol, requiring intravenous inotropic support
betaxolol •sick sinus syndrome (unless a permanent pacemaker is
•as specific β1 receptor antagonist without β2 in place)
activity is currently unavailable, therefore these •second- or third-degree atrioventricular block
drugs should generally be avoided in patients •cardiogenic shock
with asthma •severe liver impairment
•eye •known hypersensitivity
•decrease aqueous humor production, reduce •clinical applications
intraocular pressure, especially in glaucoma •depending on specific action of the drug:
•metabolic and endocrine function •cardiovascular system
•inhibit lipolysis •hypertension
•inhibit glycogenolysis in the liver •ischaemic heart disease
•increased plasma concentration of VLDL and •cardiac arrhythmias
decreased concentrations of HDL cholesterol •hypertrophic obstructive cardiomyopathy
after chronic administration, LDL •glaucoma
concentrations generally do not change •hyperthyroidism
•these change are less likely to occur with β- •neurologic diseases
blockers with intrinsic sympathomimetic •migraine
activity (partial agonists: acebutolol, celiprolol, •tremors
carteolol, pindolol, oxprenolol) •portal hypertension and bleeding from oesophageal
•intrinsic sympathetic activity varices
•drugs with retention of ISA (partial agonists)
may be useful for patients who develop Propranolol
symptomatic bradycardia or bronchoconstriction •prototype β1 and β2 adrenoceptors blocking drug
with nonselective beta receptor antagonists •may block some serotonin receptors in the brain
•acebutolol, celiprolol, carteolol, •no detectable partial agonist action at β receptors
oxprenolol, pindolol •for treatment of mild to moderate hypertension, without
•membrane stabilizing action postural hypotension
•result from typical local anaesthetic blockade •in severe hypertension, propranolol is useful in
of sodium channels preventing reflex tachycardia that often results from
•can be demonstrated in neurons, heart muscle, treatment with direct vasodilators
and skeletal muscle membrane •resting bradycardia and a reduction in heart rate during
•acebutolol, betaxolol, labetalol, exercise are indicators of beta-blocking effect
metoprolol, pindolol, propranolol, •pharmacokinetics
oxprenolol •absorption
•these drugs should not be applied topically to •highly lipophilic, almost completely absorbed
the eye after oral administration
•oral doses subjected to extensive first-pass
•adverse effects hepatic inactivation
•result of β blockade in heart, vessels and bronchial tree •bioavailability
•occur in patients with reduced myocardial •has low and dose-dependent bioavailability
reserve, asthma, peripheral insufficiency, and •distribution
diabetes •90% of the drug in circulation is bound to
•discontinuing propranolol after prolonged use plasma proteins, Vd of 4 L/kg
can precipitate withdrawal syndrome •metabolism
•nervousness, tachycardia, increased •extensively metabolized in liver, metabolites
intensity of angina, increased of blood excreted in urine
pressure, •t½β of 4 hours
•withdrawal syndrome may involve up- •one metabolite, 4-hydroxypropranolol has
regulation or supersensitivity of β adrenoceptors active β receptor antagonist activity
•gastrointestinal effects •clearance may vary with hepatic blood flow
•diarrhoea, constipation, nausea, vomiting and liver disease, and may change with
•not attributed to beta receptor blockade administration of other drugs that affect hepatic
•insomnia, lassitude, mental depression, nightmares metabolism
 NC Hwang 2008
Antihypertensive agents
Metoprolol •adverse effects
•potency compared with propranolol •postural hypotension
•equipotent at β1 adrenoceptors •dizziness, fatigue
•50-100x less at β2 adrenoceptors •diarrhoea (2.2%)
•relative cardioselectivity •bradycardia (2.1%)
•advantageous in treating hypertensive patients •insomnia (1.6%)
who suffer from asthma, diabetes or peripheral •dyspnoea (1.4%)
vascular disease, since β2 receptor activity is •oedema (1.4%)
important in the liver (for glycogenolysis) and
blood vessels (vasodilatation) Bisoprolol
•*cardioselectivity is not complete, asthma may still be •antagonist at α1 and β receptors
exacerbated by metoprolol •possesses an asymmetric carbon-atom in its structure,
and is provided as a racemic mixture
Celiprolol •S-enantiomer is responsible for most of the β
•β1 selective antagonist blocking activity
•β2 receptor agonist
•may promote bronchodilation Sotalol
•has weak vasodilator properties of uncertain mechanism •a nonselective β receptor antagonist
•efficacious in treating hypertension and angina •has marked class III antiarrhythmic effects, reflecting
potassium channel blockade
Labetalol
•available a racemic mixture Esmolol
•molecule has 2 centres of asymmetry: 2 pairs of chiral •ultra-short acting selective β1 receptor blocker
isomers (4 isomeric compounds) •40:1 affinity for β1 receptor
•RR isomer is a potent nonselective β blocker •cardioselectivity benefits asthmatic patients
•potency is less than that of propranolol •structure contains ester linkage
•has some intrinsic sympathomimetic •esterases in red blood cells rapidly metabolise esmolol
activity at β2 receptor (may contribute to a metabolite with low affinity for β receptors
to vasodilatation) •short half-life of 8 minutes
•SR isomer is a potent α1 blocker •useful in controlling supraventricular arrhythmias,
•potency is less than that of phentolamine perioperative hypertension, and myocardial ischaemia in
•SS has some α1 blocking effect acutely ill patients
•RS isomer devoid of α and β blocking effects
•β:α antagonism after oral dosing varies from 3:1 to 10:1 CALCIUM CHANNEL BLOCKERS
•mechanism of action
Carvedilol •inhibition of calcium influx into arterial smooth muscle
•administered as racemic mixture, rapidly absorbed cells, resulting in arteriolar dilatation and lowering of
following oral administration blood pressure
•both S and R isomers have approximately equal α
blocking potency •classification according to structure, of calcium
•S(-) isomer is nonselective β adrenoceptor blocker channel blockers with vasodilatory properties
•isomers are stereoselectively metabolised in the liver, •phenylalkylamines
which means elimination half-lives may differ •verapamil (not for treatment of hypertension)
•average 7-10 hours •dihydropyridine
•primarily metabolised by the liver, undergoes extensive •amlodipine, felodipine, isradipine, nicardipine,
first-pass metabolism nifedipine, nisoldipine
•3 active metabolites but none of these appears •benzothiazepines
to have beta-blocking activity •diltiazem (not for treatment of hypertension)
•<2% of given dose excreted unchanged in the urine
•other effects •classification according to generations
•calcium channel blocking activity •first generation agents (nifedipine, verapamil and
•antioxidant properties diltiazem)
•inhibits generation of oxygen free radicals and •second generation agents (subsequently developed
prevents low-density lipoprotein oxidation, dihydropyridine-derivatives)
which in turn, reduces the uptake of LDL into •greater vascular selectivity, a longer duration of
the coronary vasculature 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 α1 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
NC Hwang 2008
•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)
 NC Hwang 2008
Antihypertensive agents
•non cardiovascular effects •prompt-release, short acting nifedipine in the presence
•minimally interfere with stimulus-secretion coupling in of myocardial infarction
glands and nerve endings because of differences between •due to rapid onset of hypotension with this
calcium channels in different tissues formulation and resulting sympathetic response
•verapamil inhibit insulin secretion in humans, but the •pharmacokinetics
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 Verapamil
transporter protein is associated with the •onset of action: <1.5 minute IV, 30 minutes oral
development of resistance to chemotherapy in •metabolism and excretion
cancer cells •extensively metabolised by liver, dose
•verapamil partially reverses the resistance of reduction in patients with liver impairment
cancer cells to many chemotherapeutic drugs •70% eliminated by kidney
•adverse effects •15% by gastrointestinal tract
•bradycardia •indications
•atrioventricular block if combining verapamil or •angina, hypertension, arrhythmias
diltiazem with beta blocker •(migraine, cardiomyopathy)
•congestive heart failure from negative inotropic effecte •adverse effects
•myocardial infarction if onset of hypotension is rapid •hypotension, myocardial depression,
•cardiac arrest constipation, dependent oedema
•torsade de pointes
•bepridil prolongs cardiac action potential, Nifedipine
contraindicated in patients with prolonged QT •onset of action: 5-20 min after sublingual or oral route,
syndrome less than 1 minute after intravenous administration
•flushing, oedema, dizziness, nausea, and constipation •metabolism and excretion: metabolised to an acid
•indications lactate
•angina •80% of the drug and metabolite excreted in
•only with slow release and long acting calcium urine
channel blockers •indications
•immediate-release short acting calcium channel •angina, hypertension
blockers can increase the risk of myocardial •migraine, cardiomyopathy, Raynaud’s
infarction, therefore are contraindicated phenomenon
•in non-Q infarction, diltiazem can reduce •adverse effects
frequency of post-infarct angina •hypotension, dizziness, flushing, nausea,
•hypertension constipation, dependent oedema
•but can worsen heart failure because of
negative inotropic effect Nicardipine
•supraventricular tachyarrhythmias •onset of action:20 minutes oral
•verapamil and diltiazem •metabolism and excretion: extensively metabolised in
•caution in digitalised patient, verapamil may liver
increase plasma digoxin concentrations through •indications
pharmacokinetic interaction, (less consistent •angina
with diltiazem and nifedipine) •hypertensive emergencies, intra- and
•hypertrophic cardiomyopathy postoperative hypertension
•migraine •adverse effects
•Raynaud’s phenomenon •headache, oedema, dizziness, flushing
•atherosclerosis •precautions
•contraindications •not compatible with sodium bicarbonate
•vasodilator treatment in presence of heart failure solution or Hartmann solution
•all calcium channel blockers can worsen heart •patients with renal or liver impairment,
failure as a result of negative inotropic effect hypotension and glaucoma
•verapamil or diltiazem in combination with β-blocker •contraindications
•bepridil in the presence of arrhythmias •intracranial haemorrhage
•bepridil prolongs cardiac action potential •increased intracranial pressure
•pregnant or nursing woman
 NC Hwang 2008
Antihypertensive agents
Amlodipine NITRIC OXIDE INDUCERS /
•onset of action: 20 min NITROSOVASODILATORS
•metabolism and excretion: extensively metabolised •mechansim of action
•indications •by intracellular release of nitric oxide
•angina, hypertension •nitric oxide binds to the haem complex of guanylate
•adverse effects cyclase
•headache, oedema, fatigue, nausea, flushing, •the resulting nitrosyl-haem activates this enzyme with
dizziness increased production of cGMP and activation of cGMP-
•contraindications dependent protein kinase
•known hypersensitivity to dihydropyridines, •this is followed by phosphorylation of target proteins
pregnancy, lactation and dephosphorylation of myosin light chain
•biological activity of nitric oxide is rapidly terminated
Diltiazem due to avid binding to Hb
•onset of action: <3 minute IV, >30 minutes oral
•metabolism and excretion: extensively deacylated
•drug and metabolites excreted by
gastrointestinal tract
•indications
•angina, hypertension
•(Raynaud’s 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 •nitric oxide
vesicles •1980: endothelium dependent vascular relaxation
•displaces vesicular Ca++ demonstrated and endothelial derived relaxation factor
•these effects occur within seconds (EDRF) proposed
•independent of endothelium and is not related •1986: Furchgott and Ignarro independently proposed
to guanylate cyclase activation NO· as EDRF
•absorption: well absorbed orally •1987: production of NO· by endothelium was confirmed
•metabolism by Palmer et al.
•by acetylation (bimodal distribution of
population) Sodium nitroprusside
•rapid acetylator - greater first-pass metabolism, •a nitrovasodilator having a structure a complex of iron,
lower bioavailability (25%), less anti- cyanide groups and a nitroso moiety
hypertensive benefit from a given dose than do •mechanism of action
slow acetylators •dilates both arterioles and veins reducing both
•t½ ranges from 2-4 hours peripheral vascular resistance and venous return
•duration of action •result of activation of guanylyl cyclase, either
•due to avid binding to vascular tissue, vascular via release of nitric oxide or direct stimulation
effects persist longer than do blood of the enzyme
concentrations •increasing cyclic GMP, which relaxes smooth
•adverse effects muscle
•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

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 CN-
•1mg SNP releases 0.44mg CN-
•enzymatic 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 (sulphur-
donor)
•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 2μg/kg/min, or
•when suphur donors and methaemoglobin are
exhausted
•CN- - metabolism
•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
NC Hwang 2008
•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 μg/kg/min to 10 μg/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 S-
transferase, 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 step-
wise 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 t½ of 2-8
minutes
•partially denitrated metabolites have longer t½,
up to 3 hours
•four main metabolites, only dinitroglycerins
have significant vasodilatory efficacy
 NC Hwang 2008
Antihypertensive agents
•elimination •causes
•excreted primarily as glucuronide derivatives •decreased tissue sulphydryl groups
of the denitrated metabolites via kidney •treat with sulphydryl-generating agent
•diminished release of NO from nitroglycerin
•effects on vascular smooth muscle •may be partially reversed with thiol-
•all segments of the vascular system from aorta through containing compounds like
large veins relax in response to nitroglycerin acetylcysteine
•veins respond at lowest concentrations, arteries •decreased activation of guanylyl cyclase
at slightly higher concentrations, concentration •decreased release of endogenous CGRP
of –SH receptors greater in veins •may be partially reversed by N-
•arterioles and precapillary sphincters are acetylcysteine- or captorpil-induced
dilated less than the large vessels, partly because release of CGRP
of reflex response and partly because different •sympathetic compensation
vessels vary in their ability to release nitric •increase in vascular tone
oxide •retention of salt and water
•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 μg

•effects on platelets •adverse effects

•nitric oxide released from nitroglycerin stimulates •extension of therapeutic vasodilatation
guanylyl cyclase in platelets •orthostatic hypotension
•increase in cGMP and decrease in calcium entry •tachycardia
responsible for decrease in platelet aggregation •throbbing headache

•effects on haemoglobin POTASSIUM CHANNEL OPENERS

•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
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
•t½ about 4 hours
 NC Hwang 2008
Antihypertensive agents
•adverse effects •renin-angiotensin system
•associated with reflex sympathetic stimulation •renin
•sodium and fluid retention •release from renal cortex, stimulated by
•headache •reduced renal arterial pressure or
•sweating perfusion
•hypertrichosis •sympathetic output
•reduced sodium delivery
Diazoxide •increased sodium concentration at the
•similar chemically to thiazide diuretics but lacks diuretic distal renal tubule
activity •acts upon α2-globulin, to split off the inactive
•indications decapeptide angiotensin I
•hypertensive emergencies •angiotensin I
•hypoglycaemia secondary to insulinoma •may contribute to maintaining high vascular
•mechanism of action resistance in hypertensive states associated with
•prevents smooth muscle contraction by opening high plasma renin activity
potassium channels and stabilizing the membrane •renal artery stenosis
potential at the resting level •intrinsic renal disease
•involves ATP sensitive K+ channel •malignant hypertension
•distribution •essential hypertension
•binds extensively to serum albumin and vascular tissue •also generated in a parallel system in the heart
•metabolism •may be responsible for trophic changes such as
•both metabolised and excreted unchanged cardiac hypertrophy (myocardial remodelling)
•t½ about 24 hours •converted primarily by endothelial angiotensin
•duration of action converting enzyme (ACE) in the lung, to the
•after a rapid injection, onset in 5 minutes, lasts for 4-12 arterial vasoconstrictor octapeptide angiotensin
hours II
•adverse effects •angiotensin II converted in the adrenal
•hypotension gland to angiotensin III
•occurs after smaller doses in patients with •angiotensin II and III
chronic renal failure, due to reduced protein •both stimulate aldosterone release
binding capacity •aldosterone
•greater if pretreated with β-blockers to prevent •causes sodium retnetion, potassium and
reflex tachycardia and associated increase in magnesium loss, proinflammatory action,
cardiac output noradrenaline release, endothelial dysfunction
•can result in stroke and myocardial infarction and reduced vascular compliance
•reflex sympathetic response •angiotensin converting enzyme or peptidyl dipeptidase
•angina, ischaemia, cardiac failure •as ACE, converts angiotensin I to angiotensin
•hyperglycaemia II
•inhibits insulin release from pancreas, probably •as plasma kininase, inactivates bradykinin, a
by opening potassium channels in beta cell potent vasodilator
membrane •bradykinin works in part by
•particularly in patients with renal insufficiency stimulating the release of nitric oxide
•salt and water retention and prostacyclin
•inhibited by ACE inhibitor
INHIBITORS OF RENIN-ANGIOTENSIN SYSTEM
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
 NC Hwang 2008
Antihypertensive agents
ANGIOTENSIN CONVERTING ENZYME •nonsteroidal anti-inflammatory agents
INHIBITORS •impair the hypotensive effects of ACE
•mechanism of action inhibitors by blocking bradykinin-mediated
•inhibit angiotensin conversion, decreasing vasodilatation via the production of prostacyclin
peripheral vascular resistance •insulin or oral hypoglycaemic agents
•stimulating action on the kallikrein-kinin •hypoglycaemia
system, stimulating the release of nitric oxide •lithium
and prostacyclin •ACEi accelerates reabsorption of lithium in
•do not result in reflex sympathetic activation, renal tubules
•may be due to downward setting of •lithium toxicity (sleepiness, tremor)
baroreceptors or to enhanced parasympathetic
activity •precautions
•can be used safely in patients with ischaemic •patients who
heart disease •have severe hypertension
•are undergoing haemodialysis
•indications •are undergoing diuretic therapy
•hypertension •are on strict salt restriction
•diminishing proteinuria and stabilising renal function in •engage in hazardous activity (dizziness)
patients with diabetic nephropathy •have to undergo surgery in the next 24 hours
•probably result from improved intrarenal
haemodynamics, with decreased glomerular Captorpil
efferent arteriolar resistance and a resulting •pharmacokinetics
reduction of intraglomerular capillary pressure •absorption
•congestive heart failure •readily absorbed
•preservation of left ventricular function in years •bioavailability about 70% after fasting, but
following myocardial infarction, by reducing decreased by 30-40% if taken with food
postinfarction myocardial remodelling •distribution
•distributed to most tissues except central
•adverse effects nervous system
•severe hypotension with hypovolaemic •metabolism
•acute renal failure in the presence of bilateral renal •chiefly to disulphide conjugates with other
artery stenosis or stenosis of the renal artery of a solitary sulphydryl-containing molecules
kidney •t½ less than 3 hours
•hyperkalaemia due to decreased aldosterone secretion •excretion
•dry cough mediated by bradykinin •less than half of an oral dose is excreted
•altered sense of taste unchanged in urine
•allergic skin rashes •time course of ACEi concentrations and effects
•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
Enalapril
•drug interactions •a prodrug that is converted by de-esterification to
•potassium supplements or potassium-sparing diuretics enalaprilat
(spironolactone, triamterene) •enalaprilat available for intravenous use, for
•hyperkalaemia due to decreased aldosterone hypertensive emergencies
secretion •peak concentrations of enalaprilat occur 3-4 hours after
•diuretic antihypertensive agents dosing with enalapril
•excessive hypotension •excreted unchanged by kidneys, t½ of enalaprilat about
•diuretics increases plasma renin activity 11 hours
•other vasodilators (nitrates) •reduce dose in renal insufficiency
•enhanced hypotension
 NC Hwang 2008
Antihypertensive agents
Lisinopril Beneficial effects of ARA
•lysine derivative of enalaprilat •improvement of endothelial function
•absorption •prevention of development of atherosclerosis
•slow, peak blood concentrations at about 7 hours after a •reduction of inflammatory response
dose •reduction of platelet aggregation
•prevention of vascular remodelling
•clearance •prevention of progression of left ventricular hypertrophy
•excreted unchanged by kidneys, t½ about 12 hours •reduction of myocardial fibrosis
•reduce dose in renal insufficiency •prevention of cardiac systolic and diastolic dysfunction
•prevention of kidney dysfunction
Imidapril •prevention of hypertension-related erectile dysfunction
•a long-acting, non-sulphydryl ACE inhibitor used for •prevention of retinal hypertension or diabetic change
treatment of hypertension, chronic congestive heart •prevention of cognitive impairment in the elderly
failure, acute myocardial infarction, and diabetic hypertensive patient
•lowering of serum uric acid concentration
nephropathy
•is as potent as enalaprilat and about twice as potent as
Losartan
captopril
•pharmacokinetics
•causes a lower incidence of dry cough
•absorption
•pharmacokinetics
•well absorbed orally
•absorption
•metabolism
•well absorbed orally
•undergoes substantial first pass metabolism
•peak plasma concentration in 2 hours, t½ about
with a bioavailability of approximately 33%.
2 hours
•oxidation of the 5-hydroxymethyl group on the
•metabolism
imidazole ring produces active 5-carboxylic
•rapidly converted in the liver to its active
acid metabolite that is responsible for most of
metabolite imidaprilat.
angiotensin II antagonism
•peak plasma concentration in 6-8 hours, t½
•t½ of losartan 2 hours; active metabolite 6-9
about 8 hours
hours
•elimination
•excretion
•imidapril and its metabolites are excreted
•65% biliary excretion (losartan and its
chiefly in the urine
metabolite)
•reduce dose in renal insufficiency
•35% recovered in the urine
•contraindications
•adverse effects
•history of hypersensitivity
•similar to those of ACE inhibitors, including the hazard
•history of angioedema due to another ACEi
during pregnancy
•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