Antihypertensive drugs

• Sustained arterial hypertension damages blood vessels in kidney,

heart and brain, leading to increased incidence of renal failure,
coronary disease, cardiac failure and stroke.
• Many effective drugs are available.
• Knowledge of their antihypertensive mechanism and site of action
allows accurate prediction of efficacy and toxicity.
• It can be used alone or in combination.
• Drugs: 1) Vasomotor center; Methyl dopa, clonidine, guanabenz,
guanfacine
Antihypertensive drugs
• 2) Sympathetic nerve terminals; Guanethidine, guanadrel reserpine,
reduces NA release, decrease sympathetic stimulation of the heart
and blood vessels.
• 3) Sympathetic ganglia; Trimethaphan, ganglion blockade, reduces
sympathetic stimulation of the heart and blood vessels.
• 4)Cardiac beta1 receptors; Propranolol, beta1 blockade decreases
heart rate and myocardial contractility.
• 5)Vascular alpha1 receptors; Prazocin, alpha 1 blockade causes
vasodilation
Antihypertensive drugs
• 6) Vascular smooth muscle; Hydralazine, minoxidil, nitroprusside,
diazoxide; relaxation of vascular smooth muscle causes vasodilation.
• 7)Myocardium and S-A node; Verapamil,and othe calcium channel
blockers; decreases heart rate and contractility
• 8) Renal tubules; Thiazides, chlorothiazides; promotion of diuresis
results in decrease blood volume
• 9) Beta 1 receptors on Justaglomerular cells; Propranolol, beta1
blockade suppresss renin release, resulting in vasodilation secondary
to reduced production of angiotensin 2
Antihypertensive drugs
• 10) Angiotensin converting enzyme inhibitor; Captopril; inhibition of
ACE decreases formation of angiotensin 2 thereby causing
vasodilation
• 11) Angiotensin receptors of vessels; Losartan and other angiotensin
receptor blocker.
• The antihypertensive drugs fall into five major categories.
• 1) Diuretics, 2) sympatholytics, 3) Direct acting vasodilators e.g
hydralazine, 4) calcium channel blockers, 5) inhibitors of ACE
• Diuretics; Thiazides e.g bendrofluazide, hydrochlorothiazide
Antihypertensive drugs
• For the treatment of uncomplicated hypertension.
• Most people who require drug therapy for hypertension will have a
thiazide diuretic as part of their regimen.
• MOA: Thiazide reduces BP by decreasing blood volume and by
promoting vasodillation.
• Thiazide diuretic inhibit reabsorption of Na and Cl in the early part of
the DCT.Natrriuresis is important in determining their hypotensive
action.
• During chronic treatment total PR which is raised initially, slowly falls
suggesting an action on resistance vessels
Antihypertensive drugs
• Loss of K ion occur and also loss of Mg ion,
• Therapeutic uses: Hypertension, Heart failure, Hypercalciuria, Diabetes
insipidus.
• Kinetics: Given orally, taken 2-3 weeks to produce a stable reduction in
BP, half life 40hrs, secreted by the organic acid secretory system of the
kidney.
• Adverse effect: 1) impotence, 2) idiosyncratic reactions include rasches
and purpuria. 3) increase plasma renin i.e. decrease plasma volume
causes an increased plasma renin, 4) Metabolic and electrolyte
changes (a) hyponatremia, b) hypokalemia, 3) hypomagnesia
Antihypertensive drugs
• d) hyperuricemia, e) hyperglycaemia, f) hypercalcemia, g)
hypercholesterolemia
• Sympatholytics: The sympatholytics drugs suppress the influence of
the SNS on the heart, blood vessels and other structures.
• There are five subcategories of sympatholytic drugs:
• 1) Beta-adrenergic blockers 2) centrally acting agents, 3) Aderenergic
neurone blockers, 4) alpha 1 adrenergic blockers and 5) Labetalol-
which block alpha1 and beta adrenergic receptors
• Beta - adrenergic blockers: The beta blockers e.g Propranolol,
Antihypertensive drugs
• Atenolol and Metoprolol are one of the pillars of antihypertensive
therapy
• It serves at least three useful roles in the treatment of hypertension.
• First blockade of beta1 R on the heart decreases HR and contractility,
leading to reduction in CO and a corresponding decrease in BP.
• secondly beta blockers can suppress the reflex tachycardia that often
accompanies the use of vasodilators.
• Lastly, blockade of beta1 R on juxtaglomerular cells of the kidney
causes a reduction in renin release; the action lowes BP by
suppressing production of Angiotensin 11
Antihypertensive drugs
• Cardioselective beta blockers e.g. Atenolol, Metopronol inhibit beta1
R but exert little influence on bronchial and vascular beta2.
• Kinetics: Orally active. Propranolo undergoes extensive and higly
variable first-pass metabolism
• Adverse effect: 1) Intolerance; include fatigue, cold extremities, sexual
dysfunction. 2) Airway obstruction, 3) heart failure 4) peripheral
vascular disease and vasospasm: beta adrenoceptor antagonist
worsen symptoms of claudication in patients with symptomatic
atheromatous PVD. 5) hypoglycaemia, 6) heart block.
• Adrenergic Neurone blockers: Guanethidine and resepine decreases
Antihypertensive drugs
• BP through actions excerted within the terminals of postganglionic
sympathetic nerves.
• Guanethidine acts to inhibit release of NA, resepine causes
transmitter depletion. Both action result in decreased sympathetic
stimulation of the heart and blood vessels.
• Adverse effect: Major adverse effect of guanethidine is severe
orthostatic hypotension.
• Major adverse effect of reserpine is severe depression
• Centrally actng agents: Clonidine, Methyl dopa, act within the
Antihypertensive drugs
• vasomotor centre to sympathetic outflow to the heart and blood
vessels
• MOA: Stimulation of alpha2 adrenoceptor in the brain decreases
sympathetic nervous outflow to the periphery which produce a fall in
BP.
• Clonidine is an alpha2 agonist, alpha methyl NA a false transmitter
synthezised from alpha-methyl-dopa and released instead of NA from
the nerve terminals.
• Kinetics: Given orally and well abdorbed and excreted by the kidney
Antihypertensive drugs
• Adverse effect: 1) drowsiness, depression and nightmares. With
methyldopa, rarely extrapyramidal features, while with clonidine nasal
stuffness is prominent. Anticholinergic symptoms of dry mouth and
constipation.
• 2) sexual dysfunction, 3) hepatitis (methyldopa) 4) drug fever (metyidopa)
5) salt and water retension 6) hypertensive rebound associated with
anxiety, sweating and tachcardia (clonidine).
• Alpha adrenoceptor antagonist: Prazosin, Terazocin.
• They prevent stimulation of alpha1 R on blood vessels.
• This action prevents sympathetically mediated vasoconstriction, thus
promoting vasodilation
Antihypertensive drugs
• Usage of prazosin limited, because of severe hypotension and
collapse following the first dose, half life is short given at least twice
daily
• Doxazocin and Terazocin are structurally related to prazocin with
longer half life, permiting once daily.
• Adverse effect; nasal stuffiness, headache, dizziness, dry mouth,
impotence.
• Labetalol: is unusual in that it can block alpha1 R as well as beta R.
• Lowering of blood pressure results from a combination of action
Antihypertensive drugs
• 1) alpha1 blockade promotes vasodilation
• 2)Blockade of cardiac beta1 R suppress heart rate and contractility
• 3)Blockade of beta1 R on juxtaglomerular cells suppress relase of renin.
• Adverse effect: Exacerbated bradycardia, A-V heart block, CHF and
asthma.
• Vasodilators: Direct acting smooth muscle relaxants such as hydralazine,
Minoxidil, Diazoxide
• Vasodilators act by producing relaxation of vascular smooth muscle,
which decreases resistance and therefore blood pressure.
Antihypertensive drugs
• Minoxidil: is valuable as a drug of last resort in very severely
hypertensive patients.
• It is added as a third drug to beta blocker and diuretic and cannot be
used on its own since it cause reflex tachycardia and fluid retension.
• Diazoxide is a thiazide analog but is a powerful vasodilator and causes
salt and water retension.
• Hydralazine causes direct vasodilation, acting primarily on arteries
and arterioles. This result in a decrease peripheral resistance.
• Hydralazine is used to treat moderately severe hypertension
Antihypertensive drugs
• It is administered in combination with a beta blocker and a diuretic.
• Together the three drug decrease CO, plasma volume and PVR.
• Adverse effect: reflex tachycardia, drug induced systemic lupus
erythematosus, peripheral neuropathy, anaemia,
• Kinetics: given orally
• Sodium nitroprusside: is uniquely valuable in the management of
hypertensive encephalopathy and other hypertensive emergencies.
• The therapeutic goal is to rapidly reduce blood pressure.
• It is capable of reducing BP in all patients regardless of the cause
Antihypertensive drugs
• Nitroprussude is metabolized rapidly (t1/2 in minutes) and requires
continuous infussion to maintain its hypotensive action.
• Its metabolism results in cyanide ion production which can be treated
with an infusion of sodium thiosulfate to produce thiocyanate.
• Adverse effect: too rapid reduction in BP, nausea, palpitation,
dizziness, apprehension and muscle twitching.
• Calcium channel blockers: Recommended when the the first line
agents are contraindicated or ineffective.
• Effective in treating hypertension in patients with angina or diabetes
Antihypertensive drugs
• Divided into three/four chemical classes with different
pharmacological properties and clinical indication.
• 1) Diphenylalkylamines: Verapamil, gallopamil
• 2) Dihydropyridines: Nifedipine, nicardipine , nisoldipine
• 3) Benzothiazepine: Diltiazem
• 4) Diphenylpiperazines: Cinnarizine, flunarizine
• First generatin dihydropyridines is nifedipine, with five second -
generation namely amilodipine, felodipine, isradipine, nicardipine and
nisoldipine
Antihypertensive drugs
• All have much greater affinity for vascular calcium channels than for
calcium channel in the heart.
• They are mainly use in treating hypertension, useful addition to a
beta-blocker in patients with moderate or severe hypertension.
• Nifedipine worsens angina because of reflex tachycardia
• Actions: Calcium channel blockers inhibit the influx of Calcium ion
through voltage dependent L-type calcium channel.
• Calcium entry through such channels in vascular smooth muscle
control the contractile state of actomycin.
Antihypertensive drugs
• Calcium channel blockers there4 relax arteriolar smooth muscle,
reduce PVR and lowers arterial blood pressure.
• Uses: They have intrinsic natriuretic effect and do not require a
diuretic. in coronary artery spasm, cerebral vasospasm following
subarachnoid hemorrhage (nimodipine) and Raynauds phenomenon.
• Selectivity: Dihydropyridines selective for VSM.
• Verapamil mainly as an antiarrhythmic drug bcos of its effect on the
voltage dependent channels in cardiac conducting tissue, it also block
Ca ion entry in GIT smooth muscle and causes constipation.
• Diltiazem in angina pectoris bcos it cause less reflex tachycardia
Antihypertensive drugs
• Kinetics: Short half life (3-8hrs) following an oral dose.
• Adverse effect: Verapamil should be avoided in patients with CHF due to
its negative inotropic effects, also cause constipation. Flushing and
headache, ankle swelling in dihydropyridines.
• Angiotensin - converting enzyme inhibitors:
• Three ACEI: Captopril, enalapril and lisinopril
• They are a useful addition to a diuretic in patients with moderate or
severe hypertension not controlled by diuretic alone
• MOA: The drugs block the ACE that cleaves angiotensin 1 to
angotensin11.
Antihypertensive drugs
• Vaodilation occur bcos of lower vasoconstriction caused by diminshed
level of angiotensin11.
• Decrease of angitotensin 11 levels , the ACEI also decrease the
secretion of aldosterone, resulting in decreased sodium and water
retention
• Angiotensin 11 increases NA release from sympathetic nerve
terminals.
• Kinetics: All active when given orally, highly polar and are eliminated
in the urine
• Enalapril Quinapril are prodrugs converted to active metabolites
Antihypertensive drugs
• Enalaprilat quinaprilat.
• Enalapril quinapril and lisinopril are all given once daily, while captopril is
administered twice daily.
• Adverse effect: dry cough, rash fever, altered taste, hypotension
• Angiotensin Receptor Blockers: Orally active compounds, that are
extremely potent competitive antagonist of the angiotensin type1 R.
• Losartan is the prototype drug. ARB block completely angiotensin action
as compared to ACEI that inhibit only one enzyme responsible for the
production of angiotensin 11.
• They are substitute for ACEI in those patients who cannot tolorate the later
Antihypertensive drugs
• Actions on CVS: for hypertension, in HF as a substitute for ACEI
• Kinetics: orally active, requiring only one-a-day dosing.
• Losartan undergoes extensive first pass hepatic metabolism, including
conversion to active metabolite.
• The other drugs have inactive metabolite
• Elimination of metabolite and parent compounds occur in the urine and
feces, highly plasma protein bound except for candesartan with large
volume of distribution.
• Adverse effect: similar to ACEI, do not produce cough, contraindicated
in pregnancy