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Hypertension, Reflux tachycardia, Important side effects of Clonidine and…
Hypertension
Reflux tachycardia
Reflux tachycardia is more marked in case of drugs with shorter half lives(nifedipine)
whereas in long acting drugs like amlodipine(maximum half life),
effects of reflex activity are hardly discernible.
Due to the above reason, promptly acting nifedipine can increase the risk of angina(increases cardiac work due to increase in heart rate)
whereas sustained release preparation of nifedipine and amlodipine are safer in this regard.
Earlier nifedipine was used sublingually for hypertensive emergencies
but now this practice has been banned due to increased risk of MI and mortality.
Nifedipine in addition also possesses natriuretic property.
Important side effects of Clonidine and alpha-methyldopa
Both of these drugs can cause sedation.
Abrupt discontinuation of clonidine therapy can lead to rebound hypertension treated by phentolamine.
Therefore this drug is not suitable for people having travelling job like business executives who are likely to miss the doses.
Methyldopa can cause hemolytic anemia as an adverse effect.
Both of these drugs are safe in pregnancy (alphamethyldopa is preferred).
ganglion blockers
these drugs inhibit NN type of nicotinic receptors that are present on the autonomic ganglia(both sympathetic and parasympathetic).
The therapeutic effect(decrease in blood pressure) is due to decrease in neurotransmission through sympathetic ganglia
whereas decreased transmission through parasympathetic ganglia
is responsible for the adverse effects like urinary retention and dry mouth.
Hexamethonium and trimethaphan are the drugs in this group and are used rarely
because of the availability of drugs with lesser adverse effects.
Trimethaphan however used along with nitroprusside as a slow IV infusion for hypertensive emergencies in aortic dissection.
Mecamylamine is a ganglion blocker used for smoking cessation.
Alpha blockers
phenoxybenzamine, phentolamine and tolazoline are non-selective alpha blockers at both alpha1 and alpha2 receptors.
Phenoxybenzamine used for hypertensive crisis in pheochromocytoma
whereas phentolamine and tolazoline are drugs of choice for hypertensive emergencies in clonidine withdrawl and cheese reaction.
These drugs cause much greater tachycardia than selective alpha1 blockers like prazosin
due to inhibition of presynaptic alpha-2 receptors(alpha 2 decreases sympathetic outflow)
in addition to reflex tachycardia due to vasodilation caused by both non selective as well as selective alpha1 blockers.
selective alpha 1 blockers
Prazosin, terazosin and doxazosin are selective alpha 1 blockers and cause less tachycardia.
These drugs are the treatment of choice for patient with hypertension and benign hyperplasia of prostate.
Major adverse effect of alpha blockers is first dose hypotension(postural hypotension occurring at the start of treatment or on dose escalation).
Minoxidil
Minoxidil is a prodrug and is activated in liver to produce minoxidil sulphate by phase II reaction,
which opens potassium channels.
Its levels are not changed in renal disease
so it is particularly useful in patients with chronic renal failure.
Minoxidil can cause abnormal hair growth in females hirsutism
and this adverse effect has been utilized as treatment of alopecia in males.
Sodium nitroprusside
Nitroprusside in addition can directly stimulate guanylyl cyclase to cause increase in cGMP.
Nitroprusside is very short acting drug
therefore has to be administered by constant IV infusion
for the treatment of hypertensive emergencies.
Its solution should be freshly prepared because it is unstable and sensitive to light.
Prolonged administration of this drug can result in accumulation of cyanide leading to toxicity
particularly in patients with renal disease.
It can also result in hypothyroidism due to accumulation of thiocyanate(antithyroid compound).
Contraindicated in pregnancy.
Action on blood vessels and heart
Dihydropyridine(DHP) group has little direct cardiac activity and acts mainly on blood vessels,
therefore are also called peripherally acting CCBs.
Verapamil and diltiazem have strong direct cardiodepressant(verapamil>diltiazem) activity.
CCBs tend to cause reflex tachycardia because of their vasodilatory action, which is nullified by the direct depressant action on the heart except DHP.
Verapamil and diltiazem
Verapamil has maximum depressant effect action on heart
and it causes vasodilation by causing blockade of calcium channel.
It is indicated for the treatment of angina, PSVT, hypertension and HOCM.
Diltiazem has lesser effect on heart than verapamil and also indicated for these condition.
These drugs are especially suitable
for elderly patients,
patients with low renin hypertension,
patient with diseases like asthma, migraine or peripheral vascular disease
\and in cases of isolated systolic hypertension.
RAAS
Angiotensinogen secreted from the liver is converted to angiotensin I with the help of renin secreted by JG cells of the kidney.
JG cells are stimulated either due to less fluid delivery to the macula densa or by B1 receptors.
Angiotensin I is converted to angiotensin II mainly by angiotensin converting enzyme.
ACE is also involved in the breakdown of bradykinin, which is a potent vasodilator.
Bradykinin is involved in the causation of dry cough and angioedema.
Aldosterone is involved in sodium and water retention as well as in the causation of cardiac remodelling.
Thus RAAS results in vasoconstriction as well as salt and water retention leading to increase in blood pressure.
Therefore, drugs that antagonize the action of RAAS can be used for decreasing the blood pressure.
This group of drugs is more effective in sodium depleted states
like diuretic use because activity of RAAS is more in such cases to compensate for salt loss.
Drugs for Hypertensive urgency
Oral: Captopril, Clonidine, Labetolol
Hypertensive urgencies may be treated in an outpatient facility with oral antihypertensives;
treatment consists of a slow lowering of BP over 24 to 48 hours.
A reduction in BP of no more than 25% within the first 24 hours has been suggested.
Drugs for hypertensive emergency
IV drugs: Labetolol, Esmolol, Nicardipine, Clevidipine, Nitroglycerin, Sodium nitroprusside, Fenoldopam, Hydralazine, Enalaprilat
The primary goal would be to lower the mean arterial pressure by no more than 25% within the first hour,
followed by BP reduction to 160/110-100 mmHg within the next 2 to 6 hours.
BP reduction must be conducted in a controlled fashion in order to prevent organ hypoperfusion and subsequent ischemia or infarction.
ACC/AHA definition
The American College of Cardiology and the American Heart Association divide blood pressure into four general categories. Ideal blood pressure is categorized as normal.
Normal blood pressure: Blood pressure is 120/80 mm Hg or lower.
Elevated blood pressure: The top number ranges from 120 to 129 mm Hg and the bottom number is below, not above, 80 mm Hg.
Stage 1 hypertension: The top number ranges from 130 to 139 mm Hg or the bottom number is between 80 and 89 mm Hg.
Stage 2 hypertension: The top number is 140 mm Hg or higher or the bottom number is 90 mm Hg or higher.
Blood pressure higher than 180/120 mm Hg is considered a hypertensive emergency or crisis.
Blood pressure
Blood pressure is the product of cardiac output and total peripheral resistance (TPR).
CO and TPR
Cardiac output is dependent on total blood volume, heart rate and the pumping action of the heart
whereas peripheral resistance is determined by the diameter of arterioles
Vasoconstriction leads to increase in TPR.
Sympathetic system
Sympathetic system stimulates the heart directly B1,
causes vasoconstriction Alpha 1
and also stimulates the renin-angiotensin aldosterone system B1 stimulates renin release.
All these factors result in increased blood pressure.
4 main group of drugs in hypertension
Four main group of drugs used for controlling hypertension are
diuretics decreases blood volume and sodium retention,
sympathoplegics,
vasodilators and
the agents decreasing the activity of RAAS.
Diuretics in hypertension
Sodium ions contribute to hypertension by increasing the stiffness of blood vessels and thus TPR.
Salt restriction and diuretics reverse these effects of sodium.
Initially diuretics cause sodium and water loss that leads to decrease in cardiac output but later on cardiac output returns to normal
while there is net sodium deficit that results in decrease in TPR.
Thiazides
Thiazides are the first line drugs in hypertension.
This group of drugs includes hydrochlorothiazide, chlorthalidone, Bendroflumethiazide and indapamide.
Thiazides should be used at low doses only
because by increasing the dose, antihypertensive effects doesn’t not increase but adverse effects tend to increase.
Indapamide
Indapamide is longer acting and more potent than hydrochlorthiazide.
It is effective as an antihypertensive at lower doses than those required for the diuretic effect
due to its direct vasodilatory action.
Loop diuretics
Loop diuretics furosemide, bumetanide, torsemide, indacrinone etc. are not indicated for mild to moderate hypertension
because of the brisk diuresis leading to severe reduction in blood volume and electrolyte imbalance.
However these drugs are indicated in severe hypertension with CHF and renal dysfunction.
Indacrinone
Indacrinone can be used in patients of gout
because it inhibits the reabsorption of uric acid in the nephron(other loop diuretics and thiazides cause hyperuricemia.)
Potassium sparing diuretics
Potassium sparing diuretics amiloride, triamterene, spironolactone and eplerenone are used only in combination with thiazides or loop diuretics
to decrease the risk of hypokalemia.
Sympathoplegics
This group of drugs is aimed at decreasing the activity of sympathetic system.
This task may be accomplished with the use of drugs
that decrease central sympathetic outflow
block the autonomic ganglia
deplete the neurotransmitter store
or block the adrenergic receptors.
Drugs inhibiting the central sympathetic outflow:
Stimulation of alpha-2 receptors in CNS leads to decrease in sympathetic outflow
whereas stimulation of B receptors in the brain has opposite effects.
Therefore alpha-2 agonists and B1 antagonists can decrease the sympathetic activity
and are useful for the treatment of hypertension.
Cloninide and alpha-methyldopa
Clonidine and alpha-methyl dopa act as alpha-2 agonists in the brain.
Clonidine acts directly
whereas the effect of alpha methyl dopa is due to its conversion to alpha methyl norepinephrine
as alphamethyldopa is a prodrug and converted to its active metabolite in the brain.
Moxonidine and rilmenidine
moxonidine and rilmenidine are congeners of clonidine with longer half life.
These drugs are selective for imidazoline receptors that modulate the central alpha-2 receptor activity.
B1 receptor antagonists
B1 receptor antagonists like atenolol, metoprolol and propranolol etc. can also produce reduction in the central sympathetic outflow
by inhibiting the B1 receptor which increase the central sympathetic outflow.
These drugs also act by several other mechanism.
All of these drugs can result in sodium and water retention on prolonged use.
Diuretics can be added to these agents to restore the sensitivity.
Adrenergic neuron blockers:
Drugs of this group deplete the sympathetic neurotransmitter
and thus decrease the sympathetic system activity.
Reserpine, bretylium and guanethidine are the drugs in this group and are rarely used now.
Reserpine
Reserpine inhibits the vesicular uptake of neurotransmitter
causing the depletion of adrenaline, dopamine and serotonin in the synaptic vesicles.
Due to deficiency of serotonin in the brain,
severe depression can result with use of reserpine sometimes leading to suicidal tendencies.
Guanethidine and bretylium
Guanethidine and bretylium prevents the release of NE.
both of these drugs can be given orally.
These drugs cause postural hypotension even if used for prolonged periods
unlike alpha blockers this is not first dose phenomenon.
Adrenergic receptor antagonists:
Two main types of adrenergic receptors are alpha and beta receptors.
Alpha 1 is present on the smooth muscles of blood vessels(cause vasoconstriction)
whereas B1 is present mainly in the myocardium causing increased heart rate and cardiac output
and juxtaglomerular cells of kidney(stimulate renin release).
B blockers
MOA in hypertension includes:
inhibition of cardiac B1 receptors leading to decreased cardiac output.
Decrease in renin due to inhibition of B1 receptors in JG cells of kidney.
Inhibition of central and peripheral sympathetic outflow due to inhibition of presynaptic stimulatory B1 receptors on adrenergic neurons.
Cardioselective betablockers
Cardioselective betablockers B1 can be used in conditions like diabetes mellitus, variant angina, bronchial asthma, raynauds disease and in patients having hyperlipidemia.
This is because B2 blockers lead to (masking of symptoms of hypoglycemia) so contraindicated in DM and hyperlipidemia,
reverse bronchodilation due to B2 receptors(not used in asthma)
and can cause vasoconstriction due to blockade of vasodilatory action of B2 receptors(avoided in peripheral vascular disease and variant angina).
Selective B1 blockers
Selective B1 blockers like nebivolol, metoprolol, esmolol, atenolol, acebutolol, betaxolol, bisoprolol and celiprolol.
B blockers can lead to severe bradycardia in some patients
and in such cases drugs possessing partial agonistic activity(ISA) at B1 receptors are preferred.
beta blockers with intrinsic sympathomimetic activity
Celiprolol, oxprenolol, pindolol, alprenolol and acebutolol are the beta blockers with intrinsic sympathomimetic activity.
All beta blockers can lead to rebound hypertension on sudden withdrawl after prolonged use.
Combined alpha and beta blockers
labetolol and carvedilol are the drugs having antagonistic activity at both alpha and beta adrenergic receptors.
These are used mainly for controlling hypertension in pheochromocytoma.
Carvedilol due to its antioxidant and anti-mitogenic property also useful in CHF.
Vasodilators
Drugs may cause vasodilation
by opening potassium channels,
by releasing nitric oxide,
by blocking calcium channels or
by acting as agonists of dopamine receptors.
these drugs may be mainly arteriolar dilators(hydralazine, minoxidil, calcium channel blockers, diazoxide , fenoldopam).
Venodilators
Mainly venodilators(nitrates) or
may dilate both arterioles and venules(sodium nitroprusside, ACEI, ARBs, alpha blockers).
All vasodilators can lead to reflux tachycardia due to vasodilation
and sodium and fluid retention due to compensatory mechanism
therefore these are best utilised in combination with diuretics and beta blockers.
Major adverse effect of vasodilators is tachycardia and headache(due to dilation of cerebral blood vessels).
potassium channel openers
drugs may cause vasodilation by opening potassium channels ,
these drugs cause dilation of mainly arterioles.
These have negligible effect on venules.
Drugs acting via potassium channel opening
Hydralazine in addition acts by releasing nitric oxide NO from the endothelium.
Latter action requires the presence of intact endothelium.
Minoxidil and hydralazine can be given orally for the treatment of severe hypertension
whereas diazoxide is administered in hypertensive emergencies as rapid IV injection.
Hydralazine
Hydralazine is metabolized by acetylation
and thus its effect is genetically determined due to the presence of slow and fast acetylators.
On prolonged administration it can lead to drug induced lupus erythematosis.
Diazoxide
Diazoxide is a thiazide derivative and can cause hyperuricemia and hyperglycemia
by inhibiting insulin release from beta cells of pancreas.
The latter effects has lead to its use in insulinoma.
NO releasers
Sodium nitroprusside and hydralazine act by releasing nitric oxide from the endothelium
which in turn increases intracellular cGMP by stimulation of guanylyl cyclase leading to vasodilation.
Dopamine agonist
Fenoldopam is dopamine D1 agonist that causes dilation of peripheral arteries and natriuresis.
It can be used IV for short term control of blood pressure in hypertensive emergencies
particularly in patients with renal dysfunction
because of improved renal perfusion.
It can increase IOP and hypokalemia has also been reported with the use of this drug.
Calcium channel blockers
these are the drugs that block L-type voltage gated calcium channels present in blood vessels and heart.
Three groups of CCBs
Three groups of CCBs include phenylalkylamines(verapamil, nor-verapamil),
benzothiazepines(diltiazem)
and dihydropyridines(nifedipine, nicardipine, nimodipidine, nisoldipine, nitrendipine, isradipine, lacidipine, felodipine and amlodipine.
MOA
By inhibiting the calcium channels, these agents decrease the frequency of opening of calcium channels
leading to relaxation of smooth muscles in blood vessels(vasodilation)
and also decrease the activity of heart(decrease heart rate, AV conduction and contractility)
Nicardipine
Nicardipine is the longest acting parenteral calcium channel blocker
and is drug of choice for hypertensive emergencies.
It is combined with beta blockers to avoid tachycardia.
DOC for hypertensive emergencies
DOC for hypertensive emergencies is calcium channel blockers nicardipine or clevidipine.
nitroprusside is no longer preferred now.
Nimodipine
Nimodipine is a relectively cerebro-selective vasodilator
thus used to reverse the compensatory vasoconstriction after subarachnoid haemorrhage.
CCB contraindications
DHPs are safe in pregnancy.
CCBs(verapamil and diltiazem) should be avoided in conditions involving
decreased conductivity of the heart like sick sinus syndrome, CHF
and along with beta blockers as both causes myocardial depression.
Clevidipine
Clevidipine is an ultrashort acting DHP, recently approved for hypertensive emergencies.
Angiotensin II
Angiotensin II acts on AT1(main action) and ATII(less important) receptors.
AT1 stimulation causes vasoconstriction by direct action,
by release of adrenaline from adrenaline medulla
and by increasing central sympathetic outflow
and stimulation of aldosterone release.
Drugs decreasing the activity of RAAS
Beta blockers, renin inhibitors, ACEI, AT1 antagonists and aldosterone antagonists
can act by decreasing the activity of RAAS.
Renin inhibitors
aliskiren, remikiren and enalkiren are the drugs that inhibit the enzyme renin.
So these drugs will decrease the activity of RAAS causing fall in blood pressure.
These drugs can be used orally for the treatment of chronic hypertension.
ACEI
this group of drugs inhibits the enzyme ACE.
So these drugs decrease the activity of RAAS
and also potentiate the vasodilatory action of bradykinin.
these are preventing the conversion of angiotensinogen 1 to angiotensin II
ACEI
Captopril, enalapril, lisinopril, ramipril, perindopril, trandolapril, fosinopril and moexipril etc are the compounds in this group.
Important difference between captopril and other ACEI
Important difference between captopril and other ACEI is that
captopril is less potent, has faster onset and short duration of action and less absorption in presence of food in GIT.
Because of short and fast action, it can cause postural hypotension which is not seen with other ACEI.
Prodrugs
All ACEI are prodrugs except captopril and lisinopril.
Other drugs like enalapril are converted to its active metabolite(enalaprilat) and thus are slow acting.
Enalaprilat is available as separate drug meant for use in hypertensive emergencies by IV route.
Therapeutic uses of ACEI
ACEI are used for the treatment of hypertension, CHF, evolving MI , diabetic nephropathy, diabetic retinopathy, non-diabetic renal disease and also in scleroderma crisis.
These drugs reduce proteinuria in diabetic as well as non diabetic renal disease
and also prevent the manifestations of scleroderma crisis which are mediated by angiotensin II.
ADRs of ACEI
Most frequent adverse effect associated with these agents is dry cough.
It can be reduced by iron supplements and aspirin.
ACEI can also cause angioedema.
Both cough and angioedema is due to elevated levels of bradykinin.
These can cause hyperkalemia if used along with other agents causing elevation of serum potassium like potassium sparing diuretics.
Other adverse effects include rashes,
dysgeusia(altered taste sensation)
and acute renal failure(if used in bilateral renal artery stenosis).
ARBs:
Losartan, valsartan, irbesartan, candesartan, telmisartan and eprosartan act by antagonizing the action of angiotensin II at AT1 receptors.
These drugs donot increase bradykinin and thus have less chances of causing cough and angioedema.
ARBs act at a distal site, so these will inhibit the activity of RAAS even when angiotensin II is generated by non-ACE pathway.
Losartan
Losartan results in the production of active metabolites in the liver.
Losartan is also competitive antagonist of TXA2 and attenuates platelet aggregation.
All indications, CI and adverse effects of ACEI also apply to ARB except that incidence of cough and angioedema is less with ARBs
DOC safe for the treatment of hypertension in pregnancy
Cardioselective B blockers and labetolol
Methyldopa
Clonidine
Dihydropyridine CCB sustained release nifedipine, amlodipine
Hydralazine
Prazosin and other alpha blockers.
Antihypertensives and plasma renin activity:
Renin is secreted from JG cells, either due to stimulation by B1 receptor activation or due to decreased fluid delivery to macula densa.
Therefore the drugs that inhibit the activation of B1 receptors(directly by B blockers and indirectly by sympathoplegic drugs)
will result in decrease in plasma renin activity.
other antihypertensive drugs that increases plasma renin activity
Whereas other antihypertensive drugs will increase plasma renin activity
due to compensatory mechanisms(diuretics, ACEI, ARBs decrease the fluid volume resulting in reduction of fluid delivery to macula densa
and vasodilators increase sympathetic activity
and therefore result in activation of B1 receptors.
can you give B blockers as first line drug in hypertension?
Beta blockers are not considered first line antihypertensives by JNC-8 guidelines.
General recommendations
First line drugs include: thiazides, ACEI, ARBs and calcium channel blockers.
ACEI and ARBs should not be given simultaneously to a person.
ACEI or ARBs are first choice drugs in patients with CKD irrespective of ethnic backgrounds.
For patients with African descent without CKD, CCBs or thiazides should be preferred.
Hypertensive emergency and Hypertensive urgency
Hypertensive emergency is a condition in which there is elevation of both systolic and diastolic blood pressure with the presence of acute target organ disease.
Hypertensive urgency is a condition where the blood pressure is elevated (diastolic > 120 mmHg) with the absence of acute target organ disease.
Thiazides, ACEI, ARBs and CCBs are the first choice drugs in hypertension
unless contraindicated
according to JNC-8 guidelines.
Drugs decreasing the action of RAAS