Hypertension and antihypertensive drugs

Arvind Singh Panwar

SECTION 7

169Cardiovascular System170

Hypertension and Antihypertensive DrugsCHAPTER 1

Blood Pressure: Pressure exerted by the blood on the lateral wall of the larger blood vessels (arteries).

Systolic blood pressure: 120 ± 10 mm of Hg.
Diastolic blood pressure: 80 ± 5 mm of Hg.

Maximum normal range of BP Systolic BP ≤ 139 mm of Hg, while Diastolic BP ≤ 89 mm of Hg.

Factors Regulating Blood Pressure (Fig.7.1.1)

BP = Cardiac output × peripheral resistance
CO = Heart rate × stroke volume.
Stroke volume depends upon (a) end diastolic volume and (b) contractility.
End diastolic volume depends upon Circulating blood volume.

Fig. 7.1.1: Regulation of BP

Hypertension: Hypertension is an elevation of systolic and/or diastolic BP above 140/90 mm of Hg. It is a common cardiovascular disorder. Hypertension may be:

Primary (essential) hypertension: Where the cause (etiology) is not known about > 90% of hypertension is primary type.
Secondary hypertension: When it is secondary to other conditions like; renal, endocrine or vascular disorders.
Isolated systolic hypertension: When systolic BP ≥ 160 mm of Hg and diastolic BP ≤ 90 mm of Hg.

Based on the degree of severity, hypertension can be graded as:

Mild hypertension: Diastolic BP up to 104 mm Hg.
Moderate hypertension: 105–114 mm Hg.
Severe hypertension: More than 115 mm Hg.

Normal Homeostasis Mechanism Controlling BP

Blood pressure is determined by cardiac output (CO) and total peripheral vascular resistance (PVR).
Blood pressure is controlled by baroreceptor reflexes acting through autonomic nervous system along with the renin-angiotensin-aldosterone system.

Short-term regulation of BP (Fig. 7.1.2): Blood pressure controlled by this mechanism involves BP regulation during posture change and emergent conditions.
Long term regulation of BP: Renin – Angiotensin: Aldosterone Mechanism (Fig. 7.1.3):
- Stimulus for higher renin secretion
  1. Decrease in hydrostatic pressure in afferent arteriole.
  2. Decrease in Na concentration in Macula densa (Fig. 7.1.4).
  3. Accentuates ANS (sympathetic) stimulation.

Factors (Etiology) for Hypertension

Exaggerated adrenergic activity:
- Centrally
- Peripherally
  
  172
Fig. 7.1.2: Mechanism of short-term regulation of BP
High cardiac output due to:
- Rise in heart rate
- Rise in force of contraction
- Rise in blood volume
Increased peripheral resistance:
- Due to high vasoconstriction
High Na⁺—water retention:
- High renin
- High Angiotensin II
- High Aldosterone activity
Most important causes in primary hypertension:
- Increased in plasma renin activity.
- Increase peripheral resistance (arteriolar origin).
- Decrease vascular synthesis of NO.
- Increase in Na⁺ concentration in vascular epithelium.
- Hyper-insulinemia.
- Abnormal synthesis of steroid.
Causes of secondary hypertension (all diseases):
- Pheochromocytoma
- Polycystic kidney
- Pylonephritis
- Glomerulonephritise
- Stenosis of renal vessels

Fig. 7.1.3: Long-term regulation of BP

Prolonged hypertension damages the blood vessels of the heart, brain and the kidneys and may result in several complications like stroke, coronary artery disease or renal failure. Hence hypertension needs to be treated.

Antihypertensives act by influencing the BP regulatory systems viz the Autonomic system, Cardiovascular system, Renin-angiotensin system, Calcium channels or Sodium and water balance (plasma volume).

Postural hypotension:

Various drugs produces postural hypotension, as a side effect. It is explaind here.

When a person is standing or stand suddenly after a lying or sitting posture, about half to one liter of blood is pooled in the vessels (sp. veins) of lower extremity under the influence of gravity. Due to this occurs fall in cardiac inflow and therefore also cardiac output (↓ CO). This ultimately results in cerebral ischemia and therefore giddiness, but normally this dose not occur because of compensatory mechanism, i.e. (Short-term regulation) of Blood Pressure. But if there occur any disturbance or blockade in this STR, postaral hypotension develops.

Fig. 7.1.4: Juxtaglomerular apparatus

173

CLASSIFICATION (FIG. 7.1.5)

Diuretics:
- Thiazides: Hydrochlorothiazide, Chlorthalidone, etc.
- Loop diuretics: Frusemide (Furosemide)
- K⁺ sparing diuretics: Spironolactone, Amiloride, Triamterene.
Sympatholytics:
- Centrally acting drugs: Clonidine, Methyldopa
- Ganglion blockers: Trimethaphan
- Adrenergic neuron blockers: Guanethidine, Reserpine.
- Adrenergic receptor blockers:
  - – β-blockers: Propranolol, Atenolol, etc.
  - – α-blockers: Prazosin
  - – Mixed α- and β-blockers: Labetalol.
Vasodilators:
- Arteriolar dilators: Hydralazine, Minoxidil, Diazoxide
- Arteriolar and venular dilators: Sodium nitroprusside
Ca⁺⁺ channel blockers: Verapamil, Nifedipine, Diltiazem, Amlodipine, etc.
Angiotensin converting enzyme (ACE) inhibitors:
- Captopril, Enalapril, Lisinopril, Ramipril.
Angiotensin II receptor antagonist: Losartan.
Miscellaneous: Pepstatin, Ketanserin, Nicorandil, Veratrum, metyrosin, etc.

Diuretics: Thiazide and loop diuretics, they are the useful drugs when used alone or in combination to reduce hypertension.

The antihypertensive effect of diuretics is mild, BP falls by 10–15 mm of Hg over 15–30 days.
Diuretics act as antihypertensives as follows:
Diuretics enhance the excretion of sodium and water resulting in negative Na⁺ balance.
1. ↓ Plasma volume → ↓ cardiac output→ ↓ BP
2. ↓ Body sodium → relaxation of vascular smooth muscles (due to Na⁺ depletion) → ↓ PVR → ↓ BP

Restriction of dietary salt intake will reduce the dose of the diuretic needed.
Thiazides are the first-line, and most frequently used antihypertensives. Their initial antihypertensive effect is due to reduction in blood volume; their long-term effect is related to a reduction in peripheral vascular resistance.

Fig. 7.1.5: Site of action of the major classes of antihypertensive drugs

174
Thiazides may be used in combination with other antihypertensives. They may be combined with a K⁺ sparing diuretic (like spironolactone) to avoid hypokalemia.
Loop diuretics produce greater diuresis than the thiazides, but they have a weaker antihypertensive effect and can cause severe electrolyte imbalance. They are used only in hypertension with chronic renal failure or congestive heart failure.
For details, refer chapter on Diuretic Agents.

SYMPATHOLYTICS

Drugs acting centrally: Clonidine, α-methyldopa guanabenz and guanfacin act centrally on the vasomotor center of the brain predominatly by stimulating α_{2 -} adrenergic receptors in the CNS.

The result is decreased sympathetic outflow from CNS.

Clonidine:

Clonidine an imidazoline derivation and is a selective α₂ agonist.
Stimulation of α₂ receptors in the CNS (in the vasomotor center and hypothalamus); decreases central sympathetic outflow; blocks the release of noradrenaline from the nerve terminals leading to a fall in BP and bradycardia.
α₂-adrenergic agonists lower atrial pressure and also reduces secretion of renin.
Clonidine and guanbenz tend to decrease cardiac output and leave peripheral vascular resistance unchanged.
Guanfacin has little effect on cardiac output and decreases peripheral vascular resistance.
Adverse effects: include dryness of mouth, nose and eyes, drowsiness; parotid gland swelling and pain, fluid retention, constipation and impotence.
Sudden withdrawal of clonidine will lead to rebound hypertension, headache, tremors, sweating and tachycardia. Hence the does should be tapered.

Therapeutic uses: Mild hypertension to moderate to severe hypertension.

Clonidine can not be administered to patients taking tricyclic- antidepressants because these drugs block clonidine's hypotensive effect. Clonidine may worsen depression.

Other uses

With anesthetics: Clonidine given preoperatively reduces the dose of the general anesthetic needed due to its analgesic effects.
In Opioid withdrawal: Most withdrawal symptoms in opioid addicts are of sympathetic over-activity and can be benefited by treatment with clonidine.
Clonidine controls diarrhea by improving absorption of NaCl and water in the gut by stimulation of α₂ receptors in the intestines.

α-methyl dopa

It is an analog of DOPA and is a prodrug.
Methyldopa is metabolised by decarboxylation and beta hydroxylation in adrenergic neurons of the CNS. The metabolite α-methyl norepinephrine, which is an α₂ agonist, stimulates α₂ receptors like clonidine in the brain, inhibiting sympathetic outflow.
Methyldopa is poorly absorbed, It will be administered orally or paxenterally by slow i.v., excreated largely by the kidneys.
It reduces BP and peripheral vascular resistance. It has little effect on CO, renal blood flow and GFR. It does not abolishes sympathetic reflexes.
Left ventricular hypretrophy is reversed in about 12 weeks of treatment.
Adverse effects are sedation, dryness of mouth and nose, headache, postural hypotension, fluid retention and impotence.

Therapeutic uses: It is used in mild to moderate hypertension along with a diuretic.

Ganglion Blockers - Trimethaphan

Trimethaphan is the only rapid and short acting (15 minutes) ganglion blocker used intravenously to produce controlled hypotension during certain surgeries.
These drugs block both sympathetic and parasympathetic ganglia resulting in decreased sympathetic tone and a fall in BP.
They produce several side effects as they block both ganglia and therefore not used now.

Adrenergic Neuron Blockers

Guanethidine

It depletes the stores of noradrenaline in the adrenergic neurons.
It produces sympathetic blockade before any appreciable decrease in nor epinephrine stores has occurred; with chronic administration it impairs the release of neurotransmitter from peripheral adrenergic neurons.
It has direct inhibitory effect on skeletal muscle contraction.
It also increases the sensitivity of tissues to catecholamine.

175
It produces adverse effects like orthostatic, i.e. postural hypotension, salt and water retention, diarrhea, sexual dysfunction and muscular aching and weakness can occur, therefore it is also not used now a days.
Therapeutic use: In the treatment of moderate to severe hypertension.

Reserpine

It is an alkaloid obtained from Rauwolfia serpentina (Sarpagandha) that grown in India.
In the neurons, it binds to the vesicles that store monoamines like noradrenaline, dopamine and 5-HT and destroys these vesicles. It thus depletes the stores of these monoamines in the peripheral and central nervous system and cause impaired sympathetic nerve discharge.
It usually reduces heart rate and cardiac output and may decreases peripheral vascular resistance, therefore ultimately reduces BP.
Adverse effects: It causes episode of severe depression, drowsiness, parkinsonism, postural hypotension, edema and sexual dysfunction. Hence it is generally not preferred.
It is contraindicated in the patients with active peptic ulcer.
Therapeutic use: It is used in low doses in combination with other anti-hypertensives to control moderate hypertension.

β-blockers

They are mild to moderate antihypertensives and are useful both alone and in combination with other antihypertensive agents.
The exact mechanism of action is not known, probably:
1. They reduce the BP due to a fall in the cardiac output.
2. They also lower plasma renin activity and an additional central antihypertensive action.
They are well-tolerated and are of special value in patients who also have history of arrhythmias or angina.
They are also suitable for combination with other antihypertensives.
Atenolol is a preferable β-blocker because of advantages like once a day dosing, absence of CNS side effects and β₁ selectivity.
β-blockers should always be tapered gradually while withdrawing.
Adverse effects: They can exacerbate CHF, asthma, and COPD. They can mask symptoms of hypoglycemia in diabetic patients.

α -blockers

Prazosin is a quinazoline derivative and is a selective α₁-blocker; it dilates both arterioles and venules.
It reduces peripheral vascular resistance and lowers atrial blood pressure in both supine and erect patients with only mild tachycardia.
Prazosin does not adversely affect insulin sensitivity or blood lipid.
‘First dose’ phenomenon can be avoided by starting with a low dose (0.5 mg) given at bed time. Dose is gradually increased.
Prazosin is used in mild to moderate hypertension; it may be combined with diuretics and β-blockers.
Adverse effects: Dizziness, palpitation,
It is also used in the treatment of acute CHF

α- and β-blockers

Labetalol blocks α₁ and β-receptors.
Labetalol, is a nonselective β-blocker but possesses intrinsic sympathomimetic activity and blocks vascular postsynaptic alfa adrenergic receptors.
It is used IV in the treatment of hypertension in pheochromocytoma and in hypertensive emergencies.
Labebetalol on chronic administration may produces orthostatic hypotension and sexual disfunctions.

Vascular Smooth Muscle

Vascular smooth muscles are controlled by mediators secreted by sympathetic nerves and vascular endothelium, and by circulating hormones.
Smooth muscle cell contraction is initiated by a rise in (Ca⁺⁺) which activates myosin-light-chain kinase, causing phosphorylation of myosin or by sensitization of the my filaments to Ca⁺⁺ by inhibition of myosin-phosphates.
Agents causing contraction may:
- – Release intracellular Ca⁺⁺, secondary to receptor-mediated IP₃ formation.
- – Depolarize the membrane and thus allow Ca⁺⁺ entry through voltage-gated Ca⁺⁺ channels.
- – Allow Ca⁺⁺ entry through receptor-operated Ca⁺⁺ channels.
Agents causing relaxation may:
- – Inhibit Ca⁺⁺ entry through voltage-gated Ca⁺⁺ channels either directly (e.g. Nifedipine) or indirectly by hyperpolarizing the membrane (K⁺ activators, e.g. Nicorandil)
- – Increase intracellular cAMP or cGMP concentration; cAMP causes inactivation of myosin-light-chain kinase, and may facilities increases in [Ca⁺⁺]_i
  
  176

The role of the endothelium in controlling vascular smooth muscle

Endothelial cells release various vasoactive substances, including prostacyclin (vasodilator) and endothelin (vasoconstrictor).
Many vasodilator substances (e.g. acetylcholine and bradykinin) act via endothelial NO production when (Ca⁺⁺)_i increases in the endothelial cell.
NO causes smooth muscle relaxation by increasing cGMP formation.
Endothelin is a potent and long-acting vasoconstrictor peptide, released from endothelial cells by many chemical and exact physical factors. It is confined to blood vessels, and its exact physiological role is not clear.

Vasodilators

Vasodilators relax the vascular smooth muscles thus reduces BP due to decreased peripheral vascular resistance.
Salt and water retention and reflex tachycardia are common with vasodilators.

Arteriolar (Direct) Vasodilators

This group of drugs directly relaxes arteriolar smooth muscles.
These drugs also increase plasma renin activity, causing a pressor effect.
These drugs often cause salt and water retention and thus used in conjugation with diuretic and beta adrenergic blocking therapy.

Hydralazine

It is a phthalazine derivative, directly acting arteriolar dilator.
It reduces more diastiolic than systolic BP.
The fall in BP is associated with reflex tachycardia, renin release and fluid retention. Coronary, cerebral and renal blood flow are increased.
Adverse effects are headache, flushing, palpitation, salt and water retention. It may precipitates angina in some patients. Hypersensitivity reactions like serum sickness and lupus erythematosus may occur.
Uses: Hydralazine is used with a β-blocker and /or a diuretic in moderate to severe hypertension not controlled by the first line drugs. It can be given to treat hypretension in pregnancy.
It has also been used in the treatment of acute and chronic CHF.

Minoxidil

It is a piperidinopyrimidine derivative. It is a directly acting arteriolar dilator used in severe hypertension not responding to other drugs.
It acts by opening K⁺ channels in smooth muscles.
It reduces peripheral vascular resistance as well as renal vascular resistance while preserving renal blood flow and GFR.
Therapeutic Use: In the treatment of Severe Hypertension specially when it is coupled with renal function impairment.
Minoxidil stimulates the growth of hair on prolonged use. Hence it is used topically (2% solution) in alopecia. Young men with relative alopecia are more likely to respond.

Diazoxide

It is chemically similar to the thiazide diuretic and is a potent arteriolar dilator.
It has little action on capacitance vessels.
It's mechanism of action is like minoxidil.
It causes fall in both systolic and diastolic blood pressure, accompanied by an increase in both heart rate and cardiac output.
The drug also relaxes other smooth muscles in addition to vascular muscles.
It is used in hypertensive emergencies where monitoring of infusion is not possible. Diazoxide has a long duration of action (24 hours) and is suitable in such situations.
Diazoxide is also used orally to treat hypoglycemia that is caused by hyperinsulinemia.
Adverse effects: It includes severe hypotension, angina, worsening of MI, edema and hyperglycemia.

Arterial and Venous Vasodilators

Sodium nitroprusside

It is a rapidly acting vasodilator and it relaxes both arterial and venous smooth muscles but has little effect on other smooth muscles.
Both peripheral resistance (PR) and cardiac output (CO) are reduced resulting in lower myocardial oxygen consumption.
Nitroprusside acts through the release of nitric oxide which relaxes the vascular smooth muscles.
Renal blood flow is maintained with nitroprusside, and renin secretion is increased.
On IV administration, it is rapid (acts within 30 seconds) and short-acting (duration 3 minuter) allowing titration of the dose. This makes it suitable for use in hypertensive emergencies with close monitoring.

177
It decomposes on exposure to light; the infusion bottle and tubing should be covered with opaque foil.
Adverse reactions: It includes palpitation, sweating, weakness, nausea, vomiting and in high doses thiocyanate toxicity including psychosis.
Therapeutic uses:
1. Nitroprusside is the drug of choice in hypertensive emergencies.
2. It can also be used to produce controlled hypotension to minimize bleeding during surgery
3. It can also be used in the treatment of acute (Congestive heart failure) CHF.
4. It is used in situations where short-term reduction of myocardial work load is required as in myocardial infarction, where it can improve left ventricular function.

Calcium Channel Blockers (CCBs)

Calcium channel blockers (CCBs) are another important group of antihypertensives by virtue of their vasodilating effect.
They dilate the arterioles resulting in reduced peripheral vascular resistance.
Nifedipine produces some reflex tachycardia, while this is not seen with verapamil, dilitiazem and amlodipine as they are cardiac depressants.
Diltiazem and verapamil depress A-V conduction and should not be used with beta-blockers.
Fluid retention is negligible unlike other arteriolar dilators.
- – CCBs are well-tolerated, safe and effective.
- – Sublingual nifedipine used in hypertensive emergencies effectively lowers BP in 10 minutes.
- – CCBs are of special value in patients who also have angina.
- – Calcium channel blockers are used for short periods to control hypertension.
Diuretics may enhance the efficacy of Ca⁺⁺ channel blockers.
Verapamil can cause severe constipation.

Drugs that interfere with the Renin-Angiotensin System

The kidneys synthesize renin, which act on a plasma globulin substrate to produce angiotensin I. This, in turn, is converted (by Angiotensin Converting Enzyme, a peptidyl dipeptidase) to angiotensin II, a potent vasoconstrictor. Drug in this exert an antihypertensive effect by interfering with either reducing the formation or enhancing the utilization of angiotensin II.

Angiotensin Converting Enzyme (ACE) Inhibitors

ACE inhibitors include: Captopril, enalapril, lisinopril, benazepril, fosinopril, quinapril, and ramipril.

Angiotensin II is a potent direct vasoconstrictor agent, (directly rises BP).
Angiotensin II also stimulates the secretion of Aldosterone.
Aldosterone raises the BP by increasing the plasma volume. (See Fig. 7.1.6)

Fig. 7.1.6: Renin-angiotensin system

Fig. 7.1.7: Effect of ACE inhibitor

178

Mechanism of action of ACE inhibitors: ACE inhibitors prevent the formation of angiotensin II and (indirectly) aldosterone as shown in Figure 7.1.7.

There is vasodilation and decrease in PVR resulting in ↓ BP.
As ACE also degrades bradykinin, ACE inhibitors raise the bradykinin levels which is a potent vasodilator. This also contributes to the fall in BP.
The blood flow to the kidneys, brain and heart increases due to selective vasodilatation and thus maintains adequate blood supply to these vital organs.
Pharmacokinetics:

ACE inhibitors are generally well-absorbed.

Except captopril and lisinopril all others are prodrugs.
Adverse effects: ACE inhibitors are well-tolerated.

Adverse effects include persistent dry cough (due to - bradykinin levels), hyperkalemia, alteration of taste sensation (dysguisia), skin rashes, hypotension, headache, nausea, abdominal pain and blood disorders. Angio-edema though rare can be severe.
Dose and duration of action of some commonly used ACE inhibitors are shown in Table 7.1.1.

Table 7.1.1 Dose and duration of action of some commonly used ACE inhibitors

Drugs	Duration of action (hrs)	Daily dose (mg)
Captopril	6–12	12.5–50 mg BD
Enalapril	24	2.5–20 mg OD
Lisinopril	>24	5–40 mg OD
Ramipril	8–48	1.25–10 mg OD

Therapeutic uses

Hypertension: ACE inhibitors are useful in the treatment of hypertensions of all grades and due to all causes. Addition of a diuretic potentates their efficacy.
They are presently the first line antihypertensives. They are specially indicated as antihypertensives in:
- Patients with diabetes as ACE inhibitors slows the development of nephropathy.
- Renal diseases: ACE inhibitors slow the progression.
- Left ventricular hypertrophy is gradually reversed by ACE inhibitors.
Myocardial infarction: ACE inhibitors started within 24 hours to inhibit cardiac remodeling phenomena, and given for several weeks prevent the development of CCF Congestive Cardiac Failure and reduce mortality.
ACE inhibitors also relieve chronic CHF and afterload.
They are also useful in the management of:
- Diabetic nephropathy
- Progressive renal insufficiency

Angiotensin II Receptor Antagonists

Saralasin: Blocks both AT₁ and AT₂ receptor

It can be given only by intravenous infusion
It is primarily used diagnostically to detect a renal cause of hypertension.

Losartan

It is an angiotensin II receptor antagonist.
There are two subtypes of angiotensin II receptors —AT₁ and AT₂.
AT₁ receptors present in vascular and myocardial tissue, brain, kidney and adrenal glands. They are blocked by losartan.
Losartan relaxes vascular smooth muscles, promotes salt and water excretion and reduces plasma volume.
The advantage of AT II antagonisis over ACE inhibitors is that there is no increase in bradykinin levels and its associated adverse effects like dry cough and angioedema are also less.
Adverse effects include hypotension and hyperkalemia. It is contraindicated in pregnancy and lactation.
Therapeutic uses: Losartan (50 mg OD) is used in the treatment of hypertension in similar situations as ACE inhibitors.

Treatment of hypertension

AIMS for treatment of Hypertension:

To reduce morbidity and mortality
To prevent development of complication
To revert the changes (occurred due to hypertension)
To reduce the risk factors

Non-pharmacological measures:

Reduce risk factors, i.e. Reduce obesity and cholesterol, Reduce cigarette smoking, reduce alcohol intake, etc.
Other measures includes: Exercise, Low salt diet, weight reduction, trans-dental meditation, stress management, yoga, aerobics, naturopathy; all go simultaneously in controlling the blood pressure. These measures also help in reducing the doses of the anti-hypertensive needed.

Selection of drugs (antihypertensives) and therapy depends upon the

Safety of the drug
Cost of the drug

179
Patients complains
Other pros and cons (benefits)

Combination of antihypertensives

Usually, during the management of hypertension we proceed, in step by step manner. When it is not possible to achieve adequate control of BP with a single drug, a combination may be used.
Antihypertensives may also be combined to overcome the side effects of one another. This also allows use of lower doses of each drug.
Sympatholytics and vasodilators cause fluid retention which can be overcome by adding a diuretic.
Vasodilators like nifedipine and hydralazine evoke reflex tachycardia. This can be countered by β-blockers, while propranolol may cause initial rise in PVR (peripheral vascular resistance) which is countered by vasodilators.
Combination of ACE inhibitors and diuretics is synergistic.

Stepwise management of hypertension will be done according to categories as shown in Table 7.1.2.

Table 7.1.2 Stepwise management of hypertension

Step I	One drug only: Thiazide or beta blocker
Step II	Two drugs: Thiazide (Hydrochlorothiazide) and Sympathoplegic (BB, reserpine, prazosin, clonidine, methyl dopa) or ACE inhibitors.
Step III	Three drugs: Vasodilators or Hydralizine/ minoxidil or Ca⁺⁺ channel blockers or ACE inhibitors.
Step IV	Add Guanethidine or an ACE inhibitor to above three drugs

Step I for Mild Hypertension: Diastolic BP (90–104 mm of Hg)

Mild hypertension: Treatment is started with low does of a single drug—a thiazide diuretic or a β-blocker. If the patient does not adequately respond in 3–4 weeks, an ACE inhibitor or a calcium channel blocker should be tried. If BP is not controlled by one drug, another should be added (Table 7.1.2).

Step II for Moderate Hypertension: Diastolic BP (105–114 mm of Hg)

Moderate hypertension: A combination of a diuretic with a sympatholytic may be given. If response is inadequate a third drug may be tried.

Step III for Severe Hypertension: Diastolic BP (114–120 mm of Hg)

Severe hypertension may be associated with cardiac or renal disorder. A vasodilator with a diuretic and a β-blocker is useful.

Step IV for very Severe Hypertension: Diastolic BP (>120 mm of Hg)

Hypertensive Crisis

Hypertensive emergencies

When blood pressure is required to reduce (control) within minutes:
Conditions like hypertensive encephalopathy and acute cardiac failure due to hypertension require immediate reduction of BP. Parenteral drugs are preferred. IV sodium nitroprusside under close monitoring is the drug of choice (in some conditions BP should be lowered gradually to avoid ischemia of vital organs). Diazoxide and sublingual nifedipine are alternatives. As soon as possible switch over to oral drugs.
Hypertensive urgency:

When blood pressure is required to reduce (control) within hours:

Nifedipine :
10 mg chewed or swallowed
Clonidine :
100 mcg/oral or IM
Captopril :
25 mg oral
Hydralizine :
10–20 mg IM or IV slowely
Furosemide :
(only if there is volume overload)
Hypertension in pregnancy:
- – When Systolic BP > 135 mm of Hg or
- – When Diastolic BP > 85 mm of Hg
  
  Hypertension in pregnancy may lead to ecclempsia
  
  Hypertension → Convulsions → Fetal Death

Pre-ecl ampsia: It is the condition before eclampsia.

The drugs found to be safe in pregnancy are:

– Methyldopa
– Hydralizine
– Beta blocker (cardio selective)
– Prazosin
– Clonidine

Drugs should be avoided in pregnancy:

– ACE inhibitors
– Diuretics
– Reserpine

180
– Non selective beta blockers
– Na nitroprusside (eclampsia)

Basic four groups of drugs which are used as antihypertensives:

Calcium channel blockers: In elderly/Asthmatics/COPD/Isolated systemic hypertension/hypertension in pregnancy.
ACE inhibitors: In young patients/Diabetics/Angina and CCF patients.
Beta blockers: Tense young patients/Non obese.
Diuretics: Elderly patients/Obese/Patients with isolated systolic hypertension.

Contraindications of these groups of drugs:

Calcium channel blockers: In any cardiac patients (angina, MI, etc).
ACE inhibitors: In Pregnancy/high salt consumer/cough/patient with bilateral renal stenosis.
Beta blockers: LVF, CHF, Elder, Diabetics.
Diuretics: Young patients/Gout/Pregnency and Diabetics.

Nifedipine :	10 mg chewed or swallowed
Clonidine :	100 mcg/oral or IM
Captopril :	25 mg oral
Hydralizine :	10–20 mg IM or IV slowely
Furosemide :	(only if there is volume overload)

Chapter Notes

Hypertension and Antihypertensive DrugsCHAPTER 1