Antihypertensive Drugs (II)

By:
Prof. Dr. Adeeb Al-Zubaidy
MBChB; MSc; PhD (Pharmacology)
IV. Adrenoceptor Antagonists
α 1-Adrenoceptor-Blocking Agents: Prazosin, Terazosin, Doxazosin
- are competitive selective α1-receptors blockers → relaxation of both
arterial & venous smooth muscles→ ↓ PVR → ↓BP

- cause only minimal changes in CO, renal blood flow, & GFR

- Na+ & H2O retention occurs (combination with diuretics may be necessary)

- Concomitant use of a β-blocker may be necessary to blunt the short-term

effect of reflex tachycardia
 α 1-Adrenoceptor-Blocking Agents
Indications:
- Seldom used because of their SE profile, development of tolerance, &
the availability of safer anti-HT

- are used primarily in men with concurrent HT & benign prostatic

hyperplasia (BPH)

Adverse effects:
- 1st -dose phenomenon in patients who are salt- & volume-depleted

- Others: dizziness, palpitations, headache, and lassitude.

ẞ-Adrenoceptor-Blocking Agents:
 ẞ-Adrenoceptor-Blocking Agents

Pharmacokinetics of beta blockers

Lipophilic agents Hydrophilic agents Mixed

Properties
 Undergo hepatic clearance  Undergo renal clearance  Undergo hepatic
and renal clearance
 Penetrate the BBB
 Do not cross the BBB
→ central/neurological adverse effects
(esp. nightmares and insomnia)

Agents
Carvedilol Acebutolol Bisoprolol
Labetalol Atenolol Nebivolol
Metoprolol Pindolol
Propranolol Sotalol
 ẞ-Adrenoceptor-Blocking Agents

 β blockers ↓ BP:
 primarily by blocking β1 – receptors in heart →↓ CO
 block β1 – receptors in kidney →inhibit renin secretion → ↓ production
of angiotensin II & aldosterone.
 may also ↓ sympathetic outflow from CNS

 are not recommended as 1st -line drug therapy for HT unless there is an
associated condition required their uses including previous MI (↓
mortality), AP, chronic HF (↓ mortality), SVT, & migraine headache

 are useful in mild- moderate HT.

 In severe HT, β blockers are useful in preventing the reflex tachycardia

that results from treatment with direct vasodilators.
 more effective for treating HTẞ-Adrenoceptor-Blocking
in white than in black patients & in young
Agents

compared to elderly patients.

 Selective β1receptors blockers (metoprolol & atenolol), are among the

most commonly prescribed β-blockers

 Pindolol, acebutolol, & penbutolol are partial agonists, i.e., β-blockers with
some ISA. They ↓ Bp but are rarely used in HT.

 Esmolol:
- is a β1-selective blocker
- has a short half-life (9–10 minutes) → administered by i.v infusion
- is used for:1- intraoperative & postoperative HT, 2- HT emergencies
 ẞ-Adrenoceptor-Blocking Agents

 Labetalol:
- has both non-selective β- & α1- selective receptors blocking effect.
- ↓Bp by ↓ PVR (α1 blockade) without significant alteration in HR or CO.
- is useful in treating HT of pheochromocytoma & HT emergencies.

 Carvedilol:
- like labetalol, has both non selective β- & α1- blocking effect
- ↓ mortality in patients with HF → particularly useful in patients with
both HF & HT.

 Nebivolol:
is a β1-selective blocker with vasodilating properties that are not
mediated by α1 blockade but may be due to induction of endothelial
 ẞ-Adrenoceptor-Blocking Agents

Indications
1. HT
2. Acute MI: ↓ the size of infarction and mortality rates
3. AP: 1st -line treatment for stable AP in addition to ACEIs or ARBs
4. HF: carvedilol or metoprolol in combination with ACEIs /ARBs and
spironolactone (slows progression of CHF)
5. Arrhythmias: atrial flutter, atrial fibrillation (AF), Paroxysmal
supraventricular tachycardia (PSVT), ventricular tachycardia (VT), and
premature ventricular contractions
6. Glaucoma: topical beta blockers (timolol, betaxolol)
 ẞ-Adrenoceptor-Blocking Agents

Specific indications for propranolol

Essential tremor
Migraine prophylaxis
Portal hypertension
Hyperthyroidism and thyroid storm

Adverse effects
- CVS: bradycardia & hypotension
- CNS: fatigue, lethargy, insomnia, & hallucinations
- ↓ libido & cause impotence.
- may disturb lipid metabolism, ↓ HDL cholesterol &↑TG (triglyceride)
 ẞ-Adrenoceptor-Blocking Agents

Drug withdrawal: Abrupt withdrawal may induce angina, MI, or even

sudden death in patients with IHD; thus, doses of these drugs must be
tapered over 2 - 3weeks in patients with HT & IHD

C.I.s:
Absolute:
1. Symptomatic bradycardia
2. Cardiogenic shock
3. Decompensated HF
4. Combination with CCBs: can precipitate AV block
Relative: 1. Asthma and COPD 2.Raynaud phenomenon, 3.peripheral
artery occlusive disease
 Vasodilators
Hydralazine
Minoxidil
Sodium nitroprusside
Fenoldopam
CCBs
 Vasodilators
 act by relaxation of vascular smooth muscle (VSM)→↓ PVR →↓BP →:

I. reflex tachycardia (concomitant use of β-blockers may be necessary)

(Note: ↑myocardial contractility, HR, & oxygen consumption → AP, MI, or

HF in predisposed individuals)

II. also ↑ plasma renin concentration→ Na+ & H2O retention (concomitant
use of diuretics may be necessary)

Together, the three drugs→ ↓CO, plasma volume, & PVR.

 Hydralazine
- acting primarily on arteries & arterioles.
- interferes with Ca2+ movements within the VSM → direct vasodilation

Indications:
1. moderately severe HT
2. Hydralazine monotherapy is an accepted method of controlling BP in
pregnancy-induced HT.
3. Its combination with nitrates is effective in HF

Adverse effects: tachycardia, arrhythmia, & precipitation of angina.

A reversible lupus-like syndrome (with high dosage)
 Minoxidil:
- open K+ channels in smooth muscle membranes

- administered orally for severe-malignant HT refractory to other drugs.

- causes serious Na+&H2O retention → edema, & congestive HF.

- must be used in combination with a β blocker and a loop diuretic.

- causes hypertrichosis → minoxidil is used topically for male pattern

baldness
Sodium nitroprusside:
- a powerful vasodilator → prompt vasodilation → reflex tachycardia

- used for HT emergencies (regardless the cause) as well as severe HF.

- Activates guanylyl cyclase →↑intracellular cGMP→ VSM relaxation

→dilates both arterial and venous vessels→↓PVR → ↓ venous return
(↓cardiac preload)

- Its half-life is of minutes → given as i.v infusion.

- its metabolism results in cyanide ion production.

 Sodium nitroprusside

- Although cyanide toxicity is rare, it can be effectively treated with an

infusion of sodium thiosulfate

- [Note: Nitroprusside is poisonous if given orally because of its

hydrolysis to cyanide.]

Adverse effects:
1. accumulation of cyanide;
2. metabolic acidosis, arrhythmias,
3. excessive hypotension, and
4. death
Fenoldopam:
- a peripheral D1- receptor agonist → dilation of arteries and natriuresis
- its half-life is 10 minutes → given as i.v. infusion
- maintains or ↑ renal perfusion while it ↓ BP.
- used in all hypertensive emergencies & may be particularly beneficial in
patients with renal insufficiency.

Adverse effects:
reflex tachycardia,
headache,
flushing.
↑IOP (C.I.: glaucoma)
 Calcium-Channel Blockers (CCBs)

- block the influx of Ca2+ by binding to L-type Ca2+ channels in the heart
& in smooth muscle of the coronary & peripheral vasculature → VSM
relaxation→ dilating mainly arterioles.

- are divided into classes, each with different pharmacokinetic

properties & clinical indications.
Phenylalkylamine: Verapamil
Benzothiazepine: Diltiazem
Dihydropyridine: Amlodipine
Felodipine
Nicardipine
Nifedipine
 CCBs

1. Phenylalkylamines: Verapamil

- has significant pronounced negative inotropic effect on both cardiac &

VSM cells.

- It is used to treat angina, SVT, & migraine headache.

2. Benzothiazepines: Diltiazem
- affects both cardiac & VSM cells

- it has a less pronounced negative inotropic effect on the heart compared

to that of verapamil.
- has a favorable side-effect profile.
 CCBs

3. Dihydropyridines: Amlodipine
Felodipine
Nicardipine
Nifedipine

o have a much greater affinity for vascular Ca2+ channels than for cardiac
Ca2+ channels.

o They are therefore particularly attractive in treating HT.

o amlodipine & nicardipine have the advantage that they show little
interaction with other cardiovascular drugs, such as digoxin or warfarin
 CCBs

Indications
- are used when the preferred 1st-line agents are C.I or ineffective.
- are useful in the treatment of HT patients who also have:
asthma,
diabetes,
angina, &/or
peripheral vascular disease.

- Black hypertensives respond well to CCBs

- Short-acting nifedipine should not be used for HT because of ↑ risk

of MI due to excessive vasodilation & marked reflex tachycardia
 CCBs

Adverse effects
Constipation (verapamil).
Dizziness & headache caused by a ↓BP (more frequent with
dihydropyridines)

C.I.s:
Verapamil should be avoided in patients with congestive HF or with AV
block due to its negative inotropic & chronotropic effects.
Agents that block production or action of angiotensin
ACE Inhibitors:

Captopril
Enalapril
Lisinopril
Benazepril
Quinapril
Ramipril
Trandolapril
 ACEIs

 ACEIs are recommended within the 1st -line antihypertensive agents

 ↓PVR (without reflexively increasing CO, HR, or contractility).

A. ACEIs → vasodilation as a result of the combined effects of:

i) ↓ angiotensin II (the potent vasoconstrictor) &

ii)↑bradykinin (the potent vasodilator)

B. ACEIs →↓ circulating angiotensin II levels →↓secretion of aldosterone

→↓ retention of Na+ & H2O.

 ACEIs

 Uses:
1. most effective in white & young HT patients

2. slow the progression of diabetic nephropathy

3. effective in management of chronic HF.

4. are a standard in the care of a patient following MI. Therapy is started

24 hours after the end of MI.
 ACEIs

 Adverse effects
1. Dry cough (due to ↑ levels of bradykinin in pulmonary tree)
2. rash
3. fever
4. hypotension (in hypovolemic states)
5. hyperkalemia: K+ supplements or K+- sparing diuretics are C.I
6. Angioedema (rare) (due to ↑ levels of bradykinin)

 ACEIs are fetotoxic & should not be used by pregnant women

Angiotensin Receptor Blockers (ARBs):
Candesartan
Irbesartan
Losartan
Valsartan

o These drugs are AT1-receptors blockers; thus, do not ↑ bradykinin levels.

o Their pharmacologic effects are similar to those of ACEIs, i.e.,
→ arteriolar & venous dilation &
block aldosterone secretion→↓BP & ↓ salt & H 2O retention.
o ↓ the nephrotoxicity of diabetes, making them an attractive therapy in
hypertensive diabetics.
 ARBs

o are alternatives to ACEIs.

o adverse effects are similar to those of ACEIs, although the risks of
cough & angioedema are significantly ↓.
o are also fetotoxic.

Renin Inhibitors: Aliskiren

- A selective direct renin inhibitor
- acts earlier in renin-angiotensin-aldosterone system than ACEIs or
ARBs.
- ↓ BP about as effectively as ARBs, ACEIs, & thiazides.
- can cause cough & angioedema (but less often than ACEIs)
C.I: during pregnancy.
 Hypertensive Emergency
 is a rare but life-threatening situation in which:
the DBP is either >150 mm Hg (with SBP >210 mm Hg) in an otherwise
healthy person
or >130 mm Hg in an individual with preexisting
complications (such as encephalopathy, cerebral hemorrhage, LVF, or AS).

 The therapeutic goal is to rapidly reduce BP.

 Antihypertensive drugs may be used in its management include:
 Hypertensive Emergency

Sodium nitroprusside

Labetalol
- is given as an intravenous bolus or infusion in hypertensive
emergencies.
- does not cause reflex tachycardia.
- The major limitation is a longer half-life, which precludes rapid titration
Fenoldopam

Nicardipine
- a CCB, can be given as an intravenous infusion.
- The major limitation of nicardipine in treating hypertensive emergency
is its long half-time which precludes rapid titration.
THANKS ALOT