Antihypertensive Drugs (I)

By:
Prof. Dr. Adeeb Al-Zubaidy
MBChB; MSc; PhD (Pharmacology)
 Mechanisms for Controlling Blood Pressure (BP):
Arterial BP is directly proportional to the product of CO & PVR;
these in turn are controlled mainly by two mechanisms:

A. Baroreceptors in carotid sinus & aortic arch

Baroreflexes are responsible for the rapid regulation of BP.
i.e., regulate acute BP changes via controlling HR, contractility, & PVR.

A sudden ↑ in BP →stretch baroreceptors →↑ impulses to vasomotor

center→ ↓sympathetic drive & ↑vagal tone on SA node → ↓HR

A sudden ↓ BP→…→…→↑ HR
B. Renin-angiotensin-aldosterone system is responsible for the long-term
control of BP by altering the blood volume

 Renin is released in response to:

 ↓ arterial pressure
 Low Na+ intake &/or
 greater Na+ loss

 Renin converts angiotensinogen to angiotensin I, which is

converted in turn to angiotensin II in the presence of angiotensin
converting enzyme (ACE).
 Angiotensin II is the body's most potent circulating vasoconstrictor,
constricting both arterioles & veins →↑BP.
 Angiotensin II has several very important functions:

 Constricts blood vessels (via AT1 receptors) →↑ PVR→↑ Bp

 ↑ aldosterone release (from adrenal cortex) →↑Na+ & H2O retention

 ↑ vasopressin (ADH) release (from posterior pituitary) →↑ H2O retention

 Facilitates norepinephrine release & inhibits its re-uptake by nerve

endings → enhancing sympathetic adrenergic function

 Stimulates cardiac hypertrophy & vascular hypertrophy

 Therapeutic manipulation of this pathway is very important in treating
hypertension (HT) & heart failure (HF).
Angiotensin converting enzyme inhibitors (ACEIs), Angiotensin receptor
blockers (ARBs) & aldosterone receptor blockers are used to:

- ↓BP→ ↓ventricular afterload

- ↓blood volume → ↓ ventricular preload

- inhibit & reverse cardiac & vascular hypertrophy.

  Hypertension (HT):
 Classified into categories for the purpose of treatment
Category SBP DBP
BP:
Optimal < 120 < 80
Normal < 130 < 85
High Normal 130-139 85-89
HT
Grade 1 (mild) HT 140-159 90-99
Grade 2 (moderate) HT 160-179 100-109
Grade 3 (Severe) HT ≥ 180 ≥ 110
Isolated Systolic HT
Grade 1 140-159 < 90
Grade 2 ≥ 160 < 90
 may be essential HT (more than 90%) (of unknown origin) or
secondary HT to other disease processes
 is usually asymptomatic

 Even mild HT (BP= 140/90 mm Hg) ↑ the risk of eventual end organ
damage including CVA, MI, congestive HF, & renal damage.

 The incidence of morbidity & mortality significantly ↓ when HT is

diagnosed early & is properly treated.
 Antihypertensive Drugs

Classification:

1)Diuretics
2)Sympathoplegic agents
3)Direct vasodilators
4)Agents that block production or action of angiotensin
 Most anti-HT drugs ↓ BP by ↓ CO &/or ↓ PVR

 Mild HT can often be controlled with a single drug;

 However, most patients require more than one drug to achieve
BP control:

i. Initiate therapy with a thiazide diuretic.

If BP is inadequately controlled→ 2nd drug (β-blocker) is added.
If patients still fail to respond→3rd drug(vasodilator) can be
added

ii. ACEIs, ARBs, & CCBs can also be used to initiate therapy.
o Black patients: Diuretics & CCBs are favored
but β-blockers or ACEIs is less effective.

o Elderly patients: CCBs, ACEIs, & diuretics are favored

DRUGS THAT ALTER SODIUM & WATER BALANCE
(Diuretics)
 Low-dose diuretic therapy is safe, inexpensive, & effective in
preventing CVA, MI, & congestive HF.

 diuretics alone can be used as 1st -line drug therapy for mild -
moderate essential HT.

 In more severe HT, diuretics are used in combination with

sympathoplegic or vasodilator drugs to control the tendency toward
Na+ retention caused by these agents.
 A. Thiazide diuretics:

 inhibit Na+/Cl− transporter in distal convoluted tubules (DCT) →

↓reabsorption of NaCl
↑ reabsorption of Ca2+
↓ uric acid secretion → ↑ serum uric acid level (Thiazides are
most associated with development of gout).
 Thiazide diuretics:

Indications:
1. HT:
 appropriate for mild or moderate HT
 often used combined with K+ sparing diuretics.
 particularly useful in the treatment of black or elderly patients.
 are not effective in patients with inadequate kidney function

2- HF
3- Nephrolithiasis due to idiopathic hypercalciuria
4- Nephrogenic diabetes insipidus.
 B. Loop diuretics:

 are the most efficacious diuretic agents currently available.

 inhibit Na+/K+/2Cl− cotransporter in the thick ascending limb (TAL) of
Henle’s loop →
↓ reabsorption of NaCl
↑ excretion of Ca2+
[Note: Loop diuretics ↑Ca2+ content of urine, whereas thiazide diuretics ↓ it.]
 Loop diuretics:

 act promptly, even in patients with poor renal function or who have
not responded to other diuretics.
 cause ↓ renal vascular resistance & ↑ renal blood flow.
Indications:
1. acute pulmonary edema
2. edematous conditions (HF or cirrhosis) where Na + retention is marked
3. as an effective anti-hypertensive agent especially in the presence of
renal insufficiency.
 Other indications:
 Hypercalcemia
 hyperkalemia
 acute renal failure: ↑ the rate of urine flow & excretion of K +.
 C. Potassium-sparing diuretics:

 ↓ absorption of Na+ in the collecting tubules & ducts

 antagonizing aldosterone effects in collecting tubules→↓ excretion of K +
 Potassium-sparing diuretics:

Indications:
 avoid excessive K+ depletion, particularly in patients on digitalis
 enhance the natriuretic effects of other diuretics.
 hyperaldosteronism :
- primary (Conn’s syndrome) or secondary hyperaldosteronism (evoked
by HF, hepatic cirrhosis, or nephrotic syndrome).

Contraindications
 Chronic renal insufficiency: may cause severe, even fatal, hyperkalemia
 DRUGS THAT ALTER SYMPATHETIC NERVOUS SYSTEM FUNCTION
(Sympathoplegic agents)
I. Centrally-Acting Sympathoplegic Drugs: Clonidine, Methyldopa

II. Ganglionic-Blocking Agents: Mecamylamine, Trimetaphan (Trimethaphan)

III. Adrenergic Neuron-Blocking Agents: Guanethidine, Reserpine

IV. Adrenoceptor Antagonists:

α 1-Adrenoceptor-Blocking Agents: Doxazosin, Prazosin, Terazosin

ẞ-Adrenoceptor-Blocking Agents: , Atenolol, Metoprolol, Propranolol, …

I. Centrally-Acting Sympathoplegic Drugs: Clonidine, Methyldopa
 are rarely used today.
 ↓ sympathetic outflow from vasomotor centers in the brain stem

Clonidine:
 a partial agonist at α 2 - adrenoceptors in medulla of brain→↓ central
adrenergic outflow →↓ sympathetic →↓HR & ↓PVR →↓ CO →↓ Bp

 is used for HT that has not responded adequately to two or more drugs.

 does not ↓renal blood flow → useful in HT complicated by renal disease.

 causes Na+&H2O retention→ combination with a diuretic may be required

 Single application of its transdermal preparation →↓ Bp for 7 days
with less sedation than clonidine tablets

 Adverse effects:
- are mild, (sedation & drying of the nasal mucosa)

- Rebound severe hypertensive crisis occurs following its abrupt

withdrawal, i.e., after omitting 1 or 2 doses of the drug.
 C.I.s:
 Abrupt withdrawal. It should be done gradually while
other anti-HT agents are being substituted.

 patients with depression or who are at risk for depression

Methyldopa:
- is an analog of L-dopa
- is converted to α-methyldopamine & α-methylnorepinephrine; & stored in
adrenergic nerve vesicles, where it is released →stimulation of central α 2 -
adrenoceptors →↓ total PVR→↓ BP
Note: CO is not↓, & blood flow to vital organs is not ↓.

Indications:
- HT with renal insufficiency (does not ↓ renal blood flow)
- HT during pregnancy

Adverse effects:
Sedation, nightmares, mental depression, vertigo, & extrapyramidal signs
II. Ganglionic-Blocking Agents: Mecamylamine, Trimetaphan (Trimethaphan)

o competitively block nicotinic cholinoceptors on postganglionic neurons in

both sympathetic & parasympathetic ganglia.

o Their adverse effects include both sympathoplegia (excessive orthostatic

hypotension & sexual dysfunction) & parasympathoplegia (constipation,
urinary retention, precipitation of glaucoma, blurred vision, dry mouth,
etc.).

o Most of them are no longer available clinically because of intolerable

adverse effects
III. Adrenergic Neuron-Blocking Agents: Guanethidine, Reserpine

 Prevent NE release from postganglionic sympathetic neurons→↓Bp

 → all of adverse effects expected from “pharmacologic sympathectomy,”

including marked postural hypotension, diarrhea, & impaired ejaculation.

 Now rarely used & no longer available in the USA

THANK YOU