Antihypertensive Agents " lecture 14&15"

Cardiovascular

(=Circulatory) system –> heart and
blood vessels

Arteries –> transport blood to tissues

capillaries –> sites of exchange, fluid O2, CO2, nutrients
etc.

Venules –> collect blood from capillaries

Veins –> transport blood back to heart

Blood moves within vessels –> higher pressure to
lower pressure

  • Resistance to flow depends on **vessel diameter, length
    and viscosity of blood**

Hypertension

  • One of 4 major cardiovascular diseases: **Hypertension,
    Angina pectoris, Cardiac arrhythmias, Heart Failure**

A medical condition in which the blood pressure is
chronically elevated

  • Prevalence varies with age, race, education, diet and others

🚩 TYPES:

1- Essential

2- Secondary

No specific medical cause can be found to explain a patient’s
condition. About 95% of hypertension is essential hypertension

Indicates that the high blood pressure is a result of (i.e. secondary to) another condition, such as kidney diseases or tumor

  • is usually symptom-free

💥 Consequences:
Heart failure, Kidney damage, stroke, blindness

  • Normal blood pressure: 115/75 mmHg

⁉ How do we treat hypertension?

1- Regulation of blood pressure with diet --> avoid salty food and coffee

2- Drug therapy

3- Surgical intervention

Hypertension management

CNS: Decrease sympathetic tone

Heart: decrease cardiac Output

Veins: dilate => decrease Preload

Arterioles: dilate => Decrease afterload

Kidneys: increase diuresis; Inhibit RAA system

Antihypertensive Major Drug Groups:

1- Sympatholytic "Sympathetic nervous system suppressor"

2- direct Vasodilators

3- Renin-angiotensin System targeting drugs

4- Diuretics

❎ Calcium channel antagonists

ACE inhibitors

Angiotensin II receptor antagonists

Thiazides

Loop diuretics

K+- sparing diuretics

  • Decrease sympathetic Discharge or its effects
    on Cardiovascular System
  • Pharmacological Targets

1- Centrally acting agents --> α2 agonists

2- Ganglion blockers "nicotinic cholinergic antagonists" --> not recommended

3- Adrenoceptor Blockers

  • for Mild/moderate hypertension

✅ Clonidine

  • has some α1-agonist (vasoconstriction) properties in the periphery, but once it crosses the BBB, shows powerful agonist effect at α2-adrenoreceptors in the CNS
  • Minimal side effects, but sudden cessation causes
    severe hypertension

✅ Methyldopa

  • Prodrug
  • Its mechanism is Not related to its inhibition of norepinephrine biosynthesis
  • Due to metabolism in CNS to a-methylnorepinephrine
    an a2-adrenergic agonist

✅ Trimethaphan

  • Indication: severe hypertension --> Only use in treatment of hypertensive emergencies to reduce blood pressure rapidly
  • Mechanism: Blocks nicotinic acetylcholine receptors (nAChR) in autonomic ganglia
  • Toxicity: Intolerable (used rarely)
  • It carries a positive charge --> Cannot cross BBB + Does not have any effect on CNS

✅ Reserpine

  • One of the old and important historic drugs first isolated in 1952 from the dried root of Rauwolfia serpentine (Indian snakeroot)
  • Acts by depleting the adrenergic neurons of their norepinephrine and dopamine
  • Excess neurotransmitters are metabolized by MAO,
    sympathetic activity dramatically decreased
  • Toxicity: intolerable, CNS depletion of neurotransmitters

✅ Guanethidine

  • Mechanism reduces the release of catecholamines, such
    as noradrenaline, from adrenergic nerve endings in
    response to sympathetic nerve stimulation
  • Adverse effects include dizziness, weakness, postural or
    post-exercise hypotension

❎ Beta 1 adrenergic blockers

❎ Alpha 1 adrenergic blockers

  • Indication:
    1- Mild hypertension (α and β-blockers)
    2- Moderate-severe hypertension (β-blockers)
  • Mechanism: Antagonists of α- and β-receptors
  • Toxicity:
    Mild (α-blocker; marked 1st dose hypotension and mild tachycardia
  • Toxicity: Moderate (β-blocker; may cause asthma, bradycardia, heart failure)

✅ Propranolol --> beta receptors of heart

  • first generation + non selective
  • Wide use in treating hypertension, and certain types of glaucoma
  • By far the most lipophilic of the current β-blockers, and therefore, able to enter CNS

✅ Prazosin --> a receptors of vessels

  • Lower blood pressure by relaxing blood vessels;
  • Side effects include orthostatic hypotension

✅ Acebutolol (Spectral

✅ Carvedilol (dilatrend)

✅ Labetolol (Trandate)

✅ Timolol (Timolol)

✅ Metoprolol (Lopressor

  • Drugs relax the smooth muscle in blood vessels
  • Dilation of arterial vessels leads to a reduction in systemic vascular resistance ( low arterial blood pressure)

USES:

  • Arterial dilator drugs are used to **treat heart failure and
    angina by reducing the afterload on the left ventricle**
  • Venous dilators are used to **reduce the preload on the
    heart and decreasing cardiac output**

❎ Nitrates: NO releasing agents

❎ K+ channel activation

❎ K+ channel openers

✅ Nitroglycerine

  • Used as an active ingredient in the manufacture of
    explosives, specially dynamite since 1860’s
  • Used medically as a vasodilator to treat heart
    conditions, such as angina and chronic heart failure
  • Converted to nitric oxide in the body

Mechanism: convert inactive form of guanylate cyclase to active guanylate cyclase