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