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Antihypertensive Agents " lecture 14&15" (Hypertension (:!?:…
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**
One of 4 major cardiovascular diseases: **Hypertension,
Angina pectoris, Cardiac arrhythmias, Heart Failure**
Normal blood pressure: 115/75 mmHg
Hypertension
A medical condition in which the blood pressure is
chronically elevated
Prevalence varies with age, race, education, diet and others
:red_flag: TYPES:
1- Essential
No specific medical cause can be found to explain a patient’s
condition. About 95% of hypertension is essential hypertension
2- Secondary
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
:explode: Consequences:
Heart failure, Kidney damage, stroke, blindness
:!?: 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"
Decrease sympathetic Discharge or its effects
on Cardiovascular System
Pharmacological Targets
1- Centrally acting agents --> α2 agonists
for Mild/moderate hypertension
:check: 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
:check: 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
2- Ganglion blockers "nicotinic cholinergic antagonists" --> not recommended
:check: 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
:check: 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
:check: 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
3- Adrenoceptor Blockers
:green_cross: Beta 1 adrenergic blockers
Toxicity: Moderate (β-blocker; may cause asthma, bradycardia, heart failure)
:check: 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
:check: Acebutolol (Spectral
:check: Carvedilol (dilatrend)
:check: Labetolol (Trandate)
:check: Timolol (Timolol)
:check: Metoprolol (Lopressor
:green_cross: Alpha 1 adrenergic blockers
Toxicity:
Mild (α-blocker; marked 1st dose hypotension and mild tachycardia
:check: Prazosin --> a receptors of vessels
Lower blood pressure by relaxing blood vessels;
Side effects include orthostatic hypotension
Indication:
1- Mild hypertension (α and β-blockers)
2- Moderate-severe hypertension (β-blockers)
Mechanism: Antagonists of α- and β-receptors
2- direct Vasodilators
:green_cross: Calcium channel antagonists
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**
:green_cross: Nitrates: NO releasing agents
:check: 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
:green_cross: K+ channel activation
:green_cross: K+ channel openers
3- Renin-angiotensin System targeting drugs
ACE inhibitors
Angiotensin II receptor antagonists
4- Diuretics
Thiazides
Loop diuretics
K+- sparing diuretics
