【Pharmacology】Antihypertensive

Hypertension 

or high blood pressure is a quite common disorder affecting many people who typically don't even notice any symptoms.

Content:

1. Blood pressure regulation 
2. Antihypertensive drugs
    a. Alpha-1 blockers
    b. Selective beta blockers
    c. Non-selective beta blockers
    d. Centrally acting adrenergic drugs
    e. Calcium channel blockers
    f. Diuretics
    g. renin-angiotensin-aldosterone system
    h. Bosentan
    i. Fenoldopam 
    j. Sodium Nitroprusside and Nitroglycerin
    k. Hydralazine & Minoxidil
3. Reference

1. Blood pressure regulation 

Blood pressure: The force or tension of blood pressing against the artery walls

• maintained by
• contraction of the left ventricle
• systemic vascular resistance elasticity of the arterial walls
• blood volume

Formula: blood pressure is a product of cardiac output and systemic vascular resistance 

Arterial blood pressure is regulated by pressure sensitive neurons called baroreceptors

• Baroreceptors located in the aortic arch and carotid sinuses
• If blood pressure falls too low, baroreceptors can send signals to the adrenal medulla 
• causing release of catecholamines 
• thus increase in sympathetic activity through activation of alpha and beta receptors 
• activation of beta-1 receptors causes increase in heart rate and stroke volume
• increased cardiac output
• increase in blood pressure
• activation of alpha-1 receptors on smooth muscle causes vasoconstriction
• increase in vascular resistance
• leads to increase in blood pressure

Baroreceptors in the kidneys that respond to fall in blood pressure or reduction of blood flow (renin-angiotensin-aldosterone system)

• by releasing enzyme called renin
• renin secretion is also stimulated by sympathetic activation of beta-1 receptors in the kidneys
• renin is necessary for the production of angiotensin II
• angiotensin II is a very potent vasoconstrictor which constricts systemic blood vessels
• increasing peripheral resistance angiotensin II 
• constricts renal blood vessels
• stimulates aldosterone secretion 
• leads to sodium and water retention
• increased blood volume cardiac output
• increased blood pressure

2. Antihypertensive drugs

a. Alpha-1 blockers

Drug:

• Doxazosin
• Prazosin 
• block alpha-1 receptors on the smooth muscle
• causing decrease in systemic vascular resistance
• decrease in blood pressure

b. Selective beta blockers

Drug:

• Atenolol
• Metoprolol
• selectively block beta-1 receptors on the heart
• decrease in cardiac output
• decrease in blood pressure

c. Non-selective beta blockers

Drug: 

• Labetalol
• Carvedilol
• additionally block alpha-1 receptors
• simultaneously decrease vascular resistance
• beta blockers can inhibit beta-1 receptors present on the kidneys
• suppress release of renin, formation of angiotensin II and secretion of aldosterone
• decrease in systemic vascular resistance
• fall in blood pressure

d. Centrally acting adrenergic drugs

work by blocking sympathetic activity within the brain

Drug: 

• Clonidine
• selectively stimulates presynaptic alpha-2 receptors
• providing negative feedback to reduce catecholamine production
• decrease in systemic vascular resistance and cardiac output
• decreased blood pressure 
• Methyldopa
• lowers blood pressure through the same mechanism
• however unlike Clonidine it is not an agonist itself 
• so first it must be converted to its active metabolite called methylnorepinephrine 

e. Calcium channel blockers

divided into two main subclasses:

• dihydropyridines
• selectively inhibit L-type calcium channels in the vascular smooth muscle under normal conditions
• blocks the entry of calcium
• contraction is inhibited
• decreased resistance to blood flow 
• lowering of blood pressure
• Normal: when calcium enters the smooth muscle cell
• cause contract which leads to increased vascular resistance
• increase in blood pressure
• Drug:
• Amlodipine 
• Felodipine 
• Nicardipine
• Nifedipine

• nondihydropyridines
• non selective inhibitors of L-type calcium channels
• blocking calcium channels on vascular smooth muscle and on cardiac cells (eg, SA node and AV node)
• leads to reduced myocardial contractility
• slower heart rate and slower conduction
• but do not significantly decrease cardiac output
• most likely because of the reflex tachycardia that occurs as a result of vasodilation
• Drug:
• Diltiazem
• Verapamil 

Side effects of dihydropyridines

• dizziness 
• headache 
• flushing
• peripheral edema
• as related to systemic vasodilation
• gingival hyperplasia (swelling of gums)

Side-effects nondihydropyridines

• excessive bradycardia and cardiac conduction abnormalities
• Verapamil: constipation
• least selective calcium channel blocker can exert significant inhibition of calcium channels in the smooth muscle that lines the GI tract 

f. Diuretics

Three major classes:

i. loop diuretics 

Drug: Furosemide

• work by reducing reabsorption of sodium chloride in the kidneys
• leading to significant diuresis with less volume in the vascular space
• less blood returns to the heart
• cardiac output decreases
• decrease in blood pressure 
• particularly in patients with volume-based hypertension and chronic kidney disease

ii. thiazide diuretics

Drug: Hydrochlorothiazide

• reduce reabsorption of sodium chloride in the kidneys
• but to a much smaller degree than loop diuretics 
• leads to initial decrease in intravascular volume
• decrease in cardiac output
• lower blood pressure
• However the long term effects on blood volume are minimal and sustained

iii. potassium-sparing diuretics

Drug: 

• Triamterene
• Spironolactone 
• increase diuresis by
• interfering with the sodium potassium exchange in the kidneys
• blocking the actions of aldosterone

• often used in combination with loop and thiazide diuretics 
• to reduce loss of potassium

g. renin-angiotensin-aldosterone system

Three pharmacological targets to reduce the activity of angiotensin II:

i. renin

• the enzyme responsible for conversion of angiotensinogen to precursor of angiotensin II
• Renin inhibitors which selectively inhibit this enzyme 
• thus decreasing production of angiotensin II
• Drug: Aliskiren

ii. Angiotensin-converting enzyme

• responsible for conversion of angiotensin I to angiotensin II
• Target of ACE inhibitors
• inhibition of angiotensin-converting enzyme 
• leads to decreased production of angiotensin II
• Make it different: lowering angiotensin II levels & also elevate bradykinin levels
• bradykinin is a peptide that causes blood vessels to dilate by stimulating the release of nitric oxide and prostacyclin
• however normally angiotensin-converting enzyme inactives bradykinin 
• so it's inhibition leads to bradykinin induced vasodilation
• Drug:
• Benazepril 
• Captopril 
• Enalapril 
• Lisinopril 
• Quinapril 
• Ramipri

iii. Angiotensin II receptors type 1 (AT1 receptors)

• responsible for most of the effects of angiotensin II, including
• vasoconstriction
• stimulation of aldosterone
• Target of angiotensin II receptor blockers (ARBs)
• work by 
• block the production of angiotensin II or
• block its actions on the AT1 receptors
• decreased systemic vascular resistance but without significant changes in cardiac output
• Additionally,  reduce the effects of angiotensin II on renal hemodynamics 
• specifically angiotensin II constricts the efferent arteriole 
• generating back pressure in the glomerulus
• lead to injury 
• Hence, by reducing activity of angiotensin II
• improve renal blood flow
• reduce the risk of renal injury
• Drug: 
• Candesartan 
• Irbesartan 
• Losartan 
• Olmesartan
• Valsartan

Side effects

• hyperkalemia 
• as suppress aldosterone release
• ACE inhibitors: dry cough or angioedema (life-threatening)
• due to increased levels of bradykinin and substance P

h. Bosentan

• competitive antagonist of a potent vasoconstrictor called endothelin-1
• act on endothelin-A and endothelin-B receptors located on pulmonary vascular cells
• by blocking the action of endothelin-1 on these receptors
• vasodilation
• decreases pulmonary vascular resistance
• choice for treatment of pulmonary hypertension

i. Fenoldopam 

• selective dopamine-1 receptor agonist 
• dopamine-1 receptors are located on the 
• smooth muscle cells in the peripheral vasculature
• renal coronary cerebral
• mesenteric arteries 
• by stimulating dopamine-1 receptors
• produces generalized arterial vasodilation
• leads to decreased peripheral resistance
• lower blood pressure
• Additionally, Fenoldopam inhibits tubular sodium reabsorption 
• results in natriuresis and diuresis 
• due to its rapid onset of action and short duration of action 
• use for short-term management of severe hypertension

j. Sodium Nitroprusside and Nitroglycerin

• fast-acting agents that are also used for hypertensive emergency 
• serve as 
• a source of nitric oxide
• a potent peripheral vasodilator

k. Hydralazine & Minoxidil

• direct acting smooth muscle relaxants
• Hydralazine: mechanism of action that has not been entirely determined yet
• Minoxidil: works by stimulating opening of ATP-activated potassium channels in the smooth muscle
• leads to membrane stabilization making vasoconstriction less likely 
• Both result: 
• significantly decrease peripheral resistance
• also produce significant compensatory reflex---tachycardia and renin release
• typically administered in combination with a diuretic and a beta blocker 
• topical application of Minoxidil: promotes hair growth
• so more often for treatment of baldness, rather than hypertension

3. Reference

https://youtu.be/V2sEay-E-Ro