52.4.1 Main Drug Classes Used in the Treatment of Hypertension Flashcards
What are the main drug classes used in the treatment of hypertension?
*Diuretics
*Vasodilators
*Cardio-inhibitory drugs
*Centrally acting sympatholytic drugs
What are the different types of diuretics?
Thiazide. loop, and potassium sparring
What are the different types of vasodilators?
*Alpha-adreno antagonists (alpha blockers)
*ACE inhibitors
*ARBs
*Ganglionic blockers
*NO donors
*Ion channel modulators (Ca2+ channel blockers and K+ channel openers)
*Renin inhibitors
When are ganglionic blockers and NO donors used?
In acute hypertensive emergencies
What are the cardio-inhibitory drugs?
*Beta blockers
*Ca2+ channel blockers
What is the most common class of diuretics used to treat diuretics?
Thiazides
How do thiazide diuretics work?
- Inhibit the Na+-Cl- co-transporter in the distal convoluted tubule.
- This leads to greater excretion of salt and therefore less water retention, lowering blood pressure.
What are some examples of thiazide diuretics?
- Bendroflumethiazide
- Chlorothiazide
- Structurally unrelated drugs e.g. metolazone
Is the diuresis produced by thiazide diuretics strong?
It is weaker than with loop diuretics, but this is usually sufficient for treatment.
How do loop diuretics work?
Inhibit the NKCC (Na/K/2Cl transporter) in the thick ascending limb of the loop of Henle.
Additional effects include that they are vasodilators of:
- Systemic resistance arterioles -> Useful in lowering arterial pressure in hypertension and in reducing peripheral resistance in cardiac failure
- Renal resistance arterioles -> Useful in increasing GFR and so potentially increasing diuresis
- Vasa recta of the renal medulla -> Resulting in a “washout” of the accumulated osmotically active substances of the medullary interstitium, and so further reducing the osmotic potential there and increasing the potency of the diuresis
Give some examples of loop diuretics.
Furosemide
Compare the effects of loop and thiazide diuretics in terms of their effects on calcium.
- Loop diuretics increase calcium excretion
- Thiazide diuretics reduce calcium excretion -> This can be used in treatment of conditions such as stone formation in the urinary tract
What are some side effects of thiazide and loop diuretics?
- Metabolic alkalosis and hypokalemia
- Hypovolemia
- Hypercalcaemia (thiazides) or hypocalcaemia (loop)
How do potassium-sparing diuretics work?
There are two main classes:
- Aldosterone antagonists
- Inhibitors of the epithelial Na+ channel in the collecting duct
What are some examples of potassium-sparing diuretics?
- Aldosterone antagonists -> Spironolactone
- Inhibitors of the epithelial Na+ channel in the collecting duct -> Amiloride
When are potassium-sparing diuretics used?
They are used when:
- Aldosterone levels are too high in disease, such as:
- Cardiac failure
- Hypertension
- Aldosterone levels are too high as a natural response to diuretic therapy (sinc aldosterone conserves water indirectly by conserving salt)
Why may aldosterone levels be raised in diuretic therapy?
- Diuresis activates the juxtaglomerular apparatus, which releases renin and causes the production of aldosterone.
- Potassium-sparing diuretics may be used in these cases.
Describe how the kidney adapts to diuretics.
During diuretic action:
- Downstream nephron segments increase NaCl reabsorption as delivered NaCl load increases.
Post-diuretic NaCl retention (short term):
- As diuretic concentrations in the tubule decline, Na+ retention increases until the next dose of diuretic is administered.
Chronic increase in Na+ retention (the ‘braking phenomenon’):
- Ability to increase renal NaCl excretion declines over time. Due to both depletion of the extracellular fluid volume and structural (hyperplasia, hypertrophy) and functional (include increase in Na/K ATPase in basolateral membrane) changes in the kidney tubules.
How do beta-blockers work in treating hypertension?
- Block of β1-adrenergic receptors in the kidney, reducing renin release (remember that the juxtaglomerular cells receive sympathetic innervation)
- May also have a CNS effect to reduce sympathetic outflow to the heart and reduce cardiac output
What are some examples of beta-blockers used to treat hypertension?
‘Cardioselective’ β blockers -> e.g. Atenolol
How do alpha-blockers work in treating hypertension?
They block alpha-1 receptors in the vasculature, causing vasodilation.
What is the limitation of using alpha-blockers in treating hypertension?
Sympathetic innervation of the vasculature is important in everyday life, such as when standing up.
What are some examples of alpha-blockers?
- Prazosin
- Terazosin
How do potassium channel opener drugs work in treating hypertension?
- They open KATP channels on smooth muscle cells in the arteries
- This leads to hyperpolarisation and therefore vasodilation of the vessels
What are some examples of potassium channel opener drugs?
- Diazoxide
- Minoxidil
- Hydralazine (maybe)
How do nitric oxide donors work in treating hypertension?
- They are drugs that lead to the production or release of NO
- This NO is responsible for the dilation of blood vessels, especially the venous system
What are some example of nitric oxide donor drugs?
Nitroprusside
How do ganglionic blockers work in treatment of hypertension?
- They lead to decreased activity of post-ganglionic nerves
- Therefore, in theory, they should reduce both sympathetic and parasympathetic activity
- However, since arteries receive only sympathetic innervation, this means that vasodilation is favoured
What are some examples of ganglionic blockers used in treating hypertension?
Pentamethonium (C5) and hexamethonium (C6) found to be selective, non-depolarising ganglion blockers.
What are sympatholytic drugs and what are the main types?
Drugs that block the sympathetic nervous system at different points:
- Peripheral sympatholytic drugs (e.g. alpha-adrenoceptor and beta-adrenoceptor antagonists) block the influence of noradrenaline at the effector organ
- Ganglionic blockers block impulse transmission at the sympathetic ganglia
- Centrally acting sympatholytic drugs block sympathetic activity within the brain
How do centrally acting sympatholytic drugs work in treating hypertension?
- They are agonists of α2-adrenoceptors primarily in the brainstem.
- This reduces sympathetic outflow to the heart and vasculature.
What are some examples of centrally acting sympatholytic drugs?
- Clonidine
- Methyldopa
What are the three main classes of anti-hypertensive drugs that modulate the RAA axis that you need to know about?
- ACE inhibitors
- Angiotensin receptor blockers
- Renin inhibitors
What are some examples of ACE inhibitors?
- Captopril was the first
- Lisinopril, ramapril, enalapril, benazepril, cilazapril, fosinopril all have a slower onset of action that captopril
- Some are pro-drugs converted in the body: ramipril to ramiprilat, enalapril to enalaprilat
How do ACE inhibitors work?
- Block conversion of angiotensin I to angiotensin II (so that aldosterone is also not secreted)
- This reduce peripheral resistance (passive dilatation) and sodium retention.
- No direct effect on the heart.
Aside from hypertension, when are ACE inhibitors used?
They can also be used to treat congestive heart failure.
What are some examples of angiotensin receptor blockers?
Losortan
How do angiotensin receptor blockers work?
- They block the AT1 receptors that bind angiotensin II.
- Angiotensin II usually causes vasoconstriction and aldosterone release (which leads to salt retention).
What are some examples of renin inhibitors?
Aliskerin
How do renin inhibitors work?
- They block the enzymatic activity of renin in converting angiotensinogen to angiotensin I.
- Thus, they reduce peripheral resistance (passive dilatation) and sodium retention (thus reduce blood volume).
What are the main classes of calcium-channel blocker?
What are some examples of calcium channel blockers used to treat hypertension?
- Dihydropyridine calcium channel blockers, a group that includes amlodipine, felodipine and lacidipine, are a common choice for treatment.
- Verapamil (more cardiac-specific tbf)
How do calcium channel blockers work as antihypertensive drugs?
- Block calcium entry into cells
- This prevent contraction of smooth muscles, which leads to vasodilation
- They also inhibit cardiac contraction, which lowers cardiac ouput
- In the kidney, the afferent arteriole appears to be more affected than the efferent, so that GFR is maintained despite the falling blood pressure
