Pharmacology of Hypertension - Core Drugs & Case Study Flashcards
What are the 4 core drug classes involved in the treatment of hypertension?
- Angiotensin converting enzyme (ACE) inhibitors
- Calcium channel blockers
- Thiazide or thiazide-like diuretics
- Angiotensin receptor blockers (ARBs)
What class of drugs have the suffix -pril?
ACE inhibitors
Ramipril is an example of what drug class used in the treatment of hypertension?
ACE inhibitors
Lisinopril is an example of what drug class used in the treatment of hypertension?
ACE inhibitors
Perindopril is an example of what drug class used in the treatment of hypertension?
ACE inhibitors
What is the suffix for ACE inhibitors?
-pril
What is the primary mechanism of action of ACE inhibitors?
Inhibit the angiotensin converting enzyme
Prevent conversion of angiotensin I to angiotensin II
- Reduced vasoconstriction
- Inhibits aldosterone which usually promotes sodium reabsorption and potassium excretion
- Increased sodium reabsorption —> water retention —> increased blood volume and contributes to increased blood pressure
What is the function of angiotensin II?
Main effector molecule of the RAS
- Increases BP
- Vasoconstriction
- Influences renal tubuli to retain sodium + water
- Stimulates aldosterone release from adrenal gland
- Sympathetic nervous stimulation
What are the main side effects of ACE inhibitors?
Cough
Hypotension
Hyperkalaemia (care with K+ supplements or K+-sparing diuretics)
Foetal injury
Renal failure
Urticaria/Angioedema
Why should the use of ACE inhibitors be avoided in pregnant women?
Foetal injury is a side effect of ACE inhibitor use
What side effect do patients on ACE inhibitors who have renal artery stenosis risk having?
Renal failure
Most ACE inhibitors are pro-drugs. What do they require to be activated?
Require hepatic activation to generate the active metabolites required for therapeutic effects
Most ACE inhibitors require hepatic activation to generate the active metabolites required for therapeutic effects.
What kind of drugs are they?
Pro-drugs (sans lisinopril)
What must be monitored regularly when prescribing ACE inhibitors?
eGFR & serum potassium
What class of drugs have the suffix -pine?
Calcium channel blockers
Dihydropyridine calcium antagonists
What class of drugs have the suffix -dipine?
Calcium channel blockers
Amlodipine is an example of what drug class used in the treatment of hypertension?
Calcium channel blockers
Felodipine is an example of what drug class used in the treatment of hypertension?
Calcium channel blockers
What is the suffix for calcium channel blockers?
-dipine
What is the primary mechanism of action of calcium channel blockers?
Block L-type calcium channels - predominantly on vascular smooth muscle
Results in a decrease in calcium influx, with downstream inhibition of myosin light chain kinase
Also prevents cross-bridge formation
Resultant vasodilation —-> reduces peripheral resistance
What is the drug target for calcium channel blockers?
L-type calcium channel
What are the main side effects of taking calcium channel blockers?
Ankle oedema
Constipation
Palpitations
Flushing/headaches
How is selectivity different for dihydropyridine type calcium channel blockers?
Dihydropyridine type calcium channel blockers demonstrate a higher degree of vascular selectivity
What class of drugs have the suffix -mide or -zide?
Diuretics
Bendro-flu-methiazide is an example of drug class used in the treatment of hypertension?
Thiazide
Indapamide is an example of drug class used in the treatment of hypertension?
Thiazide-like diuretics
What is the suffix for thiazide diuretics?
-thiazide
What is the primary mechanism of action of thiazide or thiazide-like diuretics?
Block Na+, Cl- co-transporter in the early DCT
Leads to inhibited Na+ and Cl- reabsorption
As a result, the osmolarity of the tubular fluid increases, decreasing the osmotic gradient for water reabsorption in the collecting duct
What is the drug target for thiazide or thiazide-like diuretics?
Sodium/chloride co-transporter
What are the main side effects of taking thiazide or thiazide-like diuretics?
Hypokalaemia
Hyponatraemia
Metabolic alkalosis
Hypercalcaemia
Hyperglycaemia
Hyperuricemia
What can cause metabolic alkalosis in someone on thiazide or a thiazide-like diuretic?
Increased hydrogen ion excretion
What can cause hyperglycaemia in someone on thiazide or a thiazide-like diuretic?
Hyperpolarised pancreatic beta cells
For how long do thiazide and thiazide-like diuretics maintain their diuretic effects?
They both lose their diuretic effects within 1-2 weeks of treatment
For how long do thiazide and thiazide-like diuretics maintain their diuretic effects? Explain why.
They both lose their diuretic effects within 1-2 weeks of treatment
This happens as the kidney becomes tolerant to diuretics because there is a rebound activation of the RAS which counteracts the diuretic effect due to increasing sodium reabsorption
Thiazide and thiazide-like diuretics have vasodilating properties.
Which type shows more pronounced vasodilating effects?
Thiazide-like diuretics
What is the site of drug target for thiazide or thiazide-like diuretics?
Early DCT
What class of drugs have the suffix -sartan?
Angiotensin receptor blockers (ARBs)
Losartan is an example of what drug class used in the treatment of hypertension?
Angiotensin receptor blockers (ARBs)
Irbesartan is an example of what drug class used in the treatment of hypertension?
Angiotensin receptor blockers (ARBs)
Candesartan is an example of what drug class used in the treatment of hypertension?
Angiotensin receptor blockers (ARBs)
What is the suffix for angiotensin receptor blockers?
-sartan
What is the primary mechanism of action of angiotensin receptor blockers?
Act as insurmountable (i.e. non-competitive) antagonists at AT1 receptor found on kidneys and on the vasculature
What is the drug target for angiotensin receptor blockers?
Angiotensin receptor
What is the site(s) of action for angiotensin receptor blockers?
Kidneys
On the vasculature
What are the main side effects of angiotensin receptor blockers?
Hypotension
Hyperkalaemia (care with K+ supplements or K+-sparing diuretics)
Foetal injury
Renal failure
Why should the use of ARBs be avoided in pregnant women?
Foetal injury is a side effect of ARB use
What side effect do patients on ARBs who have renal artery stenosis risk having?
Renal failure
How do ACE inhibitors and ARBs compare in terms of effectiveness in hypertension treatment?
Most trials indicate that ARBs are not as effective anti-hypertensive agents as ACE inhibitors
Losartan and candesartan are ARBs.
They are also pro-drugs.
What is the significance of this?
They require hepatic activation to generate the active metabolites required for therapeutic effects
What is Q-RISK?
Q-risk is an algorithm for predicting cardiovascular risk
What is Q-RISK?
Q-risk is an algorithm for predicting cardiovascular risk
- Estimates someone’s risk of developing CVD over next 10 years
- Can be applied to those between 35-74yo
https: //www.qrisk.org/three/index.php
Hypertension can be classified into four categories.
What are these categories?
- Normal
- Prehypertension (mild)
- Stage 1 (moderate)
- Stage 2 (severe)
What are the 2 most commonly prescribed calcium channel blockers?
Amlodipine & Felodipine
Some key pharmacokinetic properties of Felodipine & Amlodipine
Plasma clearance (ml/min/kg): F = 38 A = 11
Elimination half-life:
F = 25h
A = 35-50h
Time to peak plasma levels:
F = 3-5h
A = 6-12h
Based on the above information, suggest key differences in treating a patient with amlodipine vs felodipine?
- F has greater plasma clearance - body has greater ability to remove this drug from blood over given period of time vs A
- A has greater elimination half-life
- A has greater time to peak plasma levels - has slower absorption rate (usually less important in treatment of hypertension)
A might have a higher efficacy at the same dose compared to F as it stays in the blood longer due to its longer elimination half-life.
A might take longer to have its optimum effect and cause a response as it takes longer for it to reach its peak plasma levels in comparison with F and so has a slower absorption rate
Some key pharmacokinetic properties of Felodipine & Amlodipine
Plasma clearance (ml/min/kg): F = 38 A = 11
Elimination half-life:
F = 25h
A = 35-50h
Time to peak plasma levels:
F = 3-5h
A = 6-12h
What is meant by ‘clearance’?
Clearance is the measure of the ability of the body to eliminate a drug.
Clearance by means of various organs of elimination is additive.
Elimination of drug may occur as a result of processes that occur in the liver, kidney, and other organs
Some key pharmacokinetic properties of Felodipine & Amlodipine
Plasma clearance (ml/min/kg): F = 38 A = 11
Elimination half-life:
F = 25h
A = 35-50h
Time to peak plasma levels:
F = 3-5h
A = 6-12h
What is meant by ‘elimination half-life’?
Elimination half-life is length of time required for concentration of a particular drug to decreaseto1/2 of itsstarting dose in the body
Some key pharmacokinetic properties of Felodipine & Amlodipine
Plasma clearance (ml/min/kg): F = 38 A = 11
Elimination half-life:
F = 25h
A = 35-50h
Time to peak plasma levels:
F = 3-5h
A = 6-12h
What is meant by ‘time to peak plasma levels’?
Time to peak concentration is time required for a drug to reach peak concentration in plasma
The faster the absorption rate, the lower the time to peak plasma concentration is
How do amlodipine and felodipine compare in terms of:
a) onset?
b) half-life?
a) amlodipine has a slow onset
b) amlodipine has a much longer half-life
Why might ACE inhibitors have a negative effect on eGFR and serum potassium?
eGFR
- Angiotensin II causes efferent vasoconstriction —-> increased efferent pressure
- Modulates blood flow out of glomerulus —-> helps maintain GFR
- ACE-i prevent vasoconstriction of glomerular arterioles —–> prevent efferent vasoconstriction
- This above mechanism doesn’t occur in someone taking ACE-inhibitors ——> GFR
Serum Potassium
- ACEi inhibits aldosterone
- Inhibited aldosterone —-> less potassium excretion —-> increased serum potassium
ACE inhibitors are typically used ahead of angiotensin 2 receptor blockers (partly due to cost/partly due to evidence that ACE Is are more effective).
When might ARBs be preferred?
For patients of African or Caribbean descent
Indapamide is a thiazide-like diuretic.
State its:
- Target
- Location
- Effect
- Sodium/chloride co-transporters
- Distal tubule cell
- Na+ & Water loss
- Decreased blood volume
- Decreased venous return
- Decreased cardiac output
Indapamide (and other thiazide-like diuretics) are excreted unchanged in the urine.
Why is this a vital part of the therapeutic action of thiazide-like diuretics?
The diuretic needs to move from
- Blood
to
- Transporter on basolateral side
to
- Transporter on apical side
to then access the sodium chloride transporter on the apical side of the distal tubule where it can then have its effect
Why do thiazides increase potassium excretion?
Long-term administration of thiazide diuretics reduces total blood volume
This activates RAS
Stimulates aldosterone secretion
This activates Na+/Ka+-ATPase
Thus increasing potassium excretion in urine
