Overview of Cardiovascular Pharmacology Flashcards
Major classes of cardiovascular drugs
- Diuretics
- Angiotensin converting enzyme inhibitors (ACE-I) & angiotensin receptor blockers (ARB)
- Beta blockers
- Calcium channel blockers (CCB)
- Sodium glucose co-transporter 2 inhibitors
- Antiplatelet and anticoagulation drugs
- Digoxin
- Nitrates
- Beta Adrenergic Agonists
- Alpha Receptor Blockers
- Antiarrhythmic drugs
- Vasopressors
- Others
What are the use and site of action of diuretics?
- Uses: Hypertension, Heart failure
- Site of activity determines efficacy
Proximal Convoluted Tubule
Loop of Henle
Distal Convoluted Tubule
Last (Distal) segment of DCT
Classes of diuretics
- Acetazolamide
- Osmotic agents (mannitol)
- Loop agents (eg furosemide)
- Thiazides
- Aldosterone antagonists
- ADH antagonists
How do loop diuretics work?
How do thiazides work?
What is their use and side effects?
Give examples
Thiazide diuretics act by inhibiting Na+/Cl- symporter symport at the distal convoluted tubule.
They are also ATP dependent potassium channel opener.
Use: Used for mild to moderate hypertension, edema of hepatic, renal and cardiac origin, Nephrolithiasis (calcium stones), Nephrogenic diabetes insipidus.
Major side effects: loss of K+ and Mg++,hypercalcemia, Alkalosis, hyponatremia, hypochloremia, hyperuricemia, hyperglycaemia, hyperlipidemia, Hypotension, dehydration epigastric distress, nausea, vomiting, fatigue, dizziness, impotence, jaundice, skin rash, and visual disturbance.
Examples: Hydrochlorothiazide, Benzthiazide, Cyclothiazide
Which diuretics work at the
i PCT
ii Loop of henle
iii DCT
Proximal convoluted tubules – Carbonic anhydrase Inhibitors act at this site with weak diuretic property. It has predominant effect on NaHCO3.
Loop Of Henle: Loop diuretics act at this site. Examples are furosemide, torsemide, bumetanide (highest bioavailability) and ethacrynic acid (safe in patient with sulfa allergy)
DCT: Thiazide diuretics. Has moderate diuresis but usually effective (BP) due to longer duration of action vs loop diuretic (in patients with normal renal function). It has complimentary action when used with loop diuretics
Distal segment of DCT: Increased Na delivery to distal segment of DCT stimulates the aldosterone sensitive pump and renin-angiotensin-aldosterone system leading to increased K and hydrogen ion excretion (possible metabolic alkalosis)
Spironolactone /Eplerenone are aldosterone antagonists (leading to K sparing). They also reduce renal and cardiac fibrosis (remodeling) making them to be useful in heart failure
Loop diuretics (high ceiling diuretics)
Used for hypertension, moderate to severe fluid retention of cardiac, hepatic and renal origin
Most potent diuretics available
Act by inhibiting the Na+/K+/2Cl- symporter in the ascending limb in the loop of Henle. They are also mild vasodilators by prostaglandin synthesis.
Major side effects: loss of K+ (and Ca++ and Mg++), Alkalosis, hyperuricemia, nausea, anorexia, vomiting epigastric distress, fatigue, muscle cramps, drowsiness. Others include dizziness, hearing impairment (ototoxicity) and deafness and are usually reversible.
Examples of Loop diuretics and their recommended doses
Examples are Furosemide, Bumetanide, Torsemide and Ethacrynic acid.
Furosemide 40 mg = bumetanide 1mg = torsemide 20 mg = ethacrynic acid 50 mg
Furosemide most commonly used
Bumetanide and torsemide have increased oral bioavailability
Patient may be diuretic resistance due to
- Due to increased dietary sodium intake,
- Administration of NSAIDS
- Gut wall edema
- Significant impairment of renal function or perfusion
Adverse effects, Uses and contraindications and examples of ACE inhibitors
Adverse effects: maculopapular rash, diminished taste sensation, cough (due to increase presence of bradykinin cause by inhibition of ACE which normally breaks down bradykinins), hyperkalemia, angioedema and granulocytopenia.
No significant adverse effects on plasma lipids, glucose, sexual function
Uses: Hypertension, congestive heart failure, Chronic kidney disease (use with caution in stage 4 and 5 CKD), diabetes-related early stage proteinuria
Not as effective in African-Americans
Contraindicated in pregnancy (teratogenic)
Examples captopril, enalapril, lisinopril rampiril
Potassium-sparing diuretics
They are mild diuretics
It is used with conjunction with thiazides or loop diuretics in edema due to, cardiac failure nephrotic syndrome and hepatic disease.
Act on the distal portion of the distal tube (where Na+ is exchanged for K+)
Aldosterone promotes reabsorption of Na+ in exchange for K+
Examples are Spironolactone (Aldosterone receptor antagonist) Amiloride and Trimterene (blocks epithelial sodium channels).
Adverse effects: G.I. disturbances, dry mouth, rashes confusion, orthostatic hypotension, hyperkalaemia, Hyponatraemia.
Angiotensin Converting Enzyme Inhibitors/ Angiotensin Receptor Blockers
Renin acts on angiotensinogen angiotensin1 angiotensin II (via ACE) which attaches to AT receptors.
Major systemic effects of angiotensin II:
Vasoconstriction – binding to AT1 and AT2 (not well defined)
NaCl and H2O reabsorption – direct effect on renal tubule
Increased secretion of aldosterone Na and H2O retention
Interstitial fibrosis via increased collagen deposition in the extracellular matrix of heart tissue
ACE-I
It inhibits ACE = less production of angiotensin II
Additional mechanisms ACE is a kininase –inhibiting ACE leading to increased Bradykinin (causes vasodilation and probably cough)
Reduced sympathetic activity
Increased prostaglandin synthesis –vasodilation and possible angioedema
Angiotensin Receptor Blockers
Blocks angiotensin II receptors
Angiotensin II, kinins and prostaglandins not affected so….
No cough, very limited angioedema
Same clinical effects as ACE-I
ACE-I and ARB
Class effect: Reduced pre-load, afterload, sympathetic activity, cardiac remodeling , hyperkalemia
They have more similarities than differences Start low due to hypotension and renal effect (initial eGFR decline)
Target doses if reachable
Caution: BILATERAL renal artery stenosis
Angiotensin receptor Neprilysin Inhibitor (ARNI)
Angiotensin receptor Neprilysin Inhibitor (Sacubitril / valsartan):
It’s a new therapeutic class of agents that antagonizes RAAS and inhibits the neutral endopeptidase(NEP) system, thereby Increasing the levels of natriuretic peptides, bradykinin and andremedullin.
The combination of an angiotensin receptor neprilysin inhibitor (ARNI) provides additional benefits including:
Slows the degradation of natriuretic peptides, bradykinin, and adrenomedullin, thereby enhancing diuresis, natriuresis, myocardial relaxation, vasodilation and counteract cardiac remodeling (neurohormonal)
Inhibition of the RAAS system and the sympathetic nervous system, as well as antifibrotic, antiproliferative and antithrombotic effects.
Clinical benefit ARNI
The use of a combined AT1 receptor antagonist and a neprilysin inhibitor (valsartan/sacubitril, LCZ696) was shown to have the following favorable impact on HF outcome in the PARADIGM-HF trial
Improved quality of life
Improved exercise capacity
Reduced HF hospitalization
Reduced mortality
Adverse effects of ARNI
Hypotension
Hyperkalemia
Cough
Angioedema
Others include pruritus, diarrhea,nasopharyngitis etc
NB: it is contraindicated in pregnancy
Aliskiren
It is a renin inhibitors
Block the RAAS system
It does not interfere with bradykinin degradation
Not readily use in clinical practice
BETA BLOCKERS (Beta-adrenergic Antagonists)
BETA 1 Receptors: Primary location – heart
Increased HR, Contractility, AV Conduction and reduced AV node refractoriness
BETA 2 Receptors: Primary locations – bronchial and vascular smooth muscle, heart
Examples of β1 -Selective (in low dose)
Metoprolol
*Acebutolol
Atenolol (hydrophylic)
Betaxolol
Bisoprolol
(Diabetes and Asthma)
Beta-adrenergic blocking agents
Classification
Nonselective (1st generation)
Cardioselective (b-1 selective, 2nd generation)
b-blockers with intrinsic sympathomimetic activity (ISA)
With additional CV actions (3rd generation)
Proposed mechanisms:
Block cardiac 1 receptors lower CO
Block renal 1 receptors lower renin, lower PVR
Decrease SNS output
Examples of Non-Selective β blockers
Propranolol
Timolol (hydrophylic)
*Pindolol
*Penbutolol
*Cartelol
*Labetalol (α & β)
Carvedilol (α & β)
*Carteolol
Intrinsic ISA
Pindolol
Acebutolol
Penbutolol
Cartelol
Labetalol (α & β)
(Reynaud’s)
What is filtered at the PCT?
From Glomerular filtrate:
Almost all amino acids, glucose and carbonate, some Na, K and water is also reabsorbed