Cardiac Pharmacology
Heather Melrose, Jonas de Jong
Cardiovascular pharmacology focuses on drugs that modify the function of the heart and blood vessels. This article summarizes key therapeutic targets, mechanisms, and drugs used to manage cardiovascular diseases.
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\== Renin–Angiotensin–Aldosterone System == \[\[File\:Renin-angiotensin-aldosterone\_system.png|thumb|right|300px|Schematic overview of the RAAS]] The renin–angiotensin–aldosterone system (RAAS) is a hormone-based pathway that regulates fluid balance and blood pressure. It is activated by reduced blood pressure or renal perfusion, detected by baroreceptors or the juxtaglomerular apparatus. This triggers the release of renin from kidney cells, initiating a cascade that results in the production of angiotensin II and aldosterone, hormones that elevate blood pressure and promote water retention.
Angiotensin II acts at multiple sites to raise blood pressure:
- Adrenal glands: Increases aldosterone release, promoting sodium and water retention.
- Kidneys: Enhances sodium reabsorption and affects filtration rate.
- Cardiovascular system: Acts as a vasoconstrictor and promotes hypertrophy.
- Central nervous system: Stimulates ADH release and thirst mechanisms.
Chronic RAAS activation contributes to hypertension, cardiac hypertrophy, and kidney disease.
\== Neural Control of the Cardiovascular System == \[\[File\:Sympathic\_parasympathic.svg|thumb|upright=1.2|Neural control of the heart]] \=== Sympathetic (Adrenergic) Nervous System === The sympathetic nervous system uses catecholamines (e.g., adrenaline) acting on adrenergic receptors, which are G-protein coupled receptors, to regulate cardiovascular functions.
\==== Vasculature ==== Alpha-1 adrenergic receptors on vascular smooth muscle mediate vasoconstriction via the IP3/DAG pathway.
\==== Heart ==== Beta-1 receptors increase heart rate and contractility. Beta-3 receptors exert opposing effects, reducing contractility and serving as a control mechanism. Chronic sympathetic activation can lead to cardiovascular disease.
\=== Parasympathetic Nervous System === Acetylcholine activates muscarinic receptors, particularly M2, to reduce heart rate and conduction.
\==== Vasculature ==== Although blood vessels contain muscarinic receptors, they are not innervated. Exogenous ACh causes vasodilation.
\==== Heart ==== Vagal stimulation reduces heart rate and AV conduction via M2 receptors.
\== Platelet and Clotting System == \[\[File\:Platelet\_receptors.svg|thumb|300px|Mechanism of platelet activation]] Platelets are small, anuclear cells central to haemostasis. Upon activation, they adhere to damaged vessels and to each other, releasing signals that stabilize clots.
Conditions of excessive or deficient clotting require therapeutic intervention.
\=== Anti-coagulants ===
- Aspirin: Irreversibly inhibits COX, reducing thromboxane A2 and platelet aggregation.
- P2Y12 inhibitors: (e.g., Clopidogrel) block ADP receptors, preventing platelet activation.
- GPIIb/IIIa inhibitors: (e.g., Abciximab) inhibit platelet aggregation.
\== Cholesterol and LDL in Cardiovascular Health == \[\[File\:Lipid metabolism2.svg|thumb|upright=1.2|Lipid mechanisms and drug actions]] Cholesterol is essential for biological functions, but elevated LDL contributes to atherosclerosis. HDL is protective, removing cholesterol from the bloodstream.
\==== LDL and Atherosclerosis ==== Oxidized LDL induces foam cell formation and plaque development. Plaques can rupture, causing thrombotic events.
\==== Regulation of LDL ==== Cholesterol levels are controlled by synthesis (liver), absorption, and excretion. Genetic and lifestyle factors influence levels.
\==== Management ====
- Statins: Inhibit HMG-CoA reductase.
- Fibrates: Lower triglycerides, raise HDL.
- PCSK9 inhibitors: Increase LDL receptor recycling.
- Bempedoic acid: Inhibits cholesterol synthesis upstream of statins.
\== Pharmacokinetics ==
| | | | | | | | - | --------------------------------- | - | --------- | - | ------------------------------------------------------------------------- | | | Amount of drug administered | | mg | | Defined clinically | | | | | | | | | | Drug level in plasma | | µg/ml | | = D / Vd | | | | | | | | | | Half-maximal effect concentration | | µg/ml | | y = Bottom + (Top - Bottom)/(1 + \[x/EC50]Hill) | | | | | | | | | | Theoretical tissue distribution | | L | | D / C | | | | | | | | | | Drug removal rate | | h⁻¹ | | ln(2) / t1/2 | | | | | | | | | | Fraction of usable drug | | (no unit) | | (AUCpo × Div) / (AUCiv × Dpo) | | | | | | | | | | Peak/trough plasma levels | | µg/ml | | Measured directly | | | | | | | | | | Time to Cmax | | h | | Measured directly | | | | | | | | | | Time to half concentration | | h | | ln(2) / Ke | | | | | | | | | | Plasma volume cleared per hour | | L/h | | Vd × Ke | | | | | | | |
\== Common Drug–Drug Interactions == Drug combinations can produce antagonistic or synergistic effects. Interactions can affect absorption, metabolism, and efficacy. Key interactions for cardiovascular drugs:
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