What is examined for the cardiovascular system?

Includes all of the cardio drugs and their mechanisms of action

What is the mechanism of action of ACE inhibitors?

• Angiotensin-converting enzymes (ACE) convert angiotensin 1 to angiotensin 2

• Angiotensin 2 is a powerful vasoconstrictor and stimulates aldosterone (↑ sodium + water retention which ↑ BP)

• ACEi blocks ACE so ↓ vasoconstriction and ↓ BP

• ↓ Aldosterone means ↓ sodium + water retention which ↓ blood volume

What is the mechanism of action of angiotensin 2 receptor antagonists (A2RBs)?

• Angiotensin 2 binds to angiotensin 2 type 1 (AT1) receptors

• This causes vasoconstriction and ↑ BP and releases aldosterone which ↑ sodium + water retention

• A2RBs block the AT1 receptor to prevents angiotensin 2 binding and causing vasoconstriction and fluid retention

What is the mechanism of action of calcium channel blockers (dihydropyridine)?

• CCBs block L-type calcium channels in smooth muscle and heart muscle

• Ca2+ normally enters cells via channels for smooth and cardiac muscle contraction

• Blocking calcium entry = inhibits influx of Ca2+ = less contraction = relaxation

• Vasodilation decreases blood pressure

What is the mechanism of action of thiazide-like diuretics?

• Work in distal convoluted tubule of the kidney and inhibit the sodium-chloride (Na+/Cl-) symporter (responsible for reabsorbing Na+ and Cl- from filtrate)

• ↓ sodium reabsorption ↑ sodium and water excretion in urine

• ↓ blood volume so ↓ blood pressure

What is the mechanism of action of loop diuretics?

• Work in the thick ascending limb of the loop of henle in the nephron where they inhibit Na+/K+/2Cl- co-transporter which helps to absorb Na+, K+, Cl-

• Less reabsorbed into blood so ↑ ions in urine, water follows ions so increases volume of urine output

• Results in ↓ blood volume so ↓ blood pressure

What is the mechanism of action of potassium sparing diuretics?

• Work in the late distal convoluted tubule and collecting duct of nephron

• Essentially, ↓ Na+ reabsorbed in blood, ↓ K+ secreted into urine "spared"

• Water stays in urine with Na+ so has mild diuretic effect

• 2 types:

  • Aldosterone antagonists: block aldosterone receptors so ↓ Na+ reabsorption + ↓ K+ loss

  • ENaC inhibitors: directly block epithelial Na+ channels, ↓ Na reabsorption + ↓ K+ secretion

What are the 4 classes of antiarrhythmics based on the Vaughan-Williams classification?

Class 1: sodium channel blockers

• Have subclasses: Ia, Ib, Ic

Class 2: beta blockers

Class 3: potassium channel blockers

Class 4: calcium channel blockers

What is the mechanism of action of class 1: sodium channel blockers?

• Blocks fast Na+ channels in cardiac cells - slows phase 0

• Results in slower conduction through heart muscle and stabilises abnormal rhythms

  • Ia: moderate block, prolong AP (e.g. quinidine)

  • Ib: weak block, shorten AP (e.g. lidocaine)

  • Ic: strong block, little effect on AP (e.g. flecainide)

What is the mechanism of action of class 2: beta blockers?

• Block B-adrenergic receptors (mainly B1) to reduce sympathetic stimulation of the heart

• Overall, ↓ HR, ↓ conduction through AV node, ↓ myocardial oxygen demand

• e.g. Atenolol, metoprolol

What is the mechanism of action of class 3: potassium channel blockers?

• Block K+ channels - prolongs phase 3 (repolarisation)

• ↑ refractory period and prevents re-entry circuits and stabilise rhythm

• e.g. Amiodarone, sotalol

What is the mechanism of action of class 4: calcium channel blockers (non-dihydropyridine)?

• Block L-type Ca2+ channels - mainly affects nodal tissue (SA and AV nodes)

• Slows phase 0 so slower depolarisation, slow conduction through AV node, ↓ HR

• Non-dihydropyridine CCBs work on the heart e.g. Verapamil, diltiazem

What are 2 examples of antiplatelet agents?

Aspirin, Clopidogrel

What is the mechanism of action of aspirin?

• Inhibits cyclooxygenase (COX-1 and COX-2) - COX responsible for converting AA to thromboxane A2

• Thromboxane A2 ↑ platelet aggregation and ↑ vasoconstriction - irreversibly inhibiting this essentially ↓ platelet aggregation and ↑ vasodilation

What is the mechanism of action of clopidogrel?

• P2Y12 receptor activated by ADP and promotes platelet aggregation

• Clopidogrel inhibits P2Y12 receptor

• Inhibits platelet activation and aggregation

What are some examples of anticoagulants?

Vitamin K antagonists (warfarin)

Direct oral anticoagulants (DOACs)

• Direct thrombin inhibitors

• Direct factor 10a inhibitors

• Unfractionated heparin

• Low molecular weight heparin

What is the mechanism of action of warfarin?

• Inhibits action of Vit K epoxide reductase (VKER) - which is used to regenerate Vit K to synthesise active clotting factors (factors 2, 3, 4, 5, proteins C, S)

• ↓ production of clotting factors so ↑ clotting time

What is the mechanism of action of direct thrombin inhibitors and give a drug example?

• Directly inhibit thrombin (factor 2a) so ↓ conversion of fibrinogen to fibrin

• ↓ fibrin clot formation

Dabigatran

What is the mechanism of action of direct factor 10a inhibitors and give 2 drug examples?

Inhibit factor 10a so ↓ generation of thrombin (factor 2a)

Apixaban, Rivaroxaban

What is the mechanism of action of unfractionated heparin?

• ↑ activity of antithrombin 3

• This inactivates clotting factors - specifically 10a and 2a so ↓ clotting

What is the mechanism of action of low molecular weight heparin and give a drug example?

↑ activity of antithrombin 3 - more selectively inhibits factor 10a so ↓ clotting

Enoxaparin

What is the mechanism of action of B1-adrenoceptor antagonists (beta blockers) in more detail regarding HR, contractility and conduction speed?

• Bind to beta receptors to prevent the physiological effects of catecholamines (norepinephrine + epinephrine)

• HR: ↓ HR by reducing effects of catecholamines on SA node - slower depolarisation

• Contractility: Blocking the B1 receptors ↓ force of contraction (negative inotropic effect)

• Conduction speed: They can ↓ conduction speed through AV node to control arrhythmias

• ↓ HR and contractility, ↓ cardiac output and ↓ blood pressure

What is the mechanism of nitrates?

• Prodrugs that when absorbed and metabolised are converted to nitric oxide (NO) - active component

• NO activates guanylate cyclase which ↑ cGMP

• ↑ cGMP activates PKG which leads to relaxation of smooth muscle cells and vasodilation

What is the mechanism of action of statins?

• Competitive inhibitors of HMG-CoA reductase

• By inhibiting HMG-CoA, statins ↓ production of cholesterol (mainly LDL)

• Intracellular cholesterol ↓ so liver upregulates LDL receptors on surface to pull more LDLs out of blood and into the liver for breakdown