Cardiovascular pharmacology

Question 1

Define ACS What conditions are included? What is the cause?

Answer 1

Acute coronary syndrome refers to a group of conditions characterised by reduced blood flow to the heart leading to ischaemia, severe chest pain and SOB. Includes NSTEMI, STEMI and unstable angina. Cause: occlusion of coronary artery by thrombus

Question 2

What are the principles of treatment of ACS?

Answer 2

1) increase oxygen supply to the myocardium - increase coronary blood flow - administer oxygen 2) Decrease oxygen demand of the myocardium - reduce HR and force of contraction -reduce preload -reduce afterload

Question 3

Define heart failure what is the general cause?

Answer 3

Heart failure defined by inability of the heart to pump blood and oxygen at a rate commensurate with the rate of metabolism in the tissues. General cause: abnormal structure and/ or function

Question 4

Define hypertension What can it lead to if left untreated?

Answer 4

increased blood pressure (force exerted on vascular walls). Untreated hypertension can lead to atherosclerosis which will reduce blood flow to the heart. It can also lead to heart failure by driving process of structural remodelling- hypertrophy.

Question 5

What is the treatment strategy for heart failure?

Answer 5

1) improve the contractility of the heart - Give sympathomimetic -Careful: HF can be accompanied by sympathetic NS activation which often needs to be modulated with B blocker. 2) reduce oedema - diuretics- Furosemide is common 3) reduce Preload and Afterload - ACE inhibitors -ARB’s (reduce production of ATii- vasoconstriction reduced, reduce aldosterone production and increase in effective circulating volume. )

Question 6

What are the principle targets for the treatment of heart failure? Give examples of drug classes that work at each site.

Answer 6

1) the heart itself: (acts on cardiac myocytes and VSMC’s in coronary arteries) - B blocker to modulate SNS activation -Ca2+ channel blocker -Sympathomimetic -Anticholinergic drugs 2) the kidney: (acts on renal tubular epithelium) - ACE inhibitors (prevent the increase in effective circulating volume) -ARB’s (prevent increase in ECFV) -Diuretics (reduce ECFV) -Aldosterone antagonist (prevent increase ECFV). 3) The vasculature (smooth muscle cells): -Ca2+ channel blockers -ACE i and ARB’s

Question 7

Give two other important drug target sites in the body for the treatment of ACS

Answer 7

1) the liver- regulate both its production and uptake of cholesterol (therefore atherosclerosis and ACS) 2) platelets - prevent thrombosis by regulating clotting

Question 8

Describe the blood vessel wall structure

Answer 8

1) tunica adventitia - outer later made up of connective tissue
2) Tunica media- thickest layer made up of circularly arranged elastic fibres, connective tissue and vascular smooth muscle
3) tunica intima- innermost layer, 1 cell thick made up of endothelium overlying basement membrane.

Question 9

What does an ace inhibitor do?

What does an angiotensin receptor blocker do?

What are their effects on vascular smooth muscle cell signal conduction?

how does this help hypertension and heart failure treatment?

State an important side effect of ACEi

Answer 9

ACEi’s block angiotensin converting enzyme in pulmonary capillaries from converting angiotensin i to angiotensin ii.

Angiontensin Receptor Blockers antagonise the angiotensin receptor on vascular smooth muscle cells.

Both drugs (by either inhibiting ATii production or binding) inhibit the production of IP3 and the release of Ca2+ from Sarcoplasmic reticulum. Inhibits formation of the Ca2+ calmodulin complex that activates myosin light chain kinase. Inhibits phosphorylation of mysoin light chain and therefore smooth muscle cell contraction.

Leads to smooth muscle relaxation and vasodilation. Has multiple effects:

1) reduced AFTERLOAD and BP
2) reduces aldosterone levels by inhibiting ATii promoting aldosterone release from adrenal cortex
3) inhibits increase in effective circulating volume (normally ATii increases Na+/H2O absorption via aldosterone) - Reduces cardiac PRELOAD.

ACEi side effect: persistent cough (interrupts metabolism of kinins).

Question 10

What is a calcium channel blocker and what is its effect on VSMC conduction?

How does this help treat 1) heart failure 2) hypertension 3) ACS

What are some unwanted effects/ side effects of CCB’s?

Answer 10

Prevents the opening of voltage gated L type Ca2+ channels on VSMC’s.

Prevents influx of Ca2+ into the VSMC, no Ca2+-Calmodulin complex/ activation MLCK/ Phosphorylation of MLC/ Contraction.

1) Promotes relaxation and vasodilation- decreases afterload in heart failure
2) Decreases blood pressure in hypertension.
3) Promotes vasodilation of coranary arteries (acts primarily on arteries not veins).

Unwanted effect in heart failure: Can have negative chronotropic and inotropic effects

Side effects: Palpitations and peripheral oedema (ankle swelling).

Question 11

Name two common calcium channel blockers

Answer 11

1) Nifedipine
2) Amlodipine

(dipine rhymes with time- Ca2+ needed for timing of heart contraction- Calcium channel blocker).

Say NA to Calcium:

Nifedipine

Amlodipine

Question 12

Name two nitrate vasodilator drugs

Answer 12

Glyceryl trinitrate (GTN)

Isosorbide mononitrtate (ISMN)

Question 13

How do nitrate vasodilator drugs act on the VSMC?

Answer 13

Nitrate vasodilators (Glyceryl trinitrate and isosorbide mononitrate) are metabolised by the body to release NO. NO dissolves in blood and is able to diffuse acroos the vascular wall and into the VSMC. Inside the VSMC NO activates guanylyl cyclase which produces cGMP from GTP. Increases in cGMP lead to activation of myosin light chain phosphatase (MLCP). MLCP leads to dephosphorylation of MLC and relaxation of VSM. Increases in cGMP also inhibit opening of Ca2+ channels and Ca2+ influx, and promote Ca2+ removal from the cell.

Question 14

What is the key side effect of nitrate vasodilator drugs?

Answer 14

Headache

Question 15

What are the effects of nitrate vasodilator drugs on the heart?

Answer 15

1) promotes venodilation- increased capacitance of venous system reduces cardiac preload
2) promotes moderate arteriolar dilation which reduces SVBP and reduces cardiac afterload.
3) Promotes vasodilation of coronary arteries - increasing blood supply and O2 supply to the myocardium.

Question 16

Explain how the sympathetic nervous system acts to induce contraction of the cardiac myoctye (Think signal transduction in actual cell).

Answer 16

Adrenaline binds to the Beta1 adrenoreceptor which is a GPCR. Activation of the B1 AR leads to activation of adenylyl cyclase which produces cAMP from ATP. Increase in cAMP activates protein kinase A which in turn leads to an increase in IC Ca2+ by opening voltage gated ca2+ channels and Ca2+ channels on the sarcoplasmic reticulum. Increase in Ca2+ leads to cell contraction.

Question 17

Describe the mechanism of action of beta blockers

Answer 17

B Blockers competitively inhibit noradrenaline and adrenaline binding to their receptors.

Action on the cardiomyocytes: inhibits adrenaline binding to the Beta 1 Adrenoreceptor. Leads to inhibition of downstream effects ( Activation of B1 leads to activation adenylyl cyclase, production of cAMP from ATP, activation of PKA and increase in Ca2+).

Has negative chronotropic ( decrease HR) and negative inotropic effect (decreased force of contraction).

Reduces the workload of the heart to relieve oxygen demand.

Question 18

Name 3 beta blockers

Two that are cardioselective (blocks only beta 1)

One that is not cardioselective (blocks both beta 1 and beta 2)

State two common side effects of beta blockers

Answer 18

1) Cardioselective- Bisoproplol and Atenolol
2) Non selective- Propanolol

Side effects:

Dizziness

Constipation

Question 19

What is a diuretic?

Name three classes of diuretic, which protein they act on, and name a drug from each class.

Why would a diuretic be useful in heart failure treatment?

Answer 19

A diuretic drug is a drug that acts on renal tubular epithelium and promotes the loss of Na+ and water in the urine thereby reducing plasma volume.

1) Loop diuretics- act on Na/k/2cl cotransported in the Loop of Henle. Example Furosemide and Bumetanide.
2) Thiazide diuretic acts on Na/ Cl cotransporter in the early distal tubule. Examples are: Hydrochlorothiazide and Bendroflumethiazide.
3) K+ sparing diuretics act to inhibit Na+ absorption in the principal cells of the collecting duct. Can act by direct antagonism of ENac (Amiloride) or Mineralocorticoid receptor antagonism (Spironolactone and Epleronone).

Reduction in plasma volume reduces the preload on the heart and reduces blood pressure which reduces the afterload.

Also acts to reduce oedema.

Question 20

What is neprilysin’s normal physiological role?

What would a neprilysin inhibitor then do?

Name a neprilysin inhibitor.

What condition is it indicated in and what other drug is it used in conjuction with?

Answer 20

Neprilysin is the enzyme that breaks down and inactivates Natriuretic peptides produced within the heart. The action of natriuretic peptides under normal conditions is to promote natriuresis and diuresis- reducing plasma volume.

A neprilysin inhibitor will block the breakdown of NP’s prolonging their diuretic effects. Reduction in plasma volume, blood pressure and preload on the heart. Example to learn is Sacubitril.

Indicated in the treatment of heart failure. Often used in conjuction with the ARB drug Losartan.

Question 21

State two treatments for Acute heart failure

Describe how each of these treatments acts?

Answer 21

1) IV Adrenaline
2) IV Atropine

IV Adrenaline acts as a powerful sympathomimetic and positive inotrope. . Increases the force of contraction by binding Beta 1 Adrenergic receptor on cardiac myocyte- leads to Ca2+ influx and contraction. Both increase in HR and force of contraction restore heart function.

IV Atropine acts by blocking the M2 muscarinic Ach receptor on cardiac myocytes, inhibiting parasympathetic vagal output to the heart. Increases heart rate by accelerating the rate of repolarisation of cardiac myocytes.

Question 22

State two pharmacologic methods of cardiovascular disease prevention

Answer 22

1) Antiplatelet drugs (prevent thrombosis formation)
2) HMG-CoA reductase inhibitors (reduce cholesterol levels and atherosclerosis progression).

Question 23

State two antiplatelet drugs and describe their action

Answer 23

1) Aspirin- is a COX enzyme inhibitor. Inhibits the catalysis of Arachidonic acid to thromboxane A2 in platelets via blockade of COX. Reduced levels of TXA2 inhibits the activation and aggregation of platelets. Under normal cirumstances TXA2 binds platelet receptors and initiates activation and aggregation.
2) Clopidogrel- is a P2Y12 receptor blocker, blocking the ADP receptor on platelet surfaces.Under normal circumstances activation of the ADP receptor leads to platelet activation. Activated platelet expresses the glycoportein 11b/111a receptors which normally bind vWF and fibrinogen, inhibit platelet aggregation and x-linking. Blocking this receptor inhibits platelet activation and therefore inhibits thrombus formation.

Question 24

Name two HMG-CoA reducatase inhibitors

Describe how inhibition of HMG-CoA reductase has cardioprotective effects.

Answer 24

1) Atorvastatin and Simvastatin
2) HMG-CoA reductase inhibitors inhibit the enzyme responsible for the rate limiting step in the cholesterol synthesis pathway in the liver (hepatocytes inhibited). Inhibits the catalysis of HMC-CoA into mevalonic acid. Inhibition of cholesterol synthesis reduces circulating LDL levels in the blood and promotes uptake of cholesterol from the circulation into the liver. Cardioprotective in reducing circulatin cholesterol levels to slow progression of atherosclerosis.