Heart & Diabetes Pharmacology I: Drugs and the Heart I Flashcards
What are the FOUR major components of Cardiomyocyte cells?
- Sarcolema
- T-tubules
- Sarcoplasmic Reticulum
- Myofibrils
What is the mechanism of action of Cardiomyocyte Contraction?
- Membrane depolarisation - Ca2+ entry through channels
- Ca2+ release from SR
- Actin-Myosin contraction
What are the FOUR key elements of healthy vascular function?
- Vascular Tone (vT)
- Integrity of the vascular barrier (vB)
- Vascular Content (vC)
- Blood Flow (BF)
What is Ischaemic Heart Disease (IHD)?
Inadequate supply of oxygenated blood to heart tissue
What are some of the characteristics of IHD?
- Narrowing of coronary arteries supplying blood to heart
- Decreased vessel tone (vT)
- Decreased integrity (vB)
- Decreased blood flow (BF)
- Atherosclerosis
What is Angina?
Restricted flow of oxygenated blood to cardiac muscle
What is a major symptom of Angina?
Chest pain radiating to neck, jaw, back, and arms
What causes Stable Angina Pectoris?
- Brought on by exertion: physical, cold, excitement, stress
- Goes away with rest
What causes Unstable Angina?
- Transient formation / dissolution of blood clot in artery
- Severe pain with little exertion, no warning
What causes Variant (Prinzmetal) Angina?
- Caused by coronary artery spasm
- Uncommon episodic angina
What is Heart Failure (HF)?
Impaired or damaged myocardium
What causes Heart Failure?
CAD -> Myocardial hypoxia -> Tissue damage
What are the effects of HF?
- Inadequate pumping of blood to meet metabolic demand
- Reduced cardiac output
- Fluid build up
What are the symptoms of HF?
- Oedema
- Tiredness
- Shortness of breath
- Cough
- Swelling of abdomen
What are the compensatory mechanisms of HF?
- INCREASED sympathetic activity
- INCREASED RAAS
- Cardiac remodelling (hypertrophy)
(Compensation leads to progressive heart disease)
What type of drugs are most used for the treatment of both angina and HF?
- RAAS inhibitors
- β blockers
- Organic nitrates
Why is Nitric Oxide (NO) used to treat Ischaemia?
Potent vasodilator
TRUE OR FALSE:
Nitric Oxide acts on both veins and arteries equally?
False.
Acts on veins, less so on arteries
What is the mechanism of action for Organic Nitrites?
- Organic nitrates biotransformed into NO
- NO activates guanyl cyclase
- Increase in cGMP
- Protein kinase activation
- Light chain myosin dephosphorylated
- Relaxation of Actin-Myosin
- Smooth muscle relaxation
- Vasodilation
What is PRELOAD?
Venous return of blood volume
* causes filling pressure on heart (muscle stretching)
What is AFTERLOAD?
Vascular resistance the ventricles must overcome to push blood into arteries
What is the vasodilatory effect of Organic Nitrates on Veins?
- Dilation of veins
- Reduces venous blood pressure and workload on the heart (PRELOAD)
What is the vasodilatory effect of Organic Nitrates on Arteries?
- Dilation of larger arteries
- Reduced aortic pressure (AFTERLOAD)
- Increases flow of oxygenated blood to heart
How does decreased Preload and Afterload help the heart?
Decreased preload & afterload reduces workload on the heart and myocardial O2 demand
Why is Glyceryl Trinitrate NOT given orally?
- Extensive first-pass hepatic metabolism
- Short plasma half-life (minutes)
Why is Glyceryl Trinitrate given sublingually?
- Rapidly absorbed into systemic circulation
- Rapidly metabolised (EXTRAHEPATIC HYDROLYSIS)
- Rapidly cleared
- Renal secretion - GTN metabolites
Which type of Voltage Gated Ca2+ Channel is important in cardiac & VSMC?
L-type
Which subunit is pore-forming on L-VGCCs?
α1 subunit
Which L-type Calcium Channel Blocker (CCB) drugs is selective to blood vessels?
Dihydropyridines
How do Dihydropyridines work?
- Vasodilatory
- Decrease arterial VSMC contraction
What is the mechanism of action of RAAS Inhibitors?
- ACE inhibitors REDUCE Angiotensin II
- ARBs inhibitors BLOCK AT 1-R binding to Angiotensin II
- Aldosterone antagonists BLOCK ALD-R binding to Aldosterone
What is the effect of reducing Angiotensin II?
Decreased VSMC constriction in arterioles (vasodilatory)
* SVR & BP reduced
What are the effects of reducing Angiotensin II AND Aldosterone?
- Decrease renal Na+ and water reabsorption - reduced blood volume & BP
- Decrease cardiac remodelling (hypertrophy)
- Decrease RAAS-induced sympathetic activity - reduced HR, contractility, renin
What are TWO examples of ACE Inhibitors?
- Ramipril
- Captopril
What are TWO examples of ARBs Inhibitors?
- Valsartan
- Losartan
What is an example of an Aldosterone Antagonist?
Spironolactone
What is the rationale for use of RAAS Inhibitors to treat Heart Failure and Angina?
What subtype of adrenoceptors are found in heart tissue?
Mainly β1
* increase HR and cardiomyocyte contraction
What subtype of adrenoceptors are found in vascular smooth muscle cell (VSMC) tissue?
β2
* stimulate VSMC relaxation
Which type of adrenoceptor blocking drugs are used to treat Angina?
- 1st generation: Non-selective β blockers
- Act at both β1 and β2 adrenoceptors
Which type of adrenoceptor blocking drugs are used to treat Heart Failure?
- 2nd generation: Cardio Selective β1 blockers
- Greater selectivity for β1 over β2 adrenoceptors
What is an example of a 1st Generation: Non-Selective β blocker drug?
Propanolol
What are TWO examples of 2nd Generation: Cardio Selective β1 blocker drugs?
- Metoprolol
- Bisoprolol
Which neurotransmitter do 2nd Generation: Cardio Selective β1 blocker drugs block the binding of?
NA
What is the mechanism of action of Non-Selective β blocker drugs?
- DECREASES negative regulation
- Active MLCK
- INCREASE in VSMC contraction
- Vasoconstriction
- Increase of hypertension (BP)
What is the rationale for the use of Selective β blocker drugs to treat Heart Failure and Angina?
What are TWO Positive Inotrope drugs used in the treatment of chronic heart failure?
- Cardiac glycoside
- β-agonist
What Cardiac glycoside drug is used in the treatment of chronic heart failure, and what does it do?
Digoxin
* Increases cellular Ca2+ concentration
* Increases contractility
What β-agonist drug is used in the treatment of chronic heart failure, and what does it do?
Dobutamine
* Increase sympathetic activity on heart
* Increase heart rate
* Increase myocardial contractility
What is the mechanism of action of Digoxin?
- Inhibition of Na+/K+ ATPase
- Increase levels of cellular Na+
- Slows inward Na+ in exchange for outward Ca2+ (Increasing cellular Ca2+)
- Increases actin-myosin contraction
