VIVA: Pharmacology - Cardiovascular Flashcards
What is the mechanism of action of GTN?
- Taken up by vascular smooth muscle
- Denitrited by glutathione-S-transferase to release nitric oxide
- NO activates cGMP and reduces intracellular Ca2+, resulting in smooth muscle relaxation and vasodilation
Prostaglandins may be involved
What are the clinical effects of GTN?
Beneficial effects:
- Venodilation* -> reduced VR and decreased ventricular preload -> decreased LVEDV, LV wall tension -> reduced myocardial oxygen consumption*
- Vasodilation of epicardial coronary arteries -> increased coronary collateral flow
- Decreased systemic BP*
Adverse effects:
- Hypotension
- Tachycardia
- Headache
*2/3 to pass + 2 adverse effects
What are the indications for GTN use in the ED?
- Angina*
- Acute coronary syndrome
- Hypertensive urgencies/emergencies
- APO
- Aortic dissection (with B blockade)
*needed to pass + 2 others
What is adenosine and how does it work?
- Naturally-occurring nucleoside*
- Blocks AV conduction* by activating inward rectifier K+ current (i.e. hyperpolarises the AV node)
*needed to pass
Describe the pharmacokinetics of adenosine
- Short half-life (less than 30secs)*
- Uptake by endothelial and red cells
- Less effective in presence of adenosine receptor blockers (e.g. caffeine, theophylline)
*needed to pass
What are the side effects of adenosine?
4 to pass:
1. Cardiovascular:
- Chest tightness / burning
- Flushing
- Hypotension
- Arrhythmia
2. Neurological:
- Headache
- Paraesthesias
3. Respiratory:
- Bronchospasm
4. GIT:
- Nausea
What are the possible drug interactions with adenosine?
1/3 to pass:
- Theophylline inhibits (adenosine receptor blocker)
- Dipyridamole enhances (adenosine uptake blocker)
- Interactions with other AV nodal blocking drugs
What antiarrhythmic class does amiodarone belong to?
- Class III*
- Also has class I, II and IV effects
*needed to pass
What are the effects of amiodarone on the heart?
- Increases action potential duration due to blockade of rapid component of delayed K+ current (Ikr)*
- Chronic use also blocks slow K+ rectifier
- Prolongs QT* (due to above effects)
- Blocks inactivated Na+ channels
- Weak adrenergic and Ca2+ channel blocker
*needed to pass
What other arrhythmias is amiodarone used for?
2 to pass:
- AF
- VT
- VF
- Supraventricular (re-entrant/accessory)
What arrhythmias may amiodarone cause?
1 to pass:
- TdP (rare, <1%)
- Bradycardia
- Heart block
Describe the pharmacodynamics of digoxin
- Inhibitor of Na+/K+ ATPase*:
- Increases intracellular Na+, decreases intracellular K+
- Increased intracellular Na+ leads to reduced Na+/Ca2+ exchanger activity which leads to increased intracellular Ca2+
- Increased intracellular Ca2+ causes an increase in contractility (inotropy)
- Inhibition of Na+/K+ ATPase in vascular smooth muscle causes depolarisation, which causes smooth muscle contraction and vasoconstriction - Electrical effects*:
- Direct: shortening of action potential, leading to shortened atrial and ventricular refractoriness
- Increased automaticity of the heart muscle: leads to bigeminy, followed by VT and then VF - Parasympathetic and sympathetic effects:
- At lower doses, parasympathetic effects (early signs of toxicity = bradycardia, AV block)
- At higher doses, increased sympathetic effect which may further sensitise the myocardium to automaticity
*needed to pass
What are the non-cardiac symptoms and signs of digoxin toxicity?
- GIT:
- Anorexia
- Nausea and vomiting
- Diarrhoea - CNS*:
- Disorientation
- Hallucinations
- Yellow/green vision (or some variation of)
- Chemoreceptor trigger zones
*1 example to pass
What factors may predispose a patient to digoxin toxicity?
- Electrolyte imbalances*:
- Hypokalaemia (K+ normally inhibits digoxin binding to the Na+/K+ ATPase)
- Hypercalcaemia (potentiates digoxin toxicity by increasing the intracellular Ca2+ stores, producing automaticity)
- Hypomagnesaemia - Drugs that increase digoxin effect*:
- Amiodarone (by increasing plasma digoxin concentrate)
- Diltiazem
- Verapamil
- Quinidine
- Macrolide antibiotics (azithromycin, erythromycin, clarithromycin)
- K+ depleting drugs (including diuretics)
- Spironolactone - Organ disease:
- Renal failure (important because of kinetics)
- Hypothyroidism
*1 example of each to pass
What is digoxin’s mechanism of action in heart failure?
Ca2+ accumulation in cells * (due to Na+/K+ block*, increased intracellular Na+ reduces Na+/Ca2+ exchange):
- Increased contraction strength *
- Increased SV/CO per beat (with smaller EDSV, small heart, reduced right heart pressures/volume)
- Slower HR via effects on parasympathetic fibres/AV node, further increasing SV (particularly in AF)
*2/3 to pass
Why are patients in heart failure prone to digoxin toxicity?
- Poor renal function from low CO*
- Potential dehydration and/or other drug interactions* (e.g. ACEI, diuretics, spironolactone, Ca2+ channel blockers)
- Potential effects on effective Vd
- Low K+ from other heart failure medications, especially diuretics
- Poor cardiac reserve/output, altered digoxin handling during acute HF / fluid distribution changes / other major illnesses
*1/2 to pass + 1 other
What are the features of digoxin toxicity?
- Cardiovascular:
- Arrhythmias due to increased automaticity and AV block (particularly bradyarrhythmias, but also R-on-T)
- Severe heart block (particularly if pre-existing block)
- Worsening HF
- Hypotension - Metabolic:
- Hyperkalaemia* (associated strongly with mortality) - GIT:
- Anorexia
- Nausea and vomiting
- Diarrhoea - CNS*:
- Disorientation
- Hallucinations
- Yellow/green vision (or some variation of)
- Chemoreceptor trigger zones
- Lethargy, fatigue
- Headaches
- Paraesthesias
*1 example to pass
Describe the pharmacodynamics of propranolol that make it useful in thyrotoxicosis
Competitive non-selective B-blocker, blocking both B1 and B2 receptors*
Cardiovascular effects:
- Decreased BP
- Decreased HR (especially rate control of AF)
- Negative inotropy and chronotropy
- Decreased catecholamine effects which are prominent in hyperthyroidism
Inhibition of peripheral conversion of thyroxine to triiodothyronine (especially specific to propranolol over other B-blockers)
Also has Na+-channel blocking action (“membrane stabilisation”)
*needed to pass + 2 cardiovascular effects
What are the adverse effects of propranolol?
- CVS*:
- Bradycardia
- Hypotension
- Worsening CCF
- Worsening ischaemia in PVD
- QRS widening and arrhythmias in toxicity - CNS*:
- Sedation
- Depression
- Dreams
- Coma, seizure, delirium in toxicity - Respiratory*:
- Worsening asthma/COPD - Other:
- Decreased exercise tolerance
- Fatigue
- Impotence
- Decreased libido
- Masks symptoms of hypoglycaemia
*1 example from each
Describe the mechanism of action of verapamil
- Block voltage-gated L-type Ca2+ channels* (a1 subunit) to reduce frequency of opening when depolarised, resulting in decreased transmembrane Ca2+ current* and Ca2+ influx*
- Decreases AV node conduction and contractility*, thereby reducing CO
- Also causes vascular smooth muscle relaxation (moreso with dihydropyridines)
*needed to pass
What are the toxic effects of verapamil?
- Cardiovascular*:
- Bradycardia
- AV block
- Cardiac arrest
- Heart failure
- Hypotension - Minor*:
- Flushing
- Dizziness
- Nausea
- Constipation
- Peripheral oedema
*3 cardiovascular and 1 minor needed to pass
What antidotes can be used to treat verapamil toxicity?
1 to pass:
- IV calcium
- High-dose insulin euglycaemic therapy
What is the mechanism of enalapril?
Competitive inhibitor of angiotensin converting enzyme (ACE):
- Blocks conversion of angiotensin I to II*
- Decreases vascular tone* due to prevention of vasoconstrictive effects of angiotensin II (main effect)
- Inhibits aldosterone secretion* caused by angiotensin II leading to reduced Na+ and H2O resorption, and therefore decreased BP
- Increases bradykinin*, resulting in further vasodilation (angiotensin II normally metabolises bradykinin to its inactive form)
*2/4 to pass
What are the adverse effects of ACE inhibitors?
- Cardiovascular:
- Hypotension* (first dose, especially if hypovolaemic, diuretics, NaCl restriction, GI loss) and dizziness - Neurological:
- Headache
- Weakness
- Loss of taste - GIT:
- Nausea
- Diarrhoea - Renal:
- AKI
- Hyperkalaemia (due to decreased aldosterone secretion) - Other:
- Fever
- Rash
- Joint pain
- Angioedema
- Cough, wheeze - Reproductive:
- Teratogenic
*needed to pass + 2 others
What other drugs can interact with ACE inhibitors and how?
2 to pass:
- Diuretics: hypotension, fluid loss
- K+-sparing diuretics, K+ supplements: hyperkalaemia
- Other nephrotoxins: AKI
- Lithium: hyperkalaemia, reduced effect of ACEIs, lithium toxicity
- Anaesthetics (any): hypotension
- NSAIDs: hyperkalaemia, makes ACEIs ineffective
What advantages do angiotensin receptor blockers have over ACEIs?
- No effect on bradykinin, so reduced incidence of cough and angioedema
- More complete inhibition of actions of angiotensin II (as there are enzymes other than ACE capable of generating angiotensin II)
Describe the pharmacodynamics of irbesartan
- Competitive selective antagonist of angiotensin II type 1 (AT1) receptor*
- Results in vasodilation and inhibition of aldosterone secretion
*needed to pass + 1/2 effects
What are the specific contraindications of angiotensin II receptor blockers?
2/5 to pass:
- Non-diabetic renal failure
- Pregnancy
- Allergy / previous adverse reaction
- Hyperkalaemia
- Renal artery stenosis
What is the mechanism of action of prazosin?
- Selective alpha-1 receptor antagonist* in arterioles and venules
- Reduces arterial pressure by dilating both resistance and capacitance vessels
- a1-receptor selectivity allows noradrenaline to exert unopposed negative feedback (mediated by presynaptic alpha-2 receptors) on its own release
*needed to pass
List three non-BP effects of prazosin
- Cardiovascular:
- Postural hypotension, dizziness, syncope
- Reflex tachycardia, palpitations - Neurological:
- Headache
- Lethargy - Genitourinary:
- Reduces prostate smooth muscle tone (alleviating prostatic urinary obstruction) - Metabolic:
- Decreased LDL and triglycerides, increased HDL - Other:
- Positive serum antinuclear factor
What non-antihypertensive benefits do ACEIs have in diabetes mellitus?
- Diminishes proteinuria and stabilises renal function (even in the absence of lowering of blood pressure)
- Now recommended in diabetes even in the absence of HTN
How is ramipril eliminated? Why is this important?
- Eliminated primarily by the kidneys*
- Doses of these drugs should be reduced in patients with renal insufficiency
*needed to pass
What is the mechanism of action for beta blockers in general?
- Bind to beta receptors in the heart, lung and endocrine tissue
- Beta receptor activation by circulating catecholamines is antagonised by beta blockers*
- Selective bind beta 1 receptors, non-selective bind beta 1 and 2 receptors*
- Most are pure antagonists
*needed to pass
Describe the pharmacokinetics of metoprolol
- Absorption *:
- Rapid and complete
- Given orally (onset 1-2hrs) and IV (onset 20mins when infused over 10mins)
- Oral bioavailability 50% * due to significant first pass effect - Distribution *:
- Large (3.2-5.6L/kg, >200L)
- Crosses the BBB
- 10-12% protein binding to albumin * - Metabolism *:
- Extensive hepatic metabolism via CYP2D6
- Elimination half-life 3-4hrs * - Excretion *:
- Urine 95%
- 4/7 to pass
What are the side effects of beta blockers?
- Cardiovascular*:
- Hypotension
- Bradycardia
- Heart block
- Depressed myocardial contractility
- Heart failure
- Dizziness
- Peripheral vasoconstriction, Raynaud’s, claudication - Neurological:
- Fatigue
- Sedation
- Depression
- Nightmares
- Abrupt withdrawal effects
- Sexual dysfunction - Respiratory:
- Bronchospasm - Endocrine:
- Masks signs of hypoglycaemia (e.g. tachycardia, pupil dilatation) - Interactions:
- Exacerbates Ca2+ channel blocker effects
*cardiac + 2 others to pass
What are the cardiovascular effects of metoprolol?
- Negative inotropic and chronotropic effects*
- Slows AV node conduction with increased PR interval on ECG
- Decreases BP by a mechanism not fully understood but probably includes suppression of renin release and CNS effects
*needed to pass
How does metoprolol differ from propranolol in its receptor action?
- Metoprolol is B1 specific and propranolol is not* (equipotent at B1 and B2)
- B1 equipotent (full agonist)
- B2 50-100x less potent
- At higher doses is less specific
*needed to pass