Drug Treatment of Ischaemic Heart Diesase Flashcards
Explain oxygen supply to the heart? How would you increase flow to the heart?
Coronary arteries supply blood to cardiac muscle
- O2 supply depends on coronary artery flow - To increase flow - dilate coronary arteries - decrease heart rate - arteries less compressed
What does oxygen demand depend upon?
O2 demand depends on cardiac workload
- cardiac output - HR x SV - preload - degree of stretch pre-contraction - afterload - resistance heart pumps against
Explain the condition Angina Pectoris
- Ischaemic Heart disease causes Angina
→ imbalance between O2 supply/O2 needs
→ insufficient O2 to meet cardiac demand
→ reduced perfusion rather than inadequate blood O2
What are some different types of angina?
- There are varying types:
- Stable angina (classic, effort)
- chest pain with exertion, stress
- associated with coronary artery disease
- Variant angina (vasospastic, Prinzmetal’s)
- coronary vasospasm at rest
- mediator unknown
- Unstable angina (crescendo, rest)
- angina at rest and with effort
- potential for thrombi formation
- Stable angina (classic, effort)
What are some of the aims of treatment of angina?
- treat to:
- prevent attacks
- relieve symptoms
- prevent progression to heart attack
What are angina drugs designed to do?
- increase O2 supply
- dilate coronary arteries
– under local metabolic control
– may be maximally dilated already
– difficult to dilate atheromatous arteries - reduce heart rate
– heart spends longer in relaxation phase
– coronary arteries have longer to fill
- dilate coronary arteries
- reduce O2 demand
- decrease cardiac output
– reduce heart rate
– reduce stroke volume - reduce preload
– dilate veins, reduce venous return - reduce afterload
– dilate arterioles, decrease resistance
- decrease cardiac output
Which angina drugs affect preload?
Nitrates
Which angina drugs affect afterload?
calcium channel blockers
Which angina drugs affect the myocardium?
- calcium channel blockers
- beta adrenoceptor blockers
- ivabradine
Explain the mechanism of nitrates.
drug undergoes biotransformation ↓ releases NO ↓ stimulates guanylate cyclase in vascular smooth muscle ↓ GTP converted to cGMP ↓ ↓ myosin LC-PO4 → myosin LC ↓ vascular relaxation
What is the site of action of nitrates?
relaxation of all vessels
- veins –> decrease preload (major)
- large arteries –> decrease afterload
- coronary arteries –> no increase in flow with fixed stenosis & no diversion of flow from ischemic area
What are some short acting nitrates?
Short acting
- glyceryl trinitrate (GTN)
- 1st pass metabolism
- inactive metabolite so not given orally
- sublingual for acute attack, anticipation of effort
- transdermal for prophylaxis
- i.v. for emergency
- care needed with storage – adsorbed by plastic, unstable
What are some longer acting nitrates?
Longer acting
- isosorbide dinitrate
- 1st pass metabolism
- isosorbide-5-mononitrate = active metabolite
- oral for anticipation of effort or prophylaxis
What are some adverse effects of nitrates?
- effects on other smooth muscle
– brief relaxation of gut, airways
– not clinically significant - postural hypotension - venous pooling
- headache, flushing - cerebral, head, neck arterial dilatation
- reflex tachycardia – usually used in combination with βblockers or cardiac-selective calcium channel blocker to minimise this
What are some drug interactions of nitrates?
- potential problems if cGMP increases too much, ie/ GTN can interact with Viagra
- -> Viagra is a phosphodiesterase inhibitor which stops the breakdown of cGMP. With GTN, there is a massive increase of cGMP which could massively increase vasodilation and lower BP massively. This would increase hypoxia to already infarcted heart.
Explain some mechanisms of tolerance to nitrates.
Reduced effectiveness with continuous use via :
- “classic” mechanism involves depletion of tissue thiols required for NO production from GTN
- treatment with N-acetyl cysteine restores GTN effect
- increased release of and/or sensitivity to constrictors e.g.AII
- increased endothelial free radical production scavenging NO, reducing NO bioavailability
- reduced/abnormal activity of muscle mitochondrial ALDH2, decreased NO production, increased free radicals
Drug-free period required to minimise tolerance
- remove patch over night
What are some examples of calcium channel blocking angina medications?
verapamil
diltiazem
nifedipine
What is the mechanism for calcium channel blockers?
- block Ca2+ entry into heart (SA, AV nodes, muscle) through L-type channels
- decreased heart rate, increased supply- decreased HR, SV, CO, reduced demand
- mostly verapamil and diltiazem
- block Ca2+ entry into vessels through voltage operated (L-type) & receptor operated channels
- arterial dilatation, reduced afterload and demand
- nifedipine, felodipine
What are some adverse effects of calcium channel blockers?
Adverse Effects: - used prophylactically - verapamil – flushing, headache, oedema – bradycardia, atrioventricular (AV) block - never taken with β-blocker - nifedipine – flushing, headache, oedema – hypotension – reflex tachycardia
Explain some mechanistic features of beta blocking angina medication.
- Block effects of sympathetic nervous system on cardiac β1-adrenoceptors
- first-line therapy for prophylaxis
– atenolol selective (cardiac beta1)
– propranolol non-selective (B1/ B2)
Explain the concept of combination therapy in angina treatment.
- nitrates, Ca2+ channel blockers and β-blockers are not disease-modifying
- i.e unchanged risk of MI, sudden cardiac death or all-cause mortality
- combination therapy often required
– prophylaxis to reduce frequency and severity, acute treatment to relieve symptoms
– maximise effects to increase supply, decrease demand
– minimise adverse effects (e.g. nitrates cause reflex tachycardia but atenolol or verapamil decrease HR)
What are the features of the novel therapy of ivabradine for angina treatment?
- “pure” heart rate reduction
- “specific” and selective inhibition of the inward sodium-potassium If current in the sinus node
- decreases the velocity of diastolic depolarization by reducing the ‘steepness’ of the If current slope
- reduces myocardial oxygen demand and maximizes oxygen supply
What are the indications, adverse effects and precautions associated with ivabradine?
Indications:
- Patients with IHD, LV dysfunction, HR > 70 bpm
- ivabradine decreased risk of MI, need for revascularisation
- no reduction if HR
What are the treatments for variant angina?
- relieve coronary spasm with short acting nitrate
- prophylaxis with dihydropyridine Ca2+ channel blocker
- adverse effects and contraindications as described
- β-adrenoceptor antagonists contraindicated
- vasopasm via β -adrenoceptor may be worse if β2-mediated coronary dilation blocked
What is the treatment for unstable angina?
- the same treatments as for classic angina
- include aspirin to prevent thrombosis
Explain some of the ongoing treatment needed for angina.
- Optimal medical therapy
- Risk factor reduction and prevention
- Stop smoking
- Increase physical activity, lose weight
- Treat hypertension, dyslipidaemia, diabetes
Revascularisation
- PCI – Percutaneous Coronary Intervention
- CABG - Coronary Artery Bypass Graft
