CVS 2 - Ischaemic heart disease Flashcards
Chronic Arterial disease
Stable Angina
Acute coronary syndromes
• Unstable Angina
Non ST elevated myocardial infarction (NSTEMI)
• ST-elevated myocardial infarction (STEMI)
Ischaemic heart disease
Ischaemic heart disease – reduced blood flow to region of heart Angina = resulting symptoms
Stable angina (Angina pectoris)
• Partial vessel block
• Exertion → O2 demand exceeds O2 supply because of
reduced blood flow →chest pain, radiating to arm & jaw. Pain resolves on rest. Transient ischaemia – no heart cell death
Unstable angina
- plaque ruptures →platelet aggregation →thrombus →blood vessel blocked further →pain even at rest.
- If thrombus lysed – recover blood supply
- No cardiac tissue damage
myocardial infarction
• NSTEMI – coronary artery still not fully blocked so some
tissue perfusion remains, relatively small area of tissue death
• STEMI – complete occlusion leading to a large area of tissue death
What reflects heart damage
elevated ST levels
Ischaemic heart disease Therapeutic goals: Stable Angina, NSTEMI, STEMI
Stable Angina
• Improve coronary blood flow
• Reduce cardiac oxygen demand
Unstable Angina/NSTEMI
• Prevent further thrombus formation and progression to STEMI
• Symptomatic relief
STEMI
• Re-establish perfusion
• Symptomatic relief
Stable angina : organic Nitrates
• NO - 1987: “EDRF* is NO”
• Organic nitrates produce NO
– arterial dilation (↓ resistance, ↓ workload)
– Venous dilation (major therapeutic effect) →↓ venous
return, ↓preload) → ↑ blood supply to heart, which
mostly occurs during diastole
– treat symptoms not cause
how do nitrates work
nitrates work by primarily venus dilation and improving blood supply to heart
Stable angina organic Nitrates: indications, pk, adr, caution, contraindication, interaction
• Indications
– angina, left ventricular failure
• PK
– Glycerol trinitrate
» usually preferred treatment for acute angina – fast onset
» extensive first pass metabolism & t1/2 ~ 5 min. To avoid:
– Sublingual (often used for acute attacks)
– Buccal (slow absorption formulation)
– Transdermal (slow absorption formulation)
– i.v.
– Isosorbide mononitrate
» slower onset
» Low first pass metabolism » t1/2 ~ 5h
– Isosorbide dinitrate
» Extensive first pass metabolism to mononitrate (active)
• ADR
– related to vasodilation→hypotension » dizzines, headache, flushing
– Tolerance
» Avoid with “Nitrate low” period
» once daily admin (levels fall overnight) or remove patch
• Drug interactions
– Drugs causing hypotensive effect (numerous examples including diuretics, drugs
affecting cardiac output, other drugs causing vasodilation), see diagram
– PDE inhibitors see diagram
– nitrates can increase excretion of heparin. Not understood!
• Caution
– avoid during pregnancy (affects placental blood flow)
• Contraindications
– hypotension
– hypovolemia
– hypersensitivity to nitrates
Pharmacodynamic interactions of drugs affecting b.p.
– Hypotension B antagonists Nitrates Diuretics ACE inhibitors Ca2+ antagonists (CCB’s) α2 agonists α2 antagonists Ang II receptor blocker
Combined effects augment ↓ b.p. (often called “additive effects”)
Pharmacodynamic interaction between glycerol trinitrate and sildenafil
Both drugs produce vasodilation and hence potential significant ↓ b.p.
Stable Angina: b adrenergic antagonists - Mechanism , drugs and indication
• Mechanism
– ↓rate & force of heart contraction & b.p : “negative chronotropic & inotropic effects”.
– Reduces myocardial oxygen demand
– Some drugs also cause vasodilation-
» β2 partial agonists (some peripheral vasculature)
» α1 antagonist
Don’t get confused with β1 adrenoceptor in cardiac muscle which promotes contraction (also through cAMP)
• Drugs
– atenolol, bisoprolol, metoprolol:
» relatively β1 selective antagonists -“cardioselective” –useful in patients where important to avoid β2 antagonism see diagram
– propanolol
» β1 & β2 - “non-selective” – sotalol
» non β selective and also inhibits K+ channels (useful in arrhythmia) – acebutolol, pindolol see diagram
» partial agonists (eg) →mild ↑ heart rate at rest (useful - less bradycardia)
» Still allows antagonism of b1- inhibit tachycardia during exercise (high NA)
• Indications
– For prophylactic treatment of angina – reduces cardiac workload
– also for hypertension, myocardial infarction, arrhythmia, heart failure, anxiety
• Stable Angina: b adrenergic antagonists PK – substantial differences between different drugs
– variable Foral between different b antagonists.
– some drugs -significant first pass metabolism by Cyp P450,
» extent of first pass varies between individuals
– some drugs excreted unchanged in urine
– t1⁄2 varies 10 min-22 hr
b adrenergic antagonists: Hypoglycaemia
- Hypoglycaemia activates sympathetic nervous system to restore blood Glc via β2
- β1 antagonist masks tachycardia and inhibits homeostatic response induced by hypoglycaemia.
- Hence β1 antagonists used with caution in diabetes
Stable Angina: Ca2+ channel antagonists
Prophylactic treatment for frequent attacks
- Dihydro-pyridines (eg nifedipine, amlodipine, felodipine): vascular effects only
- Verapamil, diltiazem (cardiac effects and vascular effects) so dual mechanism
dihydropyridines or verapamil and diltiazem
dihydropyridines are “vascular selective” whereas Verapamil and Diltiazem have cardiac and vascular activity
Stable Angina: Ca2+ channel antagonists (2)
Mechanism
• Smooth muscle & cardiac muscle: Ca2+ channel antagonists
- Inhibition of vascular smooth muscle contraction – reduced afterload.
- Inhibition of cardiac myocyte contraction – reduced workload
• AV node (cardiac tissue): AV node action potential
-Inhibition of rate and conduction velocity – reduced workload
Ca2+ channel antagonists: dihydropyridines - drugs, pk, adr, example, cautions, ci, i
• Drugs
– Amlodipine – long t1/2 ~30-60hr
» Slow onset minimizes reflex tachycardia
– Felodipine long t1/2 ~12-25h
– Nifedipine t1/2 ~ 3 h & rapid onset.
» Modified release formulation available
• Indications
– hypertension, angina prophylaxis
• PK
– extensive first-pass metabolism (Cyp P450) (So minimal dose adjustment needed in renal disease) except amlodipine
• ADR
– ADR resulting from vasodilation are common – flushing, headache, oedema
– can cause reflex tachycardia & increased contractility
• Cautions
– amlodipine, felodipine may be preferred in patients with heart failure as they don’t reduce cardiac contractility (verapamil, diltiazem do)
– avoid in pregnancy
• Contraindications
– breast feeding
– unstable angina or 1 month after MI (vasodilation may worsen disease)
• Drug interactions
– augment the effect of other drugs that lower bp
– avoid grapefruit juice; several potential interactions with other cytochrome P450 dependant drugs
– increases plasma ciclosporin and digoxin concentrations – inhibit renal secretion by PgP
Short acting dihydropyridines have been linked to
Short acting dihydropyridines have been linked to increased risk of M.I. – larger reflex tachycardia can increases O2 demand! (so adding a β blocker may be useful)
Ca2+ channel antagonists: diltiazem - indications, pk, adr, example, cautions, ci, i
• Indications
– hypertension, angina prophylaxis
• PK
– 50% first pass metabolism (Cyp3A4 inhibitor/substrate) and; t1/2 ~ 5hr
– modified release formulations available
• ADR
– bradycardia - inhibits cardiac AV node conduction – teratogenic
• Cautions
– reduce dose in hepatic and renal failure
• Contraindications
– breast feeding, pregnancy
– patients with heart failure – negatively inotropic
– patients with AV block
• Drug interactions
– augment the effect of other drugs that lower bp or reduce heart rate
– if used with β antagonists can significantly reduce cardiac output
– reduces clearance of propanolol – avoid this combination
– increase plasma ciclosporin by inhibiting metabolism (Cyp3A4)
– increases plasma digoxin concentrations by inhibiting renal secretion by PgP
Verapamil/diltiazem contraindication in heart failure
Heart failure –inadequate cardiac output. A non-selective Ca2+ channel blocker could reduce output and exacerbate the situation
Verapamil/diltiazem contraindication in heart block
Heart block – signals through AV node are slowed. A non-selective Ca2+ channel blocker could make this worse
Drug interaction between verapamil/diltiazem and β Antagonist
Pharmacodynamic interaction – risk of very significant fall in cardiac output/asystole - heart can stop
Ca2+ channel antagonists: verapamil - indications, pk, adr, example, cautions, ci, i
• Indications
– supraventricular tachycardia (AV node block)
– not first choice but can be used for hypertension, angina prophylaxis
• PK
– high first pass metabolism (Cyp3A4)
• ADR
– bradycardia
– hypotension resulting from vasodilation
– Constipation – due to GI tract muscle relaxation
• Cautions
– reduce dose with hepatic impairment (Because of how its cleared!)
• Contraindications
– breast feeding, pregnancy
– patients with heart failure – negatively inotropic
– patients with AV block – affects heart conduction
• Drug interactions
– augment the effect of other drugs that lower bp or reduce heart rate
– do not use with β antagonists - can significantly reduce cardiac output (both negative inotropes)
– increase plasma ciclosporin and digoxin concentrations
– grapefruit juice
K+ channel openers - pk, adr, example, cautions, ci, i
• Nicorandil – Angina – As well as K+ channel opener, also acts as NO donor – Useful when nitrate tolerance a problem • PK – Short t1⁄2 ~ 1 hour, denitration • ADR – Headache, flushing – Reflex tachycardia • Cautions – Hypovolemia • Contraindications – Cardiogenic shock, hypotension, • Interactions – Sildenafil – potentiate hypotension because of slower turnover of cGMP
Stable angina – avoiding MI
• Lifestyle changes (smoking, weight, diet- cholesterol)
• Aspirin (inhibit platelet aggregation)- see later lecture
• Statins – to reduce plasma cholesterol
• Angioplasty & stents,
– Angioplasty
» balloon introduced to open blocked coronary artery » stent may be inserted to maintain patency
• clopidogrel
• abciximab
Component in plaque
cholesterol
Unstable Angina
• Symptoms of angina while at rest – emergency – hospitalisation – 10% risk of MI • Inhibit platelet aggregation – Aspirin/heparin – ADP receptor antagonist clopidogrel – GPIIb/IIIa antagonists tirofiban, eptifibatide – b antagonist, Ca2+ channel blocker • Nitrates for symptomatic relief • ACE inhibitors – ramipril, perindopril • Cholesterol reduction – diet – statins • Angioplasty or bypass surgery maybe needed.
Acute myocardial infarction
• Occlusion of artery leading to cardiac tissue death
• Aspirin
– to inhibit platelet aggregation
• Opioid analgesia
– morphine, diamorphine
– to relieve pain & distress (& benzodiazepine to further reduce stress)
• Anti-emetic
– MI often leads to vomiting and worsened by opioids
• Thrombolytics - reduce mortality – streptokinase or alteplase
• Anticoagulants
– heparin, warfarin
• β1 antagonists
– Early “cardioprotective use” – reduces infarct size by reducing oxygen demand
• ACE inhibitors – reduce bp
• Diuretics
– to reduce pulmonary oedema
– furosemide- venous vasodilation & diuresis
What are the major therapeutic options for treating angina, and what is their mechanism of action?
- Blood flow: Nitrates
* Oxygen demand: β adrenoceptor antagonists, Ca2+ channel blockers
Which Ca2+ channel blockers are vascular selective and which are not ? How does this affect their use?
• dihydropyridines are vascular selective
– non-selective blockers are used with caution/ contraindicated if they may further worsen cardiac function
Stable Angina: b adrenergic antagonists - adr, caution, CI, I
• ADR
– Bronchoconstriction (b2 antagonism).
» Less with cardioselective drugs but can still occur, esp. in asthmatics
(caution/contraindication)
» Can even develop with eye drops over several weeks
– Bradycardia & reduced cardiac contractility
» cold hands & feet, esp. patients with peripheral vascular disease.
» Fatigue, decreased exercise capacity
» Heart failure possible in patients with left ventricular dysfunction (caution/contraindication)
– Erectile dysfunction
– Sleep disturbance, dreams
» less with atenolol (poor CNS penetration)• Caution
– avoid in pregnancy unless essential – growth
retardation
– avoid suddenly stopping therapy
» rebound hypertension due to receptor upregulation during therapy
– can mask signs of hypoglycemia
– used with caution in diabetes
• Contraindications
– asthma
– heart block or uncontrolled heart failure
– bradycardia, hypotension
– sotalol with other drugs that prolong QT
• Drug interactions
– not with verapamil – risk of asystole
– Reduced renal/hepatic perfusion, esp in patients with kidney disease, can slow metabolism of some drugs
b adrenergic antagonists - selective
Atenolol, bisoprolol, metoprolol
» relatively β1 selective antagonists -“cardioselective” –useful in patients where important to avoid β2 antagonism
b adrenergic antagonists - non selective
Propanolol
» β1 and β2 - “non-selective”
b adrenergic antagonists - non selective and inhibit K+
Sotalol
» non β selective and also inhibits K+ channels (useful in arrhythmia)
b adrenergic antagonists - partial agonists
Acebutolol, pindolol
» partial agonists (eg) →mild ↑ heart rate at rest (useful - less bradycardia)
» Still allows antagonism of b1- inhibit tachycardia during exercise (high NA)
