CVS 2 - Ischaemic heart disease

Question 1

Chronic Arterial disease

Answer 1

Stable Angina

Question 2

Acute coronary syndromes

Answer 2

• Unstable Angina
Non ST elevated myocardial infarction (NSTEMI)
• ST-elevated myocardial infarction (STEMI)

Question 3

Ischaemic heart disease

Answer 3

Ischaemic heart disease – reduced blood flow to region of heart Angina = resulting symptoms

Question 4

Stable angina (Angina pectoris)

Answer 4

• 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

Question 5

Unstable angina

Answer 5

• plaque ruptures →platelet aggregation →thrombus →blood vessel blocked further →pain even at rest.
• If thrombus lysed – recover blood supply
• No cardiac tissue damage

Question 6

myocardial infarction

Answer 6

• 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

Question 7

What reflects heart damage

Answer 7

elevated ST levels

Question 8

Ischaemic heart disease Therapeutic goals: Stable Angina, NSTEMI, STEMI

Answer 8

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

Question 9

Stable angina : organic Nitrates

Answer 9

• 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

Question 10

how do nitrates work

Answer 10

nitrates work by primarily venus dilation and improving blood supply to heart

Question 11

Stable angina organic Nitrates: indications, pk, adr, caution, contraindication, interaction

Answer 11

• 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

Question 12

Pharmacodynamic interactions of drugs affecting b.p.

Answer 12

– 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”)

Question 13

Pharmacodynamic interaction between glycerol trinitrate and sildenafil

Answer 13

Both drugs produce vasodilation and hence potential significant ↓ b.p.

Question 14

Stable Angina: b adrenergic antagonists - Mechanism , drugs and indication

Answer 14

• 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

Question 15

b adrenergic antagonists: Hypoglycaemia

Answer 15

• 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

Question 16

Stable Angina: Ca2+ channel antagonists

Answer 16

Prophylactic treatment for frequent attacks

• Dihydro-pyridines (eg nifedipine, amlodipine, felodipine): vascular effects only
• Verapamil, diltiazem (cardiac effects and vascular effects) so dual mechanism

Question 17

dihydropyridines or verapamil and diltiazem

Answer 17

dihydropyridines are “vascular selective” whereas Verapamil and Diltiazem have cardiac and vascular activity

Question 18

Stable Angina: Ca2+ channel antagonists (2)

Mechanism

Answer 18

• 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

Question 19

Ca2+ channel antagonists: dihydropyridines - drugs, pk, adr, example, cautions, ci, i

Answer 19

• 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

Question 20

Short acting dihydropyridines have been linked to

Answer 20

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)

Question 21

Ca2+ channel antagonists: diltiazem - indications, pk, adr, example, cautions, ci, i

Answer 21

• 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

Question 22

Verapamil/diltiazem contraindication in heart failure

Answer 22

Heart failure –inadequate cardiac output. A non-selective Ca2+ channel blocker could reduce output and exacerbate the situation

Question 23

Verapamil/diltiazem contraindication in heart block

Answer 23

Heart block – signals through AV node are slowed. A non-selective Ca2+ channel blocker could make this worse

Question 24

Drug interaction between verapamil/diltiazem and β Antagonist

Answer 24

Pharmacodynamic interaction – risk of very significant fall in cardiac output/asystole - heart can stop

Question 25

Ca2+ channel antagonists: verapamil - indications, pk, adr, example, cautions, ci, i

Answer 25

• 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

Question 26

K+ channel openers - pk, adr, example, cautions, ci, i

Answer 26

``` • 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 ```

Question 27

Stable angina – avoiding MI

Answer 27

• 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

Question 28

Component in plaque

Answer 28

cholesterol

Question 29

Unstable Angina

Answer 29

``` • 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. ```

Question 30

Acute myocardial infarction

Answer 30

• 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

Question 31

What are the major therapeutic options for treating angina, and what is their mechanism of action?

Answer 31

* Blood flow: Nitrates | * Oxygen demand: β adrenoceptor antagonists, Ca2+ channel blockers

Question 32

Which Ca2+ channel blockers are vascular selective and which are not ? How does this affect their use?

Answer 32

• dihydropyridines are vascular selective | – non-selective blockers are used with caution/ contraindicated if they may further worsen cardiac function

Question 33

Stable Angina: b adrenergic antagonists - adr, caution, CI, I

Answer 33

• 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

Question 34

b adrenergic antagonists - selective

Answer 34

Atenolol, bisoprolol, metoprolol | » relatively β1 selective antagonists -“cardioselective” –useful in patients where important to avoid β2 antagonism

Question 35

b adrenergic antagonists - non selective

Answer 35

Propanolol | » β1 and β2 - “non-selective”

Question 36

b adrenergic antagonists - non selective and inhibit K+

Answer 36

Sotalol | » non β selective and also inhibits K+ channels (useful in arrhythmia)

Question 37

b adrenergic antagonists - partial agonists

Answer 37

Acebutolol, pindolol » partial agonists (eg) →mild ↑ heart rate at rest (useful - less bradycardia) » Still allows antagonism of b1- inhibit tachycardia during exercise (high NA)