1. Angina pharmacology

2. Summary Drugs Stable angina management: reduce heart O2 demand
Nitrates (reduce venous return)
Beta blockers (reduce sympathetic drive)
Calcium channel blockers (reduce inotropic state)
Refractory stable angina options
Perhexiline, Ivabradine
Preventative agents
Thrombosis prophylaxis (Aspirin, clopidigrel, dipyrimadole, heparins)
Statins
ACE inhibitors
Diuretics

3. Triple Whammy
ACE Inhibitor, diuretic, and NSAID: a dangerous combination
(TGA.gov.au, Australian Adverse Drug Reactions Bulletin 2003)
NSAID + Diuretic + ACE inhibitor
Correlation with Renal failure
ADRAC wishes to remind prescribers that the combination of ACE inhibitors (or angiotensin receptor antagonists), diuretics and NSAIDs (including COX-2 inhibitors) should be avoided if possible, and great care should be taken with ACE inhibitors and NSAIDs in patients with renal impairment.

4. Nitrates Mechanism Release nitric oxide (NO)
NO dilates venules and coronary arteries
Increases venous capacitance
Decreases preload
Decreases contractility (Frank-Starling mechanism)

5. Nitrates Adverse effects Contraindications Precautions
Headaches, hypotension, flushing, palpitations, orthostatic hypotension, fainting, peripheral oedema, contact dermatitis
Contraindications
Hypovolemia or hypotension
Raised intracranial pressure
Significant anemia
G6PD deficiency (risk of hemolytic anemia)
Recent (1-5 days) use of PDE5 inhibitors (excacerbates hypotension)
hypertrophic obstructive cardiomyopathy
cardiac tamponade
Aortic stenosis, mitral stenosis, cor pulmonale.
Precautions
Tolerance hour nitrate free interval recommended each day.
Withdrawal. Reduce dose gradually.

6. Nitrates Drug Fast GTN Slow GTN Isosorbide dinitrate
Isosorbide mononitrate
Nicorandil
Route
Sublingual
Transdermal
Oral/sublingual
Oral
Example Dose
500 mcg prn
10mg daily
10mg q.i.d
60mg daily
10mg b.i.d
Trade name
Nitrolingual, Lycinate, Anginine
Minitran, Nitro-dur
Sorbidin, Isordil
Imtrate, Duride, Imdur, Monodur
Ikorel
Nicorandil
Also opens KATP channels in smooth muscle, dilating arterial as well as venous vessels.
Can cause ulcers, often in the mouth.

7. Nitrates GIT availability Route Onset Duration Glyceryl trinitrate
poor
sublingual (tablet, spray)
<5 minutes
<1 hour
patch
30–60 minutes
prolonged
IV infusion
<10 minutes
Isosorbide dinitrate
20–25%
oral tablet
15–40 minutes
4–6 hours
sublingual tablet
1–2 hours
Isosorbide mononitrate
100%
controlled release tablet
Australian Medicines Handbook

8. β-blockers Competitively antagonise beta adrenergic receptors
Blunt sympathetic stimulation
Reduce contractility and rate
No reflex rise in peripheral resistance
β-1 receptors
mainly in heart muscle
β-2 receptors
mainly in lungs and peripheral vessels
β-3 receptors
mainly in heart and adipose tissue

9. β-blockers Contraindications Adverse effects Precautions
Reversible airway disease
Cardiogenic and hypovolemic shock
Prinzmetal (vasospasm) angina
Bradycardia, 2nd and 3rd degree Heart block, Sick sinus
Adverse effects
nausea, diarrhoea, bronchospasm, dyspnoea, cold extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension, orthostatic hypotension (carvedilol, labetalol), heart failure, heart block, fatigue, dizziness, abnormal vision, decreased concentration, hallucinations, insomnia, nightmares, depression, alteration of glucose and lipid metabolism, oedema (carvedilol)
Precautions
Diabetes: hypoglycemia sign can be masked
Hyperthyroidism: signs masked
Anaphylaxis risk: Reduces epipen effect
Phaeochromocytoma: aggravates hypertension
Myasthenic symptoms: aggravated
Peripheral vascular disease or Raynaud’s phenomenon: aggravated
Renal or hepatic impairment: Choose drug with appropriate elimination route

10. β-blockers for angina Drug Receptors Elimination Daily doses
Trade name
Metoprolol
beta1
hepatic
1–2
Betaloc, Lopressor, Metohexal, Minax, Metrol
Propanolol
beta1, beta2
2–3
Deralin, Inderal
Atenolol
renal 1
Noten, Tensig, Tenormin
Oxyprenolol
beta1, beta2, symp
Hepatic
2-3
Corbiton
Pindalol
Renal
Barbloc, Visken
Australian Medicines Handbook

11. L-type Calcium channel blockers
Dihydropyridines
Strong vasodilation (arterial)
Decreases afterload
Phenylalkylamine
Verapamil
(less) Vasodilation and (more) cardiac depression
Decreases afterload, heart rate, and contractility
Benzothiazepine
Diltiazem
(more) Vasodilation and (less) cardiac depression

12. L-type Calcium channel blockers
Contraindications
Cardiogenic shock, Heart failure, Aortic stenosis
Adverse effects
Transient worsening of angina symptoms
Reflex tachycardia (short acting dihydropyridines)
Bradycardia (Diltiazem, Verapamil)
Headache, flushing, peripheral oedema (especially dihydropyridines)
Gingival hyperplasia
Constipation (Verapamil)
Rash, fatigue, dizziness, nausea, abdominal pain
Precautions
Myasthenia-like disease – exacerbated symptoms
Avoid β blockers with Verapamil
Use β blocker with dihydropyridines? (Murtagh)
CCB related oedema may not respond to diuretics

13. L-type Calcium channel blockers
Drug
Duration
Example dose
Trade name
Verapamil
80mg bid
Anpec, Isoptin, Cordilox, Veracps
Diltiazem
30mg tid
180mg daily LA
Cardizem, Coras, Dilzem, Vasocardol, Diltahexal
Amlodipine
Long
5mg daily
Amlo, Nordip, Norvapine, Norvasc
Felodipine
Short
5mg daily (LA)
Felodur, Felodil, Plendil
Nifedipine
20mg bid
Adalat, Adefin, Nifexal
Lercandipine
10mg daily
Zanidip
Australian Medicines Handbook
Nimodipine is a CCB indicated for subarachnoid hemorrhage management

14. Refractory stable angina options Perhexiline Australian Medicines Handbook
Mechanism
Unclear. Calcium channel blocker?
Carnitine palmitoyltransferase 1 inhibitor?
Adverse effects
Peripheral neuropathy
Hepatotoxicity
Precautions
CYP2D6 saturable metabolism.
Identify slow metabolizers
Monitor plasma levels
Titrate dose when changing other drugs
Trade name
Pexsig

15. Saturable hepatic metabolism
Australian Medicines Handbook – Drugs and CYP enzymes
Cytochrome P450 enzyme family
CYP1A2
CYP2B6
CYP2C8
CYP2C9
CYP2C19
CYP2D6
CYP3A4/5
Interactions
Grapefruit, Starfruit , St John’s Wort, Nicotine, Watercress
Pharmaceuticals

16. Refractory stable angina options Ivabradine Australian Public Assessment Report for Ivabradine Australian Medicines Handbook
Mechanism
Inhibits If (not so funny now)
Lowers heart rate
Side effects
Prolongs QT interval
“Luminous phenomena” (Retinal Ih current)
Trade name
Coralan
PBS
Not subsidised