Angina pharmacology

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
 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.
 Nitrates
Mechanism
Release nitric oxide (NO)
NO dilates venules and coronary arteries
Increases venous capacitance
Decreases preload
Decreases contractility (Frank-Starling mechanism)
 Nitrates
Adverse effects
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. 10-12 hour nitrate free interval recommended each day.
Withdrawal. Reduce dose gradually.
 Nitrates
Drug Fast GTN Slow GTN Isosorbide Isosorbide Nicorandil
dinitrate mononitrate
Route Sublingual Transdermal Oral/sublingual Oral Oral
Example 500 mcg prn 10mg daily 10mg q.i.d 60mg daily 10mg b.i.d
Dose
Trade Nitrolingual, Minitran, Sorbidin, Isordil Imtrate, Duride, Ikorel
name Lycinate, Nitro-dur Imdur, Monodur
Anginine

Nicorandil
Also opens KATP channels in smooth muscle, dilating arterial as well as venous vessels.
Can cause ulcers, often in the mouth.
 Nitrates
GIT
Route Onset Duration
availability
Glyceryl trinitrate
sublingual (tablet, spray) <5 minutes <1 hour
poor patch 3060 minutes prolonged
IV infusion <10 minutes
Isosorbide dinitrate
oral tablet 1540 minutes 46 hours
2025%
sublingual tablet <10 minutes 12 hours
Isosorbide mononitrate
100% controlled release tablet 12 hours prolonged

Australian Medicines Handbook

 -blockers
Competitively antagonise beta adrenergic
receptors
Blunt sympathetic stimulation
Reduce contractility and rate
No reflex rise in peripheral resistance
-1 receptors mainly in heart muscle

-2 receptors mainly in lungs and peripheral vessels

-3 receptors mainly in heart and adipose tissue

 -blockers
Contraindications
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 Raynauds phenomenon: aggravated
Renal or hepatic impairment: Choose drug with appropriate elimination route
 -blockers for angina
Drug Receptors Elimination Daily Trade name
doses
Metoprolol beta1 hepatic 12 Betaloc, Lopressor,
Metohexal, Minax,
Metrol
Propanolol beta1, beta2 hepatic 23 Deralin, Inderal

Atenolol beta1 renal 1 Noten, Tensig, Tenormin

Oxyprenolol beta1, beta2, symp Hepatic 2-3 Corbiton

Pindalol beta1, beta2, symp Renal 2-3 Barbloc, Visken

Australian Medicines Handbook

 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
Decreases afterload, heart rate, and contractility
 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 blockers with Verapamil
Use blocker with dihydropyridines? (Murtagh)
CCB related oedema may not respond to diuretics
 L-type Calcium channel blockers
Drug Duration Example dose Trade name
Verapamil 80mg bid Anpec, Isoptin, Cordilox,
Veracps
Diltiazem 30mg tid Cardizem, Coras, Dilzem,
180mg daily LA Vasocardol, Diltahexal
Amlodipine Long 5mg daily Amlo, Nordip, Norvapine,
Norvasc
Felodipine Short 5mg daily (LA) Felodur, Felodil, Plendil
Nifedipine Short 20mg bid Adalat, Adefin, Nifexal
Lercandipine Long 10mg daily Zanidip

Australian Medicines Handbook

Nimodipine is a CCB indicated for subarachnoid hemorrhage management

 Refractory stable angina options
Perhexiline
Australian Medicines Handbook

Unclear. Calcium channel blocker?

Mechanism
Carnitine palmitoyltransferase 1 inhibitor?
Adverse Peripheral neuropathy
effects Hepatotoxicity
CYP2D6 saturable metabolism.
- Identify slow metabolizers
Precautions
- Monitor plasma levels
- Titrate dose when changing other drugs
Trade name Pexsig
 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 Johns Wort, Nicotine, Watercress
Pharmaceuticals
 Refractory stable angina options
Ivabradine
Australian Public Assessment Report for Ivabradine
Australian Medicines Handbook

Inhibits If (not so funny now)

Mechanism
Lowers heart rate

Prolongs QT interval
Side effects
Luminous phenomena (Retinal Ih current)
Trade name Coralan
PBS Not subsidised