Download Angina pharmacology - Ipswich-Year2-Med-PBL-Gp-2

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
dinitrate
Route
Sublingual
Transdermal Oral/sublingual
Isosorbide
mononitrate
Nicorandil
Oral
Oral
10mg b.i.d
Example 500 mcg prn 10mg daily
Dose
10mg q.i.d
60mg daily
Trade
name
Sorbidin, Isordil
Imtrate, Duride, Ikorel
Imdur, Monodur
Nitrolingual, Minitran,
Lycinate,
Nitro-dur
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
availability
Glyceryl trinitrate
sublingual (tablet, spray)
poor
patch
IV infusion
Isosorbide dinitrate
oral tablet
20–25%
sublingual tablet
Isosorbide mononitrate
100%
controlled release tablet
Australian Medicines Handbook
Onset
Duration
<5 minutes
30–60 minutes
<10 minutes
<1 hour
prolonged
15–40 minutes
<10 minutes
4–6 hours
1–2 hours
1–2 hours
prolonged
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
β-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 Raynaud’s phenomenon: aggravated
Renal or hepatic impairment: Choose drug with appropriate elimination route
β-blockers for angina
Drug
Receptors
Elimination
Daily
doses
Trade name
Metoprolol
beta1
hepatic
1–2
Betaloc, Lopressor,
Metohexal, Minax,
Metrol
Propanolol
beta1, beta2
hepatic
2–3
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 β blockers with Verapamil
Use β 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
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
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
Mechanism
Adverse
effects
Precautions
Trade name
Unclear. Calcium channel blocker?
Carnitine palmitoyltransferase 1 inhibitor?
Peripheral neuropathy
Hepatotoxicity
CYP2D6 saturable metabolism.
- Identify slow metabolizers
- Monitor plasma levels
- Titrate dose when changing other drugs
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 John’s Wort, Nicotine, Watercress
– Pharmaceuticals
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