1. Anti-Ischaemic Medications
β Blockers and Nitrates
by: Mimoza Meholli
9/17/2003

2. Case 1
A 62 yr old male with a history of chronic Stable Angina since 1998 complains of chest pain radiating to the neck, left arm and back, occurring at rest.
Patient has DM-2, HTN, Duodenal ulcer and Hypothyroidism.
EKG shows evidence of previous inferior wall MI.

3. Pharmacological Intervention in Ischaemic Heart Disease
AIMS:
Increase coronary blood flow.
Reduce myocardial energy requirements.
To stop or reverse coronary artery occlusion in order to avoid or minimize myocardial cell death.

4. β -Blockers
Competitively antagonize the action of catecholamines at β -adrenergic receptors.
Decrease heart rate, stroke volume, and cardiac output.
Normal sympathetic control of bp is maintained in HTN due to unopposed vasoconstriction by ά-receptors, thus avoiding orthostatic hypotension.
Carvediolol sensitizes down regulated β-receptors in CHF, making mayocytes responsive to catecholamines and improves ventricular function.

5. Pharmacokinetics
Variable: depends on preparation, hepatic metabolism, renal elimination and lipid solubility.
Generally, β-Blockers have a short half-life (~4hrs), but long acting preparations are available.

6. AV conduction abnormalities
Clinical Use/Indications
Hypertension
Glaucoma
Migraine
Hyperthyroidism
Angina Pectoris
Myocardial Infarction
Compensated CHF
Contraindications
Asthma/bronchospasm
Uncompensated CHF
Bradychardia
Cardiogenic shock
AV conduction abnormalities

7. Adverse effects: Bronchostriction Arrhythmias
Sexual impairment/depression
Disturbances in metabolism
masks signs of acute hypoglycemia and hyperthyroidism;
abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm.
Caution/monitor closely in:
Wolff-Parkinson-White syndrome and renal or hepatic dysfunction

8. Drug Interactions Aluminum salts Barbiturates NSAIDs Penicillins
Calcium salts
Cholestyramine, and Rifampin may decrease effects
Calcium channel blockers, Cimetidine, Loop Diuretics, and MAOIs may increase toxicity
May increase toxicity of: Hydralazine, Haloperidol, Benzodiazepines, and Phenothiazines

9. β Blocker Brand USA ISRAEL PO Doze, mg T1/2 hrs Actions/ Selectivity
Atenolol
Tenormin
Normitem qd
6-9 β1
Metoprolol
Lopressor
Metopress
Neobloc
Bid
3-4
Acebutulol
Sectral
Bid
β1 ,ISA
Propanolol
Inderal
Deralin
20-80 qd
4-6
β1 β2
Nadolol
Cogard
N/A qd
10-24
Timolol
Blocarden
10-20 bid
Pindolol
Visken
Pinden
5-20 tid
β1 β2 ISA
Carvedilol
Coreg
Dimitone
25-50 bid
7-10
α1 β2 β1
Labetolol
Normodyne
Trandate
bid
6-8

10. Nitrates Mode of Action: Smooth muscle relaxation
Nitric oxide stimulates guanylyl cyclase, which increases intracellular cGMP leading to relaxation.
Preload (venules) and Afterload (arterioles) are reducedbp and CO
Direct coronary artery dialation ischeamic pain

11. Pharmacokinetics Large first-pass effect
Short half-lives, 1-5 min (except isosorbide mononitrate, 5 hrs)
Large individual variations in blood concentrations
Preparations available: IV, sublingual, PO, transdermal

12. Clinical use/Indications Acute Angina attacks:
administered sublingually
Prophylaxis:
slow release preparations used as maintenance therapy to prevent angina
IV used to control unstable angina, or threatened MI
Contraindications
Documented hypersensitivity
Severe Anemia
Closed-angle Glaucoma
Orthostatic hypotension
Head trauma
Cerebral hemorrhage
Constrictive Pericarditis
Coronary Pulmonade and Arterial Hypoxemia
Hypotensive Shock

13. Adverse Effects Doze related: Precautions: Orthostatic Hypotension
Flushing
Headache
Precautions:
Tolerance to vascular and antianginal effects of nitrates may develop
minimize tolerance by using smallest effective dose or pulse therapy (intermittent dosing), or by alternating with other coronary vasodilators
Caution when administering to patients with glaucoma

14. Drug Interactions
Alcohol may cause severe hypotension and cardiovascular collapse
Aspirin may increase serum concentrations and actions
Calcium channel blockers may increase symptomatic orthostatic hypotension (adjust dose of either agent)
May decrease effects of Heparin

15. Aerosol Nitroglycerin. Nitrolingual 0.4
Nitrate
Brand
USA
ISRAEL
Doze, mg
Onset min
T1/2
Subl. Nitroglycerin
Nitrostat
Angised
2-5
10-30 min
Aerosol Nitroglycerin.
Nitrolingual
0.4
Sublingual Isosorbide dinitrate
Isodril
N/A
2.5-10
10-30
1-2 hr
Oral Isosorbide Dinitrate
Sorbitrate
Isotard
5-40
30-60
4-6 hr
Oral Isosorbide Mononitrate
Monoket
Monocord
10-20
6-8 hr
Oral Sustained Release Nitroglycerin
Nitroglyn,
Nitro-Time
2.5-9
3-8 hr
Transdermal. Nitrog. Patch
Nitro-Dur
Trinipatch
5-15
>60
12-14 hr
2% Nitroglyc. Ointment
Nitrol 2%
0.5-2 inches
20-60

16. References The Washington Manual of Medical Therapeutics, 30th ed.
Lippincott’s Review of Pharmacology, 2000.
Gibbson R, et al. Guidelines for the Management of Patients with Chronic Stable Angina:Treatment. Ann. Intern. Med. 2001;135: