Angina Pectoris

“Chest pain” or angina pectoris is a symptom of ischemic heart disease caused by an imbalance between oxygen requirement of the heart and oxygen supply.

• Peculiarities of coronary circulation Functional end arteries Maximum oxygen extraction

Blood flow mainly during diastole

Angina Pectoriso Exertional angina (Stable or effort, or classic):

oMyocardial oxygen demand increase triggered by physical activity, pain persists few minutes and subsides with rest (~ 90% of angina cases).

o Vasospastic angina (or Prinzmetal, or variant):oConsequence of an abrupt reduction in blood flow due to

a vasospasm and characterized by pain at rest.o Unstable (or “crescendo angina”, acute coronary

insufficiency, preinfarction angina or intermediate syndrome): oAngina symptoms are more frequent, longer lasting,

often occurs at rest and not relieved by nitroglycerine.

Antianginal agents

oNITRATES / NITRITES

oBETA BLOCKERSoCALCIUM CHANNEL BLOCKERSoANTITHROMBOTIC AGENTS:

Aspirin, Heparino Give 160-325 mg by mouth ASAP. Chewed aspirin is

absorbed faster & is preferred.

oOTHERS : Ranolazine, Trimetazidine, Nicorandil

Antianginal drugs

Nitrates / Nitrites :1. Isosorbide dinitrate 2. Nitroglycerine (Glyceryl trinitrate)3. Isosorbide mononitrate Nitrates are available in oral tablets, sublingual tablets, intravenous, topical patches and ointment.4. Amyl nitrite - inhalant

Acute attacks

Chronic Prophylaxis

Organic nitrates exert the majority of their vasodilatory action on venous capacitance vessels at therapeutic dose

Antianginal drugs

Nitrates : Pharmacokinetics • Organic nitrates are highly lipid soluble.• Nitrates are denitrated by glutathione reductase

in liver (resulting in low bioavailability of about 20%) .

• Nitrates have short half life (5 - 60 minutes).• Denitrated metabolites are less active and

longer acting are useful in chronic prophylaxis. (isosorbide mononitrate).

Antianginal drugs

Nitrates / Nitrites : Adverse effects

• Hypotension, throbbing headache

• Reflex tachycardia due to a reduction in arterial blood pressure by higher doses of nitrates can result in a paradoxical increase in oxygen demand.

• Methemoglobinemia is seen with nitrites and rare with nitrates.

• Tolerance – activation of sympathetic activation and volume expansion.

• Contraindicated with sildenafil citrate (viagra) and head trauma.

Drug interaction between Nitrates and Viagra

Nitrates in Angina Pectoris

a) Treatment of the acute attack.–Sublingual Nitroglycerin–Sublingual Isosorbide dinitrate – Inhalant Amyl nitrite

b) Chronic prophylaxis to reduce attacks–Oral or transdermal Nitroglycerin–Oral Isosorbide dinitrate –Oral Isosorbide mononitrate

Effects of nitrates in angina

a) In exertional angina

b) In variant angina

c) In unstable angina: may involve a combination of – Decreased myocardial O2 demand

– Increased myocardial O2 supply– Decreased platelet aggregation

d) In Congestive Heart failure: used when symptoms of pulmonary congestion predominate

• CAUTION: High doses can cause undesirable effects such as reflex tachycardia and reflex increase in cardiac contractility

Nitrites in cyanide poisoning

Hemoglobin

Methemoglobin

Cyanomethemoglobin

Methemoglobin + Sodium thiocyanate (excreted in urine)

Sodium nitrite

Cyanide

Sodium thiosulfate

Hydroxocobalamin is the newly approved antidote for cyanide in US

Antianginal drugsBETA RECEPTOR BLOCKERS:• They are an important component of treatment

of angina pectoris.• They reduce the myocardial oxygen demand

by decreasing the heart rate and contractility.• Increase myocardial perfusion (subendocardial)

due to increase diastolic perfusion time.• Atenolol, metoprolol and propranolol

Antianginal drugs

BETA BLOCKERS:• These increase survival in especially in patients with

history of myocardial infarction.• These reduce the load on the heart and the heart’s

response to exercise.• These are effective in unstable angina and chronic

prophylaxis of exertional angina.• These are associated with the feeling of coldness in

the extremities.• CONTRAINDICATED IN VASOSPASTIC ANGINA

Antianginal drugsCALCIUM CHANNELS BLOCKERS : CCB

Types of calcium channels : L, N, T• Calcium channel blockers mainly block

L TYPE : SAN, AVN and smooth muscles• Amlodipine, Nifedipine, Diltiazem, Verapamil• Verapamil and diltiazem block Ca++channels

both in the heart and in the vessels• Dihydropyridines (DHP) like Nifedipine block

calcium channels in the vessels only.

Antianginal drugs

CALCIUM CHANNEL BLOCKERS : CCB • CCB cause relaxation of smooth muscles by

decreasing the intracellular availability of calcium.

• Relax mainly arteries.• Extravascular smooth muscles – bronchial,

biliary and intestinal muscle also relaxed.• Block P- glycoprotein, a multi-transporter

associated with drug resistance in cancer cells - Verapamil

Clinical uses of calcium channel - blocking drugs

Drug Indication

Amlodipine Angina, hypertension

Felodipine Hypertension, Raynaud’s disease

Nicardipine Angina, hypertension

Nifedipine Angina, hypertension, Raynaud’s disease

Nimodipine Subarachnoid hemorrhage

Diltiazem Angina, hypertension and Supraventricular arrhythmia

Verapamil Angina, hypertension, Supraventricular arrhythmias, Migraine

Adverse Effects of Ca2+ channel blockers

• Headache, dizziness, flushing and peripheral edema (DHP like nifedipine and others)• Tachycardia, palpitations and aggravation of

myocardial ischemia (nifedipine)• Gingival hyperplasia (nifedipine) • A-V block, bradycardia, arrhythmias (ver, dil)• Constipation (verapamil)• Verapamil can double the plasma

concentration of digoxin

Combination Therapy for Angina

To increase effectiveness and reduce adverse effects.

Nitrates + β-blockers or CCBs (non-DHP)– Beta-blockers or CCBs can attenuate the nitrate-induced:

a) reflex tachycardia

b) reflex increase in cardiac contractility– Nitrates can attenuate the beta-blocker-induced:

a) increased end diastolic volume

b) increased ejection time

Nitrates + β-blockers + Ca++ channel-blockers – In patients with exertional angina that is not controlled by two

types of antianginal drugs, but can increase the incidence of adverse effects.

Antianginal drugs• Ranolazine (Ranexa) is approved for use in the

treatment of chronic angina pectoris and acts by reducing calcium overload through alteration of late sodium current.

• Trimetazidine (Vastarel) is an anti-anginal agent that improves myocardial glucose utilization through inhibition of fatty acid metabolism

• Nicorandil (Ikorel, Europe) is antianginal agent that acts by stimulation of guanylate cyclase and opening of K+ channel.

Antianginal drugsAcute Emergency Treatment of Angina: Myocardial Ischemia • Oxygen:

– Limits ischemic injury • Nitroglycerin: Sublingual

– Causes coronary dilation, greater perfusion, reduces preload & afterload

• Aspirin: – Give 160-325 mg by mouth ASAP. Chewed aspirin is absorbed faster

& is preferred.• Morphine:

– reduces anxiety and relieves pain. Morphine also produces venodilation, which can reduce venous return & reduce preload (oxygen demand)

Antianginal drugs

Chronic Stable Angina of Effort:• Complete treatment : ABCDE–Aspirin & Antianginals drugs – Nitrates sublingual

–Beta blocker & BP control–Cholesterol reducing drugs & Cigarette

cessation, Calcium channel blockers (if required)–Diabetes & Diet management–Exercise & Education

Antianginal drugso Vasospastic (Variant) Angina:• Nitrates• Calcium Channel Blockers

– NOT Beta-blockers

o Unstable Angina Management:• Antiplatelet agents (aspirin) (325 mg aspirin initially)

– these patients are at a high risk for developing an MI or non-STEMI• Anticoagulants (heparin or LMWH)• Nitroglycerin (sublingually or by buccal spray; i.v. if pain persists; topical or

oral for maintenance)• Beta-blocker (reduce heart rate to 50-60 beats/min; caution in patients with

evidence of heart failure)• Statin or other lipid-lowering agent if applicable (prophylactic therapy)

Summary of Antianginal Drugs

Drug class Antianginal actions

Nitrates and nitrites

- Decrease in cardiac O2 demand by reducing preload- Increase in cardiac O2 delivery by relieving coronary spasm.

Ca++channel blocking

drugs

- Decrease in cardiac O2 demand by: a) reducing afterload b) reducing cardiac contractility and rate- Increase in cardiac O2 delivery by relieving coronary spasm.

β-blocking drugs

- Decrease in cardiac O2 demand by reducing cardiac contractility and rate