Angina drugs used

1.  Jaineel Dharod
Dept. of Pharmacology

2.  Stable/Classical/typical/exertional angina.
 Unstable/Crescendo/Pre-infraction angina.
 Prinzmetal’s or variant angina.
 Decubitus angina.
 Nocturnal angina.

5.  Rapid onset, Short acting: Amyl nitrate, nitro-glycerine
 Slow onset, Long acting: Isosorbide dinitrate, isosorbide
mononitrate

6.  Mechanism of action
1. The primary value of nitrates is venous dilation, which reduces left
ventricular volume (preload) and myocardial wall tension,
decreasing oxygen requirements (demand).
2. Nitrates may also reduce arteriolar resistance, helping reduce
afterload, which decreases myocardial oxygen demand.
3. By reducing pressure in cardiac tissues, nitrates also facilitate
collateral circulation, which increases blood distribution to
ischemic areas.
4. Pharmacological effects have been shown to improve exercise
tolerance, prolong the time to onset of angina, and the appearance
of ST-segment depression during exercise testing.

7. b. Indications
(1) Acute attacks of angina pectoris can be managed with sublingual, transmucosal
(Nitrolingual® spray or Nitrostat® sublingual tablets), or intravenous delivery.
(2) Indications include the prevention of anticipated attacks, using tablets (oral
or buccal) or transdermal paste or patches. Sublingual nitrates (Nitrostat®) can
be used before eating, or a known stressful event.
(3) Nitrates are used in treatment of stable angina. They may not be effective as
a single agent for treatment of Prinzmetal angina, although some studies have
shown nitrates to prevent or reverse vasospasm at varying doses. Intravenous
nitro-glycerine is used in the immediate treatment of unstable angina and is used
for long-term therapeutic relief.
(4) Nitrates used in combination with β-adrenergic blockers have been shown to
be more effective than nitrates or β-adrenergic blockers used alone.

8. Precautions and monitoring effects
(1) To maximize the therapeutic effect, patients should
thoroughly understand the use of their specific dosage forms
(e.g., sublingual tablets, transdermal patches or pastes,
tablets, capsules).
(2) Blood pressure and heart rate should be monitored
because all nitrates can increase heart rate while lowering
blood pressure.
(3) Preload reduction can be assessed through reduction of
pulmonary symptoms such as shortness of breath, paroxysmal
nocturnal dyspnea, or dyspnea.

9. Precautions and monitoring effects
(4) Nitrate-induced headaches are the most common side
effect. (Monday morning sickness)
(a) Patients should be warned of the nature, suddenness, and
potential strength of these headaches to minimize the anxiety
that might otherwise occur.
(b) Compliance can be enhanced if the patient understands
that the effect is transient and that the headaches usually
disappear with continued therapy.
(c) Acetaminophen ingested 15 to 30 mins before nitrate
administration may prevent the headache.

10. e. Effective therapy should result in fewer anginal attacks
without inducing significant adverse effects (e.g., postural
hypotension, hypoxia). If maximal doses are reached and the
patient still experiences attacks, additional agents should be
administered.
f. Nitrate tolerance is a major problem with the long-term
use of nitroglycerin and long-acting nitrates. Several agents
such as ACE inhibitors (sulfhydryl-containing drugs),
acetylcysteine, and diuretics have been shown to reverse
nitrate tolerance by increasing the availability of sulfhydryl
radicals. However, practical considerations suggest that less
frequent administration (8 to 12 hrs of nitrate-free intervals)
is effective without introducing additional agents.

11.  Propranolol
 Atenolol
 Nadolol
 Bisoprolol

12.  Based on the 2007 Focused Guidelines for Patients With
Chronic Stable Angina, a class 1a recommendation states
that it is beneficial to start and continue β–blocker
therapy indefinitely in all patients who have had MI, acute
coronary syndrome, or left ventricular dysfunction with or
without heart failure symptoms, unless contraindicated.

13. a. Mechanism of action. β-Blockers reduce oxygen demand, both at rest
and during exertion, by decreasing the heart rate and myocardial
contractility, which also decreases arterial blood pressure.
b. Indications
 These agents reduce the frequency and severity of exertional angina that
is not controlled by nitrates.
 Nitrates have been combined with calcium antagonists, when slow-release
dihydropyridines (e.g., felodipine [Plendil®], amlodipine [Norvasc®]) are
preferred over diltiazem (Cardizem®) or verapamil (Calan®). If patients
need to receive alfa -adrenergic blocker along with verapamil or diltiazem
owing to the added effects, they have the potential to induce
bradycardia, AV heart block, and fatigue.

14. c. Precautions and monitoring effects
(1) Doses should be increased until the anginal episodes have been reduced or until
unacceptable side effects occur.
(2) β-Blockers should be avoided in Prinzmetal angina (caused by coronary
vasospasm) because they increase coronary resistance and may induce vasospasm.
(3) Asthma is a relative contraindication because all β-blockers increase airway
resistance and have the potential to induce bronchospasm in susceptible patients.
(4) Patients with diabetes and others predisposed to hypoglycaemia should be
warned that β-blockers mask tachycardia, which is a key sign of developing
hypoglycaemia.
(5) Patients should be monitored for excessive negative inotropic effects. Findings
such as fatigue, shortness of breath, edema, and paroxysmal nocturnal dyspnea
may signal developing cardiac decompensation, which also increases the metabolic
demands of the heart.
(6) Sudden cessation of β-blocker therapy may trigger a withdrawal syndrome that
can exacerbate anginal attacks (especially in patients with IHD) or cause MI.

15.  Diltiazem
 Verapamil
 Nifedipine
 Nicardipine
 Amlodipine

16. a. Mechanism of action. Two actions are most pertinent in the treatment
of angina.
 These agents prevent and reverse coronary spasm by inhibiting calcium
influx into vascular smooth muscle and myocardial muscle. This results in
increased blood flow, which enhances myocardial oxygen supply.
 Calcium-channel blockers decrease coronary vascular resistance and
increase coronary blood flow, resulting in increased oxygen supply.
 Calcium-channel blockers decrease systemic vascular resistance and
arterial pressure; in addition, they decrease inotropic effects, resulting
in decreased myocardial oxygen demand.

17. b. Indications
 Calcium-channel blockers are used in stable (exertional) angina that
is not controlled by nitrates and -blockers and in patients for whom -
blocker therapy is inadvisable. Combination therapy—with nitrates, -
blockers, or both—may be most effective.
 These agents, alone or with a nitrate, are particularly valuable in the
treatment of Prinzmetal's angina. They are considered the drug of
choice in treatment of angina at rest.

18. (1) Diltiazem (Cardizem®) and verapamil (Calan®)
(a)These drugs produce negative inotropic effects, and patients must be
monitored closely for signs of developing cardiac decompensation (i.e.,
fatigue, shortness of breath, edema, paroxysmal nocturnal dyspnea). When
coadministered with -blockers or other agents that produce negative
inotropic effects
(b) Patients should be monitored for signs of developing bradyarrhythmias
and heart block because these agents have negative chronotropic effects.
(c) Verapamil (Calan®) frequently causes constipation that must be treated
as needed to prevent straining at stool, which could cause an increased
oxygen demand (Valsalva maneuver). Verapamil is not recommended in
patients with sick sinus syndromes, AV nodal disease, or heart failure (HF).

19. (2) Nifedipine (Procardia®)
(a) This calcium-channel blocker is believed to possess the greatest degree of
negative inotropic effects compared to the newer second-generation members of
this group, amlodipine (Norvasc®) and felodipine (Plendil®). Nifedipine 10 mg
(chewed or swallowed) has been used to treat Prinzmetal angina or refractory spasm
in patients who are not hypotensive. Controversy still exists about the use of short-
acting, rapid release agents such as Nifedipine in patients with IHD.
(b) Because Nifedipine increases the heart rate somewhat, it can produce
tachycardia, which would increase oxygen demand. Coadministration of a -blocker
should prevent reflex tachycardia.
(c) Its potent peripheral dilatory effects can decrease coronary perfusion and
produce excessive hypotension, which can aggravate myocardial ischemia.
(d) Dizziness, light-headedness, and lower extremity edema are the most common
adverse effects, but these tend to disappear with time or dose adjustment.

20. (3) Amlodipine (Norvasc®), clevidipine (Cleviprex®), felodipine
(Plendil®), isradipine (Dynacirc®), nicardipine (Cardene®), and
nisoldipine (Sular®) are second-generation dihydropyridine
derivative, calcium-channel blockers. They have been used effectively
as once- or twice-a-day agents owing to their long activity. Because
of the potent negative inotropic effects of these agents, they are
not recommended in patients with HF (amlodipine has been shown to
have less negative potential in HF than other members of the class).
Clevidipine is available in the injectable form only and is administered
as a continuous slow IV infusion.

21.  Aspirin
 Clopidogrel
 Ticlopidine
 Dipyridamole
 Cilostazole

22.  Aspirin: Based on the 2007 Focused Guidelines for Patients
With Chronic Stable Angina, a class Ia recommendation states
that aspirin should be started at 75 to 162 mg/day and
continued indefinitely in all patients unless contraindicated.

23.  Ticlopidine (Ticlid®) is a thienopyridine derivative that inhibits
platelet aggregation induced by adenosine diphosphate. However,
unlike aspirin, it has not been shown to decrease adverse
cardiovascular events in patients with stable angina.

24.  Clopidogrel (Plavix®) is also a thienopyridine derivative related
to ticlopidine, but it possesses antithrombotic effects that are
greater than those of ticlopidine. Clopidogrel is a therapeutic
option in those angina patients who cannot take aspirin because
of contraindications. Doses of 75 mg daily are recommended to
prevent the development of acute coronary syndromes.

25.  Cilostazol is a phosphodiesterase-3 inhibitor which promotes
vasodilation and inhibits platelet aggregation. It is used as an
adjuvant in antianginal therapy but mainly reserved to treat
intermittent claudication. It is metabolised by CYP3A4 and
hence concurrent use of verapamil, diltiazem and ketoconazole
etc. should be avoided.
 Usual dose is 100 mg BD orally.

26.  Dipyridamole inhibits adenosine deaminase and also
phosphodiesterase which leads to an accumulation of adenosine
and CAMP respectively. These mediators then inhibit platelet
aggregation and may also stimulate release of PGI,. It is a
powerful coronary vasodilator. It has minimal effect on BP and
cardiac work as venous return is not reduced.

27. (1) There has been added concern regarding the interaction which takes place when
patients receiving clopidogrel are also given one of the proton pump inhibitors
(PPIs), such as omeprazole (Nexium®). The following highlighted
recommendations are discussed within the consensus statement as they relate
to the combinations of clopidogrel and PPIs:
(a) PPIs are appropriate in patients with multiple risk factors for GI bleeding who
are also receiving antiplatelet therapy (e.g., clopidogrel).
(b) Although pharmacokinetic and pharmacodynamic studies have demonstrated
varying effects of PPIs on the extent of clopidogrel metabolic conversion to the
active metabolite, no evidence has established clinically meaningful differences in
outcomes.
(c) A clinically significant interaction cannot be excluded in subgroups who are poor
metabolizers of clopidogrel.
(d) Until solid evidence exists to support staggering PPIs with clopidogrel, the
dosing of PPIs should not be altered.

28. Nicorandil (potassium channel opener)
• It is a newer antianginal drug which activates ATP- sensitive K
channels and hyperpolarize vascular smooth muscle.
• It reduces pre- and afterload and produces coronary dilation.
Since Nicorandil carries a nitrate-like moiety, it also exerts a
nitrate-like effect
• Therefore, the drug combines an activation of K channel with
nitric oxide donor action.
• Its arterial vasodilator effects are attributed to K+ channel
opening whereas venodilator effects are due to nitrate-like
activity.
• However, unlike nitrates, tolerance does not develop to its
effects.

29. Nicorandil (potassium channel opener)
• Nicorandil increases coronary blood flow without causing
coronary steal phenomenon and without producing significant
cardiac effects on contractility, conduction, heart rate and
blood pressure.
• It is used to treat vasospastic and chronic stable angina; dose
10-20 mg BD orally
• Side effects include flushing, palpitation, dizziness. headache,
stomatitis, nausea and vomiting.
• Nicorandil is contraindicated in patients with cardiogenic shock,
LVF with low filling pressure, and hypotension.
• It should not be used along with sildenafil as the hypotensive
effects of nicorandil are potentiated by sildenafil.

30. Ranolizine (Cytoprotective Drug)
• Ranolizine was initially thought to act by inhibiting O2 -wasting
fatty acid metabolism which takes place during myocardial
ischaemia.
• Now it is clear that its main mode of action is through inhibition of
inward sodium current during ischaemia.
• As a result the Ca2+ load in cardiac muscle is reduced indirectly via
Na*-Ca+2* exchanger.
• The drug prolongs exercise tolerance to angina but has no effect
on heart rate or BP. Dose is 500 mg BD orally.
• It can safely be combined with CCB, B-blockers or nitrates (but
not with verapamil or diltiazem).

31. Ranolizine (Cytoprotective Drug)
• The main side effect is prolongation of QTc interval, hence
concurrent use of quinidine, dofetilide and sotalol should be
avoided.
• It is metabolised by CYP3A4 and hence drugs like verapamil,
diltiazem, ketoconazole, macrolide antibiotics, antiviral protease
inhibitors can increase its plasma concentration (and hence QTc t
prolongation).
• It not only relieves angina but reduces the incidence of serious
ventricular arrhythmias in patients with post-acute coronary
syndrome.

32. Other Agents

33. HMG-COA Reductase Inhibitors
Statins (Atorvastatin, Rosuvastatin)
• The supportive therapy for coronary artery disease has two key
components, namely, the lipid-lowering agents and antiplatelet agents.
• The low density lipoprotein (LDL) target is 100 mg/dL or less which can
be achieved by dietary modification plus statin therapy (e.g., with
atorvastatin or rosuvastatin).
• These drugs also act in ways beyond regression of atheromatous plaque,
e.g., by improving endothelial function, stabilising platelets or by
inhibiting inflammatory response associated with atherogenesis
(pleiotropic or non lipid benefits).
• The main adverse effect after prolong use is Rhabdomylosis

34. ACE inhibitors. Based on the 2007 Focused Guidelines for Patients With Chronic
Stable Angina, the following recommendations have been made for ACE inhibitors.
a. Class Ia recommendation states that ACE inhibitors should be started and
continued indefinitely in all patients with left ventricular ejection fraction 40% and
in those with hypertension, diabetes, or chronic kidney disease unless
contraindicated.
b. Class Ib recommendation that ACE inhibitors should be started and continued
indefinitely in patients who are not lower risk (lower risk defined as those with
normal left ventricular ejection fraction in whom cardiovascular risk factors are
well controlled and revascularization has been performed), unless contraindicated.
c. Class IIa recommendation that it is reasonable to use ACE inhibitors among lower
risk patients with mildly reduced or normal left ventricular ejection fraction in
whom cardiovascular risk factors are well controlled and revascularization has been
performed.
d. Current guidelines do not suggest which agent to use, and it is anticipated that
ongoing trials with additional agents will provide additional information regarding
dosing regimens and potential differences that might exist among the class of
drugs.

35. Angiotensin receptor blockers (ARBs). Based on the 2007 Focused
Guidelines for Patients With Chronic Stable Angina, three new
recommendations have been made for the use of ARBs in patients with
chronic stable angina.
a. Class Ia recommendation that ARBs are recommended for patients who
have hypertension, have indications for but are intolerant of ACE inhibitors,
have heart failure, or have had a myocardial infarction with left ventricular
ejection fraction 40%.
b. Class IIb recommendation that ARBs may be considered in combination
with ACE inhibitors for heart failure due to left ventricular systolic
dysfunction.
c. Class Ia recommendation that aldosterone blockade is recommended for
use in post-MI patients without signifi cant renal dysfunction or hyperkalemia
who are already receiving therapeutic doses of an ACE inhibitor and a -
blocker, have a left ventricular ejection fraction 40%, and have either
diabetes or heart failure.