3) Amlodipine treats angina and hypertension via calcium channel blockade

1. TREATMENT OF ISCHEMIC
HEART DISEASE
Dr.M.Zabihi
PhD of Pharmacology
Shahid Sadoughi University of Medical Sciences,Yazd, Iran

2. Ischemic Heart Disease
oThe pathophysiology
•Determine the prognosis
•The size of an obstructing plaque
•Inflammatory activity of the atherosclerotic process
•Stability of the plaque
•Platelet reactivity

3. Ischemic Heart Disease
• Triggering factors
• Acute inflammation (e.g., influenza)
• Blood pressure peaks during physical exercise or emotional stress
• e.g., during a life-threatening emergency and in avid fans during football
games
• Important factors that determine the progress of CAD
• Concentration of lipids in the blood
• Endothelial function
• Blood pressure (as a mechanical factor predisposing to plaque rupture)
• Activity of the inflammatory system
• Reactivity of pro- and antithrombotic systems

4. Ischemic Heart Disease
•Patients with CAD should be advised
•Regular exercise
•Stop smoking
•Blood pressure and body weight well controlled
•Statins, Aspirin, β blockers
•Annual vaccinations against influenza

5. Angina Pectoris
oPrimary symptom of ischemic heart disease
• Transient episodes of myocardial ischemia
o Due to an imbalance in the myocardial oxygen supply-demand relationship
• Typical and most prevalent form of angina pectoris
• Myocardial O2 demand increases, as with exertion
• Anginal symptoms may occur without any increase in myocardial O2 demand
• Coronary thrombosis (unstable angina or ACS)
• Localized vasospasm (variant or Prinzmetal angina)
• a mixed pattern of angina
• The addition of altered vessel tone on a background of atherosclerotic narrowing
othe sensation of angina is similar in most patients
oMyocardial ischemia also may be silent

6. Pharmacotherapy of Ischemic Heart Disease
• The principal pharmacological agents in the treatment of angina
• Nitrovasodilators
• β blockers
• Ca2+ channel blockers
othe principal therapeutic goal in ACSs with unstable angina
• to prevent or reduce coronary thrombus formation
• increase myocardial blood flow
• The principal therapeutic aim in variant or Prinzmetal angina is to prevent
coronary vasospasm

8. Organic Nitrates
Nitroglycerin (glyceryl trinitrate)
Isosorbide dinitrate , Isosorbide-5-mononitrate
oHistory
•Sources of NO
oNO
oActivates guanylyl cyclase
•Inhibits platelet aggregation
•Relaxes smooth muscle in the bronchi and GI tract

10. Organic Nitrates - Hemodynamic Effects
o GTN dilates large blood vessels more potently than small vessels
• This profile has important consequences for the antianginal efficacy of
nitrovasodilators
• Low-to-medium doses
opreferential venodilation decreases venous return
oSystemic vascular resistance and arterial pressure are not or only mildly decreased
• Heart rate remains unchanged or may increase slightly in response to a decrease in
blood pressure
• Pulmonary vascular resistance and cardiac output are slightly reduced
oDoses of GTN that do not alter systemic arterial pressure may still produce arteriolar
dilation in the face and neck

11. Organic Nitrates - Hemodynamic Effects
• Higher doses
ofurther venous pooling and may decrease arteriolar resistance as well
• Coronary flow is compromised, and the sympathetic increase in myocardial O2
demand overrides the beneficial action of the nitrovasodilators, leading to ischemia
oactivation of the Bezold-Jarisch reflex
• Sublingual nitroglycerin administration may produce bradycardia and hypotension
oIn patients with autonomic dysfunction and an inability to increase
sympathetic outflow
o producing potentially life-threatening hypotension and even aggravating angina

12. Organic Nitrates
•Mechanisms of Antianginal Efficacy of Organic Nitrates
oindicating that the major antianginal effect of nitrovasodilators is
mediated by preload reduction rather than coronary artery
dilation
•Other Effects
oRelaxation of smooth muscles of the bronchial tract, the
gallbladder, biliary ducts, and sphincter of Oddi and the GI tract
oNitrates can also relax ureteral and uterine smooth muscle

13. Organic Nitrates
• Nitroglycerin
• Peak concentrations in plasma : within 4 min of sublingual administration
• t1/2 : 1–3 min
• Onset of action : even more rapid if delivered as a sublingual spray rather than as a sublingual tablet
o Isosorbide Dinitrate
• Sublingual : maximal plasma concentrations of the drug by 6 min
• t1/2 : about 45 min
• ISDN is therefore suitable both for standby and sustained therapy
• ISMN : longer half-lives (3–6 h)
• Inhaled NO
o Exerts most of its therapeutic effects on the pulmonary vasculature
• It is approved for the treatment of pulmonary hypertension in hypoxemic neonates

14. Organic Nitrates
oTolerance
• Reduced capacity of the vascular smooth muscle
oTrue vascular tolerance
o Pseudotolerance
• Multiple mechanisms
o including volume expansion
• Neurohumoral activation
• cellular depletion of sulfhydryl groups
o The generation of free radicals
• Inactivation of ALDH2 and S-nitrosylation of soluble guanylyl cyclase are seen in
models of nitrate tolerance and could explain cross-tolerance to different
(nitro)vasodilators

15. Organic Nitrates
•Tolerance
•attempts to prevent nitrate tolerance based on these
mechanisms failed in clinical trials
• e.g., antioxidants, coapplication of vasodilators or diuretics
•importantly prolonged treatment with nitrates may not only
induce a loss of response to nitrates, but also actually decrease
angina threshold in the interval
oPrevention of tolerance
oMolsidomine

16. Organic Nitrates
•Toxicity and Untoward Responses
•almost all secondary to actions on the cardiovascular system
oHeadache
oPostural hypotension
•Rash
oInteraction of Nitrates With PDE5 Inhibitors
• fluids and α adrenergic receptor agonists, if needed, may be
used for support

17. Organic Nitrates - Therapeutic Uses
oStable Angina Pectoris
oShort-Acting Nitrates for Standby Therapy
o GTN is the most commonly used drug for the rapid release of angina
• ISDN, but not ISMN, is an alternative to GTN
• Anginal pain may be prevented when the drugs are used prophylactically immediately prior to
exercise or stress
oLonger-Acting Nitrates for the Prophylaxis of Angina
• Nitrates must be considered a second choice compared to β blockers
o Sustained-release ISDN and ISMN
oVariant (Prinzmetal) Angina
•Congestive Heart Failure
oUnstable Angina Pectoris (Acute Coronary Syndromes)
• Nitrates do not modify this process specifically and are second-line drugs

18. Ca2+ Channel Blockers

19. Ca2+ Channel Blockers
•Drug interaction
oFirst-pass metabolism by CYP3A4 enzymes
oVerapamil is strong CYP3A4 inhibitor
• Verapamil is a relatively efficient inhibitor of the intestinal and renal ABC
transport protein Pgp
• increase plasma levels of digoxin, cyclosporine, and loperamide
• Verapamil may also exacerbate AV nodal conduction disturbances
observed with digoxin
• both for pharmacodynamic and pharmacokinetic reasons (Pgp inhibition)
oWhen used with quinidine, verapamil may cause excessive hypotension

20. Ca2+ Channel Blockers
•Toxicity and Untoward Responses
oImmediate-release capsules of nifedipine
• Headache, flushing, and dizziness and can actually worsen myocardial ischemia
oPeripheral edema
• The adverse effects due to actions in nonvascular smooth muscle
• cause or aggravate gastroesophageal reflux
oConstipation
• Urinary retention (rare)
obradycardia, transient asystole, and exacerbation of heart failure have
been reported with verapamil
• Patients with ventricular dysfunction, SA or AV nodal conduction disturbances, and
systolic blood pressures below 90 mmHg should not be treated with verapamil or
diltiazem, particularly intravenously

21. Ca2+ Channel Blockers - Therapeutic Uses
oVariant Angina
• Exertional Angina or exercise-induced angina
odecrease the number of anginal attacks and attenuate exercise-induced
ST-segment depression
• They are therefore considered the drugs of choice if β blockers do not
achieve sufficient symptomatic benefit or are not tolerated
oConcurrent therapy of a dihydropyridine with a β blocker has proven
more effective than either agent given alone in exertional angina

22. Ca2+ Channel Blockers - Therapeutic Uses
oUnstable Angina (Acute Coronary Syndrome)
• Verapamil and diltiazem are recommended only for patients who continue to show signs of ischemia, do not
tolerate β blockers, have no clinically significant left ventricular dysfunction, and show no signs of disturbed
AV conduction
o Arrhythmia
o Hypertension
o Prophylaxis of migraine headaches
o in patients with neurological deficits secondary to cerebral vasospasm after the rupture
of a congenital intracranial aneurysm
o Raynaud disease
o may be effective in reducing preterm uterine contractions in preterm labor

23. β Blockers
othe only drug class that is effective in reducing the severity and frequency
of attacks of exertional angina and in improving survival in patients who
have had an MI
• First-line treatment of patients with stable CAD and unstable angina/ACS
oSlightly increased heart failure frequency in patients receiving β blockers
oβ Blockers are not useful for vasospastic angina

24. Antiplatelet, Anti-integrin, and Antithrombotic Agents

25. Ranolazine
• Second-line agent for the treatment of chronic angina
• may be used with a variety of other agents
• including β blockers, Ca2+ channel blockers, ACEIs, ARBs, and therapeutic
agents for lowering lipids and reducing platelet aggregation
• The mechanism of ranolazine’s therapeutic efficacy in angina is uncertain
• Its anti-ischemic and antianginal effects occur independently of reductions in heart
rate and arterial blood pressure or changes in coronary blood flow
oRanolazine inhibits several cardiac ion fluxes including IKr and INa

26. Ranolazine
oReduces cardiac fatty acid oxidation
oStimulates glucose metabolism
oWeak β receptor blocking activity
oThe most frequent adverse effects
•dizziness, headache, nausea, constipation

27. Ivabradine
oa selective blocker of hyperpolarization-activated HCN ion channels
involved in the generation of automaticity in the SA node
• The antianginal effect is explained solely by reduction of heart rate and
thereby O2 demand
• EMA approved for treating stable angina and heart failure
• in patients in whom β blockers are not tolerated or are insufficiently
effective in reducing heart rate
• FDA-approved only for the treatment of heart failure
oA typical, often transient, side effect are phosphenes

28. Nicorandil
• for the treatment of stable angina pectoris
• Nitrate-like (cGMP-dependent) properties
o an agonist at ATP-sensitive potassium (KATP) channels
o Dilates both arterial and venous vascular beds
• leading to decreases in afterload and preload of the heart
• In the absence of direct effects on contractile force of the ventricles, the decrease in
afterload causes cardiac output to increase
oIts antianginal effect is described to be stable
o Nicorandil has cardioprotective effects
• mimicking that of ischemic preconditioning
oIts antianginal effect is described to be stable
o Besides nitrate-like headache and hypotension (note contraindication of concurrent
PDE5 inhibitors), nicorandil has been associated with the appearance of ulcerations

29. Trimetazidine
oinhibition of long-chain 3-ketoacyl coenzyme A thiolase
• Reduces angina and increases exercise tolerance
• particularly in patients with diabetes and heart failure
• may increase the risk of movement disorders such as Parkinson disease,
particularly in older patients with decreased kidney function
oonly as second-line treatment of stable angina in patients inadequately
controlled by or intolerant to first-line antianginal therapies

30. A 52-year-old man who suffers from angina when he climbs stairs or
participates in similar activities receives a prescription for nitroglycerin
(glyceryl trinitrate). He is instructed to take a tablet 1 or 2 minutes before
he expects to climb stairs to prevent the angina.
• a. What is the mechanism of action of nitroglycerin that prevents angina from
developing in this patient?
• b. How and when should the nitroglycerin be administered to prevent anginal pain?
• c. What are the expected adverse effects of nitroglycerin therapy?
• d. What drug combinations should be avoided?

31. A 67-year-old woman with mild heart failure (LVEF = 45%) has
anginal pain with exercise and is prescribed a β adrenergic blocker.
• a. How does therapy with a β adrenergic blocker prevent anginal pain?
• b. What is the rationale underlying the choice of a β adrenergic blocker for this
patient?
• c. If the patient’s angina is not adequately controlled by monotherapy with a β
adrenergic receptor antagonist, what other classes of antianginal drugs could
be added to the β adrenergic blocker therapy in this patient?

32. A man with hypertension and occasional symptoms of
angina with exercise is prescribed amlodipine.
• a. What is the mechanism of action of amlodipine that is beneficial in
treating hypertension and angina?
• b. What are the potential side effects of the Ca2+ channel antagonists?
• c. What are the important contraindications for the use of Ca2+ channel
blockers?

33. A 58-year-old man with a long history of exertional angina begins
to develop more frequent episodes of anginal pain that are also
more intense. His cardiologist tells him he has unstable angina.
•a. What is the medical therapy for patients with unstable
angina?
•b. What other therapies might be considered to relieve angina
symptoms in this patient?

34. A 42-year-old woman develops symptoms of angina at rest. She
has not had angina before and has no history of cardiovascular
disease. After an exercise stress test and other tests, she is
diagnosed as having variant angina.
• a. What is variant angina and what is the main therapeutic goal in treating it?
• b. What are the treatment options to relieve this patient’s symptoms of angina?