Download I. Angina Pectoris

Cardiovascular Pharmacology - Angina Pectoris
Edward JN Ishac. Ph.D.
Professor, Department of Pharmacology & Toxicology
Office: Smith Bldg. 742
Email: [email protected]; Tel: (804) 828 2127
Learning Objectives:
I.
Demonstrate an understanding of the potential hemodynamic
mechanisms and other mechanisms for drug therapy of ischemia and
the pharmacology of the agents used in treatment with respect to:
1.
The hemodynamic basis for the action of each drug class of antianginals agents
2.
Cellular mechanisms of action, especially for the nitrates
3.
Major pharmacokinetic characteristics
4.
Primary adverse effects
5.
Unique characteristics of individual agents
6.
Potential advantages or disadvantages of using combinations of antianginal agents
7.
The mechanism of action and basis for usefulness in thrombosis prevention and
management of heparin, enoxaparin, aspirin and other platelet inhibitors, and
thrombolytic agents
Angina Pectoris
Angina pectoris is a chronic disease affecting 3 million in the USA (approx. 1% of
population) characterized by intermittent attacks of chest pain which radiates to the left
arm, shoulder, and jaw. Attacks of typical (effort, stable) angina are associated with
exertion, excitement and other factors which increase cardiac work. The development of
the disease is not fully understood, but it probably involves the following sequence:
coronary
atherosclerosis
coronary
narrowing
coronary
insufficiency
myocardial
hypoxia
angina
pectoris
A less common form, variant (Prinzmetal's) angina is characterized by attacks occurring
during rest and is caused by coronary artery spasm possibly involving prostaglandins.
A. Typical (Stable, Effort) angina: increased O2 demand - fixed supply
B. Variant (Prinzmetal) angina: ↓O2 supply, unchg. demand (coronary spasms, PGs?)
C. Unstable angina: usually at rest, ↓O2 supply, ↓blood flow due to blood clot
- acute emergency → ↑risk sudden death, MI, arrhythmia, cardiac arrest
D. Microvascular angina (Syndrome X): atherosclerosis in small coronary a.
Dr. Ishac
Angina Pectoris
2
Figure 1. Forms of angina
II.
Pharmacologic approaches to treatment angina pectoris
A.
Since angina is due to imbalance between the oxygen requirement of the heart and
oxygen supplied via the coronary arteries, the crucial consideration is improvement
of the ratio.
coronary blood flow
cardiac work
1.
or
O2 supply
O2 requirement
The primary determinants of myocardial O2 supply are:
a.
b.
c.
Coronary blood flow
O2 content of the blood
O2 extraction by the myocardium
2.
The primary determinants of myocardial O2 consumption are:
a.
Ventricular systolic pressure (afterload)
b.
Heart size (preload)
c.
Heart rate
d.
Myocardial contractility
Note: Heart extracts near maximal O2 at rest, therefore to increase O2 supply need to
increase coronary blood flow.
3.
Risk factors:
- Obesity
- High blood cholesterol
- Physical inactivity
- Smoking
- Age
- Gender
- Family history
- Hypertension
Dr. Ishac
Angina Pectoris
4.
Possible mechanisms for altering supply/demand ratio:
a.
Relaxation of resistance vessels (small arteries and arterioles)
leading to decreased peripheral resistance and a decrease in
systemic blood pressure (reduction in afterload).
Nitrates and calcium channel blockers have such effects.
b.
Relaxation of capacitance vessels (veins and venules) leading to
decreased venous return and decreased heart size (reduction in
preload).
Nitrates have such effects.
c.
Blockade or attenuation of sympathetic influence on the heart. This
would decrease O2 demand in the myocardium as a result of
decreased heart rate and contractility.
Beta-blockers, such as propranolol would have this effect.
d.
Coronary Dilation - Important mechanism for relieving vasospastic
angina. Re-distribution of coronary flow to increase tissue 02
supply. Nitrates have such effects.
III.
Classification of drugs used to treat angina
A.
Nitrates and Nitrites (vasodilation via direct smooth muscle relaxation)
1.
Mechanism of action (see figure 2 next page):
a.
the formation of nitric oxide (NO) in endothelial cells in a reaction involving tissue
sulfhydral (SH) groups
b.
interaction between NO and thiols in the smooth muscle cell to form nitrosothiols
c.
nitrosothiol activation of guanylate cyclase and increased formation of cGMP
d.
with increased cGMP there is:
1)
2)
3)
4)
5)
3
increased calcium uptake by SR
less calcium to interact with calmodulin
less activation of MLCK by calcium and calmodulin
decreased phosphorylation of MLC
decreased smooth muscle tone
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Figure 2. Mechanism of action of nitrates, nitrites
Figure 2. Mechanism of action of nitrates, nitrites and other substances that increase the
concentration of nitric oxide (NO) in smooth muscle cells. MLCK*: activated myosin light
chain kinase. Guanylate cyclase*: activated guanylate cyclase. ?: Unknown intermediate steps.
Steps leading to relaxation are shown with heavy arrows.
Figure 3. Smooth muscle contraction and action of calcium channel-blocking drugs
Figure 3. Control of smooth muscle contraction and site of action of calcium channel-blocking
drugs. Contraction is triggered by influx of calcium (which can be blocked by calcium channel
blockers) through transmembrane calcium channels. The calcium combines with calmodulin to
form a complex that converts the enzyme myosin light chain kinase to its active form (MLCK*).
The latter phosphorylates the myosin light chains, thereby initiating the interaction of myosin
with actin. Beta2 agonists (and other substances that increase cAMP) may cause relaxation in
smooth muscle by accelerating the inactivation of MLCK (heavy arrows) and by facilitating the
expulsion of calcium from the cell (not shown).
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2. Development of tolerance:
Tolerance can develop to the pharmacological effects of nitrates if large amounts are
administered frequently.
Tolerance disappears if the drug is discontinued for a short period of time (ie, remove
transdermal patch over night).
Tolerance may be due to oxidation of SH groups and formation of disulfide bonds.
3. Absorption and disposition:
Nitrates are well absorbed. Disposition is primarily by hepatic reductases. There is
considerable first-pass metabolism of most nitrates with oral administration
(bioavailability 10-20% with oral administration for nitroglycerin & isosorbide dinitrate).
4. Toxicity: Acute: - headache, flushing, nausea, hypotension, reflex tachycardia
5. Individual compounds
A. Nitroglycerin - Routes of administration:
Effective for all forms of angina, for prompt relief (oral spray or sublingual)
i.
ii.
iii.
iv.
v.
sublingual tablet (30 min; Nitrostat)
buccal tablet (4 hr; Nitrogard)
oral (translingual); spray (30 min; Nitrolingual)
oral tablet (6 hr; Nitro-Bid)
topical
- ointment (4 hr; Nitrol and Nitro-Bid)
- transdermal system (8 hr; Transderm-Nitro, Nitrodisc, Nitro-Dur, others).
vi. intravenous (Nitrostat IV, Nitro-Bid IV)
Sublingual administration of nitroglycerin is preferred for treatment of acute
attacks of angina because of its rapid onset of action. Other forms (except for
intravenous) are intended to have a longer duration of action and are used for
anginal prophylaxis.
B. Isosorbide dinitrate [ISDN] (2-4 hr; Isordil)
C. Isosorbide mononitrate [ISMN] (8 hr; Ismo)
ISDN and ISMN are intended to have a nitroglycerin-like effect with a long
duration of action and are used for prophylaxis.
Metabolite of isosorbide dinitrate, bioavailability 100%
D. Pentaerythritol tetranitrate (Peritrate)
E. Erythrityl tetranitrate (Cardilate)
F. Volatile nitrites used as “recreational drugs”
i. amyl nitrite
ii. butyl nitrite
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B. Beta-adrenergic Blockers (ie. Propranolol, Atenolol, Metoprolol, Nadolol)
By blocking cardiac beta receptors, propranolol and similar drugs decrease myocardial O2
consumption through reduction in heart rate and contractility.
Several studies have reported a reduction in the frequency of anginal attacks with
propranolol. (see more detailed notes on beta-blockers in the Hypertension syllabus)
Features of beta-adrenoceptor antagonists
- Selective vs non-selective ie. atenolol (β1-) vs propranolol (no)
- Partial agonist activity (ISA) ie. pindolol (yes) vs propranolol (no)
- Membrane stabilizing action (LA-action) ie. metoprolol (yes) vs atenolol (no)
- Lipid solubility (CNS availability): atenolol (low), propranolol (high)
Class/Drug
Non-selective
Carteolol
Carvedilol
Labetalol
Nadolol
Penbutolol
Pindolol
Propranolol
Sotalol
Timolol
β1-selective
Acebutolol
Atenolol
Betaxolol
Bisoprolol
Esmolol
Metoprolol
HT
Angina
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Arrh
MI
HF
X
X
X
X
X
X
X
X
Comments
ISA; long acting
α-blocking activity
ISA; α-blocking activity
long acting
ISA
ISA; MSA
MSA; prototype
K-channel blocker
primarily for glaucoma
ISA
X
X
X
X
X
X
MSA
X
X
X
short acting
MSA
MSA: membrane stabilizing activity; ISA: intrinsic sympathomimetic activity (partial agonist
Adverse effects:
- effects enhanced in elderly
-  myocardial reserve (blockade of cardiac 1-ARs)
- fatigue, dizziness
- asthma (blockade of bronchial beta2-ARs)
- peripheral vascular insufficiency
- diabetes (blockade of hepatic beta2-ARs)
- CNS: nightmares, mental depression, insomnia
- withdrawal syndrome (supersensitivity, rebound HT)
- may worsen Raynand’s syndrome
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C. Calcium Blockers: (see also notes on CCBs in Hypertension syllabus)
Non-dihydropyridines (non-DHPs): Verapamil, Diltiazem, Bepridil
Dihydropyridines (DHPs): Nifedipine, Amlodipine, Nicardipine, Felodipine
1. Mechanism of Action
These agents inhibit calcium movement through channels (primarily L-type) in
membranes of muscle cells. In vascular smooth muscle, the reduction in
intracellular calcium results in a decrease in muscle tone. All blockers are
dihydropyridines except verapamil, diltiazem and bepridil which bind to different
receptors in the channel.
2. Cardiovascular Effects
The decrease in vascular muscle tone results in primarily arteriolar dilation and a
fall in peripheral resistance and afterload. Coronary dilation and an increase in
coronary flow can occur in patients with variant angina. Verapamil and diltiazem
have stronger direct effects on the heart and are used to suppress cardiac
arrhythmias. They also cause cardiac depression as an adverse effect. All drugs are
vasodilators and can reduce blood pressure.
3. Pharmacokinetics
a.
b.
c.
Administration: oral - generally well absorbed
Disposition: metabolism > renal
Half-life: 2-5 hours, except bepridil (42 hr) & amlodipine (40 hr)
4. Toxicity
a.
b.
c.
d.
e.
f.
g.
Hypotension
Other effects related to vasodilation (dizziness, flushing, headache)
Constipation, especially with verapamil
Cardiac depression with verapamil and diltiazem
Tachycardia with nifedipine and nicardipine
Arrhythmias and agranulocytosis with bepridil
Gingival hyperplasia (more likely with nifedipine)
D. Other agents:
1. Dipyridamole (Persantin) – acts mainly as an inhibitor of platelet aggregation
2. Aspirin – also an inhibitor of platelet aggregation
3. Ranolazine (Ranexa) – reserve agent for chronic angina, MOA unknown.
Thought to decrease late sodium current and thus decrease intracellular
sodium level to decrease sodium-dependent calcium channels. No
significant effect on HR or BP. Can be combined with other agents.
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IV. Summary of Effects on Primary Determinants of Myocardial O2 Consumption
R = Reflex
VSP (Afterload)
Heart Size (Preload)
Heart Rate
Contractile Force
V.
VI.
VII.
Nitrates
Beta Blockers
↓
↓↓
↑ (R)
0-↑ (R)
0-↓
0-↑
↓
↓
Calcium Blockers
Verapamil/Diltiazem
Others
↓↓
↓
0-↓
↓
↓
↓
↑ (R)
0
Use of Drugs in Different Forms of Angina
A.
Stable/Effort - nitrates, calcium blockers, beta blockers, aspirin
B.
Variant - nitrates, calcium blockers
C.
Unstable - nitrates, beta blockers, aspirin, anticoagulants, thrombolytics
Aims in use of antianginal drugs
A.
Treatment of acute attack – oral spray or sublingual nitroglycerin very effective
B.
Short term prophylaxis - taking nitroglycerin prior to anticipated physical or
emotional stress may prevent attack.
C.
Long term prophylaxis - objective is to reduce frequency of anginal attacks. Many
options are now available. Long-acting nitrates, beta-blockers, calcium-blockers
Angina treatment summary
Dr. Ishac
VIII.
A.
Angina Pectoris
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AGENTS FOR PERIPHERAL VASCULAR DISEASE
Description of disease and limitations of drugs
Peripheral vascular disease can result from vascular spasm or organic vascular
damage. In either case the problem is reduced blood supply to areas served by
affected vessels. Drugs are more effective in relieving spasm than in cases of
vessel damage which may involve thrombosis and occlusion. As with anti-anginal
drugs, there has been poor correlation between vasodilation measured in the
laboratory and clinical efficacy in peripheral vascular disease.
B.
Drugs for Treatment
Many types of drugs have been used in treatment of peripheral vascular disease
with generally unsatisfactory results. These agents are classified according to their
mechanism of action.
1.
Beta-adrenergic stimulants
2.
Alpha-adrenergic blocking agents
3.
Calcium entry blockers
4.
a.
Diltiazem, Felodipine, Nifedipine - used for Raynaud's disease
b.
Nimodipine (Nimotop) - used for subarachnoid hemorrhage
Phosphodiesterase inhibitors
a.
Pentoxifylline (Trental)
Mechanism of action : Increases cAMP by inhibiting PDE4. Also inhibits TNFalpha. May improve capillary flow by
increasing erythrocyte flexibility.
Use: intermittent claudication.
b.
Cilostazol (Pletal)
Mechanism of action: Increases cAMP by inhibiting PDE3. Inhibits platelet aggregation and causes vasodilation.
Use: intermittent claudication.
c.
Sildenafil (Viagra)
Mechanism of action: increases cGMP by inhibiting PDE-5
and conversion to GMP, resulting in vasodilation.
Use: erectile dysfunction.
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Adverse effects: reports of visual disturbances, but
cause/effect relationship not established
Caution: potentiates the action of nitrates, severe
hypotension may occur if taken concurrently with nitrates
or alpha blockers
d.
Vardenafil (Levitra)
Mechanism of action: also a PDE-5 inhibitor
Use: erectile dysfunction.
Adverse effects/caution: causes a slight prolongation of the
QT interval and should not be used in patients who have
this condition or are taking drugs that increase the QT, e.g.,
quinidine, procainamide, amiodarone.
Caution: avoid if taking nitrates or alpha blockers
e.
Tadalafil (Cialis)
Mechanism of action: PDE-5 inhibitor
Use: erectile dysfunction
Pharmacokinetics: duration of action is much longer
(remains in body up to 36 hours)
Adverse effects: include back pain and muscle aches
Caution: do not use with nitrates or alpha blockers
IX.
AGENTS TO PREVENT THROMBUS FORMATION OR REMOVE THROMBI
A.
Activators of antithrombin
1.
Heparin and Fondaparinox (Arixtra) - activate antithrombin III, resulting
in an increased rate of thrombin inactivation by the antithrombin;
in addition to hemorrhage, another adverse effect is
thrombocytopenia, which is treated with Lepirudin (Refludin).
2.
Enoxaparin (Lovenox), Dalteparin (Fragmin), Ardeparin (Normiflo),
Tinzaparin (Innohep) and Danaparoid (Orgaran) - low molecular
weight heparins; more bioavailable, longer acting and perhaps less
likely to cause hemorrhage than standard heparin.
Dr. Ishac
B.
Angina Pectoris
Inhibitors of Thrombin
1.
C.
D.
11
Bivalirudin (Angiomax) - used for anticoagulation during angioplasty
Inhibitors of clotting factor synthesis (Oral anticoagulants)
1.
Warfarin (Coumadin) - interferes with the action of vitamin K, thereby
inhibiting the synthesis of prothrombin and other vitamin K
dependent clotting factors
2.
Bishydroxycoumarol (Dicumarol) - similar to warfarin, but has less
desirable pharmacokinetic properties; seldom used
Anti-platelet drugs
1.
Drugs that inhibit platelet aggregation and adhesiveness and thus prevent
thrombus formation are most useful for arterial thrombosis and
include the following:
a.
Aspirin: decrease platelet aggregation
versible acetylation, ↓TXA2,
b.
Dipyridamole (Persantin): Inhibit. TXA synthase, ↓TXA2,
decrease platelet aggregation
c.
Aggrenox - fixed dose combination of aspirin and dipyridamole
d.
Clopidogrel (Plavix)
Mechanism of action: inhibits ADP-induced platelet aggregation
by blocking binding of ADP to its receptors (glycoprotein receptors
on the platelet membrane). Prodrug, metabolized to active drug by
CYP2C19
Uses: stroke prevention in patients who have had strokes or stroke
precursors (TIAs), acute coronary syndrome, acute MI, PCI
Adverse effects: fewer than with ticlopidine, not associated with
neutropenia
1) GI effects: nausea, diarrhea (20% of patients)
2) Hemorrhage (5%)
e.
Ticlopidine (Ticlid)
Inhibits the ADP pathway for platelet activation. Introduced before
clopidogrel, but neutropenia is associated with ticlopidine and blood tests
are recommended.
f.
Other: Prasugrel (approved July 2009): ADP receptor inhibitor
Dr. Ishac
f.
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Platelet IIB,IIIA receptor blockers
Abciximab (Reopro)
Eptifibatide (Integrilin)
Tirofiban (Aggrostat)
Abciximab is a monoclonal antibody receptor antagonist.
Eptifibatide and tirofiban prevent platelet aggregation by blocking the
binding of fibrinogen and von Willebrand factor to the IIB, IIIA receptor.
These agents are used as adjunctive therapy in patients undergoing highrisk angioplasty and atherectomy and for acute coronary syndrome.
Efficacy of aspirin in preventing myocardial infarction (MI)
Unstable angina patient
Post MI patient
"Healthy" person
+++
++
+
The optimum dose of aspirin is still being determined, but relatively low
doses (e.g., 81-325 mg/day) are effective (perhaps more effective than
higher doses).
Dr. Ishac
E.
Angina Pectoris
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Thrombolytic Agents
These agents, also known as "clot busters", activate plasminogen leading to the
degradation of fibrin and the clot. Thus, they accelerate the dissolution of thrombi.
A critical factor in their use is the elapsed time between the thrombotic event and
drug administration. They are of greatest benefit if used within 2 hours.
1.
Streptokinase (Streptase; Kabikinase)
2.
Tissue plasminogen activator: Alteplase [TPA] (Activase)
3.
Reteplase (Retavase)
4.
Anistreplase (Eminase)
5.
Tenecteplace (TNKase)
The thrombolytics differ with respect to clot allergenicity, selectivity, half-life (or
duration required for infusion) and cost as compared below.
Streptokinase
Alteplase
Reteplase
Anistreplase
Tenecteplase
Allergenicity
Yes
No
No
Yes
No
Clot selectivity
Not selective
High
High
Intermediate High
Half-life
Very short
Short
Longer
Long
Long
Cost
Low
High
High
High
High
Drugs to Remember:
X.
Amyl nitrite
Anistreplase
Nitroglycerin
Aspirin
Pentoxifylline
Clopidrogel
Propranolol
Diltiazem
Reteplase
Sildenafil
Streptokinase
Heparin
Isosorbide dinitrate
Atenolol
Isosorbide mononitrate
Metoprolol
Vardenifil
Ticlopidine
Nifedipine
Verapamil
Warfarin
References
Basic and Clinical Pharmacology, B.G. Katzung, 11th ed., 2009, pp. 191-208
Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Hardman and Limbird, 10th
ed., 2005, pp. 823-844.