Transcript Angina pectoris and Calcium Channel Blockers

Nitrovasodilators & Angina
October 10, 2007
Frank F. Vincenzi
.
Nitric oxide, NO : The Physiological Vasodilator
ACh, histamine, ADP
from platelets, and
bradykinin
(Ca2+)4 CaM
endothelial
eNOS
L-arginine
cell
citrulline
NO
smooth
NO
muscle
guanylate cyclase
GTP
PDE
cGMP
relaxation
cell
Nitric oxide synthase (NOS)
• eNOS - endothelial - failure or abnormal function
of this system associated with many conditions
(atherosclerosis, hypertension, Raynaud’s
syndrome, ‘oxidant stress’, etc.)
• nNOS - nerve - involved in CNS plasticity?
• iNOS - inducible - overactive in sepsis
Pharmacodynamic mechanism of action
of nitrovasodilators
• Release nitric oxide (NO.) (or simply, NO)
• NO activates cytosolic guanylyl cyclase in
vascular smooth muscle
• Increased cGMP decreases smooth muscle
contraction
increased removal of Ca2+ ?
other mechanisms?
• General smooth muscle relaxation
Nitrovasodilators: A mechanism of action
ACh, histamine, etc.
(Ca2+)4 CaM
endothelial
eNOS
L-arginine
organic nitrites & nitrates
cell
citrulline
NO
-
NO
2
smooth
NO
muscle
guanylate cyclase
GTP
PDE
cGMP
relaxation
cell
Leslie Activa
• Les Activa is a slightly obese 60 year old male
accountant.
• Five years ago Les was diagnosed with stable
angina pectoris. He was prescribed nitroglycerin
(0.3 mg, sublingual, PRN chest pain).
• He has missed many follow up visits but requests
Rx refills on a regular basis. He consumes about
two tablets of nitroglycerin per day, although that
number has been increasing lately. Efforts to
change his lifestyle have been unsuccessful. His
activities are limited by angina, but he does not
have angina at rest.
Angina pectoris
• Stable or exertional: associated with exertion and
fixed obstruction(s) of coronary arteries, usually in
elderly (also called classic or atherosclerotic)
• Unstable: new onset, often severe and/or frequent,
or at rest; often exacerbated by extracardiac
problems, associated with plaque rupture
• Prinzmetal’s or variant: associated with coronary
arterial vasospasm (mediators unknown), often
near fixed obstructions (Dx with ACh or
ergonovine)
Angina: a symptom of ischemia
• Ischemia depends on the balance of
myocardial
– Oxygen demand
– Oxygen supply
Nitrates and nitrites (nitrovasodilators) used
mainly in acute angina
• amyl nitrite (inhalation, rapid onset (<30 sec) short
acting (3-5 min)
• nitroglycerin (sublingual tablets, rapid onset short
duration, 30 min)
• isosorbide dinitrate (sublingual 60 min, chewable
3 hours or oral 10 hours)
• organic nitrates are readily absorbed via skin and
mucous membranes and rapidly biotransformed.
Organic nitrates: pharmacokinetics
• High lipid solubility
• Rapidly absorbed from almost anywhere
rapid onset (seconds to minutes)
• Poor bioavailability orally
• Relatively short half life
1-3 min for nitroglycerin
45 min for isosorbide dinitrate
Effect of a nitrovasodilator on cardiovascular
functions in a normal human volunteer
Cardiovascular effects of nitroglycerin
• Venous vasodilation > arteriolar vasodilation
(no increase in total coronary blood flow in
patients, although there is redistribution into
ischemic areas)
• Decreased ventricular preload
• Decreased afterload (and increased subendocardial
perfusion) (can be used in the Tx of CHF)
• Reflex tachycardia
Acute decrease in cardiac work and O2 demand
Nitrates: adverse reactions and
limitations
• Headache !
• Orthostatic hypotension (dizziness, weakness)
• Tachycardia
• Tolerance (substantial)
• Short duration of action (a few minutes)
NO-mediated vasodilation of genital vasculature:
sildenafil (Viagra®)
• sildenafil is a selective inhibitor of
phosphodiesterase 5 (PDE5)
• PDE5, located in genital vascular beds, terminates
the action of cyclic GMP in vascular smooth
muscle
• sildenafil increases the response to normal
physiological signalling of NO in genital vascular
beds
Sildenafil: A mechanism of action
CNS &/or local input
non-adrenergic,
non-cholinergic
nerve cell (NANC)
L-arginine
smooth
muscle
cell
nNOS
citrulline
NO
.
NO
.
sildenafil
guanylate cyclase
corpus
cavernosum
GTP
PDE5
cGMP
relaxation
sildenafil (Viagra®)
• Indications
male erectile dysfunction (impotence)
• Contraindications
nitrite/nitrate therapy, predisposition to
priapism
• Caution
retinitis pigmentosa (genetic disorders of
retinal PDE)
• Adverse reactions
abnormal color vision (PDE6, 1/10th potency)
sildenafil (Viagra®): pharmacokinetics
•
•
•
•
Rapidly absorbed, bioavailability 40%
Vd approximately 1.5 liters/kg
Peak plasma concentration, approximately 60 min
Plasma half life (parent & metabolite)
approximately 4 hours
• Metabolized by CYP3A4 & CYP2C9
• N-desmethyl is an active metabolite
• Metabolites mainly in feces
Leslie Activa, revisited a few years later
• Has begun to have an occasional attack of angina
at rest, or with only minor exercise (the flight of
stairs to his office).
• What can we do to prevent angina attacks in Les?
• “Oh, by the way, Doc, can I also have a
prescription for that stuff, Viagra?”
sildenafil: some drug interactions
•
•
•
•
•
•
•
•
cimetidine
diltiazem
erythromycin
fluconazole
indinavir
ketoconazole
furosemide
miconazole
•
•
•
•
•
•
•
•
nitrites/nitrates
nitroprusside
omeprazole
spironolactone
quinidine
rifampin
saquinavir
verapamil
Perspective on pharmacotherapy of angina
• Organic nitrites/nitrates are effective in acute
treatment but not very effective in prophylaxis of
angina; duration of action is short
• Beta-blockers are effective prophylaxis for some
forms of angina (but may worsen variant angina)
• Calcium channel blockers are also effective in
prophylaxis of angina
Perspective on pharmacotherapy of angina
• Organic nitrites/nitrates are effective in acute
treatment but not very effective in prophylaxis of
angina; duration of action is short
• Beta-blockers are effective prophylaxis for some
forms of angina (but may worsen variant angina)
• Calcium channel blockers are also effective in
prophylaxis of angina
Beta blockers in angina
•
•
•
•
Decrease heart rate
Decrease myocardial contractility
Decrease blood pressure
Minimize sympathetically induced increases in
oxygen demand
• Reduce myocardial oxygen consumption
Prevent exercise-induced increase in O2 demand
Cardiac effects of beta blockers in angina
Potentially beneficial
Decreased:
• resting HR
• resting and exercise systolic pressure
• left ventricular dP/dt
• velocity of myofibril contraction
Potentially harmful
Increased:
• prolongation of systolic ejection period
• increased left ventricular end diastolic pressure
• increased cardiac volume and wall tension
Effect of a beta-blocker on exercise tolerance
in a patient with angina pectoris
Effects of placebo and propranolol on maximal
exercise duration (normal human volunteers)
Propranolol: selected adverse reactions
•
•
•
•
•
•
•
•
AV block
Bronchospasm
Diarrhea
Exfoliative dermatitis
Fatigue
Hallucinations
Heart failure
Hypertriglyceridemia
•
•
•
•
•
•
•
•
Hypoglycemia
Hypotension
Impotence
Libido decrease
Myalgia
Nausea/vomiting
Nightmares
Sinus bradycardia
Some factors to consider in choosing a beta blocker
for treating angina in Les Activa
Perspective on pharmacotherapy of angina
• Organic nitrites/nitrates are effective in acute
treatment but not very effective in prophylaxis of
angina; duration of action is short
• Beta-blockers are effective prophylaxis for some
forms of angina (but may worsen variant angina)
• Calcium channel blockers are also effective in
prophylaxis of angina
Calcium Channel Blockers in Angina
• Smooth muscle has low resting potential
• Smooth muscle not affected by tetrodotoxin
•
(action potential spikes carried by Ca)
• Ca channel blockers relax arteriolar smooth
muscle with little effect on venous muscle
• No change in HR x SBP product
not increased delivery, but decreased
demand for oxygen
• Caution: reflexly mediated
increases in oxygen demand possible
Calcium Channel Blockers:
Probable Mechanisms in Angina
• Variant angina: decreased coronary spasm
• Unstable: decreased spasm and cardiac work?
• Exertional: decreased cardiac work
(For angina, the advantage is with verapamil or
diltiazem - they suppress cardiac automaticity &
contractility. Dihydropyridines activate
sympathetic reflexes to a greater extent & do not
suppress SA node.
Effect of verapamil in patients with
variant angina
Combination therapy in angina:
prophylaxis plus treatment of acute attacks
• Beta-blocker chronically + nitroglycerin acutely as
needed (PRN NTG)
• Calcium channel blocker chronically + PRN NTG
• With hypertension: Beta-blocker + nifedipine
(caution in hypotension - & do not use a beta
blocker and verapamil or diltiazem, caution
possible heart block)
Summary: Therapy of Angina Pectoris
• Stable
nitrates
beta blockers
Ca channel blockers
• Unstable
admit and rule out MI, heparin then aspirin,
consider revascularization or CABG
• Variant
acute
nitroglycerin, short duration nifedipine
chronic
nitrates, CEBs, possibly prazosin
Malignant hypertension
Nifedipine (‘bite and swallow’, use decreasing)
Fenoldopam
Sodium nitroprusside
Sodium nitroprusside (Nipride®), ‘SNP’
Made fresh for IV infusion. Onset in seconds.
Half life ~ 11 min
In vivo transformation of sodium nitroprusside
Nitroprusside + oxygen
nitric oxide + cyanide
+
Too much NO causes
Oxidation of Hb - methemoglobinemia
thiosulfate
Too little thiosulfate causes
Accumulation of cyanide treat with thiosulfate
thiocyanate
Too much accumulation of thiocyanate
Causes N&V, rash, tinnitus, CNS changes
Dialyze thiocyanate