vasodilator agents
TRANSCRIPT
Cardiovascular Pharmacology
Vasodilator Agents
Department of PharmacologyCollege of Medicine, UoD
Learning Objectives
After participating in this session, it is expected that students will be able to:
• Describe The Mechanism Of Action Of Some Vasodilator Drugs (Eg Nitrites/Nitrates, Hydralazine, Alpha-adrenoceptor Antagonists)
• Discuss The Basis For Their Use In The Treatment Of Angina And/Or Heart Failure
• Describe Their Pharmacokinetics And Their Adverse Effects
Vasodilator Agents
21:20
2
Cardiovascular Pharmacology Vasodilator agents
Inotropic agents
Lipid lowering drugs
Antiarrhythmic agents
Next yearDiuretics (renal disorders)
Treatment of Hypertension 1
Treatment of Hypertension 2
Treatment of Anemia
Anticoagulant drugs
21:20
Vasodilator Agents 3
• (Ischaemic heart disease; coronary artery disease)• Includes :
Acute myocardial infarction (heart attack)o Death congestive heart failure
Angina: radiating chest paino (Coronary spasm exertional) need to decrease
metabolic demands on heart Cardiac arrhythmias o Artrial/ventricular altered rhythm/death
• Major underlying causes: Atherosclerosis Hypertension (LVH)
Coronary Heart Disease
21:20
Vasodilator Agents 4
Fig 13.22
21:20
Vasodilator Agents 5
• Coronary arteries arise above aortic valve, fill in diastole
• Arteries are external to myocardium muscle hypertrophy- vessels are stretched.
• Arteries are small calibre; any narrowing- poor flow• Only some degree of collateral supply• Sub-endocardial is vulnerable zone
21:20
Vasodilator Agents 6
Vasodilatation….
Blood Pressure = Cardiac Output x Peripheral Resistance
Artery Diameter
Vascular Smooth MuscleContraction/Relaxation
Rhythm Pumping
Heart
21:20
Vasodilator Agents 7
Resting Diameter, Normal BP
BP
Vasodilate Diameter
Peripheral Resistance
BP
Vasoconstrict Diameter
Peripheral Resistance
21:20
Vasodilator Agents 8
Mean Arterial Blood Pressure = MAP
MAP = CO x TPR
TPR? 4 1/r
Blood pressure changes across the vascular tree
21:20
Vasodilator Agents 9
Effector: Autonomic NSC
entr
al N
erv
ou
s S
yst
emSympathetic system
ACh
Parasympathetic system
ACh
ACh adrenal medulla
Somatic efferent system
21:20
Vasodilator Agents 10
Effector: Autonomic NSC
entr
al N
erv
ou
s
Syst
emSympathetic system
ACh
Parasympathetic system
ACh
ACh adrenal medulla
Somatic efferent system
NA
(NA)Adren
ACh
ACh
M
N
21:20
Vasodilator Agents 11
Endothelial Cells
Vascular Smooth
Muscle(also adrenergics…)
Vasodilators- Nitric Oxide- Prostacyclin- EDHF
Vasoconstrictors- Endothelin- Angiotensin- Thromboxane A2
Vasoconstriction Vasorelaxation
21:20
Vasodilator Agents 12
Normal blood vessela
Atherosclerotic plaque- Impaired blood flow
Vasodilate to improve blood flow
21:20
Vasodilator Agents 13
A 74-year-old man presents with a history of anterior chest pressure whenever he walks more than one block. The chest discomfort is diffuse, and he cannot localize it; sometimes it radiates to his lower jaw. The discomfort is more severe when he walks after meals but is relieved within 5–10 minutes when he stops walking. Assuming that a diagnosis of stable effort angina is correct, what medical treatments should be implemented to reduce the acute pain of an attack and to prevent future attacks?
Case Study
21:20
Vasodilator Agents 14
Commonly Used Antihypertensive Drugs
Angiotensin converting enzyme inhibitors & Angiotensin receptor blockers
Beta receptor blockers
Calcium channel blockers
Diuretics (thiazides, loop, K+ sparing)
Nitrovasodilators
21:20
Vasodilator Agents 15
Commonly Used Antianginal Drugs
Angiotensin converting enzyme inhibitors & Angiotensin receptor blockers
Beta receptor blockers
Calcium channel blockers
Diuretics (thiazides, loop, K+ sparing)
Nitrovasodilators
Digoxin
21:20
Vasodilator Agents 16
Angina PectorisSymptoms:
• Pain, severe, crushing, sub-sternal, may radiate + Shortness of breath
• lasts a few minutes (usually relieved by rest &/or sublingual nitrate)
Causes:
• Coronary artery disease, coronary vasospasm due to insufficient O2 supply to heart
• i.e. imbalance: myocardial O2 demand >> O2 supply
Urgent medical attention required for:
• Worsening angina (unstable angina)
• Chest pain lasting more than a few minutes
21:20
Vasodilator Agents 17
Types• Chronic, stable angina (atherosclerosis +/++)
Caused by exercise, coronary artery disease
• Unstable angina (atherosclerosis +++)
Unpredictable, thrombi formation
• Variant (vasospastic) angina (no atherosclerosis)
Spasm of coronary artery
Risk factors:
• Hypertension, cholesterol, smoking etc
Precipitated by:
• Exertion, cold, stress, large meals
21:20
Vasodilator Agents 18
• (Ischaemic heart disease; coronary artery disease)• Includes :
Acute myocardial infarction (heart attack)o Death congestive heart failure
Angina: radiating chest paino (Coronary spasm exertional) need to decrease
metabolic demands on heart Cardiac arrhythmias o Artrial/ventricular altered rhythm/death
• Major underlying causes: Atherosclerosis Hypertension (LVH)
Coronary Heart Disease
21:20
Vasodilator Agents 19
Atherosclerotic Lesions In Blood Vessel
Unstable rupture? AMI / stroke
Deposition of plaque (includes lipids) in the walls of medium / largeArteries reduces internal diameter
21:20
Vasodilator Agents 20
21:20
Vasodilator Agents 21
Treatment of Angina
• Modification of risk factors: smoking, obesity, hypertension, hyperlipidemia, diabetes
• Nonpharmacological: Surgery/angioplasty/stents
• Drug treatment
21:20
Vasodilator Agents 22
Balloon Angioplasty
21:20
Vasodilator Agents 23
Coronary Artery Bypass Graft
(CABG)
21:20
Vasodilator Agents 24
Human saphenous vein
Neointima
21:20
Vasodilator Agents 25
Drugs for Angina: Mechanisms• coronary perfusion to oxygen supply
• metabolic demand
• Combination of both
Determinants of myocardial oxygen requirement:
• heart rate
• contractility
• ventricular volume
• arterial pressure
VenodilatationCO oxygen consumption
Arterial dilatation peripheral resistance oxygen consumption
coronary dilatation increase oxygen supply
21:20
Vasodilator Agents 26
Nitrates
• Result in release of nitric oxide in vascular smooth muscle with consequent vasodilatation, particularly in veins (smooth muscle relaxants)
• They have no effect on cardiac or skeletal muscle
21:20
Vasodilator Agents 27
Mechanism of action of Nitric OxideEndothelial cell
L-arginine L-citrulline
NOS
NO
NO
Vascular smooth muscle
guanylate cyclase
cGMP
RELAXATION
Ca2+
21:20
Vasodilator Agents 28
Nitrovasodilators can donate NO from their structureEndothelial cell
L-arginine L-citrulline
NOS
NO
NO
Vascular smooth muscle
guanylate cyclase
cGMP
RELAXATION
Glyceryl trinitrate (GTN)nitrates
Ca2+
21:20
Vasodilator Agents 29
Nitrates: Mechanism in Angina
• Venous dilatation reduces venous pressure and pre-load, with consequent fall in cardiac oxygen consumption
• Arteriolar dilatation reduces peripheral resistance and after-load with consequent fall in cardiac oxygen consumption
• Coronary dilatation- e.g. variant angina
Limitation:
• blood pressure is associated with a reflex tachycardia tendency to increase cardiac oxygen consumption
21:20
Vasodilator Agents 30
Additional Benefit of Nitrate Over Some Vasodilators
21:20
Vasodilator Agents 31
Nitrates - Metabolism
• Large hepatic “first pass” metabolism (eg. > 90%)
• Nitroglycerin inactive orally
(give sublingually or transdermally)
21:20
Vasodilator Agents 32
Examples of Nitrates
Nitroglycerin (glyceryl trinitrate):
• Sub-lingual (tablet or spray, lasts<30 min)
• Transdermal (patch or ointment, < 24 hr)
Isosorbide dinitrate:
• Sub-lingual (lasts < 2 hr)
• Oral (lasts < 6 hr)
21:20
Vasodilator Agents 33
Use of Sublingual Nitroglycerin
• Treatment of acute attack of angina
• Immediate prophylaxis
• If using tablets rather than spray, they must be kept in a closed non-plastic container as they lose activity (volatile)
21:20
Vasodilator Agents 34
Nitrates - adverse effects
• Hypotension (fainting): should not be combined with Viagra or similar drugs
• Tachycardia
• Headache
• Flushing
Nitrates – tolerance:
• Develops after continual exposure
• A nitrate-free period (e.g. for 8 hours per 24 hours when using transdermal patches) reduces tolerance
21:20
Vasodilator Agents 35
Sildenafil (VIAGRA)• PDE5 inhibitor (many isoforms)• Potentiate ‘NO donours’ BP• Contraindicated with nitrates
21:20
Vasodilator Agents 36
Deaths Associated with Sildenafil Therapy in the United States. From: Lue: N Engl J Med, Volume 342(24).June 15, 2000.1802-1813
Side Effects- Mainly CVS
21:20
Vasodilator Agents 37
Calcium Contraction
21:20
Vasodilator Agents 38
Coronary Angiogram
before after Ca2+ channel blocker
This type of response could occur in variant angina
21:20
Vasodilator Agents 39
Calcium Antagonist
Cardiac Effects
BP HR TPR
Verapamil +++
Diltiazem ++ /-
NifedipineAmlodipinne
+ ↑↑
21:20
Vasodilator Agents 40
Blockade of L-type (voltage operated) Ca2+ channels;Reduces Ca2+ entry into vascular* / cardiac cells (not SkM)
Therefore, reduction in intracellular Ca2+
• reduce venous pressure (preload)• reduce arteriolar pressure (afterload)* Reflex
Ca Channel BlockersCause: • Vasodilatation (arterial > venous)
• Reduced cardiac contractility & reduced atrio-ventricular conduction (verapamil > diltiazem > nifedipine)
Indications:Angina, hypertension, tachyarrhythmias (SVT)
Angina:TPR & cardiac work
reduce cardiac oxygen demand
• coronary vasodilation can help variant angina (angina due to vessel spasm, not fixed block)
21:20
Vasodilator Agents 41
Ca Blockers: Adverse Effects
• Cardiac depression, bradycardia
• (Contraindicated in heart failure)
• Flushing, edema, dizziness, headache
• Constipation, nausea
Contraindications:• heart failure
• -blockers (with verapamil or diltiazem)
21:20
Vasodilator Agents 42
-Adrenoceptor Antagonists
• Decrease sympathetic drive to heart
CO ( HR); ()TPR Inhibit renin release ( angiotensin II) Reduced sympathetic outflow from central
nervous system (if lipid soluble)
ACh NAsympathetic NS
b1
heart
21:29
Vasodilator Agents 43
Uses of β-blockerse.g. propranolol (Inderal) - nonselective 1 & 2 antag
atenolol (Tenormin), metoprolol (Betaloc)- 1 selective antag
• Hypertension
• Angina
• Post myocardial infarct
• Arrhythmias
• Clinically stable heart failure (carvedilol)
• Beware contraindications….
21:20
Vasodilator Agents 44
Uses of β-blockerse.g. propranolol- nonselective 1 & 2 antag
atenolol, metoprolol- 1 selective antag
Angina:
cardiac oxygen demand
heart rate increases coronary artery perfusion time during diastole (relaxation phase) oxygen supply to the heart
21:20
Vasodilator Agents 45
b-Blockers: Adverse Effects
Respiratory: bronchoconstriction (2 effect)
Cardiovascular: Decreased heart contractility, Bradycardia, Atrio-ventricular block, Exercise intolerance, Claudication, Impotence, beware sudden withdrawal
Brain (if lipid soluble): depression, sedation, sleep problems
Diabetes: exacerbate & mask hypoglycemia
21:20
Vasodilator Agents 46
Variant Angina• Nitrates and calcium antagonists also reduce
coronary artery spasm in variant angina (not due to fixed block)
• In addition, beta blockers, by slowing heart rate, can increase coronary artery perfusion time
• Variant angina: beware b-blockersUnstable Angina
• Dipyridamol : adenosinevasodilator (variant)antiplatelet (unstable)
• Aspirin - antiplatelet
21:20
Vasodilator Agents 47
Points About Anti-anginal Drugs• Chest pain lasting more than a few minutes or
worsening (unstable) angina require urgent medical attention
• Drugs can be used for stable angina
• Nitrates can be used prophylactically (e.g. before attempting exercise)
• Beta-blockers reduce exercise ability & can cause bronchoconstriction
• Anti-anginal drugs can cause hypotension and faintness: to reduce this, patients can lie down whilst taking nitrates (especially on starting them)
21:20
Vasodilator Agents 48
A 74-year-old man presents with a history of anterior chest pressure whenever he walks more than one block. The chest discomfort is diffuse, and he cannot localize it; sometimes it radiates to his lower jaw. The discomfort is more severe when he walks after meals but is relieved within 5–10 minutes when he stops walking. Assuming that a diagnosis of stable effort angina is correct, what medical treatments should be implemented to reduce the acute pain of an attack and to prevent future attacks?
Case Study
21:20
Vasodilator Agents 49
(Esomeprazole)
(Spironolactone)
FK’s current medications(Aug 2010):
Pharmacology in the wild
Oct 2013Transderm Nitro
21:20
Vasodilator Agents 50
Answer
• The case described is typical of stable atherosclerotic angina. Treatment of acute episodes should include sublingual tablets or sprayed nitroglycerin, 0.4–0.6 mg. Relief of discomfort within 2–4 minutes can be expected. If anginal episodes are frequent, or to prevent episodes of angina, a blocker such as metoprolol should be tried first. If contraindications to the use of a blocker are present, a medium- to long-acting calcium channel blocker such as verapamil, diltiazem, or amlodipine is likely to be effective.
21:20
Vasodilator Agents 51
21:20
Vasodilator Agents 52