vasodilator agents

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


Fig 13.22

21:20


• 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


Vasodilatation….

Blood Pressure = Cardiac Output x Peripheral Resistance

Artery Diameter

Vascular Smooth MuscleContraction/Relaxation

Rhythm Pumping

Heart

21:20


Resting Diameter, Normal BP

BP

Vasodilate Diameter

Peripheral Resistance

BP

Vasoconstrict Diameter

Peripheral Resistance

21:20


Mean Arterial Blood Pressure = MAP

MAP = CO x TPR

TPR? 4 1/r

Blood pressure changes across the vascular tree

21:20


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


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


Endothelial Cells

Vascular Smooth

Muscle(also adrenergics…)

Vasodilators- Nitric Oxide- Prostacyclin- EDHF

Vasoconstrictors- Endothelin- Angiotensin- Thromboxane A2

Vasoconstriction Vasorelaxation

21:20


Normal blood vessela

Atherosclerotic plaque- Impaired blood flow

Vasodilate to improve blood flow

21:20


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


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


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


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


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


• (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


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


21:20


Treatment of Angina

• Modification of risk factors: smoking, obesity, hypertension, hyperlipidemia, diabetes

• Nonpharmacological: Surgery/angioplasty/stents

• Drug treatment

21:20


Balloon Angioplasty

21:20


Coronary Artery Bypass Graft

(CABG)

21:20


Human saphenous vein

Neointima

21:20


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


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


Mechanism of action of Nitric OxideEndothelial cell

L-arginine L-citrulline

NOS

NO

NO

Vascular smooth muscle

guanylate cyclase

cGMP

RELAXATION

Ca2+

21:20


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


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


Additional Benefit of Nitrate Over Some Vasodilators

21:20


Nitrates - Metabolism

• Large hepatic “first pass” metabolism (eg. > 90%)

• Nitroglycerin inactive orally

(give sublingually or transdermally)

21:20


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


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


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


Sildenafil (VIAGRA)• PDE5 inhibitor (many isoforms)• Potentiate ‘NO donours’ BP• Contraindicated with nitrates

21:20


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


Calcium Contraction

21:20


Coronary Angiogram

before after Ca2+ channel blocker

This type of response could occur in variant angina

21:20


Calcium Antagonist

Cardiac Effects

BP HR TPR

Verapamil +++

Diltiazem ++ /-

NifedipineAmlodipinne

+ ↑↑

21:20


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


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


-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


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


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


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


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


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


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


(Esomeprazole)

(Spironolactone)

FK’s current medications(Aug 2010):

Pharmacology in the wild

Oct 2013Transderm Nitro

21:20


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


21:20


vasodilator agents

Documents

vasodilator drugs

drugs antiarrhythmic

parasympathetic system

arterial blood pressure

coronary arteries

r blood pressure changes

normal bp bp

chest discomfort