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Anti anginal drugs. Dr.V.V.Gouripur. Ischaemic Heart Disease,. ALSO known as Coronary Artery Disease Angina pectoris Myocardial infarction (Acute coronary syndrome). Ischaemic Heart Disease,. A condition that affects the supply of blood to the heart.

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Anti anginal drugs

Anti anginal drugs

Dr.V.V.Gouripur


Ischaemic heart disease
Ischaemic Heart Disease,

  • ALSO known as Coronary Artery Disease

  • Angina pectoris

  • Myocardial infarction

    (Acute coronary syndrome)


Ischaemic heart disease1
Ischaemic Heart Disease,

  • A condition that affects the supply of blood to the heart.

  • The blood vessels are narrowed or blocked due to the deposition of cholesterol plaques on their walls.

  • This reduces the supply of oxygen and nutrients to the heart musculature, which is essential for proper functioning of the heart.

  • This may eventually result in a portion of the heart being suddenly deprived of its blood supply leading to the death of that area of heart tissue, resulting in a heart attack


Etiology
Etiology

  • Ischemia is secondary to coronary artery disease in 95% of patients.

  • A decreased oxygen supply from anemia, hypotension, vasospasm, or arrhythmias or an increase in oxygen demand secondary to exercise, emotional stress, CHF, hypertension, tachycardia, sepsis, etc., can lead to a worsening of symptoms.

  • Ischemia can occur in patients with normal coronary arteries in the setting of LV hypertrophy, aortic stenosis or insufficiency, hypertrophic cardiomyopathy, coronary vasospasm, or cocaine abuse.


Types of angina
Types of Angina

  • Stable. Intensity, character, and frequency of episodes can be predicted, and angina occurs in response to a known amount of exercise or other stress.

  • Unstable. Intensity, frequency, or duration of episodes is changed and can no longer be predicted. Pain is precipitated by less exercise or is of longer duration. This includes angina at rest and new-onset angina.

  • Variant. Pain, which may occur at rest, is secondary to vasospasm of coronary arteries.


Etiology1
Etiology

  • Stable angina can be caused by gradual, progressive coronary artery stenosis associated with hyperlipidemia and atherosclerosis.

  • These stable, fixed lesions reduce coronary artery blood flow and when myocardial workload increases the restricted coronary flow is inadequate to meet the increased myocardial demand.

  • The resultant ischemia and anoxia can then trigger the classic symptoms of anginal chest pain.

  • With rest the myocardial demand diminishes, adequate perfusion is restored and the chest pain resolves.


Etiology2
Etiology

  • Unstable angina can be defined in three ways:

    -new onset angina with frequent attacks (greater than or equal to 3 episodes/day),

    -rest angina, and

    -accelerated angina.


Indicative of worsening cardiovascular disease

May be associated with an unstable plaque of the coronary arteries that can initiate thrombus formation and total occlusion very quickly.

Also cause occlusion by flap dissection or by dislodging & becoming wedged in a smaller diameter artery.

Is a medical emergency and does not follow the predictable pattern of exertional pain alleviated with rest that is often seen with stable angina.


Etiology3
Etiology

  • Prinzmetal's variant angina is caused by coronary vasospasm.

  • It has a variable pattern and while associated with an overall low mortality rate, is associated with a high degree of morbidity..


Factors that affect myocardial oxygen demand
Factors that Affect Myocardial Oxygen Demand

  • The major determinants of myocardial oxygen consumption include

  • ventricular wall stress,

  • heart rate, and

  • inotropic state (contractility)

  • Both preload and afterload affect the stress on the ventricular wall


Preload
Preload

  • Preload is the pressure that distends the ventricular wall during diastole (ventricular-end diastolic pressure, VEDP) and is determined by venous return

  • Peripheral venodilation increases venous capacitance and thereby reduces venous return and preload

  • Decreasing preload also reduces ventricular end-diastolic volume (VEDV) which reduces ventricular wall tension as described by Laplace's law (Tension = Pressure x Radius)

  • An added benefit of reducing preload is improvement in subendocardial perfusion as a result of increasing the pressure gradient for perfusion across the ventricular wall


Afterload
Afterload

  • Afterload is the impedance against which the ventricle must pump

  • Decreasing peripheral arteriolar resistance reduces myocardial work and therefore myocardial oxygen consumption

  • A commonly used non-invasive index of myocardial oxygen demand is the "double product"

  • Heart Rate x Systolic Blood Pressure


  • Factors that affect myocardial oxygen supply
    Factors that Affect Myocardial Oxygen Supply

    • Coronary artery blood flow is the primary determinant of myocardial oxygen supply since myocardial oxygen extraction from the blood is nearly complete, even at rest

    • Coronary blood flow is essentially negligible during systole and is therefore determined by perfusion pressure (aortic diastolic pressure), duration of diastole, and coronary resistance

    • Coronary vascular resistance is determined by numerous factors including:

      • Metabolic products that vasodilate coronary arterioles

      • Autonomic activity

      • Extravascular mechanical compression

      • Atherosclerosis, -Intracoronary thrombi


    Signs and symptoms
    Signs and Symptoms

    • 25 to 30 % of ischemic episodes may be asymptomatic, :

    • Crushing, heavy, pressure, squeezing, tight sensation or aching/ pain in the chest

    • Intensity varying from mild to intense

    • Location often retrosternal with radiation to neck, ears jaw, teeth, arms (left more common than right), shoulders or back

    • Numbness, tingling, paresthesias following the above distribution

    • Shortness of breath Anxiety/nervousness, palpitations"


    Drugs used in angina
    Drugs used in angina

    Organic nitrates ---- Glyceryl trinitrite (GTN)

    (Nitroglycerin)

    Isosorbide mononitrite

    Isosorbide dinitrite

    Erythrityl tetranitrite

    Beta blockers- ------Atenalol

    -Metopralol

    Calcium channel blockers- Verapamil

    -Diltiazam

    -nifedepine

    -Amlodepine


    Nitrates
    Nitrates

    • The major beneficial effect-- is a reduction in preload and afterload, resulting in reduction in myocardial work and reduction of intramural pressure.

    • Reduction of myocardial work results in decreased oxygen demand; reduction of intramural pressure allows better perfusion of deeper layers of the myocardial tissue). Decreased myocardial wall tension is a major determinant of myocardial oxygen demand

    • Nitrates have also been shown to have a substantial antiplatelet effect .

    • Blood is preferentially redistributed to ischemic areas caused by an increase in coronary collateral blood flow



    NO is capable of dilating all blood vessels, however, there is a greater effect on large arteries and veins compared to arterioles.

    This means that low concentrations of GTN dilates veins first. In order to dilate arterioles, larger concentrations are needed.

    However, the main target to reduce preload is the effects on the veins

    GTN dilates the veins, which causes increased venous pooling (increased venous capacitance)

    This reduces venous return (preload) and hence reduces the amount of blood the heart has to pump, thus making it work less (thus reducing the O2 demand)


    In normal individuals, GTN will also act to dilate the coronary arterioles, thus allowing increased perfusion to the heart.

    However, this is not the case in people with classic angina because the arterioles are already maximally dilated, therefore there will be no increase in cardiac blood flow


    Systemic effects of gtn
    Systemic effects of GTN coronary arterioles, thus allowing increased perfusion to the heart.

    • Little effect on arterial pressure (even though it may cause dilation of arteries and arterioles). Hence it is not an effective anti hypertensive agent

    • No direct effect on the myocardium

    • It is possible to see a mild reflex tachycardia. Decreased cardiac output (due to reduced venous return)

    • Flushing due to vasodilation of the facial vessels

    • Headache due to cerebral vessel dilation

    • Effects on extravascular smooth muscle:

    • Relaxation of the smooth muscle of the bronchus and GIT (only transient effects)


    Pharmacokinetics of gtn isdn
    Pharmacokinetics of GTN &ISDN coronary arterioles, thus allowing increased perfusion to the heart.

    • GTN is rapidly metabolised by the liver, hence it is not given orally

    • It is either given sublingually (for rapid onset, short lasting) or transdermally (for constant slow administration which lasts longer)

    • ISDN can be given orally, although it is metablised by the liver (not as efficiently as GTN). It is also metabolised to an active metabolite, which lengthens its duration

      (ETN&PETN-NOT USED)


    Pharmacokinetics nitrovasodilators
    Pharmacokinetics Nitrovasodilators coronary arterioles, thus allowing increased perfusion to the heart.

    PropertyGTNISDNISMN

    • Half-life (min) 3 10 280

    • Oral bioavailability (%) < 1 20 100


    Adverse effects
    Adverse Effects coronary arterioles, thus allowing increased perfusion to the heart.

    • The major acute adverse effects of nitrates are due to excessive vasodilation:

      • Orthostatic hypotension

      • Tachycardia

      • Severe throbbing headache

      • Dizziness

      • Flushing

      • Syncope (fainting)


    Develops with all nitrates coronary arterioles, thus allowing increased perfusion to the heart.

    Is dose-dependent

    Disappears in 24 h. after stopping the drug

    Tolerance can be avoided

    - Using the least effective dose

    - Creating discontinuous plasma levels

    NITRATESTOLERANCE

    " Decrease in the effect of a drug

    when administered in a long-acting form"


    Tolerance occurs because the enzyme required to break down GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    After a drug free period, the enzymes regenerate, and are ableto convert GTN to NO again.

    The best way to overcome the tolerance is to have a drug free period - the patient puts on a patch in the morning and takes it off at night (so that nighttime is their drug free period)


    NITRATES GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    CONTRAINDICATIONS

    • Previous hypersensitivity

    • Hypotension ( < 80 mmHg)

    • AMI with low ventricular filling pressure

    • 1st trimester of pregnancy

    • Constrictive pericarditis

    • Intracranial hypertension

    • Hypertrophic cardiomyopathy


    Uses: GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    Acute attack

    • Give GTN sublingually

      In anticipation of an attack

    • Take GTN sublingually before doing some work requiring physical effort

    • ISDN can be taken orally as well

    • ISDN is not suitable for an acute attack because its onset of action is much slower

      Prophylaxis

    • GTN transdermally or ISDN orally


    Calcium channel blockers
    Calcium Channel Blockers GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    • Four chemically distinct classes of calcium channel blockers are currently used to treat angina

    • Phenylalkylamines: Verapamil (Calan)

    • Benzothiazipines: Diltiazem (Cardizem)

    • Dihydropyridines: Nifedipine (Procardia), nimodipine (Nimotop), nicardipine (Cardene)

    • Diarylaminopropylamine ethers: Bepridil (Vascor)


    Mechanism of action
    Mechanism of Action GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    • The primary action of the calcium channel blockers is to block voltage-sensitive calcium channels

    • Dihydropyridines, verapamil, and diltiazem block L-type calcium channels which are abundant in cardiac myocytes, arteriole smooth muscle cells, SA nodal tissue, and AV nodal tissue

    • Bepridil blocks L-type channels, but also has significant sodium and potassium channel blocking activity in the heart


    Mechanism of action1
    Mechanism of action GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    • Block the L type voltage operated Ca2+ channel which is present on smooth muscle and cardiac muscle and in lots of other tissues which required the inflow of Ca2+.

    • By blocking these channels, Ca2+ is prevented from entering and causing smooth muscle contraction.

    • Nifedipine is used as a vasodilator

    • It is used to decrease TPR (and hence afterload), by decreasing the tone of the arterioles and arteries.

    • Verapamil is used to decrease contractility of the heart, reducing the force and rate of contraction byinhibiting the entry of Ca2+ into the cardiac muscle


    Pharmacological effects
    Pharmacological Effects GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    • All CCBs dilate coronary arterioles and reduce afterload, but each class has different effects on heart rate and cardiac contractility

      • Verapamil, diltiazem, and bepridil have direct negative inotropic, chronotropic, and dromotropic effects

      • The dihydropyridines have negligible direct effects on heart rate or contractility, but reflex increases in sympathetic tone (due to decreased arterial pressure) can increase heart rate and contractility which may aggravate angina


    The CCBs have little effect on preload GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    CCBs may inhibit platelet aggregation

    The desired therapeutic effects of CCBs in treating angina are to:

    Reduce myocardial oxygen consumption by reducing afterload

    Reduce myocardial oxygen consumption by reducing heart rate and contractility (except for the dihydropyridines which have minimal effects on contractility)

    Improve oxygen delivery to ischemic myocardium by vasodilating coronary arteries and by reducing heart rate (increased time spent in diastole)

    May also inhibit platelet aggregation


    Pharmacokinetics
    Pharmacokinetics GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    • The calcium channel blockers are orally active

    • The calcium channel blockers exhibit high first-pass metabolism and high protein binding

    • Most of the channel blockers used to treat angina are active within about 30 minutes after oral administration and have plasma half-lives of several hours

      • Bepridil and the newer dihydropyridines have longer half-lifes (24-50 hours)


    Adverse effects1
    Adverse Effects GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    • The major adverse effects of calcium channel blockers are typically direct extensions of their therapeutic actions and are relatively rare:

      • Depression of contractility and heart failure

      • Bradycardia

      • AV block

      • Cardiac arrest

    • Short-acting dihydropyridines have been associated with an increased incidence of sudden death (cardiac arrhythmia), perhaps by increasing sympathetic tone

    • Minor toxicities include:

      • Hypotension ,Dizziness .Edema ,Flushing


    Contraindications
    Contraindications GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    • Verapamil, diltiazem, and bepridil can worsen cardiac performance in patients with overt heart failure

    • Verapamil, diltiazem, and bepridil may depress contractility and produce AV block in patients receiving beta-blockers

    • Verapamil may increase serum digoxin levels in digitalized patients


    Uses: GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    • Prophylaxis for angina-The choice of drug depends on the patients underlying cardiovascular problems. E.g.

    • If angina + hypertension use nifedipine

    • If angina + arrhythmia use verapamil

    • Anthypertensives

    • Antiarrhythmic


    Beta blockers
    Beta blockers GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    • Propranalol

    • Atanalol

    • Metaprolol


    Mechanism of action2
    Mechanism of action GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    • Competitive beta adrenergic receptor blockers

    • By blocking beta1 receptors at heart decrease cardiac contractility (decrease force and rate) there by reduce oxygen demand.

    • Decreased arterial pressure (decrease afterload)


    Uses: GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    • Prophylaxis of classic angina(stable angina)

    • Antihypertensives

    • Antiarrhythmic


    ß-ADRENERGIC BLOCKERS GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    CONTRAINDICATIONS

    Hypotension: BP < 100 mmHg

    Bradycardia: HR < 50 bpm

    Chronic bronchitis, ASTHMA

    Severe chronic renal insufficiency

    Variant angina


    Therapy of variant angina
    Therapy of variant angina GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.

    • It is necessary to relieve the coronary vasospasm

    • Acute treatment:· GTN sublingually

      GTN relieves the spasm

    • Prophylaxis: · Ca2+ channel antagonists

      (Reduce Ca2+ entry into the smooth muscle around the coronary vessels, hence preventing theirconstriction)

    • Beta antagonists are never used- they can cause a rare adverse effect whereby they can actually cause coronary vasospasm.


    THE END GTN (the tissue thiols) are depleted, and so there is lack of conversion of GTN to NO.


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