Pharmacological treatment of Angina-Part I

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-Cardiac myocytes extract  60% of oxygen out of the coronary artery whereas skeletal muscle only extracts 20%.

1. 1 Organic Nitrates (Decrease Oxygen Demand)

(a) Introduction:

-Nitrate esters (-C-O-NO2)and nitrite esters (-C-O-NO)

-Glyceral trinitrate/Nitroglycerin (Not a nitro compound but a organic nitrate compound)

-Organic nitrates of low molecular mass (e.g. nitroglycerin) are volatile (dosage form considerations), oily liquids

-High molecular mass  (e.g. erythrityl tetranitrate, isosorbide dinitrate, isosorbide mononitrate) are solids (dosage form considerations)

Organic nitrates + Nitrites => Collectively known as Nitrovasodilators (Non active)

***They must be reduced by aldehyde dehydrogenase (in vivo) to produce free radical Nitric Oxide (NO) which is the active component of the drug

(b) Mechanism of action:

NO must be formed

-Nitrites, organic nitrates, nitroso compounds, nitrogen oxide containing substances (including nitroprusside) can lead to NO formation

Organic nitrates

-NO activates GC, activates PKG, Modulates activities of Phosphodiesterase (PDE), reduces breakdown of cGMP and cAMP in endothelial cells and smooth muscles.

In smooth muscles, NO mediated increase in intracellular cGMP would activate PKG which leads to

*reduced phosphorylation of myosin light chain (MLK) and reduced calcium ion concentration in the cytosolol

*Vasodilation (Vasorelaxation)

1.2 Effects of Nitric Oxide

1) Cardiovascular effects: Hemodynamic Effects (Blood flow/Circulation effects)

At low concentrations of Nitroglycerin,

-Veins are preferentially dilated compared to arterioles

-The venodilation decreases left and right ventricular chamber size and end-diastolic pressures.

-However, there is little change in systemic vascular resistance (because arterioles are not significantly dilated). Systemic arterial pressure may decrease slightly, no change or slight increase in heart rate (baroreceptor reflex).

*Venous return to the heart affected, preload is decreased.

*****Therapeutic Point: Dose of nitroglycerin don’t alter systemic arterial pressure often produce arteriolar dilation in the face and neck, resulting in flush or dilation in the meningeal arterial vessels, resulting in headache.

At high concentrations of Nitroglycerin,

-Furthur venous pooling occurs

Aterioles are dilated (resulting in decreased arteriolar resistance)

-This decreases systolic and diastolic blood pressure (Decreases preload and afterload–>Reduces cardiac workload) and cardiac output (CO)

*Adverse effects:

1. Pallor (reduced amount of oxyhemoglobin in the skin)

2. Weakness, dizziness and activation of compensatory baroreceptor-mediated sympathetic reflexes

-Reflex tachycardia and peripheral arteriolar vasconstriction tend to restore systemic vascular resistance.

-Coronary blood may increase transiently due to vasodilation of coronary arteries but may decrease due to baroreceptor reflex which occurs if BP and CO drop too much.

2) Cardiovascular effects: Effects on Total and Regional (flow of blood through/around an organ) Blood Flow

(a) ***Ischemia is a powerful stimulus to coronary vasodilation

***Regional blood flow is adjusted by auto-regulatory mechanisms

Autoregulation: To increase blood flow to starved tissues and NO assist to restore blood flow

-In the presence of atherosclerotic coronary artery narrowing, ischemia distal to the lesion stimulates vasodilation.

Cardiac catheterization and coronary angiography i

(b) Significant coronary stenoses disproportionately reduce blood flow to the subendocardial regions of the heart

-These regions are subjected to compression of vessels during systole (less blood flow to subendocardial regions)

***For (a) and (b), Organic nitrates tend to restore blood flow in these regions. This is due to the ability of organic nitrates to cause dilation and prevent vasoconstriction of large epicardial vessels without impairing autoregulation in the small arterial vessels (unlike sildenafil, sodium nitroprusside and dipyridamole).

This results in an increase in blood flow which would be distributed preferentially to ischemic regions due to vasodilation induced by autoregulation.

*This is known as vascular steal (the diversion of blood to ischemic regions)

Vascular steal

-Nitric Oxide dilates collateral blood vessels (extra blood vessels that connect portions of the same artery)–>Blood flow to the ischemic area increased.

3) Cardiovascular effects: Effects on Myocardial Oxygen Requirements

-Organic nitrates reduce myocardial oxygen demand (increase systemic circulation means more blood flow to visceral, afterload and preload decreases)

-These nitrate drugs increase venous capacitance (circulation) which results in decreased venous return to the heart. This decreases ventricular end-diastolic volume and pressure (less preload, distention of myocytes). This reduces oxygen demand/ consumption.

Decreasing pheripheral arteriolar resistance (at high concentrations of nitrates) reduces afterload and thus cardiac work and oxygen consumption. Reduces oxygen demand.

Thus, Organic nitrates decreases both preload and afterload as a result of dilation of venous capacitance and arteriolar resistance vessels.

4) Cardiovascular effects: Relief the symptoms of Angina Pectoris

-Nitrates reduce angina pain due to

  • Fall in systemic arterial pressure (Major factor)
  • decrease in cardiac work (secondary factor)
  • Also, dilation of epicardial coronary arteries (outermost layer)

***However, high doses of organic nitrates may reduce blood pressure to such an extent that coronary flow is compromised.

 Reflex tachycardia and adrenergic enhancement of contractility also occur

-These effects may override the beneficial action of the drugs on myocardial oxygen demand

1.3 Pharmacokinetics of Organic nitrates: Absorption, Fate and Excretion

Absorption: **Peak concentrations of nitroglycerin are found in the plasma within 4 mins of sublingual administration of tablet

Fate: Drug only has half life t1/2 of 1-3 minutes.

Metabolism: No 1st pass metabolism, rapid entry

Note: Onset of action of nitroglycerin more rapid if delivered as sublingual spray

-Angina pain may be prevented when drug is used prophylatically immediately prior to exercise, sex or stress

***Very important Therapeutic Point:

If patients do not get pain relief from 3 nitrate tablets over 15 mins, myocardial infarction (Heart attack) may have occurred and medical attention should be sought immediately.

(i.e. 1st spray/tablet–>Wait 5 mins–>If pain still persists, take another tablet/spray and call the ambulance)

Dosage forms available: Sprays/Tablets/Patches

-Transdermal nitroglycerin disks use nitroglycerin impregnated polymer that permits gradual absorption and continuous plasma nitrate concentration over 24 hours.

-The onest of action is slow, with peak effects at 1-2 hours

Tolerance: Avoid continuous use. Therapy should be interrupted for at least 8 hours a day. (Advise patients to use during day time where physical activities are highest)

 

1.4 Types of organic nitrates:

  • Isosorbide Dinitrate (ISORDIL)-Sublingual route (Unstable half life)

Administration route: Sublingual,  maximal plasma concentrations of the drug by 6 mins.

Pharmacokinetics: Half life of ~45 mins

Metabolism: Major route is by enzymatic denitration (aldehyde dehydrogenase) followed by glucorinide conjugation.

*Initial metabolites: Isorbide-2 mononitrate and isosorbide-5 mononitrate have a longer half life (3-6 hours) and contribute to therapeutic effects.

 

*Therapeutic point: Sublingual organic nitrates (e.g. glyceral trinitrate) should be taken at the time of angina attack or anticipation of exercise or stress.

However, continuous exposure to high doses of organic nitrates leads to attenuation/tolerance.

 

  • Isosorbide 5-mononitrate (IMDUR)-Tablet (Relatively more stable)

+ Does not undergo significant first pass metabolism and has excellent bioavailability after oral administration

+IMDUR has a significantly longer half life than isosorbide dinitrate, thus formulated as a plain tablet or sustained release preparation

 

+Both of these dosage forms have significantly longer durations of action than the corresponding dosage of isosorbide dinitrate. 

 

-Tolerance has also been observed with isosorbide 5 mononitrate (IMDUR). A daily p.o dosing schedule maintains efficacy.

 

 

Tolerance… Why does it occur?

-As mentioned previously, continuous high doses of glyceryl trinitrate (sublingual use) will  lead to attenuation/tolerance.

1. Tolerance may result from reduced capacity of the vascular smooth muscle to convert nitroglycerin to NO (true vascular tolerance) [i.e. vascular smooth muscle cannot convert nitroglycerin to NO well]

-Inactivation of aldehyde dehydrogenase enzyme required to generate nitric oxide from organic nitrates implicated in nitroglycerin biotransformation.

-A reactive intermediate formed (superoxide) during generation of nitric oxide from organic nitrates may itself damage and inactivate the enzymes of the activation pathway.

2. Also, activation of mechanisms extraneous to the vessel wall (pseudotolerance) may occur as well [i.e. net reduction in vasodilator response due to neurohumoral response-mediated vasoconstriction]

 

***Therapeutic point: A good way to avoid tolerance is to interrupt therapy for at least 8 hours -12 hours (preferentially 10 hours) daily to restore efficacy.

 

-Usually patients with exertional (stable) angina are advised to omit dosing at night. Oral or Buccal dosages can be adjusted accordingly. Also, patches of nitroglycerin can be removed.

 

Note: Patients whose angina pattern occurs in association with orthopnoea (shortness of breath when lying flat) or paroxysmal nocturnal dyspnea (sudden attack of breathlessness which occurs at night), may benefit from continuing nitrates at night and omitting them during a quiet period of the day.

 

-Tolerance has also been observed with isosorbide 5 mononitrate (IMDUR). A daily p.o dosing schedule maintains efficacy.

 

 

1.5 Adverse effects/Side effects/Toxicity

 

1. Headache is common

-(vasodilation of meningeal vessels) Decreases over few days if treatment is continued and responds to decreasing doses. [Esp. low doses]

 

2. Dizziness, weakness and postural hypotension may develop

-(Due to vasodilation in peripheral vessels). Blood accumulates in periphery. Reaction is worsened by alcohol.

 

3. Syncope (loss of consciousness-fainting)

-Remedies include positioning head low and facilitating venous return.

 

4. Rashes

-All organic nitrates can occasionally produce rash (excessive vasodilation?)

 

5. Monday Morning disease

-Development of tolerance over work week. Over the weekend, the tolerance is lost and on monday, headache occurs due to drastic vasodilation.

 

6. Reflex tachycardia

-Occurs with high doses of nitric oxide.

-Baro-receptor mediated reflex

 

7. Erectile dysfunction

-Erectile dysfunction is a frequently encountered problem whose risk factors are similar to those with coronary artery disease (CAD)

-People with erectile dysfunction tend to also have diabetes which inhibits circulation, leads to circulation problems.

 

1.6 Drug interactions associated with nitrates

 

-As mentioned above, erectile dysfunction is a common problem.

-If nitrates were taken with erectile dysfunction medications (i.e. phosphodiesterase 5 inhibitors-Sildenafil, tadalafil and vardenafil), dramatic reduction in blood pressure occurs.

 

Recall: 

 

-cAMP and cGMP both causes smooth muscle dilation–>Relaxation

-PDE 5 breaksdown cAMP and cGMP (thus reducing muscle dilation–>Contraction)

-Since PDE 5 inhibitors prevents breakdown of cAMP and cGMP, it will prevent smooth muscle from contracting.

-In the presence of Nitrates, dramatic increase in cGMP will dramatically reduce blood pressure.

-Thus, all 3 PDE5 inhibitors are contraindicated in patients taking nitrodilators.

 

 

 

 

 

Questions associated with organic nitrates:

 

1. Difference between glyceryl trinitrate and isosorbide dinitrate (ISODRIL)

2. Does the 8 hour of non-continuous use daily mean that 2 x 4 hour intervals is equivalent?

3.  Why does organic nitrates cause rash? Due to excessive vasodilation?

4. Interactions with beta blockers? Calcium channel blockers?

 

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