GLYCERYL TRINITRATE

Renal colic [Ref: KDT 6^th/e p. 524-530]

The main pharmacological action of Nitrates

• Nitroglycerine relaxes all types of smooth muscle irrespective of the state of the preexisting muscle tone.
• The most prominent action is exerted on the vascular smooth muscle.

–   Apart _.from vascular smooth muscle nitrates also cause relaxation of the smooth muscles of the bronchi, gastrointestinal tract (including biliary system) and genitourinary tract.

• Nitrates are rapidly denitrated in the smooth muscle to release nitric oxide which activates cytosolic guanyl cyclase which in turn increases CGMP that leads to vasodilation

Effect of nitrate on cardiovascular system

• Nitrates cause relaxation of all the components of vascular system from large arteries to veins, arterioles and

capillaries. 

• Veins respond at the lowest concentrations and arteries at slightly higher one (Veins express greater amount of the enzyme that generates NO )from organic nitrates).
• The primary direct result of an effective dose of nitroglycerine is marked relaxation of veins with increased venous capacitance and decreased ventricular preload. This leads to reduction in pulmonary vascular pressure and heart 

size. 

Effect of nitrates on coronary circulation 

‘• In normal subjects without coronary disease

– Nitroglycerine can induce a significant if transient increase in total coronary blood flow.

• In patients with angina due to atherosclerosis

– There is no evidence that total coronary _.flow is increased in patients with angina due to atherosclerotic obstructive

coronary artery disease. 

However, in these patients 

– Nitrates cause redistribution of coronary blood flow from normal to ischemic regions which may play role in

therapeutic effect.

There are two types of vessels in coronary circulation :­Larger conducting arteries

• They run epicardially and send perforating branches to deeper tissue.

 Smaller resistance vessels

• These are the perforating branches of larger conducting arteries.
• These arterioles supply blood to endocardium. If there is ischemia in any region of endocardium the perforating vessels of those region are dilated due to autoregulation (hypoxia causes vasodilation).

 Nitrates preferentially dilates larger conducting vessels.

This pattern of action favours more blood flow towards the ischaemic zone as the smaller endocardial vessels are already dilated as a result of hypoxia / ischaemia.

Nitrates in heart failure

• Nitrates afford relief by causing venous pooling of blood.

– Nitrates reduce venous return (preload) decreases end diastolic volume –4 improvement in left ventricular function by Laplace law regression of pulmonary congestion.

Nitrates are used in cyanide poisoning

• Cyanide poisoning results from complexing of cytochrome iron by the CV ion.

– Methemoglobin has a very affinity for CN ion.

– Methemoglobin combines with CN to form cyamnethemoglobin which is rapidly excreted by the body.

• It is a well known fact that Nitrates generate generate Methemoglobin when they combine with Hb. – Thus administration of nitrates will generate large amount of methemoglobin.

– Due to its high offinity_.for cyanide, methemoglobin combines with cyanide _.forming cyanmethemoglobin. – This will regenerate active cytochrome.

– However this may again dissociate to release cyanide.

– The cynamethemoglobin can be further detoxified by the intravenous administration of sodium thiosulfate. This results in formation of thiocyanate ion a less toxic ion that is readily excreted.

Biliary colic

Esophageal spasm

• Sublingual GIN promptly relieves pain. Nitrates taken before a meal facilitate feeding in esophageal achalasia by reducing esophageal tone.

Also remember these important properties of Nitrates.

Oral availability of Nitrates is low

• The liver contains a high capacity organic nitrate reductase that removes nitrate groups in a stepwise _fashion from the parent molecule and ultimately inactivates the drug.
• Therefore oral bioavailability of the traditional organic nitrates e.g. nitroglycerine and isosorbidedinitrate is very low.
• For this reason sublingual route is preferred for nitrates. Nitroglycerine and isosorbide dintrate are both absorbed effectively by this route and reach therapeutic blood levels within a few minutes.

Nitrates develop tolerance

• With continued exposure smooth muscles develop tolerance to nitrates.
• The mechanism by which tolerance develops are not completely understood. As noted above diminished release of
• nitric oxide resulting from depletion of tissue thiol compounds may be partly responsible _,for tolerance to nitrates.
• Some student argue that cyanide poisoning should be the answer because nitrites not nitrates are used in cyanide poisoning but we are not convinced.
• All the standard books group them together and do not differentiate between nitrates or nitrites. More so

Nitrates have’nt found wide clinical use in Renal colic

– None of the standard text books mention use of nitrates in renal colic.

– Both Goodman Gilman and KDT says that unlike its consistent effect on muscles of biliary tract, the action

of nitrates on ureteric muscles is variable therefore it has not found application in renal colic.

– None of the studies and research papers convincingly state that nitrates should be used in renal colic.

Nitrates have been anecdotally used only in uruguay to treat renal colic.

A trial was conducted based on this but it did’nt come out with conclusive results.

– It states that large trials and studies should be undertaken before nitrates before nitrates use is begun clinically.

Ans. is ‘b’ i.e., Decrease preload

Ans. is ‘a’ i.e., By increasing the left ventricular end diastolic pressure

o Nitratets dilate veins (capacitance) vessels and decrease venous return (preload)
o This results in decreased end diastolic pressure and left ventricular size (not increased), which ultimately leads to decreased oxygen consumption.

Ans. is ‘a’ i.e., Causes AV conduction delay

Nitroglycerine and other nitrates have no effect on A-V conduction.
About other options
o Tolerance can develop if nitrates are continuously present in the body.
o Nitrates can cause reflex tachycardia and hypotension.

Ans. is ‘a’ i.e., Hypotension and bradycardia

Nitrates effect on BP & HR
o Nitrates cause vasodilatation that results in:

1. Hypotension
2. Reflex tachycardia (not bradycardia)

o Due to hypotension (caused by vasodilatation) there is reflex sympathetic stimulation –> stimulation of β₁ receptor on heart –> tachycardia.

Ans. is ‘b’ i.e., SH groups in the enzyme

o Tolerance develops to hemodynamic and antiischaemic effects of nitrates if they are continuously present in the body. No significant tolerance develops when nitrates are used intermittently. However; significant tolerance develops when nitrates are used continuously. This mechanism of nitrate tolerance is not well understood. The mechanism proposed is —> “Reduced ability to generate NO due to depletion of cellular SH radicals”.

Ans. is ‘b’ i.e., Hepatic first pass metabolism

o This question is tricky one as option b & c literally have the same meaning, i.e. any drug with high hepatic first pass metabolism will have lower oral bioavailability.

o But, we use sublingual nitroglycerine to produce immediate relief of symptoms in angina By sublingual route there is direct absortiption into systemic circulation bypassing liver.

“The sublingual route is used when terminating an attack or aborting an imminent one is the aim. The tablet may be crushed under the teeth and spread over buccal mucosa. It acts within 1-2 min because of direct absorption into systemic circulation (bypassing liver where almost 90% is metabolized)”

Ans. is ‘c’ i.e., Renal colic

Uses of nitrates

1. Angina pectoris
2. MI
3. CHF and acute LVF —> nitroglycerine i.v. can be used Act by decreasing preload (LV filling pressure).
4. Biliary colic and esophageal spasm (achalasia cardia)
5. Acute coronary syndrome (unstable angina and non-ST segment elevation Ml).
6. Cyanide poisoning

Ans. is ‘a’ i.e., Nitrates & ‘b’ i.e., CCBs

Ans. is ‘b’ i.e., Nitrates

Treatment of variant angina

Drugs are :

1.       Nitrates

2.       Calcium channel blockers (verapamil, diltiazem)

o Nitroglycerin is considered the drug of choice for the patient with variant angina.

o Prazosin a selective a-blocker may also be used because it prevents a mediated vasospasm.

o β-blocker’s are contraindicated because they cause constriction of coronary artery due to unopposed a mediated vasoconstriction.

Prevention of variant angina

o In contrast Nitrates are not used for the prevention of variant angina because of delevelopment of tolerance.

o CCBs are the DOC for prevention.

Answer is B (Nitrates)

“Sublingual nitroglycerine is the drug of choice” — CMDT

Nitrates decrease arteriolar and venous tone, reduce preload and afterload, and reduce the oxygen demand of the heart. Nitrates may also improve myocardial blood flow by dilating collateral channels in the presence of increased vasomotor tone, or coronary stenosis.

Answer is D (Idiopathic Hypertrophic Sub Aortic Stenosis):

Idiopathic hypertrophic subaortic stenosis (HOCM) is a dynamic outflow obstruction which is increased by any mechanism decreasing the preload. Nitrates decrease the preload, & the volume of blood in LV & thereby increase the dynamic obstruction & symptoms of angina.

Answer is B (Hypertrophic obstructive cardiomyopathy)

Family history of the disease and aggravation of symptoms with the intake of Nitroglycerine (Nitrates) nugget the diagnosis of Hypertrophic obstructive cardiomyopathy.

Ans. C: Evening

If nocturnal angina is a predominant symptom, long term nitrates can be given at the end of the day

Nitrates:

• They cause vasodilation, flushing, headache, dizziness, met-hemoglobinemia
• Decreases preload and afterload
• Decreases myocardial oxygen consumption
• Causes reflex tachycardia, hypotension
• Long acting nitrates are not used chronically as tolerance develops
• *Shortest acting NITRITE: Amyl nitrite
• Shortest acting nitrate: Nitroglycerine
• Longest acting nitrate: Penta-erythritol-nitrate

Ans. is `d’ i.e., Naloxone

Ans. is ‘c’ i.e., Beta blocker

Use of beta blocker and long acting nitrate combination is rational in classical angina because :

1. Tachycardia due to nitrate is blocked by beta blocker
2. The tendency of beta blocker to cause ventricular dilatation is countered by nitrate
3. The tendency of beta blocker to reduce the total coronary flow is opposed by nitrate

Ans. is ‘c’ i.e., Total coronary flow 

Mechanism of action of nitrates in Prinzmetal’s angina is endothelium independent coronary vasodilation. When metabolized, organic nitrates release nitric oxide (NO) that binds to guanylyl cyclase in vascular smooth muscle cells, leading to an increase in cyclic guanosine monophosphate, which causes relaxation of vascular smooth muscle.

“Nitrates benefit patients with variant (also known as Prinzmetal) angina by relaxing the smooth muscle of the epicardial coronary arteries and relieving coronary artery spasm.”

Pharmacological actions of nitrates

• The only major action is direct nonspecific smooth muscle relaxation. Preload reduction – Nitrates dilate veins more than arteries decreased venous return (preload) → decreased end diastolic size and pressure → decreased O₂ consumption.
• The most prominant action is exerted on vascular smooth muscles.
• Afterload reduction – Nitrates also produce some arteriolar dilatation → slightly decreased total peripheral resistance (afterload).
• Redistribution of coronary flow.
• Other smooth muscles – Nitrates cause relaxation of bronchi, biliary tract, esophagus → can be used in biliary colic and esophageal spasm.