Category: 3. Drugs acting on cardiovascular system

Drugs acting on renin angiotensin system are:

1. ACE inhibitors
2. Angiotensin receptor blockers

Angiotensin Converting Enzyme (ACE) Inhibitors

Enalapril is a prodrug, which is converted into enalaprilat in liver (active metabolite). Its duration of action is prolonged because of the active metabolite (24 hours). It is given in a dose of 5 mg which can be increased up to 40 mg.

Lisinopril is a lysine derivative of enalaprilat, but does not contain the sulphydral group. It has longer half life of about 12 hours. It is given in a dose of 5 mg, which can be increased up to 10 mg.

Mechanism of Action of ACE Inhibitors

• Renin is released from juxtaglomerular apparatus.
• Renin acts upon Angiotensinogen, to split off the inactive decapeptide Angiotensin I.
• Angiotensin I is then converted primarily by endothelial angiotensin converting enzyme (ACE) to Octapeptide, angiotensin II.
• Angiotensin II is the most powerful vasoconstrictor.
• It also stimulates the synthesis and secretion of aldosterone which retains sodium & water.
• ACE inhibitors inhibit the converting enzyme peptidyl dipeptidase & prevents formation of Angiotensin II. The same enzyme (under the name of plasma kinase) inactivates bradykinin, so it accumulates.
• Hypotensive activity results from:

1.  inhibitory action on Renin angiotensin system
2. stimulatory action on Kallikrein kinin system

Uses

1. Hypertension
2. Reverse ventricular hypertrophy
3. Decrease preload, afterload and sympathetic activity
4. Affect remodelling of heart
5. Congestive cardiac failure, improve survival of patient, providing symptomatic relief and having cardio protective effect
6. Myocardial infarction, increase survival rate
7. Diabetic neuropathy, decrease micro and macro vascular complications, decrease chances of end stage renal diseases and do not allow retinopathies to progress, increase creatinine clearance and decrease the requirement of dialysis, improving the life expectancy of patients
8.  Combination of ACE inhibitors & Angiotensin receptor blockers offer a better control of renin angiotensin aldosterone system, thus cardio protective and renoprotective effects of both these classes of drugs are combined.

Adverse Effects of ACE inhibitors (Captopril)     

1. GIT –abdominal discomfort, alteration of taste, apthous ulcers of mouth, angular stomatitis on prolonged use.
2. Renal –on prolonged use, patients of renal insufficiency have increased serum urea, creatinine levels and produce proteinurea. In patients with renal artery stenosis, can aggravate acute renal failure.
3. Allergic manifestations –skin rash, fever, urticaria
4. CVS –in sodium depleted patients cause excessive hypotension
5. CNS –headache, dizziness
6. Cough –in 30% of patients due to increase in bradykinin
7. Hyperkalemia
8. Neutropenia
9. Teratogenic Effects –in 1^st trimester damage to kidneys of fetus, can produce anuria and renal failure
10. Liver –liver injury

Angiotensin Receptor Blockers

Losartan is converted into active metabolite, which is 10-40 times more potent than losartan. It has a half life of about 2 hours, while active metabolite has a half life of 9 hours. 4% is excreted as such in urine, while the rest is metabolized in liver. It does not cross blood brain barrier, thus devoid of effects on CNS.

 Mechanism of Action

Angiotensin II is formed under the effect of two enzymes:

a.      Angiotensin converting enzyme
b.      Kinase

When ACE inhibitors are given, angiotensin II is still formed under the effects of kinase. It acts on two types of receptors:

1. Angiotensin I receptor (AT-1)
2. Angiotensin II receptor ( AT-2)

When angiotensin I receptors are stimulated, they produce effects similar to angiotensin II.

When angiotensin II receptors are stimulated, they produce effects that of opposite to angiotensin II (hypotensive activity, beneficial in treatment of hypertension).

Basically they competitive block AT-1 receptors, thus have effects of angiotensin II through angiotensin II receptors.

Uses

Uses are same as ACE inhibitors except that efficiency and safety of angiotensin receptor blockers has not been established in so many chemical studies.

Adverse Effects:

Like ACE inhibitors except dry cough, angioedema and rash are much less.

Dose

50 mg which may be increased up to 200 mg.

There are two types of calcium channels:

1. Voltage gated
2. Receptor operated

Type of Voltage gated Calcium Channels

Voltage gated channels open and close at a specific voltage. All types are found in neurons.

L Type -Muscle, Neurons ,Heart

T Type -Neurons , Heart, (thalamic neurons)           

N Type -Neurons

P Type -Cerebellar purkinje neurons

R Type -Neurons

Mechanism of Action

Blood Vessels

Arterioles are more sensitive to the effects of Ca++ channel blockers. They cause decrease in the entry of Ca++ leading to decreased Ca-calmodulin complex, decreased activation of myosin light chain kinases, resulting in dephosphorylation producing vasodilatation. This decreases blood pressure, preload and after load.

Cardiac Muscles

In cardiac muscles when given, cause decrease in entry of Ca++ into cardiac muscles. Cardiac muscles are dependent on Ca++ for normal activity. Impulse generation in SA node, conduction through AV node, excitation-contraction coupling and ultimately the contractility of heart, all decrease by the action of Ca++ channel blockers. This in turn leads to decreased cardiac output.

Dihydropyridines

Dihydropyridines have more affinity for smooth muscles of blood vessels. However, verapamil and diltiazem have more effects on cardiac muscles

Pharmacokinetics

They are well absorbed after oral administration. However, they have extensive first pass metabolism, this is why their bioavailability is decreased. They are also extensively bound to plasma proteins.

Drug	Bioavailability	Plasma protein binding
Nifedipine	55%	95%
Diltiazem	50%	80-85%
Verapamil	20%	90%

Half life varies between 4-5 hours; however, nifedipine has half life of 1.5 hours.

They are eliminated in urine, except diltiazem which is excreted in faeces.

Other Pharmacological Effects

1. Effect on other smooth muscles- bronchiolar, gastrointestinal , uterine & vascular muscles

Most smooth muscles are dependent on influx of Ca++ for tone and contractility, Ca++ blockers relax them.

2. Cardiac muscles

Effect AV conduction and contractility of heart, which are depressed by Ca++ channel blockers, thus are having cardio depressant effect.

3. Action on Skeletal muscles

Not depressed by Ca++ channel blockers as they use intracellular pools of Ca++ for their contractility, thus are not dependent on transmembrane Ca++ influx.

4. Cerebral vasospasm & infarct following subarachnoid hemorrhage

Among dihydropyridines, Nimodipine has affinity for cerebral blood vessels, so it is used to relieve cerebral vasospasm and infarcts.

5. Decreased release of insulin

Verapamil has been shown to inhibit the release of insulin, but the dose required is much higher.

6. Interfere with platelet aggregation

Due to interfere with platelet aggregation, preventing development of atheromatous lesions. However, this is not utilized in clinical practice.

7. Verapamil blocks transporter p-170 glycoprotein transporter

Can reverse resistance of cancer cells to chemotherapeutic agents.

Uses

1. Treatment of hypertension
2. Treatment of angina
3. Anti-arrhythmic (supraventricular)
4. Prophylactically in migraine
5. Subarachnoid hemorrhage
6. Raynaud’s phenomenon

Dose

10-20 mg depending upon condition of patient

Toxicity/Adverse effects

Most of the adverse cardiac effects are a direct extension of pharmacological actions, these include:

1. Cardiac depression
2.  Bradycardia
3. Aggravation of heart blocks
4. Immediate acting nifedipine as been shown to increase risk of MI in patients with HTN. Thus slow release preparations are given.
5. Dihydropyridines increase the risk of cardiac events in patients with or without diabetes.
6. Ca++ channel blockers should never be combined with beta blockers as both have cardiac depressing effects.

Minor Adverse Effects

1. Vasodilatation causing flushing
2. Headache
3. Conjunctival congestion
4. Nausea
5. Constipation
6. Dizziness
7. Peripheral edema

Hydralizine

Arterial vasodilator given parentally in emergency. It is given in combination with other drugs.

Hydralizine is a Phenelzine derivative. It is a direct arterial dilator having negligible effects on the veins. More effects are produced on the blood vessels of the heart, kidney, brain and less effects are produced on blood vessels of skin and muscles. On prolonged treatment, increase in blood pressure occurs due to:

1. Reflex increase in sympathetic activity
2. Increase in noradrenaline
3. Increase in renin

Pharmacokinetics

Hydralizine is well absorbed after oral route of administration. Peak plasma concentration occurs in 30-120 minutes. It is given I/V in hypertensive emergency. It is metabolized in the liver by the process of acetylation, with some genetic variations. In fast acetylators, half life is shorter (3-4 hours) while in slow acetylators half life is about 5 hours. It has prolonged duration of action due the active metabolite (12 hours).

Adverse Effects

1. Due to vasodilatation there is nasal congestion, flushing.
2. When given for prolonged periods, arthralgia and myalgia have been reported.
3. In high doses there is SLE like syndrome, serum sickness vasculitis, rarely hemolytic anemias are observed, glomerulonephritis is seen with it and there is polyneuropathy (responsive to pyridoxine).

Dose

1. 20-40 mg I/V in hypertensive emergencies
2. 25 mg tablet given orally twice or thrice daily depending on the blood pressure of the patient.

Diazoxide

Arteriolar vasodilator

Chemistry

Chemically related to thiazide diuretics but has no diuretic activity, rather causes salt and water retention.

Mechanism of Action

Exerts vasodilator effects, by causing increase in efflux of K+ and decrease in the influx of Ca++.

Adverse Effects

1. Excessive hypotension may occur, leading to MI and stroke.
2. In patients with ischemic heart disease, aggravates the angina due to reflex tachycardia.
3. Inhibits the release of insulin from pancreas, can be used to treat hypoglycaemia.
4. Can cause salt and water retention.

Therapeutic Uses

1. Hypertensive emergencies –main use
2. Treatment of hypoglycemias due to insulinomas (tumour secreting insulin)

Minoxidil

Arterial dilator. Prodrug, which is activated in the liver by sulphotransferrase enzyme in to minoxidil sulphate.

Mechanism of Action

It produces vasodilatation by causing increase in cGMP. In addition, causes increased efflux of K+ leading to hyperpolarization and interferes with mobilization of Ca++. It has more effect of the blood vessels of the heart, kidney, GIT, skin and has less effect on blood vessels of brain. When given for prolonged period of time, it causes increase in blood pressure, due to:

1. Reflex increase in sympathetic activity
2. Increase in noradrenaline
3. Increase in renin

This is why diuretics are added.

Pharmacokinetics

Well absorbed after oral administration. Peak plasma levels are observed in about 1 hour. 20% of the drug is eliminated as such in urine. Rest is metabolized by the liver. Half life is 3-4 hours.

Toxicity

1. Salt and water retention
2. Tachycardia due to reflex sympathetic activity
3. Hypertrichiosis (increase in growth of fine hair over scalp, abdomen and legs)
4. Allergic manifestations
5. Rarely thrombocytopenia

Dose

1. 40 mg tablet.
2. For I/V use, 10-20 mg
3. For topical preparations 2% lotions are used for treatment of baldness, but have only temporary effect.

Sodium Nitroprusside

Arteriolar and venous dilator used in hypertensive emergencies and post operation hypertension. It is given through continuous I/V infusions. It is actually a complex of cyanide, iron and nitroso group. It is metabolized in the RBCs and here cyanide is liberated. This cyanide interacts with sulphur groups in mitochondria, producing thiocyanate.

Toxicity

2 types of toxicity are seen

1. Cyanide toxicity
2. Toxicity of Thiocyanate

In cyanide toxicity, there can be metabolic acidosis, arrhythmias, hypotension and even death. It can be treated by

1. Giving sodium thiosulphate (increases metabolism of cyanide)
2. Hydroxycobalamine (cyanocobalamine formed)

Thiocyanate toxicity is seen in the elderly and patients with renal insufficiency, as it is slowly eliminated through the kidneys. Muscle weakness, muscular cramps are seen and patients can manifest in form of psychosis, hallucination disorders, etc.

Dose

50 mg in 5 ml injection.

Fenoldopam

Arterial dilator and D1 agonist. It is used in hypertensive emergency and in post operation hypertension. It is given through continuous infusions.

Adverse Effects

1. Flushing
2. Headache
3. Increased intraocular pressure
4. Reflex tachycardia

Alpha and beta blockers block alpha 1, beta 1 and beta 2 receptors, while act as partial agonist at beta 2 receptors, causing decrease in TPR.

Examples include Labetolol and Carvidolol

Uses

1. Pregnancy induced pheochromocytoma
2. Angina
3. Hypertension crisis
4. Abrupt withdrawal of clonidine

Adverse effects

Adverse effects include hypotension, weakness and headache.

Hypertension:

WHO defines hypertension as:

“Level of systolic blood pressure more than 140 mmHg and diastolic blood pressure more than 90 mmHg, done by repeated measurements over a period of several weeks”.

Hypertension is a common disorder especially after middle age. It is an important risk factor for cardiovascular diseases (mortality and morbidity).

BP Scheme for Adults (in mm Hg)

Normal:

                        systolic BP <120 and diastolic BP <80

Pre hypertension:

                        SBP 120-139 or DBP 80-89

Stage 1 hypertension:

                        SBP 140-159 or DBP 90-99

Stage 2 hypertension:

                        SBP> 160 or DBP> 100

Predisposing factors

1. Diabetes mellitus
2. Renal diseases
3. Hyperlipidemias
4. Cardiovascular diseases
5. Smoking

Types

1. Primary (Essential)

Most common, where non cause is known.

2. Secondary

Secondary to other diseases present in patient e.g. kidney diseases, heart diseases, pheochromocytoma.

BP = CO x PVR

Cardiac output and total peripheral resistance are controlled by moment to moment control.

There are four sites at which blood pressure is regulated:

1. Arterioles
2. Venules
3. Heart
4. Kidney

In addition, there is baroreceptor reflex system and control of blood pressure through rennin-angiotensin system.

Most of the drugs controlling blood pressure act at one of these sites.

• Some drugs act at arterioles causing dilatation, decreasing the after load.
• Drugs acting on venules cause decrease in preload.
• Drugs acting on heart decrease heart rate and cardiac output.
• Drugs acting on kidney decrease peripheral vascular resistance, decreasing water retention and blood volume.  

Most of these drugs control blood pressure completely

Some drugs do cause postural hypotension e.g. alpha blockers and adrenergic neuron blockers.

Choice of drugs involves those interfering minimally with hemodynamic mechanism.

On prolonged use, increase in blood pressure due to reflex increase in sympathetic activity occurs. This is because of increase in noradrenaline and increase in renin. Thus antihypertensives are used in combination with diuretics and ACE inhibitors.

Treatment

Non Pharmacological

If increase in blood pressure is not very severe, one should go for non-pharmacological treatment, including:

1. Restriction of salt intake
2. Removal of stress from life
3. Avoiding smoking
4. Moderation in use of alcohol
5. Regular exercise
6. Taking less cholesterol in diet

Pharmacological

If blood pressure is not controlled, we have to go for drug treatment.

Classification:

1. Diuretics
2. Sympathoplegics
3. Calcium channel blockers
4. Drugs acting on renin angiotensin system

i.      Ace inhibitors
ii.      Angiotensin receptor blockers

5. Vasodilators

1. Diuretics

a. Thiazides & related agents

• Hydrochlorthiazide
• Chlorthiazide
• Bendrofluzide
• Chlorthalidone
• Indapamide

b. Loop diuretics

• Frusemide
• Bumetanide
• Ethacrynic acid

c. Potassium Sparing Diuretics

• Triamterene
• Spironolactone
• Amlioride

2. Sympathoplytics

a. Centrally sympathoplegics

• Methyldopa
• Clonidine
• Guanabenz
• Guanfacine

 b. β-Adrenergic receptor antagonists

• Propranolol
• Metoprolol
• Atenolol

c.  α-Adrenergic receptor antagonists

• Prazosin
• Terazosin
• Doxazosin
• Phenoxybenzamine
• Phentolamine

d. Alpha & Beta Blockers

• Labetalol
• Carvedilol

e. Adrenergic Neuron Blockers

• Guanethidine
• Reserpine

f. Ganglion Blocking Agents

• Trimetaphan

3. Calcium – Channel Blockers

a. Dihydropyridines

• Nifedipine
• Nicardipine
• Nimodipine
• Amlodipine
• Felodipine
• Isradipine

b. Phenylalkylamines

• Verapamil

c. Benzothiazepines  

• Diltiazem

4. Drugs Acting On Renin Angiotensin System

a. Angiotensin Converting Enzyme (ACE) Inhibitors

• Captopril
• Enalapril
• Lisinopril
• Benzapril
• Quinapril
• Ramipril

b. Angiotensin II Receptor Blockers (Competitive antagonists)

• Losartan
• Valsartan
• Candesartan
• Eprosartan
• Irbesartan
• Telmisartan

5. Vasodilators

a. Arterial

• Hydralazine
• Minoxidil
• Diazoxide
• Fenoldopam

b. Venodilators

• Nitroglycerine

c. Arterial and Venous

• Sodium Nitroprusside

Continue Reading

Alpha and Beta blockers

Vasodilators

Calcium Channel Blockers

Drugs Acting on Renin Angiotensin System

Mannitol is the most commonly used osmotic diuretic.

It is given I/V and not orally as it might produce diarrhea. To be osmotically active it must have some properties:

1. Freely filtered from glomerulus
2. Should not be reabsorbed
3. Pharmacologically inert

Mannitol acts by physical property. It increases osmotic pressure and does not interfere with chemical processes.

Mechanism of Action:

1. Act throughout nephron, PCT mostly and thin descending limb.
2. Reaches the site of action by tubular secretion
3. Within the nephron increase osmolarity. Net movement of water out is impeded.
4. First increase osmolarity of vascular compartment, extracting water out from other compartments. Blood volume increases, while viscosity decreases. This increases renal blood flow, with greater washout of NaCl and urea. The hypertonicity of interstitium is decreased.

More water is excreted. Ions are still excreted but is very handy when greater water diuresis is required.

 Indications:

Raised Intracranial Pressure:

It is common after head injury, brain tumors and in meningitis. To reduce the pressure, mannitol can be given I/V in the form of infusion. Initially it increases the osmolarity of vascular compartment, extracting out water from CSF.

Raised Intraocular Pressure:

In glaucoma, to stabilize the patient before operation (angle closure glaucoma).

Increase Urine Volume:

In acute tubular necrosis, secondary to pigment overload or muscle breakdown, hemoglobinurea or myoglobinurea, tubular casts can physically block the nephrons which become edematous. To flush out, osmotic diuretics are used. (produce pressure diuresis and reduce edema).

Dialysis disequilibrium syndrome:

In peritoneal dialysis or hemodialysis, more solutes are lost decreasing the osmolarity and water from vascular compartment moves into intracellular spaces. Mannitol is used with diuretics to regain the balance.

Side Effects:

1. Hyponatremia initially, as blood volume is increased.

When excess diuresis occurs, hyponatremia turns to hypernatremia.

2. Precipitation of CCF, if increased blood volume, it worsens.

Potassium sparing diuretics act on the collecting tubule.

Chemistry:

Eplerenone is more selective for aldosterone receptors.

Canrenone is an active metabolite of aldosterone.

Triamterene and amiloride act independent of aldosterone. They are basic in nature, which are secreted in PCT by base secretory mechanism. All others are secreted by acid secretory methods.

Spironolactone is a synthetic compound which competitively blocks aldosterone receptors.

 Pharmacokinetics:

Spironolactone is 65% absorbed and metabolized in liver.

Canrenone has half life of 16.5 hours, and undergoes enterohepatic circulation.

Amiloride is basic in nature, secreted by base secretory mechanism.

Triamterene and hydroxyl triamterene are actively eliminated by kidneys. Toxicity might occur if liver or kidney failure occurs (metabolized in liver, excreted by kidneys)

Mechanism of Action:

1. Site of action is collecting tubule.
2. Reach the site of mechanism by two mechanisms:

Aldosterone antagonists differ from others as they have intracellular receptors and diffuse though blood. No tubular secretion occurs.

3. Normal Physiology

Sodium moves in while potassium moves out, a gradiant is established which pumps in chloride ions by transcellular pathway.

4. Ionic Changes

Aldosterone is a steroid having intracytoplasmic receptors. The receptor drug complex enters the nucleus, leading to protein synthesis and increased activity of certain silent Na+ channels and pumps (aldosterone induced proteins). They cause greater reabsorptive capacity of Na+. More Na+ present in cells is pumped into interstitium. More potassium is present in lumen. Which is titrated by hydrogen.

Aldosterone antagonists competitively antagonize the effects of aldosterone. This leads to decreased reabsorption of Na+ and decreased excretion of K+. So called K+ sparing diuretics.

Minimal NaCl is reabsorbed at this site but is the final site which determines Na+ excretion.

Non aldosterone antagonists physically block the channels. No sodium moves in and no potassium is lost, having K+ sparing effect. Decreased Na+ reabsorption leads to increased excretion of Na+, H+ and water.

These diuretics are weak. Only 2-5% NaCl reabsorption occurs.

5. No hemodynamic changes occur.

Indications

Aldosteronism

1. Primary –due to adenoma secreting aldosterone (Conn’s syndrome), tumor, ectopic
2. Secondary –due to CCF, cirrhosis, nephritic syndrome

The body senses hypovolemia and increases renin secretion.

Diuretics are used to mobilize the fluid (spironolactone like drugs)

Hypertension

In combination with thiazide diuretics. Moduretic (Amiloride and Hydrochlorothiazide) is an example.

Edema

To guard the development of hypokalemia, K+ sparing diuretics can be combined to counter alkalosis.

 Side Effects

Hyperkalemia

Decreased K+ excretion occurs if given with beta blockers, ACE inhibitors, renin antagonists, angiotensin receptor blockers.

Electrolytes levels must be checked.

Metabolic Acidosis

Due to blockage of H+ excretion.

Hormonal Effects

Spironolactone has steroid nature, due to which it might lead to:

1. impotence
2. menstrual abnormalities
3. hirsuitism
4. gynecomastia

Due to interference with androgens and progesterone receptors.

Thiazide diuretics are also known as NaCl symporter inhibitors.

Thiazide diuretics act on the distal convoluted tubule. They were discovered accidentally when people were trying to increase the carbonic anhydrase property. They found compounds which instead of increasing NaHCO3 secretion increase NaCl excretion. The name thiazide diuretics was coined for these compounds.

Chemistry

These are chemically sulphonamides and produce allergic manifestations.

As they act on luminal side, they reach the site of action through tubular secretion.

Pharmacokinetics

They are absorbed orally. Hydrochlorothiazide is the prototypical drug. Among others, Chlorothiazide can be given in large doses.

Chlorothiazide is slowly absorbed. Duration is 24-74 hours.

Metalazone is metabolized in liver, but enough drug reaches the kidneys in unchanged form.

Opposite to loop diuretics, these are given in a single dose. This is one reason why they are preferred in hypertension.

Duration Of Diuretic Action Of Thiazides

	Drug	Oral Dose(mg/day)	Duration(Hours)
Short Acting	ChlorothiazideHydrochlorothiazideHydroflumethiazideBenzofluazideCyclopenthiazide	500 – 200025 – 10025 – 2002.5 – 150.5 – 1	6-12“   ““   ““   ““   “
Intermediate Acting	MetolazoneCyclothiazideQuinethazoneMethyclothiazideTrichlormethiazide	2.5 – 201 – 250 – 20025 – 51 – 4	12 – 2418 – 2418 – 2424 ———“       “
Long Acting	IndapamidePolythiazideChlor – Thalidone	2.5 – 51 – 425 – 200	24 – 3624 – 4824 – 74

Mechanism of Action

1. Site of action is distal convoluted tubule.

2. Reach the site of action by active tubular secretion

3. Normal physiology

Distal convoluted tubule is responsible for reabsorption of 8-10% NaCl, and is relatively impermeable to water. Thus dilution of urine occurs here.

4. Ionic Changes

Thiazide diuretics block NaCl pump on luminal side. As Na+K+ pump is working overtime, relative deficiency of Na+ occurs; this stimulates the Na+ Ca++ exchanger. Na+ moves in while Ca++ moves out, leading to deficiency of Ca++, but is reabsorbed under control of PTH.

Greater the load of Na+ entering the tubules, greater is K+, Cl- and H+ loss. Also Mg++ depletion occurs by some unknown mechanism.

Hypocalcemia does not occur, sometimes hypercalcemia might occur by:

After some time, volume depletion occurs leading to increased Ca++ reabsorption at proximal tubule.

5. Hemodynamic Changes

a. As thiazide diuretics are responsible for prostaglandin stimulation, they produce vasodilatation independent of diuretic effect.
b. Sodium is itself responsible for stiffness of blood vessels and increased neural activity of blood vessels. After 6-8 week therapy, sodium depletion occurs leading to decreased calcium, which helps in producing vasodilatation.

Clinical Indications

1. Hypertension

Thiazide diuretics are the most preferred in hypertension because:

1. Once daily dose
2. Are active as antihypertensives in low doses (hydrochlorothiazide 25mg once daily)
3. PG mediated vasodilatation
4. Contributed after 6-8 weeks by sodium depletion
5. Action of diuretic (decreased blood volume and cardiac output) is blunted after some time (tolerance) but vasodilatation remains.
6. Various studies show that these are as effective as the beta blockers or angiotensin converting enzyme inhibitors
7. Are cost effective

Therefore, thiazide diuretics should be used as the 1^st line of defense. They are also used in combination with others. As pseudo tolerance develops, they are combined with beta blockers, ACE inhibitors, vasodilators (hydrillazine) and other diuretics.

2. Congestive Heart Failure

When heart is failing, kidneys perceive hypovolemia, and stimulate renin-angiotensin-aldosterone mechanism. Although this is helpful but in the long term, causes extra load on heart, which goes into perpetual failure.

Loop diuretics are preferred as they increase the efficacy of sodium and water elimination mechanisms. Thiazide diuretics may be combined for long term management. Also ACE inhibitors may be used.

In acute left ventricular failure, loop diuretics are used because they:

1. increase diuresis
2. decrease pulmonary congestion

3. Nephrolithiasis –idiopathic hypercalciuria

Most of the stones in the kidney are calcium phosphate. Because diuretics lead to increased calcium reabsorption from nephron, calcium excretion in urine is decreased. Thus precipitation of calcium within kidneys is reduced. Thus these are helpful in reducing stone formation.

4. Diabetes insipidus

It occurs in two forms:

1. Neurogenic –decreased ADH, increased dilute urine formation
2. Nehprogenic –ADH is present but kidneys are not responding

Copious amounts of urine is produced, up to 20 liters/day. Specific gravity is less than 1.006.

Thiazide diuretics when given, after some time produce volume depletion, leading to decreased GFR and increased reabsorption of fluid in PCT. Less fluid enters the distal segment. Thus urine volume may be reduced by 50%.

5. Bromide intoxication

Bromide ion is excreted and reabsorbed similar to Cl-. In intoxication, increased excretion occurs like Cl-.

Side Effects

1. Hypokalemic Metabolic Alkalosis

Greater entry of sodium in collecting tubules leads to greater loss of water and sodium.

2. Hypochloremia
3. Hypomagnesemia

4. Hyponatremia

May be worsened when increased loss occurs with ADH increased. Because of loss of sodium thirst occurs and person drinks more water which adds to hyponatremia.

5. Hyperglycemia and hyperlipidemia

Increased total cholesterol, triglycerides, low density lipids, this can be partially reversed if hypokalemia is adjusted.

6. Blockage of release of insulin from pancreas
7.Decreased peripheral utilization

8. Hyperuricemia

Due to competitive inhibition in S2.

9. Allergic Reactions

Due to sulphonamide nature.

10. Other toxicities

1. Weakness –due to K+ loss
2. Paresthesias
3. Fatigue
4. Impotence

Which are carbonic anhydrase inhibitors like properties

K+ has a narrow normal range (3.5-5.5 mg/dl), which should be kept in mind when using diuretics. If hypokalemia is present, it must be corrected by K+ supplements given orally. KCl can be injected I/V if critical condition arises, 25 ml of which are diluted up to 500 ml. It is given slowly, otherwise instantaneous death might occur.

Caution:

1. Cirrhosis –diuretics are used with caution, in case of overzealous treatment, problems might arise
2. CHF –if venous return decreases, CHF may aggravate
3. Renal –if blood flow is compromised, it is detrimental to renal functions

Interactions

With diuretics, loop and thiazide diuretics show synergism and potentiate each other’s effects.

Because thiazide diuretics produce hypokalemia, they are combined with K+ sparing diuretics.

Loop diuretics are also known as high ceiling diuretics or Na+K+2Cl- cotransporter inhibitors.

Loop diuretics act at the ascending thick limb. The ascending thick limb has the greatest capacity to reabsorb NaCl.

Why called high ceiling diuretics??

Where dose is on x-axis while Na+ excretion is on y-axis.

Maximum response is called ceiling effect. As loop diuretics have highest ceiling so called high ceiling diuretics.

Chemistry

Sulphonamide and carboxylic acid derivatives except ethacrynic acid (phenoxy acetic acid derivative).

Pharmacokinetics

Can be absorbed orally.

1. Torsemide takes 1 hour to reach peak levels. Duration of action is 4-6 hours.
2. Frusemide takes 2-3 hours to reach peak levels. Duration of action is shorter, 2-3 hours.

Site of action is within the lumen of nephron. They reach the site of action partly by filtration and mostly by active tubular secretion. After I/V injection, they produce dieresis within minutes.

Mechanism of action

1. Site of action is the ascending thick limb.
2. Reach the site of action by active tubular secretion in S2 segment.
3. Normal physiology

Greater K+ leads to extrusion leading to greater positivity, which pumps K+ by transcellular pathway along with Mg++ and Ca++.

4. Ionic Changes

Na+ and K+ are not reabsorbed and positive potential does not develops. They indirectly lead to decreased Mg++ and Ca++ reabsorption. Na+, K+ and Cl- are excreted along with Ca++, Mg++. Chronic use may lead to

1. hypomagnesemia
2. hypokalemia.

But hypocalcaemia does not develop because calcium is reabsorbed by distal convoluted tubule by separate mechanism.

5. Hemodynamic changes

Hemodynamic changes are probably prostaglandin mediated, producing vasodilatation. Redistribution of blood occurs, mainly in the kidneys. Intra renal blood flow increases under the action of loop diuretics. Venous return to the heart decreases, secondary to vasodilatation. Decrease in pulmonary congestion occurs, as well as decrease in left ventricular filling and decreased work load (preload). This effect is seen before any diuretic effect and is separate form it.

Indications

Acute pulmonary edema and CCF

Acute pulmonary edema is an emergency and the patient may die within minutes. Loop diuretics are used along with morphine and oxygen therapy. Loop diuretics are given I/V and are effective within minutes. They produce two types of effects:

1. PG mediated (decrease left ventricular filling pressure and pulmonary congestion)
2. Diuretic effect (reduce blood volume)

Pulmonary edema might be a complication of CCF but CCF, itself is different. Loop diuretics are effective in CCF as they decrease work load, as heart is not pumping enough blood,

If CCF is secondary to hyperaldosteronism (nephritic syndrome, cirrhosis, CCF) it puts extra pressure on heart.

Hypertension (emergency)

Loop diuretics are effective within minutes. Thiazide diuretics are better for long standing hypertension.

Loop diuretics decrease the blood volume and Na+ load, decreasing the neural activity along with Ca++ levels, while increasing the vasodilatation.

Torsemide has short duration of action.

Hypercalcemia

Used in emergency. Hypercalcemia might occur due to:

1. chronic renal failure
2. vitamin D excess
3. hyperthyroidism
4. tumors like carcinoma
5. breast and lung cancer
6. ectopic parathyroid hormone
7. milk alkali syndrome (overuse of NSAIDS or increased ingestion of milk)

These conditions can be treated by loop diuretics. They reduce the reabsorption of Ca++, but by themselves, do not produce hypocalcaemia because:

1. Separate mechanism is present in distal tubules
2. Volume depletion leads to activation of mechanism in proximal tubules to reabsorb Ca++

If combined with infusion of 0.9% NaCl, can lead to increased excretion of Ca++. In this case there is no volume depletion. Although some calcium is still reabsorbed, Ca++ excretion does take place.

 Refractory Edema

Loop diuretics are most efficacious in mobilizing the fluid.

 Hyperkalemia

In emergency, K+ excretion can be increased by

1. insulin therapy, which increases K+ entry into cells
2. Loop diuretics, which increase K+ excretion by increased Na+ excretion and increased load of Na+ at distal tubule.

Hypovolemia must not develop, so are combined with 0.9% NaCl.

 Acute Renal Failure

(Due to toxins or pigments overload)

Normally acute renal failure resolves automatically. Hemodialysis or peritoneal dialysis may be used. If secondary to hemolysis, loop diuretics can be used I/V as test drug. It can convert oliguric phase to non oliguric phase, which is helpful in excretion of K+. Loop diuretics do not shorten the duration of disease, but are still helpful.

 Halide Overdosage

Halides are reabsorbed at ascending thick limb, just like Cl-. Their reabsorption is also blocked, as are also univalent ions. In cases of poisoning due to these ions, loop diuretics can be given along with 0.9% NaCl.

 Adverse Effects

Hypokalemic metabolic alkalosis

Greater the load of Na+ entering nephron, more Na+ is reabsorbed and more K+ is excreted, so called hypokalemic metabolic alkalosis.

Ototoxicity

Main complaint is the fullness of ear, tinnitus, hearing loss and disturbance of ionic balance of endolymph. As Na+K+2Cl- is present in internal ear, so ionic balance is also disturbed, leading to ototoxicity.

Ethacranic acid is mostly ototoxic. If combined with amino glycosides, more ototoxic effects are seen.

Hyperuricemia

a. Same mechanism is present in S2 for loop diuretics and uric acid. Competitive inhibition of tubular secretion leads to hyperuricemia.
b. Volume depletion leads to increased reabsorption of uric acid, which may precipitate gout

As loop diuretics are used for hypertension and in CCF, basic investigations of uric acid levels must be done prior to starting the treatment.

Hypomagnesemia

No separate mechanism is present for Mg++, the levels of which decrease by long term usage. This might be a risk factor in cardiac arrhythmias.

Allergic Reactions

Suphonamids are notorious for allergic manifestations. Ethacranic acid is associated with far less allergic effects.

Other Adverse Effects:

Loop diuretics may also lead to:

1. Hyperglycemia
2. Disturbance of lipid levels ( increased LDL and decreased HDL)

Caution:

a. Cross – reactivity with sulphonamides

Loop diuretics cross react with sulphonamides. If person is hypersensitive, doctor should refrain from giving loop diuretics.

b. Hepatic Cirrhosis

If liver is not functioning, hypoproteinemia and decreased plasma oncotic pressure occurs, leading to exudation of fluid and development of edema or ascitis, known as third space hypovolemia.

As a result kidneys perceive hypovolemia and increase renin secretion. In this condition, aldosterone antagonists are preferred. Sometimes loop diuretics may be combined. But overuse is counter productive, as will lead to decreased volume and decreased blood flow to liver, worsening liver functions.

c. CCF

If heart is not pumping enough blood, salt and water retention occurs. Blood volume has to be decreased. If it is reduced too much, it decreases venous return. Overaggressive therapy might be harmful.

Drug Interactions:

1. As causes hypokalemia, in patients taking digoxin chances of cardiac arrhythmias are increased.
2. NSAIDS (aspirin) can blunt the action of loop diuretics by blocking the PG mediated effects.
3. If combined with amino glycosides, ototoxicity might occur.
4. Synergistic effects occur when combined with K+ sparing diuretics or thiazide diuretics, which increases their efficacy.

Increased efficacy with K+ sparing diuretics occurs in two ways:
a. Loop diuretics act on ascending thick limb, while K+ sparing diuretics on collecting tubule, different site of action enhances the effect.
b. Loop diuretics are associated with hypokalemia; K+ sparing diuretics spare K+.

Thiazide diuretics act at distal tubule, when combined leads to increased efficacy.

Carbonic anhydrase inhibitors act on the proximal convoluted tubule.

Drugs:

1. Acetazolamide
2.  Dorzolamide
3.  Brinzolamide

Dorzolamide and Brinzolamide are used topically for treatment of glaucoma.

Any diuretic acting at the proximal convulated tubule must be strong. These diuretics are weak and are chemically sulphonamides (associated with allergic manifestations)

Pharmacokinetics:

Drugs are well absorbed orally. When used produce HCO3- secretion producing urinary alkylation within 30 minutes. Maximum effect is observed within 2-3 hours. Single dose effect persists for 12 hours.

Mechanism of action

1.  Site of Action

Proximal convoluted tubule

2. How reaches site of action??

By tubular secretion

3. Normal physiological events

Sodium potassium pump is present in every portion of nephron. It pumps Na+ from intracellular space to interstitium, thus Na+ is reabsorbed and is decreased intracellularly. This is used by Na+H+ antiporter (NHE3) which pumps Na+ inside and H+ outside into the lumen, where H+ combines with HCO3- to form carbonic acid. Carbonic acid is acted upon by carbonic anhydrase, regenerating CO2 which is reabsorbed and forms carbonic acid once again. Once it is again acted upon by carbonic anhydrase HCO3- is produced, which is pumped into interstitium, while H+ is reused.

In later portion of nephron, not enough HCO3- remains. Decrease in pH stimulates Cl- base transporter. Cl- is pumped inside the cells, while base moves to the lumen.

4. What drug does??

Diuretic inhibits the luminal carbonic anhydrase and cytoplasmic carbonic anhydrase. This reabsorption of NaHCO3 does not take place. NaCl passive reabsorption dos not take place and there is loss of water as well.

In the distal portion of nephron, mechanism for is independent of HCO3- reabsorption. Most of NaCl is reabsorbed in distal portion.

Although carbonic anhydrase inhibitors act on proximal tubule, still they are weak because:

1. Action of diuretics is blunted by distal portion
2. Not enough HCO3- is present, depletion of HCO3- and excess of H+ occurs in plasma leading to metabolic acidosis

5. Ionic changes

Increased excretion of NaHCO3 momentarily, then over.

6. Circulatory changes

Located near distal convoluted tubule are specialized cells called macula densa. If increased Na+ reaches the distal tubule, tubuloglomerular feedback immediately reduces blood flow. Because it is active under influence of carbonic anhydrase inhibitors, this is another reason for decrease in action of carbonic anhydrase inhibitors.

Clinical Uses

Topically applied and instilled into eye.

1. Treatment of Glaucoma

HCO3- is secreted in aqueous humour similar to kidneys. When decreased secretion of HCO3- within eye by ciliary processes occurs, decreased production of aqueous humour occurs. Acetazolamide is still used.

2. Urinary Alkalinization

As increased HCO3- is lost, alkaline urine is produced, which enhances the excretion of weak acids, uric acid, aspirin, etc.

3. Metabolic alkalosis

Normally treated by volume replenishment and K+ replenishment, but sometimes in settings of CCF, these can be used to reverse metabolic alkalosis and produce dieresis as well. They produce an excess of H+ in plasma.

4. Acute mountain sickness

Those who rapidly ascend to 3000 feet or more, develop pulmonary edema, cerebral edema. CSF is produced by choroid plexus, which secretes HCO3- and water under carbonic anhydrase influence. If blocked, decreased production of CSF occurs. Thus, can be utilized in high altitude sickness. These drugs are more important if used prophylactically.

Other Uses

1. Epilepsy

Acetazolamide may be effective as metabolic alkalosis suppressive activity occurs on abnormal electrical activity of brain. Thus these drugs can be used when others fail.

2. Hyperphosphatemia

As alkaline urine is produced, increased phosphate and Ca++ are excreted.

3. Hypokalemic periodic paralysis

Patient suffers from paralysis and weakness, but recovers automatically. Genetic disorder, these drugs may be used.

Toxicity

1. Hyperchloremic metabolic acidosis

HCO3- is lost in urine while Cl- is reabsorbed distally, combined effect produces hyperchloremic metabolic acidosis.

2. Renal stones

As alkaline urine is produced, increased phosphates are lost along with calcium, which do not remain soluble and may precipitate.

3. K⁺ wasting

As increased sodium reaches the distal portion and collecting tube, increased reabsorption occurs along with increased K+ loss, which sometimes manifests in form of weakness.

4. Paresthesias & drowsiness

CSF effect.

5. Allergic manifestations

Bone marrow suppression, interstitial nephritis

Contraindications

Hepatic cirrhosis

If liver is not functioning, ammonia is not handled properly, leading to hyperammonemia hepatic encephalopathy.

NH4+ is converted into NH3 and is reabsorbed. H+ combines with bicarbonates.