Quinapril Hydrochloride




Credit: pfizer.com

It is an ethyl ester of non-sulfhydryl compound, quinaprilat.

Mechanism of Action:
It is an angiotensin converting enzyme inhibitor (ACE) inhibitor. ACE is an enzyme that converts the angiotensin-I to angiotensin-II.

Pharmacokinetics:
Peak plasma concentration of quinapril hydrochloride is found within 1 hour after administration. The extent of absorption is about 60%.

After absorption about 38% of quinapril is converted into its major active metabolite i.e. quinaprilat. About 97% of quinapril or quinaprilat is bound to plasma proteins.
Uses:
It is used in hypertension and congestive heart failure.

Contraindications:

ACE inhibitors are contraindicated in second and third trimester of pregnancy as they may cause injury and sometimes death of the developing fetus.

Brand Name:

Accupril
Accuretic (Quinapril Hydrochloride and hydrochlorothiazide)

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Crystallization

Definition:

It is the (natural or artificial) process of formation of solid crystals precipitating from a solution, melt or more rarely deposited directly from a gas.

Crystallization is also a chemical solid-liquid separation technique in which mass transfer of a solute from the liquid solution to a pure solid crystalline phase occurs.

Process of crystallization:
There are two major events in the process of crystallization

a. Nucleation
b. Crystal growth

Nucleation:
A step where the solute molecules dispersed in the solvent start together into clusters on the nanometer scale. These become stable under the current operating conditions.
However, when the slucters are not stable they redissolve. Therefore, the clusters need to reach a critical size in order to become stable nuclei.
It is at the stage of nucleation that the atoms arrange in a defined and periodic manner that defines the crystal growth.

Crystal growth:
It is the subsequent growth of the nuclei that succeed in achieving the critical cluster size.
Supersaturation:
Nucleation and crystal growth continue to occur simultaneously while the supersaturation exists.

Supersaturation is the driving force of the crystallization hence the rate of nucleation and growth is driven by the existing supersaturation in the solution.

Once the supersaturation is exhausted, the solid-liquid system reaches equilibrium and the crystallization is complete.

Polymorphism:
Many compounds have the ability to crystallize with different crystal structures a phenomenon called polymorphism.

Each polymorph is in fact a different thermodynamic solid state crystal polymorphs of the same compound exhibit different physical properties such as dissolution rate, shape and melting point etc.

So, polymorphism is of major importance in industrial manufacture of crystalline product.

Artificial method for crystallization:
For crystallization to occur from a solution, it must be supersaturated. This can be achieved by solution cooling, addition of a second solvent to reduce the solubility of the solute (techniques known as antisolvent or drawn out), chemical reaction or change in pH being the most common methods used in industrial practice.

Other methods such as solvent evaporation can also be used.

Applications:
Crystal production such as powdered slat for food industry, silicon crystal wafer production and production of sucrose from sugar beet, where the sucrose is crystallized out from an aquous solution.

Purification:
Crystallization separates out a product from a liquid (feedstream) often in extremely pure form by cooling the feedstream or adding precipitants which lower the solubility of the desired product so that it forms crystals.

Well formed crystals are expected to be pure because each molecule or ion must fit perfectly into the crystal as it leaves the solution.

Apparatus for crystallization:
Tank crystallizers:
Saturated solutions are allowed to cool in open tanks. After a period of time the mother liquid is drained and the crystals removed. In this method, nucleation and size of crystal are difficult to control. Labor costs are high.

Scrapped surface crystallizers:
One type of scraped surface crystallizer consists of Swensen-Walker crystallizer consisting an open of an open trough 0.6 meter wide with a semicircular bottom having a cooling jacket outside.

A slow speed spiral agitator rotates and suspends the growing crystals on turning the blades pass close to the walls and break off any deposits or crystals on the cooled wall.

Adsorption

Definition:

“it is a phenomenon in which accumulation of a substance at the boundary on interface between the hetergenous phases takes place.”

Explanation:
It is difficult from absorption, as the absorption is the distribution of a substance throuth the bulk solution while adsorption is a surface phenomenon.

Sorption:
It is sometimes very difficult to define clearly the interface of highly porous solids, so for these system the term sorption is used as we cannot distinguish wether it is adsorption or absorption.

The substance that is attached to the surface of the solid is called adsorbate and the surface on which it gets adsorption is called adsorbent.

Occurance:
Adsorption can occur on following interfaces:

• Solid/Liquid
• Solid/gas
• Liquid/gas
• Liquid/liquid

Since adsorption is a surface phenomenon. The most effective adsorption are those with high surface area e.g. finely divided solids.

Positive adsorption:
Adsorption shows the ratio of a substance at the interface and the bulk phase if the concentration of the substance at the interface is greater. Than the concentration of the substance in bulk phase then it is called as positive adsorption.

Negative adsorption:
If the volume concentration of substance is higher than the concentration of bulk is known as negative adsorption.

Types of adsorption:
There are two types of adsorption:

Physical adsorption

Negative adsorption

1. Physical adsorption:
In physical adsorption the adsorbate is attached with adsorbent by Vander Waals or Electrostatic weak forces and it is characterized by low heat of adsorption.

Physical adsorption of gases is common at low temperature and high pressure. The gas in the adsorbent layer is in equilibrium with the gas molecule. In the bulk gas the equilibrium depends upon the nature of the adsorbent.

2. Chemical adsorption:
This involves the chemical combination of adsorbate at the surface of adsorbent. It is characterized by high heat of adsorption and unlike physical adsorption is irreversible. In many cases the chemical adsorption is slow because the molecule has to acquire an energy of interaction before they can react with the adsorbent, the rate of uptake will increase with increase of temperature.

Factors affecting the adsorption:

Solubility of adsorbate:
The adsorption is inversely proportional to the solubility of the adsorbate in the adsorbent.

Adsorption α 1/Solubility

pH:
it does not effect the adsorption directly pH of the solution affect the degree of ionization.

Usually the drug with a single molecule has more adsorption.

Nature of the adsorption:
Nature of the adsorbent have major effect on the adsorption by increasing the surface area, the adsorption rate could be increased. It can be increased by making it porous or finely divided.

Temperature:
Adsorption is an Exothermic process so increase in temperature will decrease. The adsorption and vice versa.

Pressure:
Adsorbed amount of adsorbate is directly proportional to the pressure applied.

Loop Diuretics (Some Questions)

Q:1. Why loop diuretics are often called as high ceiling diuretics?

Ans: They are often called as high ceiling diuretics because they are highly effective in inhibition of coupled transport of Na+/K+/2Cl- through luminal membrane of thick ascending limb of Henle’s loop as ascending limb results in reabsorption of 20-30 percent of NaCl which has already been filtered.

Q:2. Compare loop diuretics and thiazide diuretics.
Ans:
Differences between loop diuretics and thiazide diuretics:
1. Loop diuretics are more effective than thiazide diuretics.
2. The onset of action and duration of action of loop diuretics is shorter than the thiazide diuretics.
3. Loop diuretics show efficacy even in the presence of electrolyte and acid base disturbance unlike thiazide siuretics.
4. Loop diuretics are not good than thiazide diuretics against uncomplicated mild to moderate hypertension.
5. Loop diuretics increase renal blood flow whereas thiazide diuretics have the ability of lessening renal flow of blood.
6. Loop diuretics tend to increase Ca2+ in urine whereas thiazide diuretics cause a decrease in Ca2+ in urine.

Similarities between loop diuretics and thiazide diuretics:
1. They have almost identical side effects.

Loop diuretics

These diuretics act on the medullary and cortical (thick) ascending limb of Henle’s loop, although to some extent they also act on the proximal and distal tubules. They are more effective than thiazide diuretics.


Mechanism of action:

They inhibit Na+/K+/2Cl- symport on luminal membrane of thick ascending limb of Henle’s loop causes
a. Decreased reabsorption of NaCl
b. Lessen the normal lumen positive potential that derives from K+ recycling resulting in increased excretion of Mg2+ and Ca2+

They tend to decrease renal vascular resistance and resulting in increased renal blood flow.

They also promote prostaglandin synthesis. Prostaglandins also have some role as diuretic.

Therapeutic uses:

They produce large amount of urine.
1. Acute pulmonary edema of heart failure
2. Acute pulmonary edema (When given IV)
3. Impaired renal function
4. Hypercalcemia
They causes an increased tub ular Ca2+ excretion.

5. Hyperkalemia
6. Increased intracranial pressure
7. Diabetic nephropathy
8. Hypertensive situations

Pharmacokinetics:
They have short duration of action of approximately 2-4.5 hours. They are eliminated by glomerular filtration and tubular secretion. Their half life depends on the renal function. They are excreted through urine.

Adverse effects:
They have almost similar adverse effects as those of thiazide diuretics. But they may cause severe electrolytic imbalances and water depletion.

• Hypersensitivity reactions:
Skin rash, interstitial nephritis

• Water, electrolytes and acid-base balance:
Voiding of extra water, Hypercalcemia, hyponatremia, Hypomagnesemia,

Hypokalemic metabolic alkalosis:
More Na+ at the collecting tubule results in more K+ exchange with Na+ in the tubule. This results in hypokalemia.

More K+ loss results in more H+, resulting in hypokalemic alkalosis.

This can be reduced by the use of potassium sparing diuretics or potassium rich foods.

• Blood:
Transient granulocytopenia and thrombocytopenia

• Muscles:
Severe pain and tenderness in patients with renal failure

• Miscellaneous:

Ototoxicity:
Affect on hearing.

Hyperuricemia:
Blocks secretion of uric acid by competitively working at renal and biliary secretary systems. This results in gouty attacks.

Acute hypovolemia:
They cause a reduction in blood volume. This results in hypotension, shock and cardiac arrhythmias.

Contraindications:
It is contraindicated in patients with hepatic coma, hypokalemia, hypotension and hypersensitivity to sulfonamides.

Interaction:
Indomethacin interferes with the production of prostaglandin synthesis, so that is why causes some inhibitory effects on diuretic action of loop diuretics.

Chlorothiazides

Chlorothiazed is the prototype of thiazide diuretics. This is used widely, orally effective and well tolerated.

They are effective in edema of hepatic cirrhosis and heart failure.

Pharmacokinetics:
Onset of action is 2 hours after oral administration and 10-15 minutes after IV administration. Its duration of action is about 4-12 hours.

Thiazides and related agents

They are developed in efforts to develop more potent carbonic anhydrase inhibitors. So, that is why they are structurally similar to the carbonic anhydrase inhibitors.

Mechanism of action:
1. They cause the inhibition of Na+/Cl- cotransporter reabsorption from luminal side of epithelial cells in
    a. early distal convoluted tubule and also
    b. in late proximal tubule but not to a lesser degree.

This causes an increase in the concentration of NaCl in the tubular fluid resulting in urinary excretion of sodium and water.
2. They also cause an increase in Ca2+ reabsorption in distal convoluted tubule that may be due to lowering of cell Na+.
3. They also increase excretion of chloride, potassium and to some extent bicarbonate ions.

The excretion of Na+ and Cl- result in a very hyperosmolar urine.

4. They also directly relax arteriolar smooth muscle and cause a decrease in peripheral vascular resistance, resulting in continued hypotensive effect.

The hypotensive effect is also attributed to the decreased sodium level and as a result in the reduction of plasma volume which leads to decreased cardiac output.

5. They also decrease glomerular filtration rate.
Thiazide diuretics interfere with the dilution of the urine but not with the concentration of the urine due to the site of action.

Therapeutic uses:
1. Mild to moderate cases of Hypertension:
Three to seven days of continued treatment leads to lower peripheral resistance resulting in the stabilization of blood pressure.

2. Congestive cardiac failure:
They have the ability of reducing plasma volume helping in mild to moderate heart failure.

3. Diabetic nephropathy

4. Edema which may be due to congestive heart failure, renal dysfunction or corticosteroid therapy

5. Nephrosis

6. Prevent the formation of calcium stones in hypercalciuric and normal calciuric patients. As thiazide diuretics have the ability of inhibiting urinary Ca2+ excretion

Pharmacokinetics:
They are effective orally. There half life is about 35-42 hours. They are excreted by the kidney by organic acid secretary system of proximal tubule.

Adverse effects:
1. Gastrointestinal
Gastric irritation, anorexia, nausea, vomiting, diarrhea, constipation

2. Central nervous system
Weakness, fatigability, dizziness, vertigo, headache

3. Hematological
Leukopenia, agronulocytosis, aplsatic anemia

4. Cardiovascular
Orthostatic hypotension can be caused by volume depletion.

5. Hypersensitivity
Generalized dermatitis, hemolytic anemia, photosensitivity, rash, purpura

6. Hypercalcemia

7. Hypokalemia
Decreased intravascular volume activates rennin angiotensin aldosterone system resulting in K+ loss with urine.

This potassium loss can be decreased by spironolactone which interferes with aldosterone action or by giving triamterene. This can also be done by in creasing the intake of citrus fruits and bananas which are rich in potassium.


8. Hyponatremia:
This can be decreased by less water intake and decreasing the dose of thiazide diuretics.


9. Muscle spasm.

10. Hyperglycemia:
This may be due to impaired release of insulin and the uptake of glucose by the tissues.

11. Hyperuricemia:
Thiazide diuretics decrease the amount of acid excretion from the organic acid excretory system resulting in increased uric acid in the serum. This results in the gouty attacks.

Contraindications:
It is contraindicated in patients who are hypersensitive to thiazide or sulfonamides. It is also contraindicated in anuria, healthy pregnant women and hepatic cirrhosis.

Precautions:
It should be used with caution in patients of renal disease, gout or diabetes. In patients of renal disease it may initiate azotemia.

Drug Interaction:

Classification of Diuretics

Classification according to different groups:

Antidiuretic (ADH) hormone antagonists:
Lithium salts, demeclocycline, conivaptan

Carbonic anhydrase inhibitors:
Acetazolamide, Acetazolamide sodium

Loop (High ceiling) diuretics:
Bumetanide, Ethacrynic acid, Ethacrynate sodium, Furosemide, Torsemide, Umetanide, Piretanide

Mercurial diuretics:
Mercaptomerin, Calomel, Mercuhydrin, Meralluride, Mercumatilin, Mersalyl

Methylxanthine diuretics:
Aminophylline, Theobromine, caffeine, Theophylline, Oxtriphylline (A salt of theophylline)

Osmotic diuretics:
1. Osmotic electrolytes:
Sodium and potassium salts

2. Osmotic non-electrolytes:
Mannitol, Urea, Isosorbide, Sucrose, Glycerin

3. Acid-forming salts:
Ammonium chloride

Plant products:
Taraxacum, Cornsilk, Allium (Syn. Garlic), Buchu (dried leaves of Barosma betulina), Oleander, Turpentine oil

Potassium sparing diuretics:
Amiloride hydrochloride, Triamterene

Aldosterone antagonist:
Spironolactone, Aldadiene (A metabolite of apironolactone)

Thiazide diuretics:
Buthiazide, Chlorothiazide, Chlorthalidone, Hydrochlorothiazide, Indapamide, Metolazone, Cyclothiazide

Uracil derivatives:
Aminometramide

Miscellaneous diuretics:
Dextran, Ammonium benzoate, Dimethylpiperazine tartarate

Classification according to site of action:

Direct diuretics
1. Drugs acting on proximal tubule
Osmotic diuretics, Carbonic anhydrase inhibitors, Methylxanthine diuretics

2. Drugs acting on ascending limb of loop of henle
Loop (high ceiling) diuretics, Mercurial diuretics

3. Drugs acting on distal tubule
Thiazide diuretics

4. Drugs acting on collecting tubule
Potassium sparing diuretics, ADH antagonists, Aldosterone antagonists

Indirect diuretics
Cardiac diuretics

Diuretics

Introduction:

Diuretics are the drugs that cause the increased outflow of urine.

General action of diuretics:
Many types of diuretics
1. Decrease that amount of fluid which is reabsorbed by the renal tubules, from where the fluid returns to the blood
2. Increase glomerular filtration

General uses of diuretics:
They are used to remove excess water from the body which may contain some salts, toxins and other accumulated waste products such as urea.

They have the ability of getting rid of excess fluid from the body which may cause edema, which contains an abnormal accumulation of fluid from serum resulting in some of the disease.

Aprotinin

It is inhibitor of proteolytic enzymes.


It causes blockage of plasmin resulting in stoppage of bleeding.

It can cause inhibition of streptokinase.

It is used prophylactically for reducing blood loss around the time of operation. It is also used for hyperplasminaemia developed as a result of fibrinolytic drug overdosage.

It may start certain inflammatory conditions.

Vitamin K

It can be used for oral anti-coagulants.

Mechanism of action:
It causes post-translational modification of factors VII, IX and X.

Therapeutic uses:
It is usually administered to all newborn babies in order to prevent vitamin K deficiency leading to hemorrhagic diseases which is common in premature infants.

It is also used as an antidote of warfarin.

Adverse effects:
Rapid infusion of vitamin K may lead to chest pain, back pain and dyspnea.

Protamine sulfate

It is an antidote for heparin.

It is obtained from fish sperm.

It is strongly basic macromolecule due to the presence of more amount of arginine.

In this positive charge of protamine forms complex with negative charge of heparin (a polyanionic macromolecule) neutralizing its activity.

It is administered IV after proper dilution with physiological salt solution. Its duration of affect is 2 hours.

Hypersensitivity reactions may develop. On rapid injection, flushing, dyspnea, hypotension, and bradycardia may be caused.

Aminocaproic acid and Tranexamic acid

These are synthetic inhibitors of plasminogen activator with antiplasmin activity.

These are active orally and excreted in urine. Tranexamic acid can cross placenta.

Therapeutic uses:
Aminocaproic acid is effective in the treatment of complications caused by fibrinolysis such as in the treatment of cardiac bypass or major thoracic surgery. It is also found useful in the treatment of subarachnoid hemorrhage and angioedema.

The most important use of tranexamic acid is in the treatment of ovarian tumor which is malignant.

Adverse effects:
They may cause IV thrombosis.

Aminocaproic acid may cause rash, erythema, nausea, diarrhea and heartburn. It also some of the antiadrenergic effects leading to hypotension and nasal stuffiness.

Dosage:
Tranexamic acid is administered as 15mg/kg orallyas a loading dose then 30 mg/kg four times a day.

Classification of Coagulants

Introduction:

These are the substances which are helpful in the coagulation of the blood.

Bleeding can be caused by
1. Fibrinolytic states arising after prostatectomy or gastrointestinal surgery.
2. Hemophilia

In this case, hemophilia can be caused due to decrease of plasma coagulation factors such as factor VIII or IX.

Classification of Coagulants:
Protamine sulfate, Vitamin K, Aprotinin

Fibrinolytic inhibitors:
Aminocaproic acid, Tranexamic acid

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Atorvastatin

Salt form of Atorvastatin is used i.e. atorvastatin calcium. It belongs to a drug calss of Statins.

Structure:

Credit: Drugbank.ca

Mechanism of Action:
It works by inhibiting the enzyme HMG-CoA (Hydroxymethyl glutaryl Coenzyme-A) reductase, which is present in the tissues of the liver and is responsible for the production of cholesterol in the body via mevalonate pathway.

Pharmacokinetics:
Maximum plasma concentrations is found within 1 to 2 hours. Absorption increases with increasing the dose of the drug. The absolute bioavailability is found to be 14%.

Uses:

It is used for the treatment of Cholesterol i.e. hyperlipidemia, dyslipidemia and hypercholesterolemia. It is used to reduce the risk of myocardial infarction, stroke and angina.

Side effects:
It may cause diarrhea, apin in extremeties and urinary tract infections.

Brand Names:

• Atogal (Ingers (Czech Republic))
• Atorpic
• Cardyl (Pfizer (Spain))
• Faboxim (Fabop (Argentina))
• Hipolixan (Pasteur (Chile))
• Lipitor (Pfizer, Elea (Argentina))
• Lipotropic (Drugtech (Chile))
• Lipovastatinklonal (Klonal (Argentina))
• Liprimar (Pfizer (Hungary, Ukraine), Goedecke (Russia))
• Lowden (Saval (Chile))
• Normalip (Quesada (Argentina))
• Sincol (Indeco (Argentina))
• Sortis (Pfizer (Austria, Czech Republic, Germany, Hungary, Poland, Portugal, Switzerland), Godecke (Germany), Parke, Davis (Germany))
• Sotis
• Torvacard (Zentiva (Czech Republic, Hungary, Poland, Russia, Ukraine))
• Torvast (Pfizer (Italy))
• Totalip (Guidotti (Italy))
• Tozalip
• Tulip (Lek (Czech Republic, Russia), Wermar (Mexico), Sandoz (Poland, Ukraine), Pharmacia (Spain))
• Vastina (Penn (Argentina))
• Xanator (Sieger (Greece))
• Xarator (Parke, Davis (Italy))
• Xavator
• Zurinel (Prater (Chile))

It is also available in the combination with amlodipine with the name of "Caduet".

Serotonin receptor blockers

5-HT3 serotonin receptor blockers include Ondansetron and granisetron.

Action:
It blocks 5-HT3 receptors in the periphery (visceral afferent fibers) and in the brain (chemorecptor trigger zone).

Pharmacokinetics:
• Orally or IV
• Prevents vomiting in 50 – 60% of patients treated with Cisplatin.

Clinical Uses:
It is used as prophylaxis of nausea and vomiting associated with cancer chemotherapy.

Side affects:
Headache.

5-HT1c and 5-HT2 receptor blockers include Ketanserin.

Action:

This drug potently blocks vascular α1-adrenoceptors resulting in hypotensive action. It antagonizes platelet aggregation caused by serotonin by blocking 5-HT2 receptors on platelets.

Uses:
It is used in hypertension and vasospastic conditions.

Serotonin

It is also known as 5-Hydroxy Tryptamine. It is an indole-ethylamine.
Synthesis:

Mechanism of action:
Seven families of 5-HT receptor sub-types (subscripts 1-7) are there. They act through a variety of cell membrane receptors that include:
1. Six involved G-protein coupled receptors.
2. One uses ligand gated ion channels.

Action:
It acts as a neurotransmitter causing strong inhibitory effect. It acts on chemosensitive endings causing bradycardia and hypotension. It can cause aggregation of platelets. It may cause hyperventilation due to chemoreceptor reflex.

Clinical uses of serotonin analogues:
1. Buspirone (a 5-HT1A agonist) is used as non-benzodiazepine anxiolytic.
2. Sumatriptan can be used in acute migraine and cluster headache.
3. Appetite suppression appears to be caused by the agonist action at 5-HT2C receptors in the central nervous system.
4. Cisapride (a 5-HT4 agonist) was used for gastroesophageal reflux disease and motility disorders.

Ergot Alkaloids

Ergot alkaloids are produced by Claviceps Purpurea.


Pharmacokinetics of Ergot Alkaloids:
It is effective in 50% of patients. The oral dose is about 10 times larger than IM dose although gastrointestinal absorption can be increased by caffeine.

Action of Ergot alkaloids:
As described of ergotism, some of the naturally occurring alkaloids are powerful hallucinogens. They constrict most human blood vessels which may be due to partial agonist effects at α-adrenoceptors. In very low doses, ergot preparations can evoke rhythmic contraction and relaxation of the uterus.

Clinical uses of ergot alkaloids:
1. Migraine.
2. Hyperprolactinemia.

Increased serum level of prolactin (Anterior pituitary hormone).

3. Postpartum Haemorrhage.
Oxytocin is usually used to control postpartum haemorrhage but if this is insufficient than ergonovine maleate can be used.

4. Senile Cerebral Insufficiency.
Once the headache starts, Analgesics or NSAIDs can be helpful in reducing the pain such as aspirin, naproxen, propoxyphene and caffeine.

Dihydroergotamine

Derivative of ergotamine, IV use, ≈ sumatriptan, nausea may occur.

Ergotamine

Same action as that of sumatriptan but has less specificity for 5-HT receptors and is weak α-adrenoceptor blocker. It can be given orally, sublingually, nasally or rectally. Side effects include diarrhea, nausea and vomiting.

Sumatriptan

Introduction:

It is 5-HT receptor agonist acting on 5-HT1D that innervates the intracranial vasculature.

Action:
It decreases the release of sensory neuropeptides, such as substance P.

Pharmacokinetics:
• Use orally or SC.
• Its onset of action is 20 minutes parenterally and 1-3 hours orally.
• T1/2 = 2 hrs.
It is effective in 80% of patients.

Headache

Headache is of three types:

1. Cluster Headache
2. Tension type headache
3. Migraine headache

Characteristics of Cluster Headache:
1. Males are more often attacked by this than females.
2. It usually occurs during sleep.
3. It is unilateral and its location is behind and around eyes.
4. It is excruciating, sharp and steady.
5. Its duration is from 10 minutes to 3 hours.
6. It can cause unilateral sweating, facial flushing, nasal congestion and lacrimation.

Characteristics of Tension Type headache:
1. It is more often in females than in males.
2. It occurs usually under stress.
3. It is bilateral in band around head.
4. It is dull and persistant.
5. It occurs in episodes from 30 minutes to 7 days and.
6. It can cause mild intolerance to light and noise.

Tension type headaches respond very well to over the counter analgesics.

Characteristics of Migraine:
1. It occurs in females more often than males.
2. It is variable and can start any time.
3. It is unilateral.
4. The pain caused by this is pulsating and throbbing.
5. It can last, in episodes, from 2 to 72 hours.
6. It can cause visual auras, sensitivity to light and sound, pale facial appearance, nausea and vomiting.

Types of Migraine headache:

Note: Migraine and cluster headaches are the types of “Vascular headaches”, whereas Tension headache is the most common form of “Myogenic / Muscular headache”.

Biologic basis of Migraine Headache:
Hypoperfusion occurs in Migraine with aura. Migranious aura is due to abnormally high release of serotonin from platelets.

Firstly: There is a spreading depression of neuronal activity.
Secondly: Reduced blood flow in the most posterior part of the cerebral hemisphere.
Thirdly: This hypoperfusion spreads on the surface of the cortex.

These hypoperfused regions show an abnormal response to changes in arterial pCO2 (this is alteration of function) and there is an increase in the amplitude of temporal artery pulsations.

Hypoperfused state remains during aura and headache phase and after that hyperperfused state comes.

No hypoperfusion occurs in Migraine without aura.

Pain in migraine headaches is considered to be due to extra cranial and intracranial arterial dilation that results in release of neuro-active molecules such as substance P.

In woman, whose headache is related to menstrual cycle, migraine is due to
1. Falling levels of estrogen.
2. Elevated levels of prostaglandin E1.

Phases in Migraine headache:
There are three phases:
1. Asymptomatic phase: No symptoms or pathologic features are found between the previous attack and until next attack.
2. Prodromal Phase: It starts with visual disturbances. In this phase there is vasoconstriction of arteries and release of serotonin.
3. Headache Phase: Here pain starts along with nausea and vomiting. Here, cerebral vasodilation occurs and due to release of serotonin, there is a large amount of serotonin.

Treatment of Migraine:

Prophylaxis of Migraine headache:
When there is recurrence of migraine headache two or more times in a month. Drugs on prophylactic bases can be taken such as β-blockers (propranolol, nadolol) can be taken. Some ergot alkaloids like Methysergide are also effective.

Acute migraine headache:
When the first symptoms of migraine headache started, following medicines are effective to prevent the near future headache:
1. Sumatriptan
2. Ergotamine
3. Dihydroergotamine

Prastaglandins

We will study Prostaglandins only in Eicosanoids . Prostaglandins are unsaturated fatty acids found in almost all mammals and have the activity very closely to the hormones such as controlling smooth muscle contraction, blood pressure, inflammation and body temperature.


They contain cyclic ring structure made with the help of 20 carbon atoms.

Prostaglandins act on the tissues in which they are synthesized and within no time metabolized to useless products at the site of action.

Synthesis of Prostaglandins and Leukotrienes:

Action:
Prostaglandins bind to various membrane receptors via G-proteins, subsequently resulting in the activation or inhibition of adenylyl cyclase or stimulate phospholipase C. This causes an enhanced formation of diacylglycerol and IP3.

PGF2α, leukotrienes and thromboxane A2 mediate certain actions by:
1. Activating phosphatidylinositol metabolism.
2. Causing an increase of intracellular Ca2+.

Functions:
These are released in allergic and inflammatory processes. They act as local signals and very specifically. They functions vary widely among the tissues. For example, TXA2 triggers contraction in certain smooth muscles while their release from platelets triggers the recruitment of new platelets for aggregation.

Therapeutic Uses:
1. Abortion (Dinoprost, dinoprostone, carboprost, misoprostol alongwith methotrexate in terminating pregnancy in the 1st trimester).
2. Peptic Ulcers (misoprostol, a synthetic PGE1, is used to inhibit the secretion of HCL in stomach).
3. Alprostadil (PGE1), A vasodilator used for palliative therapy (treating symptoms only) to temporarily maintain patency of the ductus arteriosus (a fetal vessel in the 1st two months after birth) in neonates with congenital heart defects.
4. Dinoprost (PGF2α), It is used as an oxytocic agent (A drug that speeds up the child birth).
5. Dinoprostone (PGE2), An oxytocic agent used as an abortifacient.

Metabolism:
Prostaglandins are rapidly catabolized in the body by:
1. 15-Hydroxydehydrogenase pathway.
2. Cytochrome P450 system.

Histamine

A depressor amine (as it causes lowering of the blood pressure). It is derived from histidine (as shown below) and is also present in ergot and animal tissues.
Synthesis:

Storage:

It is stored in most tissues in
(1) mast cells and in blood, in
(2) basophil. Histamine is stored in their secretary granules.
It is also present in
(3) cells of the epidermis,
(4) cells in the gastric mucosa,
(5) neurons in the central nervous system and
(6) cells in regenerating or rapidly growing tissues.

Release of Histamine:
Histamine is released by the process of exocytosis. This is stimulated
1. Either by the interaction of complement components C3a and C5a with specific receptors on the cell surface or
2. Interaction of antigen with cell fixed IgE antibodies.

This secretion of histamine is initiated by Ca2+.

Some drugs like morphine and tubocurarine, release histamine by some non-receptor action.

Metabolism:

Metabolized by
1. Histaminase
2. Methylating enzyme “Imidazole N. Methyltransferase” which converts this into methylhistamine.

Histamine receptors:
Following are the histamine receptors and the table shown below is giving an overview histamine receptors:

Clinical Uses of Histamine agonists:
1. As a provocative test of bronchial asthma hyperactivity.
2. As a diagnostic agent in testing for gastric acid secreting ability.

Histamine antagonists:

Mechanism of action of Histamine antagonists:
They block the action of histamine receptors at all level.

Generations of H1 receptor blocking agents:
There are two generations of H1 receptor blocking agents:

1st generation:

Key Members

• Diphenhydramine
• Chlorpheniramine
• Doxylamine
• Hydroxyzine

Characteristics
• High lipophilicity, easily enters CNS
• Highly sedative (Triprolidine, Promethazine, Hydroxyzine)
• Anti-muscarinic, anti-α-adrenergic, anti-5HT
• Some have anti-motion sickness effect (Dimenhydrinate)
• Some have local anaesthetic effect.
• May cause increase appetite and weight gain. (Cyproheptadine)

2nd generation:

Key Members
• Desloratadine (loratadine)
• Fexofenadine (terfenadine)
• Cetirizine
• Azelastine
• Astemazole

Characteristics
• No CNS entry (Low lipophilicity, most ionized; also protein binding)
• Non-sedating
• No significant autonomic receptor blocking effect
• Generally long-acting
• Some are cardiotoxic
• May cause anorexia. (Loratidine)

Pharmacokinetics:
1. Orally they are well absorbed with maximum serum levels occur after 1-2 hours.
2. Average plasma T1/2 is 4-6 hours.
3. H1 receptor blockers distribute to all the tissues.
4. Biotransformation is mainly in the liver.
5. Excreted in the urine.

Clinical uses of H1 receptor antagonists:
1. Allergic conditions.
2. Motion sickness and nausea.
3. Somnifacients. Diphenhydramine can be used for the treatment of insomnia.

Clinical uses of H2 receptor antagonists:
1. In the treatment of ulcers.
2. Treatment of Zollinger-Ellison syndrome (severe hypersecretion and ulceration).
3. Gastro-esophageal reflux disease (GERD).

Adverse effects:
Sedation, Headache, Flushing, tachycardia, Diarrhea, Cause itching and pain.

Classification of autacoid antagonists

1. Histamine antagonists
a. H1 receptor antagonists
Cyclizine, Meclizine, Diphenhydramine, Dimenhydrinate, Fexofenadine

b. H2 receptor antagonists
Cimetidine, Famotidine, Nizatidine, Ranitidine

c. H3 receptor antagonists
Impromidine

2. Serotonin Antagonists
Ondansteron, Ketanserin

3. Eicosanoids
a. Thromboxanes
b. Leukotrienes
c. Prostaglandins
Carboprost, Dinoprost, Dinoprostone, Misoprostol

4. Drugs used to treat migraine headache
β-blockers, Dihydroergotamine, Ergotamine, Methysergide, Sumatriptan

Autacoids

Autacoids are local biological factors which act like local hormones.

Speciality:

1. They have a short life time.
2. They act near their site of synthesis.

These things are differentiating them from other hormones and neurotransmitters.

Acetylcysteine

It is a mucolytic agent. It is also referred to as N-acetyl, l-cysteine. Here l-cysteine is used as a mucolytic agent that reduces the viscosity of mucus secretions and is a sulfhydryl donor.


Action:
This reduces the viscosity of the festering or non-festering pulmonary secretions and makes it easy for their removal by coughing, postural drainage, or mechanical means.

Its mucolytic effect is thought to be done by free sulfhydryl group which through two way traffic reduce disulfide linkages resulting in a mixed disulfide. This action is effective at pH 7-9.

Therapeutic uses:
1. It is used in the treatment of cough.
2. It is used as antidote for acetaminophen over dosage. Acetylcysteine may protect the liver by maintaining or restoring glutathione levels so that it can metabolize the intermediate metabolite, which is thought to be responsible for liver necrosis.
3. It can also be used in acute and chronic bronchitis.
4. It is used in the prevention of acute renal failure associated with radiographic contrast media. It is thought that this media may reduce anti-oxidant activity. As acetylceyteine is a thiol containing anti-oxidant, so it may increase this activity and helpful in this respect.

Administration and dosage:
Acetylcysteine may be given by nebulization, direct application or intratracheal instillation. The dosage varies according to the dosage form and disease.

Pharmacokinetics:
Orally, Acetylcysteine is absorbed from the GI tract.

Most of the administered drug participates in sulfhydryl disulfide reaction and the remainder is absorbed by the pulmonary epithelium.

It is deacetylated by the liver and subsequently metabolized.

Adverse Effects:
This drug may cause stomatitis, nausea, vomiting, drowsiness or fever. Sometimes GI symptoms may appear.

Guaifenesin

It is an expentorant. This is also called as Glyceryl guaiacolate. This is one of the medicine to be used Over the Counter. It is often used in combination with anti-histamines, decongestants and anti-tussives in combination products.


Action:
It is used for reducing the viscosity of the sputum by increasing respiratory tract fluid and thus helps in expectoration.

Therapeutic Uses:
This is used for symptomatic treatment of cough associated with common cold, influenza, pertussis, pharyngitis or bronchitis. (If there is persistant cough for more than one week than a physician should be consulted).

Administration and dosage:
It is taken orally and in some cases extended release tablets are also there. Its usual dosage in adults and children over 12 years is 200-400 mg every 4 hours.

Adverse Effects:
GI tract disturbance at ordinary dosage level is rare. Higher doses may cause emesis.

Dextromethorphan HCl

A synthetic morphine derived from levorphanol . Dextromethorphan HBr salt is also in use.


Action:
They have the same anti-tussive activity as other morphine derivatives. And it is almost similar in depressing the cough as codeine.

Therapeutic Uses:
It is used for cough in minor throat and bronchial irritation such as that in common cold. It is most effective in reducing chronic non-productive cough.

Administration and dosage:
It is administered orally and its lozenges are also used for adults. The usual dosage of Dextromethorphan HBr is 10-20 mg every 4 hours for adults and children above 6 years.

Pharmacokinetics:
1. It is absorbed rapidly from GI tract.
2. Its onset of action is 12-30 minutes.
3. Its duration of action is 2-6 hours.

Adverse Effects:
Very rare but nausea and GI tract disturbances may occur sometimes.

Benzonatate

It is a local anesthetic anti-tussive drug.


Mechanism of Action:
It acts as cough depressant in two ways:
1. It anesthetizes the stretch receptors of vagal afferent fibers in bronchi, alveoli and pleura that are involved in cough reflex.
2. It depresses the cough reflex at the level of medulla at the point where afferent impulse is transmitted to the motor nerves.

Therapeutic Uses:
1. Cough:
It is used for the symptomatic treatment of cough. It can be effective in reducing cough in conditions like pneumonia, common cold, bronchial asthma and tuberculosis.

2. As local anesthetic:
It is used in liquid filled capsules (Which are chewed), as local anesthetic of oropharyngeal cavity for attentive intubation.

Administration and dosage:
It is given orally. And its dose for adults and children older than 10 years of age is 100 to 200 mg 3 times daily.

Pharmacokinetics:
1. Its onset of action is 15-25 minutes.
2. Its duration of action is 2.5-8 hours.
3. Anesthesia of oropharyngeal cavity occurs within 1 minute.

Adevrse Effects:
Sedation, Headache, Nausea, Pruritis and skin eruptions, Hypersensitivity and nasal congestion.

Hydrocodone

(Similar to Codeine)

Hydrocodone are used as Hydrocodone bitartrate.

They are more sedative than codeine at equal therapeutic doses.

Elimination half life is 3.8 hours.

Codeine (Sulphate or phosphate)

It is phenanthrene derivative-opiate agonist.

Mechanism of Action:
It lowers the cough reflex by direct effect on the cough center in medulla of the brain that appears to exert a drying effect on respiratory tract mucosa and increased viscosity of bronchial secretions.

Action:
It has less effect on cough than morphine if we consider treatment on weight basis.

Therapeutic uses:
1. Cough:
It can be used for the (symptomatic) treatment of non-productive cough.

2. Analgesic

Administration and dosage:
It is administered orally for anti-tussive effect. Its dosage is 10-20 mg every 4-6 hours for adults and children above 12 years age. The dosage is half for children between 6-12 years.

Pharmacokinetics:
1. It is well absorbed from G.I. Tract.
2. Peak anti-tussive effect occurs after 0.5 to 2 hours and remains for (may) up to 4-6 hours.
3. It can be distributed into milk.
4. It is metabolized in the liver and excreted in the urine.

Adverse effects:
Its side effect is rare, which may show nausea, vomiting, constipation with repeated doses, dizziness and sedation.

Classification of Drugs used to treat cough

1. Anti-tussives
Codeine, Hydrocodone, Hydromorphone, Benzonate, Dextromethorphan HCl, Carbetapentane

2. Expectorant:
Guaifenesin, Guaiacol, Terpene hydrate, Creosate

3. Mucolytic agents:
Acetylcysteine, Bromohexine, Proteolytic enzymes such as trypsin, Ambroxol

Cough

It is the process of releasing air through the windpipe and mouth in a sudden noisy manner. Cough is initiated when there is a mechanical or chemical irritation to bronchi and trachea or by pressure from adjacent structures. Larynx and carina are especially sensitive to chemical stimuli such as SO₂ gas or chlorine gas.

Useful aspects of cough:
It is a physiological mechanism which:
1. Clears the respiratory pathways from foreign materials and extra secretions
2. May help to prevent sudden collapse of lungs.

Capreomycin

It is obtained from Streptomyces capreolus. It is peptide protein synthesis.


Its 1 gm IM injection leads to 10μg/ml of blood level.

It is used for the treatment of tuberculosis.
It may cause nephrotoxicity, ototoxicity, tinnitus and deafness.

Ethionamide

It is chemically related to INH and therefore it blocks the production of mycolic acids.


Pharmacokinetics:
It is given orally. It is metabolized by liver. Its dosage of 1 gm/day gives 20μg/ml of serum concentrations in plasma and tissues.

Adverse effects:
It is hepatotoxic.

Para-aminosalicylic acid

It is structurally similar to para-aminobenzoic acid (PABA).


Mechanism of action:
It competes for the enzyme involved in the conversion of PABA to dihydrpteroic acid that results in the inhibition of Purine and as a result DNA synthesis is stopped.

Pharmacokinetics:
It is widely distributed in tissues and rapidly excreted in urine.

Dosage:
Its usual adult dose is 8-12 g/day orally in divided doses.

Adverse effects:
It may cause anorexia, nausea, fever and skin rashes. Furthermore, nephrotoxicity, hepatotoxicity and granulocytopenia.

Pyrazinamide

It is closely related to nicotinamide.


Mechanism of action:
Its exact mechanism of action is unknown but it is thought to be converted into pyrazinoic acid (active form of the drug) with the help of mycobacterial pyrazinamidase, which causes the inhibition of tubercle bacilli at concentration of 20 μg/ml at 5.5 pH.

Therapeutic uses:
In combination with isoniazid and rifampin. It is also used for tuberculosis for short course that is 6 months.

Pharmacokinetics:
It is well absorbed from GIT. It is widely distributed in body tissues. Its half life is 8-11 hours.

Ethambutol

The word ethambutol is made by the combination of “ethyl” + “amine” + “butanol”. It is bacteriostatic in nature.


Mechanism of action:
It causes inhibition of mycobacterial arabinosyl transferases which is involved in polymerization reaction of arabinoglycan, which is an essential component of mycobacterial cell wall.

It is also thought to inhibit RNA synthesis.

Pharmacokinetics:
It is well absorbed from the gut. It is well distributed throughout the body. Peak level of 2-5 μg/ml is achieved in 2-4 hours. It can cross the blood brain barrier when the meninges is inflamed. 20% percent of the metabolites are excreted in feces and 50% is excreted in urine.

Therapeutic uses:
Ethambutol is found to be more effective against M. tuberculosis and M. kansasii.

It can be used for tuberculous meningitis.

Dosage:
Its usual dose is 15mg/kg/day.

Adverse effects:
It may cause fever and skin rashes. It may cause optic neuritis and reduction in visual acuity. It may also cause a loss of red and green color discrimination.

Rifampin

It is also called as rifampicin. It is a semisynthetic derivative of rifamycin which is an antibiotic produced by a bacterium Streptomyces mediterranei.


Rifampin is a blend of rifamycin and piperazine.
Mechanism of action:

Rifampin is bactericidal for mycobacteria. Human RNA polymerase is not affected by rifampin.

Pharmacokinetics:
It is well absorbed orally.

It readily penetrates most of the tissues and phagocytic cells and that is why it is widely distributed in body fluids and tissues.

It is excreted through liver into the bile where it undergoes enterohepatic recirculation.

Deacylated metabolite is excreted in feces and small amount is excreted through urine.

Therapeutic uses:
It is used in mycobacterial infections such as tuberculosis and leprosy. It is also used in prophylaxis in contact of children with Haemophilus influenzae type b disease.

In combination therapy, it is also used for serious Staphylococcal infections.

Dosage:
Its usual dose is 600mg/day with isoniazid, ethambutol or other anti-tuberculous drugs.

Adverse effects:
It produces harmless orange colour to urine, sweat and tears. It may cause rashes, light chain proteinuria, thrombocytopenia and nephritis.

Resistance:
Resistance is found to be due to alteration in the genetic material of bacteria DNA dependent RNA polymerase.

Isoniazid

It is also referred to as INH as its full name is “Isonicotinic acid hydrazide”.
Mechanism of action:
It causes a decreased synthesis of mycolic acid. Mycolic acid is a constituent of mycobacterial cell wall that is thought to be responsible for the acid fastness of the bacteria.

Where,

KatG is mycobacterial catalase (peroxidase),

AcpM is Acyl carrier protein,

KaSA is Beta ketoacyl carrier protein synthetase.

Here in the above diagram, mycolic acid synthesis is blocked as mycolic acid is produced by the incorporation of cyclopropane ring near the centre of acyl chain.

Pharmacokinetics:
It is readily absorbed by GIT. 300 mg of oral dose achieves peak plasma concentration of 3-5μg/ml in 1-2 hours. The drug diffuses easily into bodily fluids and cells.

It is metabolized by liver N-acetyltransferase (in which its acetylation occurs).

Average half life in peoples with rapid acetylation is 1 hour and in peoples with slow acetylation it is 3 hours.

Elimination is done via urine.

Therapeutic uses:
It is used in the prophylaxis as well as treatment of tuberculosis.

Dosage:
The usual adult dose is 5mg/kg/day to a maximum of 300 mg/day.

Adverse effects:
It may cause fever, skin rashes, Insomnia and restlessness. It may also induce hepatitis characterized by loss of appetite, nausea and vomiting. Hepatitis is thought to be associated to the metabolite monoacetylhydrazine.

Sometimes peripheral neuropathy (neuropathy is caused by pyridoxine deficiency and isoniazid causes an increased pyridoxine excretion) is also observed.

Resistance:

Resistance is found to be due to chromosomal alterations resulting in change in genetic material of KatG or due to over expression of enoyl acyl carrier protein reductase.

Classification of anti-tuberculosis

First line drugs:

Isoniazid, Rifampin, Ethambutol, Streptomycin, Pyrazinamide

Second line drugs:
Ethionamide, Cycloserine, Tetracycline, para-aminosalicylic acid, Amikacin, Fluoroquinolones

Tuberculosis

Symptoms of tuberculosis:


Early symptoms:
Usually no symptoms develop but sometimes influenza is present.

Symptoms in second stage:
1. Low fever
2. Weight loss
3. Chronic fatigue
4. Heavy sweating especially at night

Later stages:
1. Cough with sputum that becomes progressively bloody, yellow, thick or grey
2. Chest pain
3. Shortness of breath
4. Reddish or cloudy urine

Mycobacteria

Characteristic features of mycobacteria are:

1. Slender rod shaped bacteria
2. Lipid rich cell wall
3. Acid fast

Major diseases caused by mycobacteria:
1. Leprosy
2. Tuberculosis

An Interview with Mr. Pharmaceutics

Jeepakistan Team (J. T.): Tell something shortly about yourself.

Mr. Pharmaceutics (P): I am an art from patient’s and customer’s point of view and science from doctor and scientist’s point of view.

J. T.: Your family members!

P: I’ve many brothers, children and grand children. My powerful brothers are biotechnology, medicine, chemistry and botany. My most favourite children are Hospital pharmacy, industrial pharmacy, forensic pharmacy and retail pharmacy. My grand children are computer education, biostatistics, quality control and many others.

J. T.: Some thing about your life!

P: Peoples love me. In most cases you’ll find me present everywhere from urban to rural areas, from jungles to desert, from air to water and from east to west. Even I love peoples very much. That’s why, I try to give them not only healthy life but also good employment opportunities.

J. T.: The hidden reality you want to tell peoples!

P: The best cure for every pain are not NSAIDs nor any other type of painkillers. But many types of pain can only be cured by the world’s best medicine, that’s love.

J. T.: I can’t understand, what you have said!

P: For example, in very old age the pain felt in the body is due to loneliness, if the children don’t leave their parents alone then the severity of the pain will be reduced.Even that pain will not be felt in many cases if the children give their parents much happiness.

J. T.: Your interview will be published. Do you want to give your readers some message?

P: I can’t do anything for disable peoples, genetically ill peoples and many peoples, who are in very poor or far off areas. Please, for the sake of God, help those peoples as much as you can.

J. T.: Thank you.

Sulfinpyrazone

It is a derivative of phenylbutazone.


Mechanism of Action:
Same as that of probenecid.

Therapeutic Uses:
It is used for the treatment of Uric acid.
Pharmacokinetics:
It shows renal excretion.

Adverse effects:
Same as that of probenecid.

Probenecid

Action:

It acts generally as an inhibitor of the tubular secretion of organic acids.

Mechanism of action:
It causes blockage of resorption of uric acid by proximal tubular resorption.

Therapeutic Uses:
It is used for the treatment of Uric Acid.
Pharmacokinetics:
It is well absorbed by renal tubules. Its plasma half life is about 5-8.5 hours.

Adverse effects:
It may show gastric discomfort.

Interaction:
Probenecid stops tubular secretion of penicillin and that is why it sometimes is used for increasing the levels of the antibiotic.

It also inhibits excretion of naproxen, ketoprofen and indomethacin.

Uricosuric agents

The uricosuric drugs are weak organic acids that cause an increased uric acid clearance through kidneys by stoping urate anion exchanger in the proximal convulated tubule of nephron that mediates the reabsorption of urate crystals (i.e. uricosuric agents act at the anionic transport site of renal tubule).

It includes
1. Probenecid
2. Sulfinpyrazone

Allopurinol

Introduction:

Allopurinol is a purine analog. It is also an isomer of hypoxanthine.

Mechanism of action:
Allopurinol inhibits xanthine oxidase enzyme which is required for the synthesis of Uric acid. This enzyme is required when purine is oxidized to Uric acid.

Therapeutic uses:
This is effective in the treatment of gout, which may be due to;
1. Primary hyperuricemia
2. Secondary hyperuricemia (Such as those caused from the use of chemotherapeutic agents or diseases of the kidneys).

It is also effective as an anti-protozoal agent.

Pharmacokinetics:
It is well absorbed (approximately 70-85%) orally. One of its metabolite is alloxanthine (also called as oxypurinol) which is also effective in the inhibition of xanthine oxidase. Allopurinol takes action along with this metabolite.

The plasma half life of allopurinol is 2 hours and that of oxypurinol is 15 hours. The drug and its metabolites are excreted in the urine and feces.

Dosage:
Due to the long half life of oxypurinol the dosage can be maintained at the rate of 1 dose/day. Its initial dose is 100 mg/day.

Adverse effects:
Hypersensitivity reactions such as rashes may occur. GI disturbances such as nausea and diarrhea can also be there.

Interactions:
It may cause an increase of the effect of cyclophosphamide. It may interfere with anti-cancer drugs such as 6-mercaptopurine and the immunosuppressant such as azathioprine.

Colchicine

Introduction:

It is an alkaloid obtained from plant, Colchicum autumnale. It has been found effective in the treatment of acute gout.

Mechanism of action:
It causes the disruption of cellular activities such as movement of granulocytes to the affected area and phagocytosis. It also inhibits the synthesis and release of leukotriene B4.

Action:

It relieves pain. Though it cannot prevent the progression of gout to acute gouty attacks but it is used as a prophylactic drug in this case so helps to keep down pain and frequency of acute attacks. It is now used in combination with probenecid.

Indomethacin is now replacing Colchicine.

Therapeutic Uses:
It is used for the relief of pain and inflammation in acute gout within 12-24 hours.

Pharmacokinetics:
It is absorbed rapidly from GI tract. Its peak plasma level is attained within 2 hours. Its plasma half life is 9 hours. It is recycled in the bile and excreted unchanged in the feces or urine.

Dosage:
The usual dosage of colchicines is 0.6 mg one to three times daily as a prophylaxis of gout.

Adverse effects:
It may cause nausea, vomiting, abdominal pain and diarrhea.
Prolonged administration may cause myopathy, aplastic anemia and alopecia.

Contraindications:
It is contraindicated in pregnancy.

Precautions:
It should be used with caution in hepatic, renal or cardiovascular diseases.

Gout

Purine metabolism is responsible for the production of Sodium urate. When the quantity of Urate in the blood goes up than normal, it may result in gout which may show inflammation and produces more oxygen metabolites in the blood.

Therapeutic strategies:
First of all it is better to use purine free diet i.e. we must use dairy products, fruits and cereals. The sequence, in the diagram, show that most effective medicine in treating gout is that which causes reduced entry of leukocyte into the affected joint which may be achieved by colchicine.

Other ways of therapy include:

1. Disturbing uric acid synthesis with the help of allopurinol.

2. Promoting excretion of uric acid with probenecid or sulfinpyrazone.

3. Use of NSAIDs.

Types of Gout:
There are two types of gout:

1. Acute gout.

2. Chronic gout.

Acute gout:
Causes:
The main causes of acute gout are as follows:

1. Diet which is rich in purine.

2. Kidney diseases.

3. Alcohol consumption.

Treatment:
In this we can use Indomethacin in combination with Aspirin. Indomethacin slows the movement of granulocytes in the area which is affected and aspirin decreases pain and inflammation.

Chronic gout:

Causes:
The main causes of chronic gout are as follows:
1. Genetic defect.
2. Renal deficiency
3. Lesch Nyhan syndrome.
4. Excessive synthesis of uric acid associated with cancer chemotherapy.

Treatment:
In this we can use Uricosuric drugs such as probenecid and sulfinpyrazone and Allopurinol.

Uricosuric drugs (e.g. Probenecid or sulfinpyrazone) promote excretion of uric acid resulting in reduced concentration of uric acid in plasma. It is preferred for patients with normal excretion of uric acid through urine.

Allopurinol selectively inhibits some steps in the middle of the biosynthesis of uric acid. It is preferred for patients with excessive uric acid excretion (which may be due to renal insufficiency).