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).

Anakinra

Introduction:

Anakinra is an IL-1 receptor antagonist.

Action:
The treatment with this drug causes slowing of process of moderate to serious rheumatoid arthritis.

The drug may be used alone or in combination with other drugs.

Administration:
It is administered subcutaneously.

Adverse effects:
It may cause headache, nausea, vomiting and injection site reactions.

Adalimumab

Introduction:

It is a fully human recombinant monoclonal antibody (MAB).

Mechanism of action:
It gets bind to human TNF-α receptor site thus stops endogenous TNF- α activity by preventing its interaction with p55 and p75 cell surface receptors.

Action:
It decreases symptoms of Rheumatoid arthritis and stops erosion of the (bone) structure.

Therapeutic uses:
It is used in Rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. (As increased TNF in the synovial fluid cause pain and joint destruction in Rheumatoid arthritis).

Pharmacokinetics:
It is used subcutaneously and its half life is 10-20 days.

Dose and Administration:
Its usual dose is 40 mg every other week. It is used Subcutaneously only.

Adverse effects:
It may cause headache, nausea, rashes and reactions at the site of injection.

Infliximab

Introduction:

It is a chimeric IgGκ monoclonal antibody made up of human (75%) and animals (25%) such as rats and mice.

Mechanism of Action:
Infliximab binds to human TNF-α and as a result neutralize the cytokines.

Action:
It removes the progression of damage or erosion to structure so that patient can perform functions more efficiently.

Pharmacokinetics:
It is administered intravenously and slowly in about 2 hour’s time in doses of 3 mg/kg to 10 mg/kg. Its half life is about 9-10 days. It is distributed equally in vascular compartments.

It is not approved for therapy continuously after 6th week.

Therapeutic uses:
It is used in Rheumatoid arthritis and Crohn’s disease. It has been found that the combination with methotrexate is more effective.

Adverse effects:
It may cause upper respiratory tract infections, nausea and vomiting. The production of anti-infliximab antibodies have also been studied after prolonged use of infliximab. It may cause some of the reactions at the site of infusion such as fever, chill and pruritis.

Leukopenia, neutropenia and thrombocytopenia have also been found.

Etanercept

Introduction:

Etanercept is a biotechnological product as it is genetically engineered fusion protein.
It is composed of:

1. Two identical chains of the recombinant human TNF-receptor p75 monomer.

2. Fc domain of IgG1 (human immunoglobulin).

These two are fused together.

Mechanism of action:

Etanercept binds two molecules of TNF thereby resulting in no binding of TNF to cellular receptors.

Action:
Etanercept, Infliximab and adalimumab decrease the activity of TNF. TNF is important for immunity system and must rest in the rheumatic synovium for the action to take place.

Pharmacokinetics:
It is given subcutaneously, 25 mg, two times a week. Maximum serum concentration is obtained within 72 hours after parenteral administration. Its half life is 4-6 days.

Therapeutic Uses:
Rheumatic and psoriatic arthritis.

Adverse effects:
No important adverse effects have been found.

Contraindications:
In serious type of infections like sepsis, etanercept should not be given to patient.

NOTE:
Etanercept and methotrexate are more effective when used together (than alone) in slowing the

1. Disease process

2. Improvement in function

3. Stoppage of the symptoms.

Anticytokine Therapies in Rheumatoid Arthritis

Anticytokines act on the proinflammatory cytokines i.e. interleukin-1b (IL- 1b) and Tumor necrosis factor- α (TNF- α).

Gold salts

Gold compounds are of two types:

1. Those used for intramuscularly such as gold sodium thiomalate and aurothioglucose. They are made up of about 50% elemental gold.

2. Those used in oral formulation such as auranofin containing 26-29% elemental gold.

Mechanism of action:
It is thought that these gold compounds are taken up by macrophages and thus suppresses the phagocytosis and lysosomal enzyme activity.

This process is responsible for the reduction of bone and articular destruction.

Pharmacokinetics:
They tend to accumulate in the synovial fluid and bone marrow. 1/3 of the gold compounds are excreted in the urine and remaining goes through feces.

Adverse effects:
Pruritic (itching) skin rashes may occur.

D-Penicillamine

It is a metabolite of penicillin and an analog of cysteine (an amino acid).


Action:
It slows the advancement of the bone erosion and rheumatoid arthritis.

Adverse effects:
It may cause some of the very serious effects such as some of the dermatologic problems, nephritis and aplastic anemia.

Chloroquine and hydroxychloroquine

These drugs are mainly used in malaria.


Mechanism of action:
These drugs may cause the lowering of T lymphocytes for action in Rheumatoid arthritis.

Action:
These drugs are used in Rheumatoid arthritis, when NSAIDs are not effective to that extent. They may be used alone or in combination with other NSAIDs. When it is used in combination it must be used in lower doses.

These drugs slow the gradual change in the bones due to continuous wear & tear and sometimes they may cause temporary disappearance of the disease.

Adverse effects:
This may cause ocular toxicity, nausea, vomiting and dyspepsia.

Leflunomide

Leflunomide is a drug that causes modification of the immune system while undergoing treatment (this modification or alteration is a part of the treatment so that is why it is also called as immunomodulatory agent) and disease modifying anti-rheumatic agent.


Mechanism of action:
Leflunomide causes inhibition of:

1. Multiplication or propagation of T cells

2. Production of autoantibodies by B cells.

Leflunomide inhibit the enzyme Dihydroorotate dehydrogenase (DHODH). This causes Uridine 5’-monophosphate (UMP) not to be produced.

UMP is essential in two ways:

1. It is an important component of RNA synthesis.

2. It is pioneer in making nucleotide which is composed of thymidine, which is required for DNA synthesis.

As a result there is a cell arrest.

Action:

It is a reversible inhibitor of DHODH. It helps to reduce pain and inflammation and along with this function it also helps to reduce the decay or erosion cause to the bones or any other body parts due to inflammation.

It can be used alone or in combination with other drugs like methotrexate.

Pharmacokinetics:
It is well absorbed orally. Its half life is 13-19 days. The binding of this drug to serum albumin is about more than 85%. It is excreted both through biliary and renal excretion. It readily converts to metabolites and the metabolites are excreted in the urine and feces.

The metabolite which is still effective goes back to do some work. Cholestyramine enhances leflunomide excretion.

Adverse effects:
It may cause headache, diarrhea (loose bowels) and nausea. Alopecia, Weight loss or weight gain and allergic reactions like skin rash are its rare side affects.

Contraindications:
It is contraindicated in pregnancy.

Precautions:
As this drug may cause an increase in liver enzyme level so it must be used with caution in liver diseases.

Methotrexate

It is thought that methotrexate is the cornerstone of the therapy for the patients, who have not responded well to other NSAIDs in severe rheumatoid arthritis or psoriatic arthritis.


Action:
As this is an immunosuppressant, this may be responsible for its effectiveness in reducing arthritis which according to some experts is an autoimmune disease.

Methotrexate slows the decay within moving joints, which may be due to the inhibition of thymidylate synthetase and some other related enzymes.

Pharmacokinetics:
The drug is found to be absorbed about 65%-75% after oral administration. Its serum half life is about 6-9 hours.

It has been found that methotrexate shows response usually sooner than the other agents i.e. it may be within 3 to 6 weeks of treatment.

Dosage:
Small doses are effective for the treatment of Arthritis than those needed for the treatment of cancer as this drug is also useful for the treatment of cancer. The dose is reduced to once a week administration.

Adverse Effects:
In small doses it may cause mucosal ulceration and nausea. Some of the following adverse effects may also be seen:

1. Cytopenia

2. Liver cirrhosis (it is particularly dose related)

3. Pneumonia like syndrome (hypersensitivity lung reaction)

Disease modifying anti-rheumatic agents

Disease modifying anti-rheumatic drugs (DMARDs) or slow acting anti-rheumatic drugs (SAARDs)


1. Slow the course of the disease and can induce remission.

2. Reduce or prevent the joint damage.

Drugs to be choosen:
Many experts start therapy with the conventional drugs i.e. methotrexate or hydroxychloroquine. But if these do not work properly then they go to the newer agents i.e. anakinra, adalimumab, leflunomide, and infliximab. Often it is also prescribed that the combination therapy is more effective.

Acetaminophen

Action:

It inhibits prostaglandin synthesis in CNS (so analgesic and anti-pyretic) but has less effect on COX so (weak anti-inflammatory).

Therapeutic Uses:
It is used as analgesic and anti-pyretic. It is analgesic /anti-pyretic of choice for children with viral infections or chicken pox.

Drug interactions:
It does not antagonize the uricosuric agent (probenecid) and so may be used in patients with gout who are taking this drug.

Pharmacokinetics:
Rapidly absorbed from GI tract. 1st pass metabolism occurs in the luminal cells of the intestine and in the hepatocytes. It is conjugated in the liver to form inactive glucoronidated or sulfated metabolites. It is excreted in the urine.

Adverse effects:
It may cause skin and minor allergic reactions. Prolonged use may cause renal tubular necrosis and hypoglycemic coma.

Celecoxib

Action:

Inhibition of COX-2 by celecoxib is time dependent and reversible.

Pharmacokinetics:
It is readily absorbed orally. Its peak concentration is approximately 3 hours. It is metabolized in the liver by cytochrome P450 (CYP2C9). It is excreted in feces and urine. Its half life is 11 hours, so its dose is adjusted according to once a day.

Adverse Effects:
It may cause abdominal pain, Diarrhea, Dyspepsia and Kidney toxicity may also occur.

Drug interactions:
It inhibits CYP2D6 and so can elevate levels of ß-blockers, anti-depressants and anti-psychotic drugs.

Fluconozole, fluvastatin and zafirlukast may increase serum level of celecoxib.

Precautions:

It should be avoided in patients;

- with chronic renal insufficiency

- Severe heart disease

- Volume depletion

- Hepatic failure

COX-2 selective NSAIDs

COX-2 is better in providing space for inhibitors than COX-1.


Uses:
It is used as a pain reliever.
Adverse effects:
It may cause renal insufficiency and hypertension.

Diflunisal

It is diflurophenyl derivative of salicylic acid.


Action:
3-4 times more potent than aspirin but cannot be used as antipyretic.

Pharmacokinetics:
It is not metabolized to salicylate and therefore cannot cause salicylate intoxication. It cannot enter CNS, so cannot relieve fever.

Nabumetone

Same as aspirin with little side effects.

Tolmetin

Same as aspirin with little side effects.

Ketorolac

Action:

Similar to NSAIDs.

Administration:
It can be administered

• Orally

• Intramuscularly (for post operative pain)

• Topically (for allergic conjunctivitis)

Pharmacokinetics:
It undergoes metabolism in the liver. The drug and its metabolites are excreted in the urine.

Adverse effects:
It is similar to NSAIDs.

Diclofenac

Action:

It is more potent in action than naproxen and indomethacin. It is cyclooxygenase inhibitor.

Pharmacokinetics:
It accumulates in the synovial fluid. It is excreted into urine.

Therapeutic Uses:
It is used for the long term treatment of:
• Rheumatoid arthritis
• Osteoarthritis
• And ankylosing spondylitis.

Adverse effects:
Its adverse effects are similar to those of the NSAIDs.

Fenamates

They are used as a pain releiver.

Adverse effects:


• Diarrhea

• Hemolytic anemia (rare)