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

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.

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