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.