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.