Migraine MIGRAINE AND OTHER - PowerPoint Presentation

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Migraine

MIGRAINE AND OTHER

CLINICAL CONDITIONS

IN WHICH 5-HT

PLAYS A ROLE

(

carcinoid syndrome and pulmonary

hypertension

.)

The

most common types of headaches

are:

migraine, tension-type,

and cluster

headaches.

Migraine

is a common and debilitating condition affecting 10-15% of people. Although the causes are not well understood, both

genetic

and

environmental

factors seem to be important.

Sometimes attacks are precipitated by particular foods or by visual stimuli, but more often they occur without obvious cause. The

frequency

of attacks varies,

with about

three-quarters of

migraineurs

(as they are called) having more than one episode per month.

Generally

, the onset of attacks begins at puberty and wanes with

increasing

age. Women are threefold more likely than are men to

suffer

from the

disorder and

the attacks are often linked to the

menstrual

cycle or other reproductive events. It appears that rapidly falling estrogen levels can precipitate attacks in susceptible subjects.

Types

of

migraine

There

are two main types of migraine headaches. The first,

migraine without

aura (Common type)

,

is a severe, unilateral, pulsating headache that typically lasts from 2 to 72 hours. These headaches are often aggravated by physical activity and are

preceded

by a

premonitory phase

with

nausea, vomiting, photophobia (hypersensitivity to light), and phonophobia (hypersensitivity to sound). The majority of patients with migraine do not have aura

.

In the second type,

migraine with

aura (Classic type)

,

the headache is preceded by neurologic symptoms called auras, which can be visual, sensory, and/or cause speech or motor disturbances. Most commonly, these prodromal symptoms are

visual such

as a slowly moving blind spot with associated flashing lights (‘scintillating

scotoma

’) or geometric

patterns

of

colored

lights (‘fortification spectra’) or the illusion of looking through the wrong end of a telescope

.

and occur approximately 20 to 40 minutes before headache pain begins. In the 15% of migraine patients whose headache is preceded by an aura, the aura itself allows diagnosis.

The headache in migraines with or without auras is similar.

The

headache phase

proper

is

characterized

by a moderate or severe headache, starting unilaterally, but then usually spreading to both sides of the head. It may have a pulsating or throbbing quality accompanied by nausea, vomiting and prostration. This phase may persist for hours or even days.

Following resolution of the headache, is

the

postdromal

phase

. This may include feelings of fatigue, altered cognition or mood changes.

PATHOPHYSIOLOGY

The causes of migraine are incompletely understood.

Historically

there have been three main hypotheses

advanced to

account for the

symptoms:

1.

The

'brain' hypothesis

:

links migraine to the phenomenon of

cortical spreading depression

. In the depressed area, the ionic balance is grossly disturbed, with an extremely high extracellular K+ concentration, and the blood flow is reduced. There is strong evidence to suggest that the aura phase of a migraine attack is associated with a wave of spreading

depression

of neuronal activity accompanied by reduced blood flow in the most posterior part of the cerebral hemisphere. This

hypoperfusion

gradually spreads forward over the surface of the cortex to other contiguous areas of the brain. The vascular alteration is accompanied by functional changes. The

hypoperfusion

persists throughout the aura and well into the headache phase. Patients who have migraine without aura do not show

hypoperfusion

.

2.

The classic 'vascular' theory

:

implicated an initial

intracerebral

vasoconstriction causing the aura, followed by an

extracerebral

vasodilatation causing the headache.

The headache originates not in the brain itself, but in

extracerebral

structures lying within the cranial cavity innervated by nociceptive sensory nerve fibers of the trigeminal pathway, such as the meninges and large arteries. The vascular theory attributes the headache to dilatation in these large arteries.

3.

The 'inflammation' hypothesis

: proposes that activation of trigeminal nerve terminals in the meninges and

extracranial

vessels is the primary event in a migraine attack. This would cause pain directly and also induce inflammatory changes through the release of neuropeptides and other inflammatory and

vasodilatory

mediators  as

substance P,

neurokinin

A

and

calcitonin gene-related peptide (CGRP

)

from the sensory nerve terminals

(

neurogenic Inflammation).

Serotonin,5HT, seems to be important factor in the pathogenesis of migraine because of the following:

1-There is a sharp increase in the urinary excretion of the main 5-HT metabolite, 5-HIAA, during the attack.

The blood concentration of 5-HT falls,

probably because

of depletion of platelet 5-HT.

2-Many of the drugs that are effective in treating migraine are 5-HT receptor agonists or antagonists.

Treatment of Migraine

Management

of headaches involves avoidance of headache triggers (for example, alcohol, chocolate, and stress) and use of abortive treatments for acute headaches, as well as prophylactic therapy in patients with frequent or severe migraines.

Acute attack

Nonspecific

treatment

i

ncludes

analgesics such as

nonsteroidal

anti-inflammatory drugs (NSAIDs)

e.g

aspirin, ibuprofen and indomethacin

and

antiemetics

(for example,

prochlorperazine

or metoclopramide

to also

hasten

absorption

of NSAIDs) to control vomiting. Opioids are reserved as rescue medication when other treatments for a

severe migraine

are not

successful.

Triptans

:

Triptans

are the first line treatment of acute migraine. They are synthetic

tryptamines

. This class of drugs includes

sumatriptan

(the prototype drug)

,

zolmitriptan

,

naratriptan

,

rizatriptan

,

eletriptan

,

almotriptan

and

frovatriptan

These agents rapidly and effectively abort or markedly reduce the severity of migraine headaches in 70-80 % of patients.

Their

action is due to their agonist effects on serotonin

5-HT1

B

5-HT

1

D

and

5-HT

1F

receptors.

Agonist

activity at these receptors in cerebral blood vessels produces vasoconstriction, thereby reversing the vasodilation that contributes to the throbbing migraine headache

.

Stimulation of presynaptic

5-HT

1B/1D/1F

receptors

on trigeminal nerve endings also inhibits the release of peptides that cause vasodilation, neurogenic inflammation, and pain.

Finally

, stimulation of 5-HT

1B/1D/1F

receptors in the brain stem prevents activation of pain fibers in trigeminal nerves involved in migraine headache

.

Sumatriptan

is given subcutaneously,

intranasally

, or orally.

Zolmitriptan

is available orally and by nasal spray, all other agents are taken orally. The onset of the parenteral drug (which is also indicated for treatment of cluster headaches) is about 20 minutes, compared with 1 to 2 hours when the drug is administered orally.

Sumatriptan

has a short duration of action, with an elimination half-life of 2 hours. Headache commonly recurs within 24 to 48 hours after a single dose of drug, but in most patients, a second dose is effective in aborting the headache.

Rizatriptan

and

eletriptan

are modestly more effective than

sumatriptan

, whereas,

naratriptan

and

almotriptan

are better tolerated.

Frovatriptan

is the longest-acting

triptan

, with a half-life of more than 24 hours.

Individual responses to

triptans

vary, and more than one drug trial may be necessary before treatment is successful.

Adverse effects:

Significant elevation of blood pressure and cardiac events as coronary spasm have been reported with

triptan

use. Therefore,

triptans

should not be administered to patients with risk factors for coronary artery disease without performing a cardiac evaluation prior to administration. Other adverse events with the use of

triptans

include pain and pressure sensations in the chest, neck, throat, and jaw

. the use of

triptans

include pain and pressure sensations in the chest, neck, throat, and jaw. Dizziness and malaise have also been seen with the use of

triptans

.

Ergotamine

(

5-HT

1D

receptor partial agonist) &

dihydroergotamine

(5HT

2

antagonist, 5HT

1

partial agonist) are ergot alkaloids.

They also affect

α

-

adrenoceptors

and

dopamine receptors.

They act as vasoconstrictors & inhibitors of trigeminal nerve transmission.

Ergotamine

tartrate is available for oral, sublingual, suppository containing both ergotamine and caffeine and inhaler

use It is

mostly effective when used in the early stages of the migraine. The vasoconstriction induced by ergotamine is long-lasting and cumulative when the drug is taken repeatedly, as in a severe migraine attack. Patients must be carefully informed that no more than 6 mg of the oral preparation may be taken for each attack and no more than 10 mg per

week.

Dihydroergotamine

is available as intranasal and injectable preparations. administered intravenously or

intranasally

and has an efficacy similar to that of

sumatriptan

. The use

of

dihydroergotamine

is limited to severe cases of migraines.

Adverse

effects are :Peripheral vasoconstriction, including coronary vessels. Nausea and vomiting.

Contraction of gravid

uterus

and may damage

fetus.

Prophylaxis

Therapy to prevent migraine is indicated if the attacks occur two or more times a month and if the headaches are severe or complicated by serious neurologic signs. Apart from 5-HT

2

receptor antagonists, the drugs used prophylactically are a mixed bag, and their mechanism of action is poorly understood

.

β-

Adrenoceptor

antagonists

(e.g. propranolol,

metoprolol

). Effective and widely used for migraine (first line agents).

Pizotifen

(5-HT

2

receptor antagonist) also histamine antagonist.

pizotifen

is reasonably effective, its use is limited by side effects, principally drowsiness and weight gain, and it is usually not the first choice drug for preventing migraines. 

Other 5-HT

2

receptor antagonists:

Cyproheptadine

:

also has antihistamine actions.

Methysergide

: rarely used because of risk of retroperitoneal fibrosis.

Tricyclic antidepressants

(e.g. amitriptyline) & SSRIs.

Clonidine

, an α2

adrenoceptor

agonist which can inhibit excitatory neurons.

Anticonvalsants

:

Topiramate

.

Calcium antagonists

(e.g.

dihydropyridines

, verapamil): headache is a side effect of these drugs but, paradoxically, they may reduce frequency of migraine attacks.

Drugs used for tension and cluster headache

Analgesics such as NSAIDs for example,

naproxen

and

ibuprofen

,

acetaminophen

, and

aspirin

are used for symptomatic relief of tension headaches. Acetaminophen and/or aspirin may also be combined with caffeine. [

Note:

Caffeine is believed to increase the central effectiveness of acetaminophen and aspirin.]

Butalbital

, a barbiturate, in combination with acetaminophen or aspirin with or without caffeine is also used in tension headaches.

Treatment of cluster headache: Inhalation

of 100% oxygen

(It has been shown that oxygen causes a marked decrease in cerebral blood flow that is coincident with the reduced degree of pain in cluster headache) and

triptans

(especially

sumatriptan

) are used as first-line abortive strategies for cluster headache.

CARCINOID SYNDROME

Carcinoid syndrome

is

a rare disorder associated with malignant

tumors of

enterochromaffin

cells, which usually arise in the

small intestine

and

metastasize

to the liver. These

tumors

secrete a variety of chemical

mediators. 5-HT

is the most

important.

The release of these substances

into the

bloodstream results in several unpleasant symptoms, including flushing,

diarrhea,

bronchoconstriction and hypotension, which may cause dizziness or fainting. Fibrotic stenosis of heart valves, which can result in cardiac failure, also occurs.

The

syndrome is readily diagnosed by measuring the urinary excretion of the main metabolite of 5-HT, 5-HIAA. This may increase by as much as 20-fold when the disease is

active.

5-HT2

antagonists, such as

cyproheptadine

, are effective in controlling some of the symptoms of carcinoid syndrome. A complementary therapeutic approach is to use

octreotide

(a long-acting agonist at somatostatin receptors), which suppresses hormone secretion from neuroendocrine, including carcinoid, cells

PULMONARY

HYPERTENSION

Pulmonary hypertension

is

an extremely serious disease

characterized

by the progressive

remodelling

of the pulmonary vascular tree. This leads to

rise

in pulmonary arterial pressure which, if untreated (and treatment is difficult), inevitably leads to right heart failure and death.

The

role of 5-HT in this pathology was suggested by the fact that at least one form of the condition was precipitated by the use of appetite suppressants (e.g.

dexfenfluramine

and

fenfluramine

) that were at one time widely prescribed as ‘weight loss’ or

‘slimming

’ aids. These drugs apparently blocked SERT

and so serotonin promotes

the growth and proliferation of pulmonary arterial smooth muscle cells and also

produces

a net

vasoconstrictor effect

in this vascular

bed

that may cause pulmonary hypertension.

Treatment is through drugs which cause

vasodilation

such as calcium channel blockers,

prostacyclin

 (prostaglandin I2)

endothelin

receptor antagonists and

phosphodiesterase

type 5 inhibitors