AUTACOID 

    

 
This term is derived from Greek:

autos—self, akos—healing substance or remedy.

These are diverse substances produced by a wide variety of cells in the body,
having intense biological activity, but generally act locally (e.g. within
inflammatory pockets) at the site of synthesis and release.

They have also been called ‘local hormones’. However, they differ from
‘hormones’ in two important ways—hormones are produced by specific
cells, and are transported through circulation to act on distant target tissues.

Autacoids are involved in a number of physiological and pathological processes

(especially reaction to injury and immunological insult) and even serve as
transmitters or modulators in the nervous system, but their role at many sites is not
precisely known. A number of useful drugs act by modifying their action or
metabolism. The classical autacoids are—

Amine autacoids Histamine, 5Hydroxytryptamine (Serotonin)

Lipid derived autacoids Prostaglandins, Leukotrienes, Platelet activating factor

Peptide autacoids Plasma kinins (Bradykinin, Kallidin), Angiotensin

 
In addition, cytokines (interleukins, TNFα, GMCSF etc.) and several peptides like
gastrin, somatostatin, vasoactive intestinal peptide and many others may be
considered as autacoids.

HISTAMINE
 

Histamine, meaning ‘tissue amine’ (histos— tissue) is almost ubiquitously present

in animal tissues and in certain plants, e.g. stinging nettle. Its pharmacology was
studied in detail by Dale in the beginning of the 20th century when close
parallelism was noted between its actions and the manifestations of certain allergic
reactions. It was implicated as a mediator of hypersensitivity phenomena and
tissue injury reactions. It is now known to play important physiological roles.

Histamine is present mostly within storage granules of mast cells. Tissues rich in
histamine are skin, gastric and intestinal mucosa, lungs, liver and placenta.
Nonmast cell histamine occurs in brain, epidermis, gastric mucosa and growing
regions. Turnover of mast cell histamine is slow, while that of nonmast cell
histamine is fast.

Histamine is also present in blood, most body secretions, venoms and pathological
fluids.

SYNTHESIS, STORAGE AND DESTRUCTION

 

Histamine is β imidazolylethylamine. It is synthesized locally from the amino acid

histidine and degraded rapidly by oxidation and methylation (Fig. 11.1). In mast
cells, histamine (positively charged) is held by an acidic protein and heparin
(negatively charged) within intracellular granules. When the granules are extruded
by exocytosis, Na+ ions in e.c.f. exchange with histamine to release it free (Fig.
11.2). Increase in intracellular cAMP inhibits histamine release. Histamine is
inactive orally because liver degrades all histamine that is absorbed from the
intestines.
HISTAMINE RECEPTORS     
 

Analogous to adrenergic αand β receptors, histaminergic receptors were classified

by Asch and Schild (1966) into H  and H  : those blocked by then available
1 2

antihistamines were labelled H . Sir James Black (1972) developed the first
1

H  blocker burimamide and confirmed this classification. Both H  and H  receptors

2 1 2

have now been cloned. A third H  receptor, which serves primarily as an

3

autoreceptor controlling histamine release from neurones in brain was identified in

1983. Though some selective H  agonists and antagonists have been produced,
3

none has found any clinical application. Features of these 3 type of histaminergic
receptor are compared in Table 11.1.

Molecular cloning has revealed yet another (H ) receptor in 2001. It has

4

considerable homology with H  and binds many H  ligands. Eosinophils, mast cells
3 3

and basophils are the primary cells expressing H  receptors; activation enhances
4

chemotaxis of these cells. The H  receptor may be playing a role in allergic

4

inflammation: H  antagonists are being explored as potential drugs for allergic

4

inflammatory conditions like rhinitis and asthma. Intestines and brain are the other
sites where H  receptors have been located.
4

PHARMACOLOGICAL ACTIONS - HISTAMINE

 

1.   Blood Vessels
 
Histamine causes marked dilatation of smaller blood vessels, including arterioles,
capillaries and venules. On s.c. injection flushing, especially in the blush area,
heat, increased heart rate and cardiac output, with little or no fall in BP are
produced. Rapid i.v. injection causes fall in BP which has an early short lasting
H  and a slow but more persistent H  component. With low doses only the
1 2

H  component is manifest since H  receptors have higher affinity. Fall in BP due to

1 1

large doses is completely blocked only by a combination of H  and H  antagonists.

1 2

Dilatation of cranial vessels causes pulsatile headache.

 

Like ACh and many other autacoids, vasodilatation caused by histamine is partly
(H  component) indirect, mediated through ‘endothelium dependent relaxing
1

factor’ (EDRF): the receptor being located on the endothelial cells. H  receptors 2

mediating vasodilatation are located directly on the vascular smooth muscle.

Larger arteries and veins are constricted by histamine: mediated by H  receptor on

1

vascular smooth muscle. Histamine also causes increased capillary permeability

due to separation of endothelial cells → exudation of plasma. This is primarily a
H  response.
1

Injected intradermally, it elicits the triple response consisting of:

Red spot: due to intense capillary dilatation.

Wheal:   due to exudation of fluid from capillaries and venules.

Flare:  i.e. redness in the surrounding area due to arteriolar dilatation

mediated by axon reflex.

2.   Heart
 
Direct effects of histamine on in situ heart are not prominent, but the isolated heart,
especially of guinea pig, is stimulated—rate as well as force of contraction is
increased. These are primarily H  responses but a H  mediated negative
2 1

dromotropic (slowing of AV conduction) effect has also been demonstrated.

 
3. Visceral smooth muscle

Histamine causes broncho-constriction; guinea pigs and patients of asthma are

highly sensitive. Large doses cause abdominal cramps and colic by increasing
intestinal contractions. Guineapig uterus is contracted while that or rat is relaxed;
human uterus is not much affected as are most other visceral smooth muscles.

Smooth muscle contraction is a H  response. In few instances H  mediated

1 2

relaxation is also seen, e.g. bronchial muscle of sheep, human bronchi after
H  blockade.
1

4. Glands
 
Histamine causes marked increase in gastric secretion—primarily of acid but also
of pepsin. This is a direct action exerted on parietal cells through H  receptors and
2

is mediated by increased cAMP generation, which in turn activates the membrane

proton pump (H+ K+ ATPase).
 

Histamine can increase other secretions also, but the effect is hardly discernable.

5. Sensory Nerve Endings

 
Itching occurs when histamine is injected i.v. or intracutaneously. Higher
concentrations injected more deeply cause pain. These are reflections of the
capacity of histamine to stimulate nerve endings.
 

6. Autonomic Ganglia And Adrenal Medulla

 
These are stimulated and release of Adr occurs, which can cause a secondary rise
in BP.

7. CNS
 
Histamine does not penetrate bloodbrain barrier—no central effects are seen on i.v.
injection. However, intracerebroventricular administration produces rise in BP,
cardiac stimulation, behavioural arousal, hypothermia, vomiting and ADH release.
These effects are mediated through both H  and H  receptors.
1 2

PATHOPHYSIOLOGICAL ROLES - HISTAMINE

 

Gastric Secretion

Histamine has dominant physiological role in mediating secretion of HCl in the

stomach. Non-mast cell histamine occurs in gastric mucosa, possibly in cells called
‘histaminocytes’; situated close to the parietal cells, and has high turnover rate. It is
released locally under the influence of all stimuli that evoke gastric secretion
(feeding, vagal stimulation, cholinergic drugs and gastrin) and activates the proton
pump (H+K+ ATPase) through H  receptors.
2

H  blockers not only suppress acid secretion induced by histamine but also
2

markedly diminish that in response to ACh and gastrin. By a mutually synergistic

interaction the three secretagogues amplify responses to each other with histamine
playing the dominant role. As such, antimuscarinic drugs dampen the response to
histamine and gastrin also. All three secretagogues activate the same proton pump
(H+K+ATPase) in the parietal cell membrane, but through their own receptors.

Allergic Phenomena

Mediation of hypersensitivity reactions has been the first role ascribed to

histamine. However, histamine is only one of the mediators of such phenomena.
Released from mast cells following AG : AB reaction on their surface (involving
IgE type of reaginic antibodies;) in immediate type of hypersensitivity reactions,
histamine is causative in urticaria, angioedema, bronchoconstriction and
anaphylactic shock. The H  antagonists are effective in controlling these
1

manifestations to a considerable extent, except asthma and to a lesser extent

anaphylactic fall in BP in which leukotrienes (especially LTD ) and PAF appear to
4

be more important. Histamine is not involved in delayed or retarded type of

allergic reactions.
 

As Transmitter

Histamine is believed to be the afferent transmitter which initiates the sensation of

itch and pain at sensory nerve endings.
 

Nonmast cell histamine occurs in brain, especially hypothalamus and midbrain. It

is involved in maintaining wakefulness; H  antihistaminics owe their sedative
1

action to blockade of this function. In the brain H  agonism suppresses appetite;

1

certain H  antagonists stimulate appetite. Histamine also appears to act as a

1

transmitter regulating body temperature, cardiovascular function, thirst, hormone

release from anterior pituitary and possibly other functions.

 
Inflammation

Histamine has been implicated as a mediator of vasodilatation and other changes

that occur during inflammation. It promotes adhesion of leukocytes to vascular
endothelium by expressing adhesion molecule Pselectin on endothelial cell
surface, sequestrating leukocytes at the inflammatory site. It may also regulate
microcirculation according to local needs.
 

Tissue Growth And Repair

Because growing and regenerating tissues contain high concentrations of

histamine, it has been suggested to play an essential role in the process of growth
and repair.

 
Headache

Histamine has been implicated in certain vascular headaches, but there is no

conclusive evidence.

USES - HISTAMINE
 

Histamine has no therapeutic use. In the past it has been used to test acid secreting
capacity of stomach, bronchial hyperreactivity in asthmatics, and for diagnosis of
pheochromocytoma, but these pharmacological tests are risky and obsolete now.

Betahistine It is an orally active, somewhat H  selective histamine analogue, which

1

is used to control vertigo in patients of Meniéré’s disease: possibly acts by causing

vasodilatation in the internal ear. It is contraindicated in asthmatics and ulcer
patients.

VERTIN 8 mg tab., 1/2 to 1 tab. QID.

HISTAMINE RELEASERS
 

A variety of mechanical, chemical and immunological stimuli are capable of

releasing histamine from mast cells.

1. Tissue damage: trauma, stings and venoms, proteolytic enzymes, phospholipase

A.

2. Antigen: antibody reaction involving IgE antibodies.

 
1.  Polymers like dextran, polyvinyl pyrrolidone (PVP).

4. Some basic drugs—tubocurarine, morphine, atropine, stilbamidine, polymyxin

B, vancomycin and even some antihistaminics directly release histamine without
an immunological reaction.

5. Surface acting agents like Tween 80, compound 48/ 80 etc. The primary action
of these substances is release of histamine from mast cells, therefore they are
called histamine liberators. They produce an ‘anaphylactoid’ reaction—itching and
burning sensation, flushing, urticaria, fall in BP, tachycardia, headache, colic and
asthma. Most of these symptoms are controlled by a H  antihistaminic, better still if
1

H  blocker is given together.

2

H1 ANTAGONISTS
(Conventional Antihistaminics)

These drugs competitively antagonize actions of histamine at the H  receptors. The

1

first compounds of this type were introduced in the late 1930s and have
subsequently proliferated into an unnecessary motley of drugs. Nevertheless, they
are frequently used for a variety of purposes. More commonly employed now are
the less sedating second generation H  antihistamines that have been added after
1

1980. Seemingly, H  antihistaminics have diverse chemical structures, but majority

1

have a substituted ethylamine side chain.

Pharmacological Actions

 
Qualitatively all H   antihistaminics have similar actions, but there are quantitative
1

differences, especially in the sedative property.

 
1. Antagonism Of Histamine

They effectively block histamine induced bronchoconstriction, contraction of

intestinal and other smooth muscle and triple response—especially wheal, flare
and itArticle No. Fall in BP produced by low doses of histamine is blocked, but
additional H  antagonists are required for complete blockade of higher doses.
2

Pretreatment with these drugs protects animals from death caused by i.v. injection
of large doses of histamine. Release of Adr from adrenal medulla in response to
histamine is abolished. Constriction of larger blood vessel by histamine is also
antagonized. Action of histamine on gastric secretion is singularly not affected by
these drugs.

2. Antiallergic action
 
Many manifestations of immediate hypersensitivity (type I reactions) are
suppressed. Urticaria, itching and angioedema are well controlled. Anaphylactic
fall in BP is only partially prevented. Asthma in man is practically unaffected
though anaphylactic bronchoconstriction in guinea pig is largely prevented. This
tissue and species dependence of response probably reflects extent of involvement
of histamine in the reaction. It is now well established that leukotrienes (C  and D )
4 4

and PAF are more important mediators for human asthma.

 

3. CNS
 
The older antihistamines produce variable degree of CNS depression. This appears
to depend on the compound’s ability to penetrate bloodbrain barrier and its affinity
for the central (compared to peripheral) H  receptors. Individual susceptibility to
1

different agents varies considerably, but an overall grading of the sedative property
is presented in Table 11.2. Some individuals also experience stimulant effects like
restlessness and insomnia. Excitement and convulsions are frequently seen at toxic
doses. The second generation anti-histaminics are practically non-sedating.
 

Certain H  antihistamines are effective in preventing motion sickness. It is not

1

certain whether this is due to antagonism of histamine in the brain or reflects

antimuscarinic property of these drugs. Promethazine also controls vomiting of
pregnancy and other causes.

 
Promethazine and few other antihistaminics reduce tremor, rigidity and sialorrhoea
of parkinsonism. Anticholinergic and sedative properties underlie the benefit.

Some H  antihistamines are also effective antitussives.

1

1.     Anticholinergic Action

Many H  blockers in addition antagonize muscarinic actions of AArticle No. The

1

anticholinergic action can be graded as:

High Low  Minimal/Absent

 

Promethazine        Chlorpheniramine Fexofenadine

Diphenhydramine Hydroxyzine         Astemizole

Dimenhydrinate    Triprolidine Loratadine

Pheniramine Cyclizine     Cetirizine

Cyproheptadine              Mizolastine

                  

If used concurrently with atropine or its substitutes, phenothiazines, tricyclic

antidepressants or disopyramide, the anticholinergic action adds up.

2.     Local Anaesthetic

 
Some drugs like pheniramine, have strong while others have weak membrane
stabilizing property. However, they are not used clinically as local anaesthetic
because they cause irritation when injected s.c.

Membrane stabilizing activity also confers antiarrhythmic property to these

compounds.

6. BP
 
Most antihistaminics cause a fall in BP on i.v. injection (direct smooth muscle
relaxation). However, this is not evident on oral administration.
 

Pharmacokinetics
 

The classical H  antihistaminics are well absorbed from oral and parenteral routes,
1

metabolized in the liver and excreted in urine. They are widely distributed in the
body and enter brain. The newer compounds penetrate brain poorly. Duration of
action of most agents is 4–6 hours, except meclizine, loratadine, cetirizine and
fexofenadine which act for 12–24 hours or more.

Side Effects And Toxicity

 

Side effects with first generation H  antihistaminics are frequent, but are generally
1

mild. Individuals show marked differences in susceptibility to side effects with

different drugs. Some tolerance to side effects develops on repeated use.

Sedation, diminished alertness and concentration, light headedness, motor

incoordination, fatigue and tendency to fall asleep are the most common. Objective
testing shows impairment of psychomotor performance. Patients should be
cautioned not to operate motor vehicles or machinery requiring constant attention.
Alcohol synergises in producing these effects as do other CNS depressants. Few
individuals become restless, nervous and are unable to sleep. Second generation
compounds are largely free of CNS effects.

Dryness of mouth, alteration of bowel movement, urinary hesitancy and blurring of

vision can be ascribed to anticholinergic property.

Epigastric distress and headache are also common.

Local application can cause contact dermatitis.

Some like cyclizine and fexofenadine are teratogenic in animals; but not in
humans; caution is nevertheless to be exercised during pregnancy.

Acute overdose produces central excitation, tremors, hallucinations, muscular

incordination, convulsions, flushing, hypotension, fever and some other features of
belladonna poisoning. Death is due to respiratory and cardiovascular failure.

Second Generation Antihistaminics

 

The second generation antihistaminics (SGAs) may be defined as those H  receptor

1

blockers marketed after 1980 which have one or more of the following properties :

        Higher H  selectivitiy: no anticholinergic side effects.

1

        Absence of CNS depressant property.

 

        Additional antiallergic mechanisms apart from histamine blockade: some

also inhibit late phase allergic reaction by acting on leukotrienes or by
antiplatelet activating factor effect.
 

Some recent compounds like fexofenadine and cetirizine that are active
metabolites of earlier drugs have also been referred as ‘third generation
antihistamines’, but this has not been accepted by an international concensus group
of experts.

These newer drugs have the advantage of not impairing psychomotor performance
(driving etc. need not be contraindicated), produce no subjective effects, no
sleepiness, do not potentiate alcohol or benzodiazepines. Some patients do
complain of sedation, but incidence is similar to placebo. However, they have a
narrow spectrum of therapeutic usefulness which is limited by the extent of
involvement of histamine (acting through H  receptors) in the disease state. Their
1

principal indications are:

        Allergic rhinitis and conjunctivitis, hay fever, pollinosis—control sneezing,

runny but not blocked nose, and red, watering, itchy eyes.
 

        Urticaria, dermographism, atopic eczema.

 

        Acute allergic reactions to drugs and foods. They have poor antipruritic,
antiemetic and antitussive actions.
 

Fexofenadine 
It is the active metabolite of terfenadine, the first nonsedating SGA that was
withdrawn because of several deaths due to polymorphic ventricular
tachycarida (Torsades de pointes) occurring with its higher doses or when it
was coadministered with CYP3A4 inhibitors (erythromycin, clarithromycin,
ketoconazole, itraconazole, etc.). This toxicity is based on blockade of delayed
rectifier K+ channels in the heart at higher concentrations. Astemizole is another
SGA banned for the same reason. Fexofenadine has a low propensity to block
delayed rectifier K+ channels, does not prolong QTc interval; no interaction with
CYP3A4 inhibitors have been reported. It is largely free of arrhythmogenic
potential, but some cases of ventricular arrhythmia in patients with preexisting
long QT interval have been reported. Thus, it is not entirely safe in patients with
long QT, bradycardia or hypokalemia.

Fexofenadine does not cross blood-brain barrier—does not produce sedation or

impair psychomotor performance and is free of atropinic side effects. It is rapidly
absorbed, excreted unchanged in urine and bile, has plasma t½ 11– 16 hours and
duration of action 24 hours. Though erythromycin and ketoconazole increase its
blood levels, but no arrhythmias have been observed.

Dose: For allergic rhinitis 120 mg OD; for urticaria and other skin allergies 180
mg OD.

Loratadine

Another longacting selective peripheral H  antagonist which lacks CNS depressant

1

effects and is fast acting. It is partly metabolized by CYP3A4 to an active

metabolite with a longer t½ of 17 hr, but has not produced cardiac arrhythmia in
overdose, though seizures are reported. No interaction with macrolides or
antifungals has been noted. Good efficacy has been reported in urticaria and atopic
dermatitis.

Desloratadine

It is the major active metabolite of loratadine effective at half the dose.

Noninterference with psychomotor performance and cardiac safety are
documented.

Cetirizine

It is a metabolite of hydroxyzine with marked affinity for peripheral H  receptors;

1

penetrates brain poorly, but subjective somnolence has been experienced at higher
doses. It is not metabolized; does not prolong cardiac action potential or produce
arrhythmias when given with erythromycin/ketoconazole.

 
Cetirizine in addition inhibits release of histamine and of cytotoxic mediators from
platelets as well as eosinophil chemotaxis during the secondary phase of the
allergic response. Thus, it may benefit allergic disorders by other actions as well. It
attains high and longer lasting concentration in skin, which may be responsible for
superior efficacy in urticaria/atopic dermatitis, as well as for once daily dosing
despite elimination t½ of 710 hr. It is indicated in upper respiratory allergies,
pollinosis, urticaria and atopic dermatitis; also used as adjuvant in seasonal
asthma.
 

 
Levocetirizine

It is the active R(–) enantiomer of cetirizine. It is effective at half the dose and
appears to produce few side effects.

 
Azelastine
 
This newer H  blocker has good topical activity; in addition inhibits histamine
1

release and inflammatory reaction triggered by LTs and PAF; and has
bronchodilator property. After intranasal application it has been shown to down
regulate intracellular adhesion molecule1 (ICAM1) expression on nasal mucosa.
Its t½ is 24 hr, but action lasts longer due to active metabolite. Its metabolism is
inhibited by CYP 3A4 inhibitors. Given by nasal spray for seasonal and perennial
allergic rhinitis it provides quick symptomatic relief lasting 12 hr. Stinging in the
nose and altered taste perception are the local side effects. Some somnolence has
been reported on nasal application and a tendency to weight gain noted after oral
use.
 

Mizolastine

This nonsedating antihistaminic is effective in allergic rhinitis and urticaria by

single daily dosing despite a t½ of 8–10 hr and no active metabolite.

Ebastine
 
Another newer SGA that rapidly gets converted to the active metabolite carbastine
having a t½ of 10–16 hr. It is non-sedating and active in nasal and skin allergies.
Animal studies have found it to prolong QTc interval which makes it liable to
arrhythmogenic potential and CYP3A4 interaction, but actual reports are still few.
 

Rupatadine

This recently introduced antihistaminic has additional PAF antagonistic property,

and is indicated in allergic rhinitis.

Uses
 

The uses of H  antihistaminics are based on their ability to block certain effects of
1

histamine released endogeneously, as well as on sedative and anticholinergic

properties.

1. Allergic Disorders
 
Antihistaminics do not suppress AG: AB reaction, but block the effects of released
histamine—are only palliative. They effectively control certain immediate type of
allergies, e.g. itching, urticaria, seasonal hay fever, allergic conjunctivitis and
angioedema of lips, eyelids, etc. However, their action is slow—Adr alone is
lifesaving in laryngeal angioedema. Similarly, they cannot be relied upon in
anaphylactic shock and have a secondary place to Adr. Benefits are less marked in
perennial vasomotor rhinitis, atopic dermatitis and chronic urticarias; combination
with an H  antagonist succeeds in some cases of chronic urticaria not responding to
2

H  antagonist alone.
1

The antihistaminics are ineffective in bronchial asthma: reasons may be—

a.   Leukotrienes (C , D ) and PAF are more important mediators than histamine.

4 4

b.     Concentration of antihistamines attained at the site may not be sufficient to

block high concentration of histamine released locally in the bronchi.
 

Certain newer compounds like cetirizine have adjuvant role in seasonal asthma.

Antihistaminics are also ineffective in other types of humoral and cell mediated
allergies because histamine is not involved. They do suppress urticaria and
swellings in serum sickness, but not other components of the syndrome.

Type I hypersensitivity reactions to drugs (except asthma and anaphylaxis) are

suppressed. Some skin rashes also respond.

2. Other Conditions Involving Histamine

Antihistaminics block symptoms produced by histamine liberators; afford

symptomatic relief in insect bite and ivy poisoning. Abnormal dermographism is
suppressed. They have prophylactic value in blood/saline infusion induced rigor.

3. Pruritides
 
Many conventional antihistamines have antipruritic action independent of
H  antagonism. Though relief is often incomplete, older antihistaminics remain the
1

first choice drugs for idiopathic pruritus.

 

4. Common Cold
 
Antihistaminics do not affect the course of the illness but may afford symptomatic
relief by anticholinergic (reduce rhinorrhoea) and sedative actions. The newer
nonsedating antihistamines are less effective in this respect.
 
5. Motion Sickness
 
Promethazine, diphenhydramine, dimenhydrinate and cyclizine have prophylactic
value in milder types of motion sickness; should be taken one hour before starting
journey. Promethazine can also be used in morning sickness, drug induced and
postoperative vomiting, radiation sickness. Cyproheptadine has appetite
stimulating effect; has been used in underweight children.
 

6. Vertigo
 
Cinnarizine is the H  antihistamine having additional anticholinergic, anti5HT,
1

sedative and vasodilator properties which has been widely used in vertigo. It
modulates Ca2+ fluxes and attenuates vasoconstrictor action of many endogenous
substances.
 

Cinnarizine inhibits vestibular sensory nuclei in the inner ear, suppresses

postrotatory labyrinthine reflexes, possibly by reducing stimulated influx of Ca2+
from endolymph into the vestibular sensory cells. Beneficial effects have been
reported in Méniére’s disease and other types of vertigo. Side effects are sedation
and mild g.i. upset.

SECOND GENERATION ANTIHISTAMINICS

 

The second generation antihistaminics (SGAs) may be defined as those H  receptor

1

blockers marketed after 1980 which have one or more of the following properties :

        Higher H  selectivitiy: no anticholinergic side effects.

1

        Absence of CNS depressant property.

 

        Additional antiallergic mechanisms apart from histamine blockade: some

also inhibit late phase allergic reaction by acting on leukotrienes or by
antiplatelet activating factor effect.
 

Some recent compounds like fexofenadine and cetirizine that are active
metabolites of earlier drugs have also been referred as ‘third generation
antihistamines’, but this has not been accepted by an international concensus group
of experts.

These newer drugs have the advantage of not impairing psychomotor performance
(driving etc. need not be contraindicated), produce no subjective effects, no
sleepiness, do not potentiate alcohol or benzodiazepines. Some patients do
complain of sedation, but incidence is similar to placebo. However, they have a
narrow spectrum of therapeutic usefulness which is limited by the extent of
involvement of histamine (acting through H  receptors) in the disease state. Their
1

principal indications are:

        Allergic rhinitis and conjunctivitis, hay fever, pollinosis—control sneezing,

runny but not blocked nose, and red, watering, itchy eyes.
 

        Urticaria, dermographism, atopic eczema.

 

        Acute allergic reactions to drugs and foods. They have poor antipruritic,
antiemetic and antitussive actions.
 

Fexofenadine 

It is the active metabolite of terfenadine, the first nonsedating SGA that was
withdrawn because of several deaths due to polymorphic ventricular
tachycarida (Torsades de pointes) occurring with its higher doses or when it
was coadministered with CYP3A4 inhibitors (erythromycin, clarithromycin,
ketoconazole, itraconazole, etc.). This toxicity is based on blockade of delayed
rectifier K+ channels in the heart at higher concentrations. Astemizole is another
SGA banned for the same reason. Fexofenadine has a low propensity to block
delayed rectifier K+ channels, does not prolong QTc interval; no interaction with
CYP3A4 inhibitors have been reported. It is largely free of arrhythmogenic
potential, but some cases of ventricular arrhythmia in patients with preexisting
long QT interval have been reported. Thus, it is not entirely safe in patients with
long QT, bradycardia or hypokalemia.

Fexofenadine does not cross blood-brain barrier—does not produce sedation or

impair psychomotor performance and is free of atropinic side effects. It is rapidly
absorbed, excreted unchanged in urine and bile, has plasma t½ 11– 16 hours and
duration of action 24 hours. Though erythromycin and ketoconazole increase its
blood levels, but no arrhythmias have been observed.

Dose: For allergic rhinitis 120 mg OD; for urticaria and other skin allergies 180
mg OD.

Loratadine

Another longacting selective peripheral H  antagonist which lacks CNS depressant

1

effects and is fast acting. It is partly metabolized by CYP3A4 to an active

metabolite with a longer t½ of 17 hr, but has not produced cardiac arrhythmia in
overdose, though seizures are reported. No interaction with macrolides or
antifungals has been noted. Good efficacy has been reported in urticaria and atopic
dermatitis.

 
 

Desloratadine

It is the major active metabolite of loratadine effective at half the dose.

Noninterference with psychomotor performance and cardiac safety are
documented.

Cetirizine

It is a metabolite of hydroxyzine with marked affinity for peripheral H  receptors;

1

penetrates brain poorly, but subjective somnolence has been experienced at higher
doses. It is not metabolized; does not prolong cardiac action potential or produce
arrhythmias when given with erythromycin/ketoconazole.

 
Cetirizine in addition inhibits release of histamine and of cytotoxic mediators from
platelets as well as eosinophil chemotaxis during the secondary phase of the
allergic response. Thus, it may benefit allergic disorders by other actions as well. It
attains high and longer lasting concentration in skin, which may be responsible for
superior efficacy in urticaria/atopic dermatitis, as well as for once daily dosing
despite elimination t½ of 710 hr. It is indicated in upper respiratory allergies,
pollinosis, urticaria and atopic dermatitis; also used as adjuvant in seasonal
asthma.
 

Levocetirizine

 
It is the active R(–) enantiomer of cetirizine. It is effective at half the dose and
appears to produce few side effects.

 
Azelastine
 
This newer H  blocker has good topical activity; in addition inhibits histamine
1

release and inflammatory reaction triggered by LTs and PAF; and has
bronchodilator property. After intranasal application it has been shown to down
regulate intracellular adhesion molecule1 (ICAM1) expression on nasal mucosa.
Its t½ is 24 hr, but action lasts longer due to active metabolite. Its metabolism is
inhibited by CYP 3A4 inhibitors. Given by nasal spray for seasonal and perennial
allergic rhinitis it provides quick symptomatic relief lasting 12 hr. Stinging in the
nose and altered taste perception are the local side effects. Some somnolence has
been reported on nasal application and a tendency to weight gain noted after oral
use.
 

Mizolastine

This nonsedating antihistaminic is effective in allergic rhinitis and urticaria by

single daily dosing despite a t½ of 8–10 hr and no active metabolite.

Ebastine
 
Another newer SGA that rapidly gets converted to the active metabolite carbastine
having a t½ of 10–16 hr. It is non-sedating and active in nasal and skin allergies.
Animal studies have found it to prolong QTc interval which makes it liable to
arrhythmogenic potential and CYP3A4 interaction, but actual reports are still few.
 
Rupatadine

This recently introduced antihistaminic has additional PAF antagonistic property,

and is indicated in allergic rhinitis.

Uses of H1 Antagonists / Conventional Antihistaminics

USES
 

The uses of H1 antihistaminics are based on their ability to block certain effects of
histamine released endogeneously, as well as on sedative and anticholinergic
properties.

1. Allergic Disorders
 
Antihistaminics do not suppress AG: AB reaction, but block the effects of released
histamine—are only palliative. They effectively control certain immediate type of
allergies, e.g. itching, urticaria, seasonal hay fever, allergic conjunctivitis and
angioedema of lips, eyelids, etc. However, their action is slow—Adr alone is
lifesaving in laryngeal angioedema. Similarly, they cannot be relied upon in
anaphylactic shock and have a secondary place to Adr. Benefits are less marked in
perennial vasomotor rhinitis, atopic dermatitis and chronic urticarias; combination
with an H2 antagonist succeeds in some cases of chronic urticaria not responding to
H1 antagonist alone.
 

The antihistaminics are ineffective in bronchial asthma: reasons may be—

a.   Leukotrienes (C4, D4) and PAF are more important mediators than histamine.
b.     Concentration of antihistamines attained at the site may not be sufficient to
block high concentration of histamine released locally in the bronchi.
 

Certain newer compounds like cetirizine have adjuvant role in seasonal asthma.
 

Antihistaminics are also ineffective in other types of humoral and cell mediated
allergies because histamine is not involved. They do suppress urticaria and
swellings in serum sickness, but not other components of the syndrome.

Type I hypersensitivity reactions to drugs (except asthma and anaphylaxis) are

suppressed. Some skin rashes also respond.

2. Other Conditions Involving Histamine

Antihistaminics block symptoms produced by histamine liberators; afford

symptomatic relief in insect bite and ivy poisoning. Abnormal dermographism is
suppressed. They have prophylactic value in blood/saline infusion induced rigor.

3. Pruritides
 
Many conventional antihistamines have antipruritic action independent of
H1 antagonism. Though relief is often incomplete, older antihistaminics remain the
first choice drugs for idiopathic pruritus.
 

4. Common Cold
 
Antihistaminics do not affect the course of the illness but may afford symptomatic
relief by anticholinergic (reduce rhinorrhoea) and sedative actions. The newer
nonsedating antihistamines are less effective in this respect.
 

5. Motion Sickness
 
Promethazine, diphenhydramine, dimenhydrinate and cyclizine have prophylactic
value in milder types of motion sickness; should be taken one hour before starting
journey. Promethazine can also be used in morning sickness, drug induced and
postoperative vomiting, radiation sickness. Cyproheptadine has appetite
stimulating effect; has been used in underweight children.
 

6. Vertigo
 
Cinnarizine is the H1 antihistamine having additional anticholinergic, anti5HT,
sedative and vasodilator properties which has been widely used in vertigo. It
modulates Ca2+ fluxes and attenuates vasoconstrictor action of many endogenous
substances.
 

Cinnarizine inhibits vestibular sensory nuclei in the inner ear, suppresses

postrotatory labyrinthine reflexes, possibly by reducing stimulated influx of Ca2+
from endolymph into the vestibular sensory cells. Beneficial effects have been
reported in Méniére’s disease and other types of vertigo. Side effects are sedation
and mild g.i. upset.

Drugs For Vertigo

 

The therapy of vertigo occurring in Méniére’s disease and other conditions is

imperfect. A variety of approaches have been tried and have met with partial
success.

1. Labyrinthine Suppressants
 
They suppress endorgan receptors or inhibit central cholinergic pathway (in
vestibular nuclei).
 
a.     Antihistaminics (with anticholinergic action)— cinnarizine, cyclizine,
dimenhydrinate, diphenhydramine, promethazine.
b.     Anticholinergics—atropine,  hyoscine.
 
 c.      Antiemetic phenothiazines—prochlorperazine, thiethylperazine.
 

2. Vasodilators
 
They improve blood flow to labyrinth and brainstem—betahistine, codergocrine,
nicotinic acid, naftidrofuryl.
 

3. Diuretics
 
They decrease labyrinthine fluid pressure —acetazolamide, thiazides, furosemide.
 

4.   Anxiolytics, Antidepressants
 
These drugs appear to modify the sensation of vertigo—diazepam, amitriptyline.
 

5. Corticosteroids
 
They suppress intra-labyrinthine edema due to viral infection or other causes.
 

Parenteral prochlorperazine is the most effective drug for controlling violent

vertigo and vomiting.

7. Preanaesthetic Medication
 
Promethazine has been used for its anticholinergic and sedative properties.
 

8. Cough
 
Antihistaminics like chlorpheniramine, diphenhydramine and promethazine are
constituents of many popular cough remedies. They have no selective cough
suppressant action, but may afford symptomatic relief by sedative and
anticholinergic property.
 
9. Parkinsonism
 
Promethazine and some others afford mild symptomatic relief in early cases—
based on anticholinergic and sedative property.
 

10. Acute Muscle Dystonia

 
Caused by antidopaminergicantipsychotic drugs is promptly relieved by parenteral
promethazine or hydroxyzine. This is again based on central anticholinergic action
of the drugs.
 

11. As Sedative, Hypnotic, Anxiolytic

Antihistamines with CNS depressant action have been used as sedative and to
induce sleep, especially in children. However, promethazine has produced serious
respiratory depression in young children; few deaths are on record; it is not
indicated in children aged 2 years or less. For promoting sleep, antihistaminics are
not as dependable as benzodiazepines. Hydroxyzine has been used in anxiety
associated with autonomic manifestations.

(Combinations of antihistaminics with antidiarrhoeals or bronchodilators, or those

containing more than one antihistaminic are banned in India.)

DRUGS FOR VERTIGO

 

The therapy of vertigo occurring in Méniére’s disease and other conditions is

imperfect. A variety of approaches have been tried and have met with partial
success.

1. Labyrinthine Suppressants
 
They suppress endorgan receptors or inhibit central cholinergic pathway (in
vestibular nuclei).
 
a.     Antihistaminics (with anticholinergic action)— cinnarizine, cyclizine,
dimenhydrinate, diphenhydramine, promethazine.
b.     Anticholinergics—atropine,  hyoscine.
 

c.      Antiemetic phenothiazines—prochlorperazine, thiethylperazine.

 

2. Vasodilators
 
They improve blood flow to labyrinth and brainstem—betahistine, codergocrine,
nicotinic acid, naftidrofuryl.
 

3. Diuretics
 
They decrease labyrinthine fluid pressure —acetazolamide, thiazides, furosemide.
 

4.   Anxiolytics, Antidepressants
 
These drugs appear to modify the sensation of vertigo—diazepam, amitriptyline.
 

5. Corticosteroids
 
They suppress intra-labyrinthine edema due to viral infection or other causes.
 

Parenteral prochlorperazine is the most effective drug for controlling violent

vertigo and vomiting.

H  ANTAGONIST
2

The first H  blocker Burimamide was developed by Black in 1972. Metiamide was

2

the next, but both were not found suitable for clinical use. Cimetidine was
introduced in 1977 and gained wide usage. Ranitidine,
famotidine, roxatidine, and many others have been added subsequently. They are
primarily used in peptic ulcer and other gastric hypersecretory states.

H  ANTAGONIST
3

Though a selective H  antagonist thioperamide has been produced, it has not found

3

any clinical utility.

5 HYDROXYTRYPTAMINE

(5HT, Serotonin)
 

Serotonin was the name given to the vasoconstrictor substance which appeared in

the serum when blood clotted and Enteramine to the smooth muscle contracting
substance present in enterochromaffin cells of gut mucosa. In the early 1950s both
were shown to be 5hydroxytryptamine (5HT). About 90% of body’s content of
5HT is localized in the intestines; most of the rest is in platelets and brain. It is also
found in wasp and scorpion sting, and is widely distributed in invertebrates and
plants (banana, pear, pineapple, tomato, stinging nettle, cowhage).

SYNTHESIS, STORAGE AND DESTRUCTION

 

5HT is βaminoethyl5hydroxyindole. It is synthesized from the amino acid

tryptophan and degraded primarily by MAO and to a small extent by a
dehydrogenase (Fig. 12.1).
 

There is close parallelism between CAs and 5HT. The decarboxylase is

nonspecific, acts on DOPA as well as 5hydroxytryptophan (5HTP) to produce NA
and 5HT respectively. Like NA, 5HT is actively taken up by an amine
pump serotonin transporter (SERT), a Na+ dependent carrier, which operates at
the membrane of platelets (therefore, 5HT does not circulate in free form in
plasma) and serotonergic nerve endings. This is inhibited by selective serotonin
reuptake inhibitors (SSRIs) and tricyclic antidepressants. Platelets do not
synthesize but acquire 5HT by uptake during passage through intestinal blood
vessels. Again like CAs, 5HT is stored within storage vesicles, and its uptake at the
vesicular membrane by vesicular monoamine transporter (VMAT2) is inhibited
by reserpine, which causes depletion of CAs as well as 5HT. The degrading
enzyme MAO is also common for both. The isoenzyme MAOA preferentially
metabolizes 5HT.

SEROTONERGIC (5HT) RECEPTORS

 
Gaddum and Picarelli (1957) classified 5HT receptors into musculotropic (D type)
and neurotropic (M type) on the basis of pharmacological criteria. The classical
5HT antagonists methysergide and cyproheptadine blocked D type receptors.
Subsequently 5HT receptors were differentiated by their high or low affinity for
[3H] 5HT in radioligand binding studies. The present system of classifying 5HT
receptors is based on molecular characterization and cloning of the receptor
cDNAs.

Four families of 5HT receptors (5HT , 5HT , 5HT , 5HT ) comprising of 14

1 2 3 47

receptor subtypes have so far been recognized. However, only some of these have
been functionally correlated or their selective agonists/antagonists defined.
Knowledge of subtypes of 5HT receptors has assumed importance because some
newly developed therapeutically useful drugs can only be described as 5HT
receptor subtype selective agonists or antagonists.

All 5HT receptors (except 5HT ) are G protein coupled receptors which function
3

through decreasing (5HT ) or increasing (5HT , 5 HT , 5HT ) cAMP production or

1 4 6 7

by generating IP / DAG (5HT ) as second messengers. The 5HT  is ligand gated
3 2 3

cation (Na+,K+) channel which on activation elicits fast depolarization.

5HT  Receptors
1

Five subtypes (5HT 1A, ) have been identified. The 5HT  receptor is now
B, D, E, F 1C

designated 5HT . All subtypes of 5HT  receptor inhibit adenylyl cyclase; 5HT  in
2c 1 1A

addition activates K+ channels (resulting in hyperpolarization) and inhibits Ca2+

channels. These receptors function primarily as autoreceptors in brain— inhibit
firing of 5HT neurones or release of 5HT from nerve endings.

The most important location of 5HT  receptor are raphe nuclei of brainstem and
1A

hippocampus. The antianxiety drug buspirone acts as a partial agonist of

5HT  receptor. The 5HT  receptor has been shown to regulate dopaminergic tone
1A 1D

in substantia nigra–basal ganglia, and

5HT  to cause constriction of cranial blood vessels. The antimigraine

1B/1D

drug sumatriptan is a selective 5HT agonist. Other functions subserved by

1B/1D 

5HT   receptors are inhibition of NA release from sympathetic nerve endings and
1D

that of inflammatory neuropeptides from nerve endings in cranial blood vessels.

5HT  Receptors
2

There are 3 subtypes of 5HT  receptor; all are coupled to phospholipase C and

2

function through generation of IP /DAG. 5HT  receptor also inhibits K  channels

3 2A
+

resulting is slow depolarization of neurones. αmethyl 5HT is a selective agonist for

all 3 subtypes.

5 HT  is the most widely expressed postjunctional 5HT receptor (designated earlier
2A

as D type) located on vascular and visceral smooth muscle, platelets and cerebral
neurones especially prefrontal cortex. It mediates most of the direct actions of 5HT
like vasoconstriction, intestinal, uterine and bronchial contraction, platelet
aggregation and activation of cerebral neurones. Ketanserin is a 5HT  antagonist
2

more selective for 5HT .

2A

Contraction of rat gastric fundus is mediated by 5HT  receptor.

2B

5HT  receptor is located on vascular endothelium— elicits vasodilatation through

2C

EDRF release. Choroid plexus expresses large number of 5HT  receptors.

2C

 
5HT  Receptor
3

This is the neuronal 5HT receptor which rapidly depolarizes nerve endings by

opening the cation channel located within it and corresponds to the original M type
receptor. It mediates the indirect and reflex effects of 5HT at:

        Somatic and autonomic nerve endings → pain, itch, coronary chemoreflex

(bradycardia, fall in BP due to withdrawal of sympathetic tone, respiratory
stimulation or apnoea elicited by stimulation of receptors in the coronary
bed), other visceral reflexes.
 

        Nerve endings in myenteric plexus → augmentation of peristalsis, emetic

reflex.
 

        Area postrema and nucleus tractus solitarious in brainstem → nausea,

vomiting.
 

Ondansetron is a selective 5HT  antagonist which inhibits vomiting by blocking

3

these receptors in brainstem as well as in gut wall. 2Methyl 5HT is a selective

5HT  agonist.
3

5HT  Receptors
4–7

The 5HT  receptor has been demonstrated in the mucosa, plexuses and smooth
4

muscle of the gut → probably involved in augmenting intestinal secretion and

peristalsis. It is also located in brain, especially hippocampus and the colliculi
where it causes slow depolarization by decreasing K+ conductance.

 
Cisapride and renzapride are selective 5HT   agonists. The recently cloned
4

5HT , 5HT  and 5HT  receptors are closely related to the 5HT  receptor. These are
5 6 7 4

mainly located in specific brain areas, but their functional role is not known. An
interesting finding is that clozapine (atypical neuroleptic) has high affinity for
5HT  and 5HT  receptors in addition to being a 5HT  antagonist.
6 7 2A/2C

Actions of 5 Hydroxytryptamine

ACTIONS
 

5HT is a potent depolarizer of nerve endings. It thus exerts direct as well as reflex
and indirect

5HT  :     Autoreceptors; inhibit serotonergic neural activity in brain.

1

5HT —present in raphe nuclei and hippocampus; buspirone may act through
1A

these receptors.

5HT —Constricts cranial blood vessels and inhibits release of

1B/1D

inflammatory neuropeptides in them; sumatriptan acts through these receptors.

 
5HT  :    Previously D type receptor; most important postjunctional receptor
2A

mediating direct actions of 5HT like vascular and visceral smooth muscle
contraction, platelet aggregation, neuronal activation in brain; ketanserin blocks
these receptors.

5HT  :     Previously M type receptor; depolarizes neurones by gating cation

3

channels; elicits reflex effects of 5HT—emesis, gut peristalsis, bradycardia,

transient hypotension, apnoea, pain, itch; ondansetron acts by blocking these
receptors.

5HT  :     Mediate intestinal secretion, augmentation of peristalsis. Renzapride is a

4

selective 5HT  agonist effects. Tachyphylaxis is common with repeated doses of

4

5HT. The overall effects therefore are often variable.

CVS
 
Arteries are constricted (by action on smooth muscle) as well as dilated (through
EDRF release) by direct action of 5HT, depending on the vascular bed and the
basal tone. In addition, 5HT releases Adr from adrenal medulla, affects ganglionic
transmission and evokes cardiovascular reflexes. The net effect is complex. Larger
arteries and veins are characteristically constricted. In the microcirculation 5HT
dilates arterioles and constricts venules: capillary pressure rises and fluid escapes.
The direct action to increase capillary permeability is feeble.
 

Isolated heart is stimulated by 5HT: both directly and by release of NA from nerve
endings. In intact animals, bradycardia is mostly seen due to activation of coronary
chemoreflex (Bezold Jarisch reflex) through action on vagal afferent nerve endings
in the coronary bed, evoking bradycardia, hypotension and apnoea.

BP: a triphasic response is classically seen on i.v. injection of 5HT in animals.

Early sharp fall in BP—due to coronary chemoreflex.

 Brief rise in BP—due to vasoconstriction and increased cardiac output.
Prolonged fall in BP—due to arteriolar dilatation and extravasation of fluid.

However, 5HT is not involved in the physiological regulation of BP.

Smooth Muscles
 
5HT is a potent stimulator of g.i.t., both by direct action as well as through enteric
plexuses. Several subtypes of 5HT receptors are present in the gut (See box).
Peristalsis is increased and diarrhoea can occur (also due to increased secretion). It
constricts bronchi, but is less potent than histamine. Action on other smooth
muscles in man are feeble and inconsistent.
 

Glands
 
5HT inhibits gastric secretion (both acid and pepsin), but increases mucus
production. It thus has ulcer protective property. Effect on other glandular
secretions is not significant.
 
Nerve Endings And Adrenal Medulla
 
Afferent nerve endings are activated—tingling and pricking sensation, pain.
Depolarization of visceral afferents elicits respiratory and cardiovascular reflexes,
nausea and vomiting. 5HT is less potent than histamine in releasing CAs from
adrenal medulla.
 

Respiration
 
A brief stimulation of respiration (mostly reflex from bronchial afferents) and
hyperventilation are the usual response, but large doses can cause transient apnoea
through coronary chemoreflex.
 

Platelets
 
5HT causes changes in shape of platelets and is a weak aggregator through
5HT  receptors. However, it does not induce the release reaction.
2A

CNS
 
Injected i.v., 5HT does not produce central effects because it poorly crosses
bloodbrain barrier. However, it serves as a transmitter, primarily inhibitory. Direct
injection in the brain produces sleepiness, changes in body temperature, hunger
and a variety of behavioural effects.
 

PATHOPHYSIOLOGICAL ROLES
 

1. Neurotransmitter  5HT is a confirmed neurotransmitter in the brain; brain 5HT

has a fast turnover rate. Cells containing 5HT are present in the raphe nuclei of
brainstem, substantia nigra and few other sites—send axons rostrally (to limbic
system, cortex and neostriatum) as well as caudally to spinal cord. 5HT is probably
involved in sleep, temperature regulation, thought, cognitive function, behaviour
and mood (imbalance may result in affective disorders and schizophrenia),
vomiting and pain perception. Some serotonergic fibres are present in intestines
also.
 

2. Precursor Of Melatonin in pineal gland. It is believed to regulate biological

clock and maintain circadian rhythm.

3. Neuroendocrine Function The hypothalamic neurones that control release of

anterior pituitary hormones are probably regulated by serotonergic mechanism.

4. Nausea And Vomiting Especially that evoked by cytotoxic drugs or

radiotherapy is mediated by release of 5HT and its action on 5HT  receptors in the
3

gut, area postrema and nucleus tractus solitarious.

5. Migraine 5HT is said to initiate the vasoconstrictor phase of migraine and to

participate in neurogenic inflammation of the affected blood vessels. Methysergide
(5HT antagonist) is an effective prophylactic and sumatriptan (5HT  agonist) can
1B/1D

control an attack. However, the role of 5HT in this condition is not precisely
known.
 

6. Haemostasis Platelets release 5HT during aggregation at the site of injury to

blood vessel. Acting in concert with collagen and other mediators, this 5HT
accelerates platelet aggregation and clot formation. Thus, it serves to amplify the
response. Its contractile action appears to promote retraction of the injured vessel.
Both the above actions contribute to haemostasis.
 

7. Raynaud’s Phenomenon Release of 5HT from platelets may trigger acute

vasospastic episodes of larger arteries. Ketanserin has prophylactic value in
Raynaud’s.
 
8. Variant Angina Along with thromboxane A , 5HT released from platelets has
2

been implicated in causing coronary spasm and variant angina. However, the
inefficacy of anti 5HT drugs in this condition points to involvement of other
mediators.
 

9. Hypertension Increased responsiveness to 5HT as well as its reduced uptake

and clearance by platelets has been demonstrated in hypertensive patients.
Ketanserin has antihypertensive property. 5HT has been held responsible for
preeclamptic rise in BP.
 

10. Intestinal Motility Enterochromaffin cells and 5HT containing neurones may

regulate peristalsis and local reflexes in the gut. This system appears to be
activated by intestinal distension and vagal efferent activity.
 

11. Carcinoid syndrome The carcinoid tumours produce massive quantities of

5HT. Bowel hyper motility and bronchoconstriction in carcinoid is due to 5HT but
flushing and hypotension are probably due to other mediators. Pellagra may occur
due to diversion of tryptophan for synthesizing 5HT.

DRUGS AFFECTING 5HT SYSTEM

 

1. 5HT Precursor

Tryptophan increases brain 5HT and produces behavioural effects because

tryptophan hydroxylase in brain is not saturated by the amount of tryptophan
available physiologically.

2. Synthesis Inhibitor

p-Chlorophenylalanine (PCPA) selectively inhibits tryptophan hydroxylase (rate

limiting step) and reduces 5HT level in tissues. It is not used clinically due to high
toxicity.

3. Uptake Inhibitor
Tricyclic antidepressants inhibit 5HT uptake along with that of NA. Some like
fluoxetine, sertraline are selective serotonin reuptake inhibitors (SSRI).

4. Storage Inhibitor

Reserpine blocks 5HT (as well as NA) uptake into storage granules and causes
depletion of all monoamines. Fenfluramine selectively releases 5HT and has
anorectic property.

5. Degradation Inhibitor

Nonselective MAO inhibitor (tranylcypromine) and selective MAOA inhibitor

(chlorgyline) increase 5HT content by preventing its degradation.

6. Neuronal Degeneration

5, 6 dihydroxytryptamine selectively destroys 5HT neurones.

7. 5HT Receptor Agonists

A diverse range of compounds producing a variety of actions have been found to

activate one or more subtypes of 5HT receptors. Notable among these are:

a.      D-Lysergic acid diethyl amide (LSD)—Synthesized as an ergot

derivative LSD was found to be an extremely potent hallucinogen. It is a
nonselective 5HT agonist— activates many subtypes of 5HT receptors
including 5HT  on raphe cell bodies, 5HT  (probably responsible for the
1A 2A/2C

hallucinogenic effect) and 5HT  in specific brain areas. However, it

57

antagonizes 5HT  receptors in the ileum. A number of other

2A

hallucinogens also interact with brain 5HT receptors.

 
 b.     Azapirones like buspirone, gepirone and ipsapirone are a new class of
antianxiety drugs which do not produce sedation. They act as partial
agonists of 5HT  receptors in the brain.
1A

c.      8-Hydroxydipropylamino tetraline (8OH DPAT) is a highly selective

5HT  agonist which is used only as an experimental tool.
1A

d.     Sumatriptan and other triptans are selective 5HT  agonists, constrict

1B/1D

cerebral blood vessels and have emerged as the most effective treatment
of acute migraine attacks.
 

e.      Cisapride This prokinetic drug which increases gastrointestinal motility

is a selective 5HT  agonist. Renzapride is still more selective for
4

5HT  receptors.
4

f.       m-chlorophenyl piperazine (mCPP) It is an active metabolite of the

antidepressant drug trazodone; found to be an agonist of 5HT  as well as
1B

5HT  receptors in the brain. In human volunteers it induces anxiety and

2A/2C

enhances release of prolactin, ACTH, and growth hormone.

 

8. 5HT Receptor Antagonists

A variety of drugs block serotonergic receptors; many are nonselective, but some

newer ones are highly subtype selective.

5HT ANTAGONISTS
 

The ability to antagonize at least some actions of 5HT is found in many classes of
drugs, e.g. ergot derivatives (ergotamine, LSD, 2bromo LSD, methysergide),
adrenergic α blockers (phenoxybenzamine), antihistaminics (cyproheptadine,
cinnarizine), chlorpromazine, morphine, etc., but these are nonselective and
interact with several other receptors as well. Many are partial agonists or
antagonize certain actions of 5HT but mimic others. The salient features of drugs
which have been used clinically as 5HT antagonists and some newly developed
selective antagonists are described below:

1.    Cyproheptadine
 
It primarily blocks 5HT  receptors and has additional H  antihistaminic,
2A 1

anticholinergic and sedative properties. Like other antihistaminics, it has been used
in allergies and is a good antipruritic, but the anti 5HT action has no role in these
conditions. It increases appetite and has been recommended in children and poor
eaters to promote weight gain. An action on growth hormone secretion has been
suggested to account for this.
 

The anti 5HT activity of cyproheptadine has been utilized in controlling intestinal
manifestations of carcinoid and postgastrectomy dumping syndromes as well as in
antagonizing priapism/orgasmic delay caused by 5HT uptake inhibitors like
fluoxetine and trazodone.

Side effects drowsiness, dry mouth, confusion, ataxia, weight gain.

2.    Methysergide
 
It is chemically related to ergot alkaloids; antagonizes action of 5HT on smooth
muscles including that of blood vessels, without producing other ergot like effects:
does not interact with α adrenergic or dopamine receptors. Methysergide is a
potent 5HT  antagonist with some tissue specific agonistic actions as well; but is
2A/2C

nonselective—acts on 5HT  receptors also. It has been used for migraine

1

prophylaxis, carcinoid and postgastrectomy dumping syndrome. Prolonged use has

caused abdominal, pulmonary and endocardial fibrosis, because of which it has
gone into disrepute.
 

3.   Ketanserin
 
It has selective 5HT  receptor blocking property with negligible action on 5HT ,
2 1

5HT  and 5 HT  receptors and no partial agonistic activity. Among 5HT  receptors,
3 4 2

blockade of 5HT  is stronger than 5HT  blockade. 5HT induced vasoconstriction,
2A 2C

platelet aggregation and contraction of airway smooth muscle are antagonized but
not contraction of guinea pig ileum or rat stomaArticle No. It has additional
weak α1, H  and dopaminergic blocking activities.
1

Ketanserin is an effective antihypertensive, but α1 adrenergic blockade appears to

be causative rather than 5HT  blockade.
2A

Trials of Ketanserin in vasospastic conditions have shown symptomatic

improvement only in Raynaud’s disease.

Ritanserin is a relatively more 5HT  selective congener of ketanserin.

2A

4.   Clozapine
 
In addition to being a dopaminergic antagonist (weaker than the typical
neuroleptics), this atypical antipsychotic is a 5HT  blocker. Clozapine may also
2A/2C

exert inverse agonist activity at cerebral 5HT  receptors which may account for its
2A/2C

efficacy in resistant cases of schizophrenia.

 

5.   Risperidone
 
This atypical antipsychotic is a combined 5HT  + dopamine D2 antagonist, similar
2A

to clozapine. Like the latter, it especially ameliorates negative symptoms of

schizophrenia, but produces extrapyramidal side effects at only slightly higher
doses.
 

Other atypical antipsychotics like olanzapine and quetiapine are also combined

5HT and DA antagonists, but interact with other neurotransmitter receptors as well.
 

6.   Ondansetron
 
It is the prototype of the new class of selective 5HT  antagonists that have shown
3

remarkable efficacy in controlling nausea and vomiting following administration

of highly emetic anticancer drugs and radiotherapy.
 

Granisetron and Tropisetron are the other selective 5HT  antagonists.

3

ERGOT ALKALOIDS
 

Ergot is a fungus Claviceps purpurea which grows on rye, millet and some other

grains. The grain is replaced by a purple, hard, curved body called ‘sclerotium’.
Epidemics of ergot poisoning (ergotism), due to consumption of contaminated
grains, have been recorded from the beginning of history. It still occurs in epidemic
and sporadic forms. Dry gangrene of hands and feet which become black (as if
burnt) is the most prominent feature. Miscarriages occur in women and cattle. A
convulsive type is also described.

Ergot had been used by midwives to quicken labour since the middle ages. This
use received medical sanction in the 19th century, but its dangers were recognized
by the beginning of the present century and then it was advocated only after
delivery. Dale and Barger (1906 onwards) isolated the ergot alkaloids and studied
their pharmacology. Ergometrine was isolated in 1935.

Ergot contains a host of pharmacologically active substances—alkaloids, LSD,

histamine, ACh, tyramine and other amines, sterols, etc.

Natural Ergot Alkaloids

 
These are tetracyclic indole containing compounds which may be considered as
derivatives of lysergic acid. They are divided into—

a)     Amine alkaloid Ergometrine (Ergonovine): which is oxytocic

b)    Amino acid alkaloids Ergotamine, Ergotoxine (mixture of ergocristine +
ergocornine + ergocryptine): they are vasoconstrictor and α adrenergic blocker.
 

Other Semisynthetic Derivatives

a)     Dihydroergotamine (DHE), Dihydroergotoxine (Codergocrine): are

antiadrenergic, cerebroactive.
b)    2Bromoαergocryptine (Bromocriptine): is a dopaminergic agonist.
c)     Methysergide: it is mainly anti 5HT.
 

Synthetic non-lysergic acid derivatives which pharmacologically resemble ergot

alkaloids are — Lisuride, Pergolide, Lergotrile and Metergoline. The ergot alkaloid
related compounds have diverse pharmacological properties. They act as agonists,
partial agonists and antagonists on certain subtypes of α adrenergic, serotonergic
and dopaminergic receptors in a tissue specific manner.

Actions
 

Ergotamine

It acts as a partial agonist and antagonist at α adrenergic and all subtypes of

5HT  and 5HT   receptors, but does not interact with 5HT  or dopamine receptors:
1 2 3

produces sustained vasoconstriction, visceral smooth muscle contraction,

vasomotor centre depression and antagonizes the action of NA and 5HT on smooth
muscles. The overall effect of oral/rectal doses of ergotamine on BP is
insignificant. It is a potent emetic (through CTZ) and moderately potent oxytocic.
At high doses CNS stimulation and paresthesias may be experienced. On chronic
exposure (ergot poisoning) vasoconstriction is accompanied by damage to capillary
endothelium—thrombosis, vascular stasis and gangrene.

Dihydroergotamine (DHE)

Hydrogenation of ergotamine reduces serotonergic and αadrenergic agonistic

actions, but enhances αreceptor blocking property. Consequently DHE is a less
potent vasoconstrictor; primarily constricts capacitance vessels and causes less
intimal damage. It is a weaker emetic and oxytocic, but has some antidopaminergic
action as well.

Dihydroergotoxine (Codergocrine)

This hydrogenated mixture of ergotoxine group of alkaloids is a more

potent α blocker and a very weak vasoconstrictor. In the brain, a variety of partial
agonistic/ antagonistic actions on 5HT receptors, metabolic and vascular effects
and enhancement of ACh release in cerebral cortex have been demonstrated. It has
been advocated for treatment of dementia (see Article No. 35).

Bromocriptine

The 2 bromo derivative of ergocryptine is a relatively selective dopamine D2

agonist on pituitary lactotropes (inhibits prolactin

release), in striatum (antiparkinsonian) and in CTZ (emetic—but less than

ergotamine). In certain brain areas weak antidopaminergic action has also been
shown. It has very weak anti 5HT or α blocking actions and is not an oxytocic.
 

Ergometrine (Ergonovine)

This amine ergot alkaloid has very weak agonistic and practically no antagonistic
action on α adrenergic receptors: vasoconstriction is not significant. Partial
agonistic action on 5HT receptors has been demonstrated in uterus, placental and
umbilical blood vessels and in certain brain areas. It is a moderately potent
5HT  antagonist in g.i. smooth muscle and a weak dopaminergic agonist on the
2

pituitary lactotropes as well as CTZ; emetic potential is low. The most prominent
action is contraction of myometrium; used exclusively in obstetrics.

Pharmacokinetics
 

Oral bioavailability of amino acid ergot alkaloids and their hydrogenated

derivatives is poor (< 1%) due to slow and incomplete absorption as well as high
firstpass metabolism. Bioavailability is better after sublingual and rectal
administration, but still often erratic. They are metabolized in liver and excreted
primarily in bile. Ergotamine is sequestrated in tissues—produces longer lasting
actions compared to its plasma t½ of 2 hours. Ergot alkaloids effectively cross
bloodbrain barrier.

Adverse Effects
 

Nausea, vomiting, abdominal pain, muscle cramps, weakness, paresthesias,

coronary and other vascular spasm, chest pain are the frequent side effects. These
drugs are contraindicated in presence of sepsis, ischaemic heart disease, peripheral
vascular disease, hypertension, pregnancy, liver and kidney disease.

 
Preparations And Dose
 

Ergotamine: For migraine 1–3 mg oral/sublingual, repeat as required (max 6 mg

in a day); rarely 0.25–0.5 mg i.m. or s.c.; ERGOTAMINE, GYNERGEN,
INGAGEN 1 mg tab, 0.5 mg/ml and 1 mg/ml inj.

Dihydroergotamine: For migraine 2–6 mg oral (max 10 mg/ day), 0.5–1 mg i.m.,

s.c. repeat hourly (max 3 mg); DIHYDERGOT, DHE 1 mg tab, MIGRANIL 1
mg/ml inj. Also used for postural hypotension, herpes zoster, mumps.

Dihydroergotoxine (codergocrine) For dementia 1–1.5 mg oral or sublingual,

0.15–0.6 mg i.m., HYDERGINE 1.5 mg tab, CERELOID 1 mg tab.

DRUG THERAPY OF MIGRAINE

 

Migraine is a mysterious disorder characterized by pulsating headache, usually

restricted to one side, which comes in attacks lasting 4–48 hours and is often
associated with nausea, vomiting, sensitivity to light and sound, flashes of light,
vertigo, loose motions and other symptoms. Two major types are—migraine with
aura (classical migraine) in which headache is preceded by visual or other
neurological symptoms, and migraine without aura (common migraine). Pulsatile
dilatation of certain large cranial vessels is the immediate cause of pain. The
pathogenic mechanisms are not well understood. The Vascular theory holds that
initial vasoconstriction or shunting of blood through carotid arteriovenous
anastomoses produces cerebral ischaemia and starts the attack. The Neurogenic
theory considers it to be a spreading depression of cortical electrical activity
followed by vascular phenomena. Some triggering event appears to produce
neurogenic inflammation of the affected blood vessel wall which is amplified by
retrograde transmission in the afferent nerves and release of mediators like 5HT,
neurokinin, substance P, calcitonin gene related peptide (CGRP), nitric oxide, etc.

Changes in blood/urinary levels of 5HT and its metabolites during migraine attack,
its precipitation by 5HT releasers and efficacy of drugs having actions in the
serotonergic system to prevent/abort/terminate migraine attacks suggests a pivotal
role of 5HT in this disorder.

Drug therapy of migraine has to be individualized: severity and frequency of

attacks and response of individual patients to drugs used earlier determine the
choice. The strategy mostly adopted is summarized in the box.

Mild Migraine

Cases having fewer than one attack per month of throbbing but tolerable headache
lasting upto 8 hours which does not incapacitate the individual may be classified as
mild migraine.

1. Simple analgesics like paracetamol (0.5– 1 g) or aspirin (300–600 mg) taken at

the first indication of an attack and repeated 4–6 hourly abort and suppress most
mild attacks.
 

2. Nonsteroidal anti-inflammatory drugs (NSAIDs) and their combinations Drugs

like ibuprofen (400–800 mg 8 hourly), naproxen (500 mg followed by 250 mg 8
hourly), diclofenac (50 mg 8 hourly), mephenamic acid (500 mg 8 hourly),
indomethacin (50 mg 6–8 hourly) either alone or combined with
paracetamol/codeine/diazepam or another sedative/diphenhydramine or another
antihistaminic/caffeine are found more satisfactory by some patients. These drugs
are more effective in migraine without aura, but certain patients of migraine with
aura also prefer them over ergot alkaloids. Drugs are taken only till the attack
passes off. Taken in the prodromal stage they also have a prophylactic effect, but
longterm treatment on a regular schedule to ward off migraine attacks is not
advised.
 
3. Antiemetics Gastric stasis occurs during migraine which delays absorption of
oral drugs. Metoclopramide (10 mg oral/i.m.) is frequently used: relieves nausea,
vomiting and gastric stasis. Domperidone (10–20 mg oral) and prochlorperazine
(10–25 mg oral/i.m.) are also effective. Diphenhydramine or promethazine exert
sedative as well as antiemetic action.
 

Moderate Migraine
 

Migraine may be labelled as moderate when the throbbing headache is more

intense, lasts for 6–24 hours, nausea/vomiting and other features are more
prominent and the patient is functionally impaired. One or more attacks occur per
month.

Simple analgesics are usually not effective, but stronger NSAIDs or their
combinations mentioned above are beneficial in many cases. The remaining are
treated with an ergot preparation or sumatriptan. Antiemetics are almost regularly
needed. Prophylactic therapy is advised only when attacks are more frequent than
2–3 per month.

Severe Migraine
 

These patients suffer 2–3 or more attacks per month of severe throbbing headache
lasting 12–48 hours, often accompanied by vertigo, vomiting and other symptoms;
the subject is grossly incapacitated during the attack.

Analgesics/NSAIDs and their combinations usually donot afford adequate relief—

specific drugs like ergot alkaloids/sumatriptan have to be prescribed along with
antiemetics. Prophylactic regimens lasting 6 months or more are recommended.

Ergotamine It is the most effective ergot alkaloid for migraine. Given early in

attack, relief is often dramatic and lower doses suffice, but when pain has become
severe—larger doses are needed and control may be achieved only after few hours.
Oral/sublingual route is preferred, 1 mg is given at half hour intervals till relief is
obtained or a total of 6 mg is given. Parenteral administration, though rapid in
action is more hazardous.

Ergotamine acts by constricting the dilated cranial vessels and/or by specific

constriction of carotid AV shunt channels. Ergotamine and DHE have also been
shown to reduce neurogenic inflammation and leakage of plasma in duramater that
occurs due to retrograde stimulation of perivascular afferent nerves. These actions
appear to be mediated through partial agonismat 5HT1B/1D receptors in and around
cranial vessels.

 
Dihydroergotamine (DHE) It is nearly as effective as ergotamine and preferred
for parenteral administration because injected DHE is less hazardous.

Because of erratic oral absorption, frequent side effects, especially nausea and
vomiting, and availability of triptans, ergot preparations are not preferred now,
except for considerations of cost.

Ergot alkaloids have no prophylactic value: regular use is not justified—may itself
produce a dull background headache and an attack may be precipitated on
discontinuation. Caffeine 100 mg taken with ergotamine enhances its absorption
from oral and rectal routes and adds to the cranial vasoconstricting action. Many
combination preparations are available.

MIGRANIL: Ergotamine 1 mg, caffeine 100 mg, belladonna dry ext 10 mg,
paracetamol 250 mg tab. MIGRIL: Ergotamine 2 mg, caffeine 100 mg, cyclizine
50 mg tab.

VASOGRAIN: Ergotamine 1 mg, caffeine 100 mg, paracetamol 250 mg,

prochlorperazine 2.5 mg tab. ERGOPHEN: Ergotamine 0.3 mg, belladonna dry
ext. 10 mg, phenobarbitone 20 mg tab.

Selective 5HT1B/1D  Agonists

 

These are a new class of antimigraine drugs that selectively activate

5HT1B/1D receptors, and are called ‘triptans’. Currently, they are the preferred drugs
for patients who fail to respond to analgesics. Ergot alkaloids are now required
only in few cases. Because these drugs have been designed to act on the same
subtype of 5HT receptor, pharmacodynamic differences among them are minor,
but there are significant pharmacokinetic differences. All have higher oral
bioavailability than sumatriptan. Fewer headache recurrences in an attack are
reported with naratriptan and frovatriptan due to their longer t½, but may be slower
in affording initial pain relief.

Sumatriptan It is the first selective 5HT1B/1D receptor agonist; activates other

subtypes of 5HT1 receptors only at very high concentrations, and does not interact
with 5HT2, 5HT3, 5HT47, or β adrenergic, dopaminergic, cholinergic or GABA
receptors. Administered at the onset of an attack of migraine, sumatriptan is as
effective and better tolerated than ergotamine. About 3/4 patients obtain
complete/significant relief within 2–3 hours. However, recurrence of headache
within 24 hr has been noted in 20–40% patients, probably due to short t½ of
sumatriptan. It tends to suppress nausea and vomiting of migraine, while
ergotamine accentuates these symptoms.

The antimigraine activity of sumatriptan has been ascribed to 5HT1B/1D receptor

mediated constriction of dilated cranial extracerebral blood vessels, especially the
arteriovenous shunts in the carotid artery, which express 5HT1B/1D receptors.
Dilatation of these shunt vessels during migraine attack is believed to divert blood
flow away from brain parenchyma. In addition it can reduce 5HT and
inflammatory neuropeptide release around the affected vessels as well as
extravasation of plasma proteins across dural vessels. Like ergotamine, the triptans
have been found to suppress neurogenic inflammation of cranial vessels.
Suppression of impulse transmission in the trigeminovascular system has also been
implicated.
 
 
Pharmacokinetics:
 
Sumatriptan is absorbed rapidly and completely after s.c. injection. Oral
bioavailability averages 15%. It is rapidly metabolized by MAOA isoenzyme and
metabolites are excreted in urine; elimination t½ is ~2 hours.
 
Side Effects:  to sumatriptan are usually mild. Tightness in head and chest,
feeling of heat and other paresthesias in limbs, dizziness, weakness are short
lasting, but dose related side effects.
 
These are more common after s.c. injection, which is painful. Slight rise in BP
occurs, but has little clinical relevance, because sumatriptan is not a drug for
regular use. Bradycardia, coronary vasospasm and risk of myocardial infarction are
the serious, but infrequent adverse effects. Few cases of sudden death have been
ascribed to sumatriptan. Seizures and hypersensitivity reactions are rare.
 
Contraindications: are in patients with ischaemic heart disease, hypertension,
epilepsy, hepatic or renal impairment and during pregnancy. Patients should be
cautioned not to drive.
 
Sumatriptan and ergotamine should not be administered within 24 hours of each
other. Interaction with 5HT uptake inhibitors, MAO inhibitors and lithium has
been reported.
 
Dose: 50–100 mg oral at the onset of migraine attack, may be repeated once
within 24 hours if required. Those not responding to the first dose should not be
given the second dose. It is the only triptan available for parenteral use; 6 mg s.c.
may be given to patients who cannot take the drug orally or in whom the pain
develops very rapidly; acts in 10–20 min and is more consistently effective.
 
MIGRATAN, 50, 100 mg tabs, SUMINAT 25, 50, 100 mg tab, 60 mg/5 ml inj;
SUMITREX 25, 50, 100 mg tab, 6 mg/0.5 ml inj.
 
Rizatriptan: This congener of sumatriptan is more potent, has higher oral
bioavailability with slightly faster onset of action.
 
Dose: 10 mg; repeat once after 2 hr (if required).
 
RIZACT 5, 10 mg tab.
 
Naratriptan,       Zolmitriptan,     Almotriptan,    
Frovatriptan         and Eletriptan  are  other  triptans  used  in  some  countries.
 
Features of some triptans are compared in the box.
 
 

* Tmax: Time to peak plasma concentration after oral dosing.

Prophylaxis Of Migraine
 

Regular medication to reduce the frequency and/or severity of attacks is

recommended for moderate to severe migraine when 2–3 or more attacks occur per
month. Diverse classes of drugs are used but none is effective in all cases, and
none abolishes the attacks totally. It may be prudent to discontinue pophylaxis
every 6 months to check whether its continuation is needed or not. It is important
to avoid the precipitating factor(s).

Β-Adrenergic blockers Propranolol is the most commonly used drug: reduces

frequency as well as severity of attacks in upto 70% patients. Effect is generally
seen in 4 weeks and is sustained during prolonged therapy. The starting dose is 40
mg BD, which may be increased upto 160 mg BD if required. The mechanism of
action is not clear; that it is due to β adrenergic blockade has been
questioned. Other nonselective (timolol) and β1 selective (metoprolol, atenolol)
agents are also effective, but pindolol and others having intrinsic sympathomimetic
action are not useful.
 

Tricyclic antidepressants Many tricyclic compounds of which amitriptyline has

been most extensively tried (25–50 mg at bed time) reduce migraine attacks. It is
effective in many patients but produces more side effects than propranolol. It is not
known whether its 5HT (and other monoamine) uptake blocking property is
causally related to the prophylactic effect. The antimigraine effect is independent
of antidepressant property, but this class of drugs are better suited for patients who
also suffer from depression.

Calcium channel blockers Verapamil was found to reduce migraine attacks, but

was judged inferior to propranolol. Flunarizine is a relatively weak Ca2+ channel
blocker that also inhibits Na+ channels. It is claimed to be as effective as
propranolol, but convincing proof is lacking. Frequency of attacks is often reduced,
but effect on intensity and duration of attacks is less well documented. It is claimed
to be a cerebroselective Ca2+ channel blocker; may benefit migraine by reducing
intracellular Ca2+ overload due to brain hypoxia and other causes. Side effects are
sedation, constipation, dry mouth, hypotension, flushing, weight gain and rarely
extrapyramidal symptoms.

Dose: 10–20 mg OD, children 5 mg OD, NOMIGRAIN, FLUNARIN 5 mg, 10

mg caps/tab.

Anticonvulsants Valproic acid (400–1200 mg/day) and gabapentin (300–1200

mg/day) have some prophylactic effect in migraine. The newer drug topiramate has
recently been approved for migrain prophylaxis. A 50% reduction in the number of
attacks in half of the patients was noted in 2 randomized trials. Start with 25 mg
OD and gradually increase to 50 mg OD or BD. Efficacy of anticonvulsants in
migraine is lower than that of β blockers. They are indicated in patients
refractory to other drugs or when propranolol is contraindicated.
 
5HT   antagonists  The   prophylactic   effect   of methysergide and
cyproheptadine is less impressive than β blockers. They are seldom used now for
migraine.
 
SELECTIVE 5HT   AGONISTS
1B/1D

These are a new class of antimigraine drugs that selectively activate

5HT  receptors, and are called ‘triptans’. Currently, they are the preferred drugs
1B/1D

for patients who fail to respond to analgesics. Ergot alkaloids are now required
only in few cases. Because these drugs have been designed to act on the same
subtype of 5HT receptor, pharmacodynamic differences among them are minor,
but there are significant pharmacokinetic differences. All have higher oral
bioavailability than sumatriptan. Fewer headache recurrences in an attack are
reported with naratriptan and frovatriptan due to their longer t½, but may be slower
in affording initial pain relief.

Sumatriptan

It is the first selective 5HT  receptor agonist; activates other subtypes of

1B/1D

5HT  receptors only at very high concentrations, and does not interact with 5HT ,
1 2

5HT , 5HT , or β adrenergic, dopaminergic, cholinergic or GABA receptors.

3 47

Administered at the onset of an attack of migraine, sumatriptan is as effective and

better tolerated than ergotamine. About 3/4 patients obtain complete/significant
relief within 2–3 hours. However, recurrence of headache within 24 hr has been
noted in 20–40% patients, probably due to short t½ of sumatriptan. It tends to
suppress nausea and vomiting of migraine, while ergotamine accentuates these
symptoms.

The antimigraine activity of sumatriptan has been ascribed to 5HT  receptor1B/1D

mediated constriction of dilated cranial extracerebral blood vessels, especially the

arteriovenous shunts in the carotid artery, which express 5HT  receptors.
1B/1D

Dilatation of these shunt vessels during migraine attack is believed to divert blood
flow away from brain parenchyma. In addition it can reduce 5HT and
inflammatory neuropeptide release around the affected vessels as well as
extravasation of plasma proteins across dural vessels. Like ergotamine, the triptans
have been found to suppress neurogenic inflammation of cranial vessels.
Suppression of impulse transmission in the trigeminovascular system has also been
implicated.
 
 
Pharmacokinetics:
 
Sumatriptan is absorbed rapidly and completely after s.c. injection. Oral
bioavailability averages 15%. It is rapidly metabolized by MAOA isoenzyme and
metabolites are excreted in urine; elimination t½ is ~2 hours.
 
Side Effects:  to sumatriptan are usually mild. Tightness in head and chest,
feeling of heat and other paresthesias in limbs, dizziness, weakness are short
lasting, but dose related side effects.
 
These are more common after s.c. injection, which is painful. Slight rise in BP
occurs, but has little clinical relevance, because sumatriptan is not a drug for
regular use. Bradycardia, coronary vasospasm and risk of myocardial infarction are
the serious, but infrequent adverse effects. Few cases of sudden death have been
ascribed to sumatriptan. Seizures and hypersensitivity reactions are rare.
 
Contraindications: are in patients with ischaemic heart disease, hypertension,
epilepsy, hepatic or renal impairment and during pregnancy. Patients should be
cautioned not to drive.
 
Sumatriptan and ergotamine should not be administered within 24 hours of each
other. Interaction with 5HT uptake inhibitors, MAO inhibitors and lithium has
been reported.
 
Dose: 50–100 mg oral at the onset of migraine attack, may be repeated once
within 24 hours if required. Those not responding to the first dose should not be
given the second dose. It is the only triptan available for parenteral use; 6 mg s.c.
may be given to patients who cannot take the drug orally or in whom the pain
develops very rapidly; acts in 10–20 min and is more consistently effective.
 
MIGRATAN, 50, 100 mg tabs, SUMINAT 25, 50, 100 mg tab, 60 mg/5 ml inj;
SUMITREX 25, 50, 100 mg tab, 6 mg/0.5 ml inj.
 
Rizatriptan: This congener of sumatriptan is more potent, has higher oral
bioavailability with slightly faster onset of action.
 
Dose: 10 mg; repeat once after 2 hr (if required).
 
RIZACT 5, 10 mg tab.
 
Naratriptan,       Zolmitriptan,     Almotriptan,    
Frovatriptan         and Eletriptan  are  other  triptans  used  in  some  countries.
 
Features of some triptans are compared in the box.
 

* Tmax: Time to peak plasma concentration after oral dosing.

PROPHYLAXIS OF MIGRAINE
 

Regular medication to reduce the frequency and/or severity of attacks is

recommended for moderate to severe migraine when 2–3 or more attacks occur per
month. Diverse classes of drugs are used but none is effective in all cases, and
none abolishes the attacks totally. It may be prudent to discontinue pophylaxis
every 6 months to check whether its continuation is needed or not. It is important
to avoid the precipitating factor(s).

Β-Adrenergic blockers
 
Propranolol is the most commonly used drug: reduces frequency as well as severity
of attacks in upto 70% patients. Effect is generally seen in 4 weeks and is sustained
during prolonged therapy. The starting dose is 40 mg BD, which may be increased
upto 160 mg BD if required. The mechanism of action is not clear; that it is due
to β adrenergic blockade has been questioned. Other nonselective (timolol)
and β1 selective (metoprolol, atenolol) agents are also effective, but pindolol and
others having intrinsic sympathomimetic action are not useful.
 

Tricyclic antidepressants

Many tricyclic compounds of which amitriptyline has been most extensively tried

(25–50 mg at bed time) reduce migraine attacks. It is effective in many patients but
produces more side effects than propranolol. It is not known whether its 5HT (and
other monoamine) uptake blocking property is causally related to the prophylactic
effect. The antimigraine effect is independent of antidepressant property, but this
class of drugs are better suited for patients who also suffer from depression.

Calcium Channel Blockers

Verapamil was found to reduce migraine attacks, but was judged inferior to

propranolol. Flunarizine is a relatively weak Ca2+ channel blocker that also
inhibits Na+ channels. It is claimed to be as effective as propranolol, but
convincing proof is lacking. Frequency of attacks is often reduced, but effect on
intensity and duration of attacks is less well documented. It is claimed to be a
cerebroselective Ca2+ channel blocker; may benefit migraine by reducing
intracellular Ca2+ overload due to brain hypoxia and other causes. Side effects are
sedation, constipation, dry mouth, hypotension, flushing, weight gain and rarely
extrapyramidal symptoms.

Dose: 10–20 mg OD, children 5 mg OD, NOMIGRAIN, FLUNARIN 5 mg, 10

mg caps/tab.
 

Anticonvulsants
 
Valproic acid (400–1200 mg/day) and gabapentin (300–1200 mg/day) have some
prophylactic effect in migraine. The newer drug topiramate has recently been
approved for migrain prophylaxis. A 50% reduction in the number of attacks in
half of the patients was noted in 2 randomized trials. Start with 25 mg OD and
gradually increase to 50 mg OD or BD. Efficacy of anticonvulsants in migraine is
lower than that of β blockers. They are indicated in patients refractory to other
drugs or when propranolol is contraindicated.
 

5HT   Antagonists 
 
The   prophylactic   effect   of methysergide and cyproheptadine is less impressive
than β blockers. They are seldom used now for migraine.

PROSTAGLANDINS AND LEUKOTRIENES

(Eicosanoids)

Prostaglandins (PGs) and Leukotrienes (LTs) are biologically active derivatives of

20 carbon atom polyunsaturated essential fatty acids that are released from cell
membrane phospholipids. They are the major lipid derived autacoids.

In the 1930s human semen was found to contract isolated uterine and other smooth
muscle strips and to cause fall in BP in animals. The active principle was termed
‘prostaglandin’, thinking that it was derived from prostate. Only in the 1960s it
was shown to be a mixture of closely related compounds, the chemical structures
were elucidated and widespread distribution was revealed. In 1970s it became
clear that aspirin like drugs act by inhibiting PG synthesis, and that in addition to
the classical PGs (Es and Fs), thromboxane (TX), prostacyclin (PGI) and
leukotrienes (LTs) were of great biological importance. Bergstrom, Samuelsson
and Vane got the Nobel prize in 1982 for their work on PGs and LTs. Over the
past 40 years they have been among the most intensely investigated substances.

CHEMISTRY, BIOSYNTHESIS AND DEGRADATION

 

Chemically, PGs may be considered to be derivatives of prostanoic acid, though

prostanoic acid does not naturally occur in the body. It has a five membered ring
and two side chains projecting in opposite directions at right angle to the plane of
the ring. There are many series of PGs and thromboxanes (TXs) designated A, B,
C....I, depending on the ring structure and the substituents on it. Each series has
members with subscript 1, 2, 3 indicating the number of double bonds in the side
chains.

Leukotrienes are so named because they were first obtained from leukocytes
(leuko) and have 3 conjugated double bonds (triene). They have also been
similarly designated A, B, C.....F and given subscripts 1, 2, 3, 4.

In the body PGs, TXs and LTs are all derived from eicosa (referring to 20 C atoms)
tri/tetra/ penta enoic acids. Therefore, they can be collectively
called eicosanoids. In human tissues, the fatty acid released from membrane
lipids in largest quantity is 5,8,11,14 eicosa tetraenoic acid (arachidonic
acid). During PG, TX and prostacyclin synthesis, 2 of the 4 double bonds of
arachidonic acid get saturated in the process of cyclization, leaving 2 double bonds
in the side chain. Thus, subscript 2 PGs are most important in man, e.g. PGE , 2

PGF α, PGI , TXA . No cyclization or reduction of double bonds occurs during LT

2 2 2

synthesis— the LTs of biological importance are LTB , LTC , LTD .

4 4 4

Eicosanoids are the most universally distributed autacoids in the body. Practically
every cell and tissue is capable of synthesizing one or more types of PGs or LTs.
The pathways of biosynthesis of eicosanoids are summarized in Fig. 13.1.

There are no preformed stores of PGs and LTs. They are synthesized locally at
rates governed by the release of arachidonic acid from membrane lipids in
response to appropriate stimuli. These stimuli activate hydrolases, including
phospholipase A, probably through increased intracellular Ca2+.

The cyclooxygenase (COX) pathway generates eicosanoids with a ring

structure (PGs, TXs, prostacyclin) while lipoxygenase (LOX) produces open
chain compounds (LTs). All tissues have COX—can form cyclic endoperoxides
PGG  and PGH  which are unstable compounds. Further course in a particular
2 2

tissue depends on the type of isomerases or other enzymes present in it. PGE  and
2

PGF α are the primary prostaglandins (name based on the separation procedure:
2

PGE partitioned into Ether while PGF into phosphate [Fosfat in Swedish]

buffer; α in PGF α refers to orientation of OH group on the ring). PGs A, B and C
2

are not found in the body: they are artifacts formed during extraction procedures.
Lung and spleen can synthesize the whole range of COX products. Platelets
primarily synthesize TXA  which is —chemically unstable, spontaneously changes
2

to TXB . Endothelium mainly generates prostacyclin (PGI ); also chemically

2 2

unstable and rapidly converts to 6keto PGF α.

1

Cyclooxygenase is now known to exist in two isoforms COX1 and COX2. While
both isoforms catalyse the same reactions, COX1 is a constitutive enzyme in most
cells—its activity is not changed once the cell is fully grown. On the other hand,
COX2 normally present in insignificant amounts, is inducible by cytokines, growth
factors and other stimuli during the inflammatory response. It is believed that
eicosanoids produced by COX1 participate in physiological (house keeping)
functions such as secretion of mucus for protection of gastric mucosa, haemostasis
and maintenance of renal function, while those produced by COX2 lead to
inflammatory and other pathological changes. However, certain sites in kidney and
brain constitutively express COX2 which may play physiological role.

A splice variant of COX1 (designated COX3) has been found in the dog brain.
This isoenzyme is inhibited by paracetamol, but its role in humans is not known.

Lipoxygenase pathway appears to operate mainly in the lung, WBC and

platelets. Its most important products are the LTs, (generated by 5LOX)
particularly LTB  (potent chemotactic) and LTC , LTD  which together constitute
4 4 4

the ‘slow reacting substance of anaphylaxis’ (SRSA) described in 1938 to be

released during anaphylaxis. A membrane associated transfer protein called FLAP
(five lipoxygenase activating protein) carrys arachidonic acid to 5LOX, and is
essential for the synthesis of LTs. Platelets have only 12LOX.

 
HPETEs produced by LOX can also be converted to hepoxilins, trioxilins and
lipoxins. A third enzymatic pathway involving cytochrome P450 can metabolize
arachidonic acid into 19 and 20HETEs and epoxyeicosatrienoic acids. Free
radicals can attack arachidonic acid to produce isoprostanes nonenzymatically.
Brain cells couple arachidonic acid with ethanolamine to
produce anandamide which has cannabinoid like action. The above named
metabolites of arachidonic acid have a variety of vascular, inflammatory and other
actions, but their pathophysiological role is not clear.

Inhibition of synthesis Synthesis of COX products can be inhibited by

nonsteroidal anti-inflammatory drugs (NSAIDs). Aspirin acetylates COX at a
serine residue and causes irreversible inhibition while other NSAIDs are
competitive and reversible inhibitors. Most NSAIDs are nonselective COX1 and
COX2 inhibitors, but some newer ones like celecoxib, rofecoxib are selective for
COX2.

The sensitivity of COX in different tissues to inhibition by these drugs varies;

selective inhibition of formation of some products may be possible

at lower doses. NSAIDs do not inhibit the production of LTs: this may even be
increased since all the arachidonic acid becomes available to the LOX pathway.

Zileuton inhibits LOX and decreases the production of LTs. It was used briefly in
asthma, but has been withdrawn.

Glucocorticosteroids inhibit the release of arachidonic acid from membrane lipids

(by stimulating production of proteins called annexins or lipocortins which
inhibit phospholipase A ) — indirectly reduce production of all eicosanoids— PGs,
2

TXs and LTs. Moreover, they inhibit the induction of COX2 by cytokines at the
site of inflammation.

 
Degradation of arachidonates occurs rapidly in most tissues, but fastest in the
lungs. Most PGs, TXA  and prostacyclin have plasma t½ of a few seconds to a few
2

minutes. First a specific carrier mediated uptake into cells occurs, the side chains
are then oxidized and double bonds are reduced in a stepwise manner to yield
inactive metabolites. Metabolites are excreted in urine. PGI  is catabolized mainly
2

in the kidney.

ACTIONS AND PATHOPHYSIOLOGICAL ROLES

 

Prostaglandins, Thromboxanes And Prostacyclin

 

The cyclic eicosanoids produce a wide variety of actions depending upon the
particular PG (or TX or PGI), species on which tested, tissue, hormonal status and
other factors. PGs differ in their potency to produce a given action and different
PGs sometimes have opposite effects. Even the same PG may have opposite effects
under different circumstances. The actions of PGs and TXA  are summarized in
2

Table 13.1. Since virtually all cells and tissues are capable of forming PGs, they
have been implicated as mediators or modulators of a number of physiological
processes and pathological states.
 

CVS

PGE  and PGF α cause vasodilatation in most, but not all, vascular beds. In isolated
2 2

preparations, they are more potent vasodilators than ACh or histamine.

PGF α constricts many larger veins including pulmonary vein and artery. Fall in BP
2

occurs when PGE  is injected i.v., but PGF α has little effect on BP.
2 2

1.     PGI  is uniformly vasodilatory and is more potent hypotensive than PGE .
2 2

2.     TXA  consistently produces vasoconstriction.

2

3.     PG endoperoxides (G  and H ) are inherently vasoconstrictor, but often

2 2

produce vasodilatation or a biphasic response due to rapid conversion to

other PGs, especially PGI  in the blood vessels themselves.
2

4.     PGE  and F α stimulate heart by weak direct but more prominent reflex
2 2

action due to fall in BP. The cardiac output increases.

 

Role
 a.    PGI  is probably involved in the regulation of local vascular tone as a dilator.
2

b.     PGE  and PGI  are believed to be continuously produced locally in the ductus
2 2

arteriosus during foetal life—keep it patent; at birth their synthesis is inhibited

and closure occurs. Aspirin and indomethacin induce closure when it fails to
occur spontaneously. These PGs may also be important in maintaining
placental blood flow.
 

c.        PGs, along with LTs and other autacoids may mediate vasodilatation and
exudation at the site of inflammation.
 

Platelets
 
TXA , which can be produced locally by platelets, is a potent inducer of
2

aggregation and release reaction. The endoperoxides PGG  and PGH  are also
2 2

proaggregatory. On the other hand PGI  (generated by vascular endothelium) is a

2

potent inhibitor of platelet aggregation. PGD  has antiaggregatory action, but much
2

less potent than PGI . PGE  has inconsistent effects.

2 2

Role

TXA  produced by platelets and PGI  produced by vascular endothelium probably

2 2

constitute a mutually antagonistic system: preventing aggregation of platelets while

in circulation and inducing aggregation on injury, when plugging and thrombosis
are needed.

Aspirin interferes with haemostasis by inhibiting platelet aggregation which is due

toTXA  production. Before it is deacetylated in liver, aspirin acetylates COX in
2

platelets while they are in portal circulation. Further, platelets are unable to
regenerate fresh COX (lack nucleus: do not synthesize protein), while vessel wall
is able to do so (fresh enzyme is synthesized within hours). Thus, in low doses,
aspirin selectively inhibits TXA  production and has antithrombotic effect lasting >
2

3 days.

Uterus
 
PGE  and PGF α uniformly contract human uterus, pregnant as well as
2 2

nonpregnant in vivo. The sensitivity is higher during pregnancy and there is a

further modest increase with progress of pregnancy. However, even during early
stages uterus is quite sensitive to PGs though not to oxytocin. PGs increase tone as
well as amplitude of uterine contractions.
 

When tested in vitro, PGF α consistently produces contraction while PGE  relaxes
2 2

nonpregnant but contracts pregnant human uterine strips.

At term, PGs at low doses soften the cervix and make it more compliant.

Role

1.     Foetal tissues produce PGs and at term PGF α has been detected in maternal
2

blood. It has been postulated that PGs mediate initiation and progression of
labour. Aspirin has been found to delay the initiation of labour and also
prolongs its duration.
 
2.     Because PGs are present in high concentration in semen and can be rapidly
absorbed when lodged in the vagina at coitus, it is believed that they so
coordinate movements of the female genital tract that transport of sperms
and fertilization is facilitated.
 
3.     Dysmenorrhoea in many women is associated with increased PG synthesis
by the endometrium. This apparently induces uncoordinated uterine
contractions which compress blood vessels → uterine ischaemia → pain.
Aspirin group of drugs are highly effective in relieving dysmenorrhoea in
most women.
 

Bronchial Muscle
 
PGF α, PGD  and TXA  are potent bronchoconstrictors (more potent than histamine)
2 2 2

while PGE  is a powerful bronchodilator. PGI  produces mild dilatation. Asthmatics
2 2

are more sensitive to constrictor as well as dilator effects of PGs. PGE  and 2

PGI  also inhibit histamine release and are effective by aerosol—but produce
2

irritation of the respiratory tract and have a brief action.

 

Role

Asthma may be due to an imbalance between constrictor PGs (F  α, PGD , TXA )
2 2 2

and LTs on one hand and dilator ones (PGE , PGI ) on the other. In few individuals
2 2

aspirinlike drugs consistently induce asthma, possibly by diverting arachidonic

acid to produce excess LTC  and D . This sensitivity is not shared by selective
4 4

COX2 inhibitors, indicating that suppression of COX1 at the pulmonary site is

responsible for the reaction. In allergic human asthma, LTs are more important and
COX inhibitors are without any effect in most patients.

GIT
 
(i) In isolated preparations, the longitudinal muscle of gut is contracted by
PGE  and PGF α while the circular muscle is either contracted (usually by PGF α) or
2 2 2

relaxed (usually by PGE ). Propulsive activity is enhanced in man, especially by

2

PGE  → colic and watery diarrhoea are important side effects. PGE  acts directly
2 2

on the intestinal mucosa and increases water, electrolyte and mucus secretion.
PGI  does not produce diarrhoea and infact opposes PGE  and toxin induced fluid
2 2

movement.
 

Role

PGs may be involved in mediating toxin induced increased fluid movement in

secretory diarrhoeas. In certain diarrhoeas, aspirin can reduce stool volume, but is
not uniformly effective. PGs appear to play a role in the growth of colonic polyps
and cancer. Association of low incidence of colon cancer with regular intake of
aspirin is now established. NSAIDs afford relief in familial colonic polyposis by
reducing polyp formation.

PGE  markedly reduces acid secretion in the stomaArticle No. Volume of juice and
2

pepsin content are also decreased. It inhibits fasting as well as stimulated secretion
(by feeding, histamine, gastrin). The gastric pH may rise upto 7.0. PGI  also 2

inhibits gastric secretion, but is less potent. Secretion of mucus in stomach and
mucosal blood flow are increased; PGs are antiulcerogenic.
 

Role

PGs (especially PGI ) appear to be involved in the regulation of gastric mucosal

2

blood flow. They may be functioning as natural ulcer protectives by enhancing

gastric mucus production. The ulcerogenic action of NSAIDs may be due to loss of
this protective influence.

Normally, gastric mucosal PGs are produced by COX1. Selective COX2 inhibitors
are less ulcerogenic. However, COX2 gets induced during ulcer healing, and
COX2 inhibitors have the potential to delay healing.

Kidney
 
PGE  and PGI  increase water, Na  and K+ excretion and have a diuretic effect.
2 2
+

PGE  has been shown to have a furosemide like inhibitory effect on Cl¯
2

reabsorption as well. They cause renal vasodilatation and inhibit tubular

reabsorption. PGE  antagonizes ADH action, and this adds to the diuretic effect. In
2

contrast, TXA  causes renal vasoconstriction. PGI , PGE  and PGD  evoke release
2 2 2 2

of renin.
 

Role

1.     PGs appear to function as intrarenal regulators of blood flow as well as

tubular reabsorption in kidney. The NSAIDs tend to retain salt and water.
The diuretic action of furosemide is blunted by indomethacin— indicating a
facilitatory role of PGs by increasing renal blood flow and/or augmenting
inhibition of tubular reabsorption.
 

2.     Renin release in response to sympathetic stimulation and other influences

may be facilitated by PGs.
 
 3.     Bartter’s syndrome, characterized by decreased sensitivity to angiotensin II
is associated with increased PG production; many of the manifestations are
improved by prolonged use of NSAIDs.
 

CNS
 
PGs injected i.v. penetrate brain poorly and central effects are not prominent.
However, injected intracerebroventricularly PGE  produces a variety of effects—
2

sedation, rigidity, behavioral changes and marked rise in body temperature.

PGI  also induces fever, but TXA  is not pyrogenic.
2 2

Role

1.     PGE  may mediate pyrogen induced fever and malaise. Aspirin and other
2

inhibitors of PG synthesis are antipyretic. Pyrogens, including cytokines

released during bacterial infection, trigger synthesis of PGE  in the
2

hypothalamus, which resets the thermostat to cause fever. COX2 is the

major isoenzyme involved; selective COX2 inhibitors are equally
efficacious antipyretics. A role of COX3 has also been proposed.
 

2.     PGs may be functioning as neuromodulators in the brain by regulating

neuronal excitability. A role in pain perception, sleep and some other
functions has been suggested.
 

ANS
 
Depending on the PG, species and tissue, both inhibition as well as augmentation
of NA release from adrenergic nerve endings has been observed.
 

Role

PGs may modulate sympathetic neurotransmission in the periphery.

Peripheral Nerves
 
PGs (especially E  and I ) sensitize afferent nerve endings to pain inducing
2 2

chemical and mechanical stimuli (Fig.7.2). They irritate mucous membranes and
produce long lasting dull pain on intradermal injection.

Role

PGs appear to serve as algesic agents during inflammation. They cause tenderness

and amplify the action of other algesics. Inhibition of PG synthesis is a major anti-
inflammatory mechanism. Aspirin injected locally decreases pain produced by
injection of bradykinin at the same site.

Eye:
 
PGF α induces ocular inflammation and lowers i.o.t by enhancing uveoscleral
2

outflow.
Non irritating congeners like latanoprost are now first line drugs in wide angle
glaucoma.

Role

Locally produced PGs appear to facilitate aqueous humor drainage, since COX2

expression in the ciliary body has been found to be deficient in wide angle
glaucoma patients.

Endocrine System
 
PGE  facilitates the release of anterior pituitary hormones—growth hormone,
2

prolactin, ACTH, FSH and LH as well as that of insulin and adrenal steroids. It has
a TSH like effect on thyroid.
 

PGF α causes luteolysis and terminates early pregnancy in many mammals, but this
2

effect is not significant in humans. Though PGs can terminate early pregnancy in
women, this is not associated with fall in progesterone levels.

Metabolism
 
PGEs are antilipolytic, exert an insulin like effect on carbohydrate metabolism and
mobilize Ca2+ from bone: may mediate hypercalcaemia due to bony metastasis.
ACTIONS AND PATHOPHYSIOLOGICAL ROLES

Leukotrienes
 
The straight chain lipoxygenase products of arachidonic acid are produced by a
more limited number of tissues (LTB  mainly by neutrophils; LTC  and LTD —the
4 4 4

cysteinyl LTs—mainly by macrophages), but probably they are

pathophysiologically as important as PGs.

CVS and blood

 
LTC  and LTD  injected i.v. evoke a brief rise in BP followed by a more prolonged
4 4

fall. The fall in BP is not due to vasodilatation because no relaxant action has been
seen on blood vessels. It is probably a result of coronary constriction induced
decrease in cardiac output and reduction in circulating volume due to increased
capillary permeability. These LTs markedly increase capillary permeability and are
more potent than histamine in causing local edema formation. LTB  is highly
4

chemotactic for neutrophils and monocytes; this property is shared by HETE but
not by other LTs. Migration of neutrophils through capillaries and their clumping
at sites of inflammation in tissues is also promoted by LTB .
4

Role

LTs are important mediators of inflammation. They are produced (along with PGs)
locally at the site of injury. While LTC  and D  cause exudation of plasma,
4 4

LTB  attracts the inflammatory cells which reinforce the reaction. 5HPETE and
4

5HETE may facilitate local release of histamine from mast cells.

Smooth Muscle
 
LTC  and D  contract most smooth muscles. They are potent bronchoconstrictors
4 4

and induce spastic contraction of g.i.t. at low concentrations.

 

They also increase mucus secretion in the airways.

Role
The cysteinyl LTs (C  and D ) are the most important mediators of human allergic
4 4

asthma. They are released along with PGs and other autacoids during AG: AB
reaction in the lungs. In comparison to other mediators, they are more potent and
are metabolized slowly in the lungs, exert a long lasting action. LTs may also be
responsible for abdominal colics during systemic anaphylaxis.

Afferent Nerves
 
Like PGE  and I , the LTB  also sensitizes afferents carrying pain impulses—
2 2 4

contributes to pain and tenderness of inflammation.

PROSTANOID RECEPTORS
 

PGs, TX and prostacyclin act on their own specific receptors located on cell
membrane. Five major types of prostanoid receptors have been designated, each
after the natural PG for which it has the greatest affinity. This has been supported
by receptor cloning. All prostanoid receptors are Gprotein coupled receptors which
utilize the IP / DAG or cAMP transducer mechanisms. Some selective antagonists
3

of prostanoid receptors have been produced. The prostanoid receptors are:

DP Has greatest affinity for PGD , but PGE  also acts on it; activation increases
2 2

cAMP which inhibits platelet aggregation.

EP Has greatest affinity for PGE ; enprostil is a selective agonist. It has been

2

subdivided into EP  which causes smooth muscle contraction through IP /DAG

1 3

pathway and EP  which mediates smooth muscle relaxation by increasing cAMP.

2

Cloning studies have identified two more subtypes EP  and EP . PGE  enhances Cl¯
3 4 2

and water secretion in intestinal mucosa also by increasing cAMP. However, in

some tissues (adipocytes) PGE  inhibits cAMP formation—responsible for its
2

antilipolytic action. EP  receptors are activated by PGF α also.

1 2

 
FP Has greatest affinity for PGF α; fluprostenol is a selective agonist. The most
2

prominent effect of activation of this receptor is smooth muscle contraction

mediated through IP /DAG formation.
3

IP Has greatest affinity for PGI ; PGE also acts on it and cicaprost is a selective
2

agonist. It functions by activating adenylyl cyclase in platelets (inhibiting

aggregation) and smooth muscles (relaxation).

TP Has greatest affinity for TXA ; PGH  also acts on it. It utilizes IP /DAG as
2 2 3

second messengers which mediate platelet aggregation and smooth muscle

contraction.

LEUKOTRIENE RECEPTORS
 

Separate receptors for LTB  (BLT) and for the cysteinyl LTs (LTC , LTD ) have
4 4 4

been defined. Two subtypes, cys LT  and cysLT  of the cysteinyl LT receptor have
1 2

been cloned. All LT receptors function through the IP /DAG transducer

3

mechanism. The cysLT  receptor antagonists, viz. Montelukast, Zafirlukast, etc

1

are now valuable drugs for bronchial asthma (see Ch. No. 16).

USES
 

Clinical use of PGs and their analogues is rather restricted because of limited
availability, short lasting action, cost, side effects and other practical
considerations. Their approved indications are:

1. Abortion

 
During first trimester, termination of pregnancy by transcervical suction is the
procedure of choice. Intravaginal PGE  pessary inserted 3 hours before attempting
2

dilatation can minimise trauma to the cervix by reducing resistance to dilatation.

Medical termination of pregnancy of upto 7 weeks has been achieved with high
success rate by administering mefepristone (antiprogestin) 600 mg orally 2 days
before a single oral dose of misoprostol 400 μg. Uterine contractions are provoked
and the conceptus is expelled within the next few hours. Ectopic pregnancy should
be ruled out beforehand and complete expulsion should be confirmed afterwards.
Uterine cramps, vaginal bleeding, nausea, vomiting and diarrhoea are the possible
complications. Methotrexate administered along with misoprostol is also highly
successful in inducing abortion in the first few weeks of pregnancy.

PGs have a place in midterm abortion, missed abortion and molar gestation, though
delayed and erratic action and incomplete abortion are a problem. The initial
enthusiasm has given way to more considered use. PGs convert the oxytocin
resistant midterm uterus to oxytocin responsive one: a single extraamniotic
injection (PGE ) followed by i.v. infusion of oxytocin or intraamniotic (PGF α) with
2 2

hypertonic solution produces 2nd trimester abortion in a high percentage without

undue side effects. Pretreatment with mifepristone improves the efficacy of PGE as
abortifacient.

2. Induction/Augmentation Of Labour

PGs do not offer any advantage over oxytocin for induction of labour at term. They
are less reliable and show wider individual variation in action. PGE  and 2

PGF α (rarely) have been used in place of oxytocin in toxaemic and renal failure
2

patients, because they do not cause fluid retention. PGE  may also be used to
2

augment labour, if it is slow, in primipara. Intravaginal route is preferred now: side

effects are milder; extra/intra amniotic route is infrequently used.

 
3. Cervical Priming

Applied intravaginally or in the cervical canal, low doses of PGE  which do not
2

affect uterine motility make the cervix soft and compliant. This procedure has
yielded good results in cases with unfavourable cervix. If needed labour may be
induced 12 hours later with oxytocin: chances of failure are reduced.

4. Postpartum Haemorrhage (PPH)

 
Carboprost (15methyl PGF α) injected i.m. is an alternative for control of PPH due
2

to uterine atony, especially in patients unresponsive to ergometrine and oxytocin.

 

PGE  (Dinoprostone) PROSTINE  for induction/ augmentation of labour, midterm

2 2

abortion.

Vaginal gel (1 mg or 2 mg in 2.5 ml) 1 mg inserted into posterior fornix, followed

by 1–2 mg after 6 hour if required.

Vaginal tab (3 mg) 3 mg inserted into posterior fornix, followed by another 3 mg

if labour does not start within 6 hour.

Extraamniotic solution (10 mg/ml in 0.5 ml amp.) infrequently used.

Intravenous solution (1 mg/ml in 0.75 ml amp., 10 mg/ml in 0.5 ml amp) rarely

used.

 
Oral tablet PRIMIPROST 0.5 mg tab, one tab. hourly till induction, max 1.5 mg
per hr; rarely used.

Cervical gel CERVIPRIME (0.5 mg in 2.5 ml prefilled syringe) 0.5 mg inserted

into cervical canal for preinduction cervical softening and dilatation in patients
with poor Bishop’s score.

Gemeprost CERVAGEM 1 mg vaginal pessary: for softening of cervix in first

trimester—1 mg 3 hr before attempting dilatation; for 2nd trimester abortion/molar
gestation—1 mg every 3 hours, max. 5 doses.

PGF2α (Dinoprost) PROSTIN F  ALPHA intraamniotic injection 5 mg/ml in 4 ml

2

amp. for midterm abortion/ induction of labour (rarely used).

15methyl PGF2α (Carboprost) PROSTODIN 0.25 mg in 1 ml amp; 0.25 mg i.m.

every 30–120 min for PPH, midterm abortion, missed abortion.

TPILL + MISO Mifepristone 200 mg tab (3 tabs) + misoprostol 200 μg (2

tabs); mifepristone 3 tab orally followed 2 days later by misoprostol 2 tab orally,
for termination of pregnancy of upto 49 days.

5. Peptic Ulcer
 
Stable analogue of PGE  (misoprostol) is occasionally used for healing peptic
1

ulcer, especially in patients who need continued NSAID therapy or who continue
to smoke (see Ch. No. 46).
 
6. Glaucoma
 
Topical PGF α analogues like latanoprost and isopropyl unoprostone are one
2

of the first choice drugs in wide angle glaucoma.

 

7. To Maintain Patency Of Ductus Arteriosus in neonates with congenital heart

defects, till surgery is undertaken. PGE  (Alprostadil) is used; apnoea occurs in few
1

cases.

PROSTIN VR 0.5 mg in 1 ml amp; dilute and infuse i.v.

 
8. To Avoid Platelet Damage
 
PGI  (Epoprostenol) can be used to prevent platelet aggregation and damage
2

during haemodialysis or cardiopulmonary bypass. It also improves harvest of

platelets for transfusion. Few cases of primary pulmonary hypertension have been
successfully maintained on epoprostenol infusion.
 

FLOLAN 0.5 mg vial for reconstitution.

The other suggested uses of PGs are:

1. Peripheral vascular diseases PGI  (or PGE ) infused i.v. can relieve rest pain
2 1

and promote ulcer healing in severe cases of intermittent claudication and in

Raynaud’s disease.

2. Impotence Alprostadil (PGE ) injected into the penis causes erection lasting 1–

1

2 hours. However, oral sildenafil/ tadalafil is now preferred for erectile

dysfunction.
SIDE EFFECTS
 

Side effects are common in the use of PGs, but their intensity varies with the PG,
the dose and the route. These are: nausea, vomiting, watery diarrhoea, uterine
cramps, unduly forceful uterine contractions, vaginal bleeding, flushing, shivering,
fever, malaise, fall in BP, tachycardia, chest pain.

  PLATELET ACTIVATING FACTOR (PAF)

Like eicosanoids, platelet activating factor (PAF) is a cell membrane derived polar
lipid with intense biological activity; discovered in 1970s and now recognized to
be an important signal molecule. PAF is acetyl glyceryl etherphosphoryl choline.

Synthesis And Degradation

 

PAF is synthesized from precursor phospholipids present in cell membrane by the

following reactions:
The second step is rate limiting. Antigen-antibody reaction and a variety of
mediators stimulate PAF synthesis in a Ca2+ dependent manner on demand: there
are no preformed stores of PAF. In contrast to eicosanoids, the types of cells which
synthesize PAF is quite limited—mainly WBC, platelets, vascular endothelium and
kidney cells.

PAF is degraded in the following manner:

Actions     
PAF has potent actions on many tissues/organs.

Platelets Aggregation and release reaction; also releases TXA ; i.v. injection

2

results in intravascular thrombosis.

WBC PAF is chemotactic to neutrophils, eosinophils and monocytes. It stimulates

neutrophils to aggregate, to stick to vascular endothelium and migrate across it to
the site of infection. It also prompts release of lysosomal enzymes and LTs and
generation of superoxide radical by the polymorphs. The chemotactic action may
be mediated through release of LTB . It induces degranulation of eosinophils.
4

 
Blood Vessels Vasodilatation mediated by release of EDRF occurs → fall in BP
on i.v. injection. Decreased coronary blood flow has been observed on
intracoronary injection, probably due to formation of platelet aggregates and
release of TXA . 2

PAF is the most potent agent known to increase vascular permeability. Wheal and
flare occur at the site of intradermal injection.

Injected into the renal artery PAF reduces renal blood flow and Na+ excretion by
direct vasoconstrictor action, but this is partly counteracted by local PG release.

Visceral Smooth Muscle Contraction occurs by direct action as well as

through release of LTC , TXA  and PGs. Aerosolized PAF is a potent
4 2

bronchoconstrictor. In addition, it produces mucosal edema, secretion and a

delayed and longlasting bronchial hyperresponsiveness. It also stimulates intestinal
and uterine smooth muscle.

Stomach PAF is ulcerogenic: erosions and mucosal bleeding occur shortly after

i.v. injection of PAF. The gastric smooth muscle contracts.

 
Mechanism Of Action
 
Membrane bound specific PAF receptors have been identified. The PAF receptor is
a Gprotein coupled receptor which exerts most of the actions through intracellular
messengers IP /DAG → Ca2+ release.
3

 
As mentioned above, many actions of PAF are mediated/augmented by PGs,
TXA  and LTs which may be considered its extracellular messengers. PAF also
2

acts intracellularly, especially in the endothelial cells; rise in PAF concentration

within the endothelial cells is associated with exposure of neutrophil binding sites
on their surface. Similarly, its pro-aggregatory action involves unmasking of
fibrinogen binding sites on the surface of platelets.
 
PAF Antagonists
 
A number of natural and synthetic PAF receptor antagonists have been
investigated. Important among these are ginkgolide B (from a Chinese plant), and
some structural analogues of PAF. The PAF antagonists have many fold
therapeutic potentials like treatment of stroke, intermittent claudication, sepsis,
myocardial infarction, shock, g.i. ulceration, asthma and as contraceptive. Some of
them have been tried clinically but none has been found worth marketing.
Alprazolam and triazolam antagonize some actions of PAF.
 
 
Pathophysiological Roles
 
PAF has been implicated in many physiological processes and pathological states,
especially those involving cell to cell interaction. These are:
 
1. Inflammation: Generated by leukocytes at the site of inflammation PAF
appears to participate in the causation of vasodilatation, exudation, cellular
infiltration and hyperalgesia.
 
2. Bronchial asthma: Along with LTC  and LTD , PAF appears to play a major
4 4

role by causing bronchoconstriction, mucosal edema and secretions. It is unique in

producing prolonged airway hyperreactivity, so typical of bronchial asthma patient.
 
3. Anaphylactic (and other) shock conditions: are associated with high
circulating PAF levels.
 
4. Haemostasis and thrombosis: PAF may participate by promoting platelet
aggregation.
 
5. Rupture of mature graafian follicle and implantation: Early embryos which
produce PAF have greater chance of implanting. However, PAF is not essential for
reproduction.
 
6. Ischaemic states of brain, heart and g.i.t., including g.i. ulceration.

Opioid autocids

Opioid Classification
 1. Based on intrinsic activity
o Agonists (morphine, fentanyl)
o Pure antagonists (naloxone, naltrexone)
o Mixed agonist-antagonists (nalbuphine, butorphanol)
2. Based on interaction with μ, κ, or δ opioid receptor subtypes
o All three receptors have been cloned, and knockout mice created.
o Each receptor thought to have 2-3 (or more) subtypes, but no distinct gene
products have been identified. All belong to the superfamily of G-protein coupled
receptors.
o Most opioid analgesics are relatively selective μ opioid agonists. The various μ
effects are discussed below.
o A few analgesics (pentazocine, nalbuphine, butorphanol) are κ agonists, although
they are not highly selective. Experimental selective κ drugs produce analgesia, but also
unique effects like diuresis and dysphoria.
o The selective δ agonists are mainly peptides. Receptor may function permissively
with μ receptor (allosteric interaction?).

Endogenous Opioid Peptides

1. Enkephalins include several compounds derived from a large proenkephalin molecule

(also called proenkephalin A).
o Most important compounds are pentapeptides, methionine- and leucine-
enkephalin. Relatively selective δ ligands.
o Widely distributed in CNS
o Act like morphine to modulate neurotransmitter release (see p. 3)
o Found with catecholamines in sympathetic terminals and adrenal.
2. Endorphins (chiefly β-endorphin) are derived from the large precursor molecule pro
opiomelanocortin (POMC).
o POMC also the precursor for ACTH and MSH, which are found together withβ-
endorphin.
o β-endorphin is a 31 amino acid peptide which has analgesic activity in man and
animals. It binds preferentially to μ receptors.
o Localized primarily in pituitary and hypothalamus.
3. Dynorphins are derived from a prodynorphin molecule (also called proenkephalin B).
o Dynorphin A is a 17 amino-acid peptide which is a potent and highly selective
agonist at κ receptors.
o Similar distribution to the enkephalins.
4. Opioid peptides are located in places which allow them to function as neurotransmitters
or neuromodulators.
5. Probably modulate pain transmission in the cord and alter acetylcholine release in the
myenteric plexus.
 6. Postulated to play fundamental roles in areas as diverse as hormonal secretion,
thermoregulation, and cardiovascular control.

Opioid Agonists -Pharmacodynamics

1. General Mechanisms

o Opioids inhibit adenylyl cyclase via interaction with Gi/G0.

o Hyperpolarize postsynaptic neurons by increasing outward K+ currents
o Act presynaptically to block Ca++ uptake and consequently inhibit neurotransmitter release. Opioids have been
shown to inhibit the release of many neurotransmitters, including substance P, acetylcholine, norepinephrine, glutamate,
and serotonin.
o Opioids produce highly specific depressant and stimulant effects by acting at discrete CNS sites. For example,
morphine stimulates the vagal nuclei in the medulla while depressing respiratory centers only a few millimeters away.
o The mechanism for neuronal stimulation is often the depression of an inhibitory interneuron .
2. General Clinical Properties

Acute and Chronic Effects of Opioids

o All of the clinically-used μ opioid agonists produce these effects.
o The few qualitative differences between drugs (e.g. histamine release) usually do not involve specific opioid
receptor mechanisms.
o Opioids differ greatly in physicochemical properties as well as speed of onset and duration of action, so clinical
selection is frequently based on pharmacokinetic considerations.
3. CNS Effects
o Analgesia and Mood

Mechanisms:

Clinical characteristics:

 Processing of pain information is inhibited by a direct spinal effect at the dorsal horn. Probably
involves presynaptic inhibition of the release of tachykinins like substance P.
 Rostrad transmission of pain signals decreased by activation of descending inhibitory pathways in the
brainstem.
 Emotional response to pain altered by opioid actions on the limbic cortex.
 Opioids may act at receptors located peripherally on sensory neurons. Possibly important in painful
conditions accompanied by tissue inflammation.
 Selective relief of pain at doses which do not produce hypnosis or impair sensation.
 Typically, patients report that pain is still present, but the intensity is decreased and it no longer
bothers them as much.
 Mood elevation, sometimes frank euphoria can occur. Sense of well-being and cloudy detachment
thought to be an important reason for opioid abuse.
 Some types of pain more responsive to opioids than others. More effect in prolonged, burning pain
than sharp pain of an incision. Neuropathic pain (e.g. pain of nerve root compression) can be very resistant.
 Relative potencies (see text) usually determined in postoperative pain. Similar data for other pain
states generally not available. Actual dose administered will vary greatly from patient to patient.
o Sedation-Hypnosis
 Drowsiness, feelings of heaviness, and difficulty concentrating are common.
 Sleep may occur with relief of pain, although these drugs are not hypnotics.
 Most likely to occur in elderly or debilitated patients and in those taking other CNS depressants (EtOH, benzodiazepines).

o CNS Toxicity
 Dysphoria and agitation occur infrequently (incidence higher with meperidine and codeine).
 Seizures can be produced by meperidine—major metabolite, normeperidine, is a convulsant.
 Opioids generally avoided in head injury or when elevated intracranial pressure (ICP) is suspected.
1. ↓ ventilation can ↑ PaCO2 and raise ICP further.
2. Pupil effects may mask changing neurologic signs.
o Respiratory Depression

Mechanisms:

Clinical Characteristics:

 Direct effects on respiratory centers in the medulla.

 Dose-related depression of ventilatory response to hypercarbia and hypoxia. This shifts CO2 response
curve to the right (see figure).
 May involve a distinct subset of μ2 receptors.
 With usual analgesic doses, arterial O2 saturation often decreases.
 Drive to breathe may be abnormal despite an apparently normal respiratory rate and state of
consciousness.
 Effects are dose related. First CO2 and hypoxic response are depressed, then respiratory rate slows.
Very large doses may cause irregular or periodic breathing and eventually apnea.
 Trouble most likely to occur with pre-existing pathology (such as hypothyroidism, pulmonary or CNS
disease) or previous drug administration (alcohol, general anesthetics, benzodiazepines).
 Sleep depresses the response to CO2 and potentiates the opioid effect.
 Respiratory depression is the major toxicity of opioids and nearly always the cause of death from
overdose.
 Equianalgesic doses of all opioids produce equivalent amounts of respiratory depression. There is no
convincing evidence than any analgesic is more or less dangerous than morphine in this regard.
 Both analgesia and respiratory depression are reduced by administration of an opioid antagonist or
by the development of tolerance. This has two important clinical implications:
1. Tolerant individuals who require large amounts of opioid for relief of pain are not at
proportionately increased risk for respiratory depression
2. Respiratory depression is difficult to reverse without reversing some analgesia (see
"Naloxone").
o Cough Suppression
 Depression of cough centers in the medulla (and possibly, the periphery).
 Different molecular mechanism than analgesia or respiratory depression— cough suppressed by
dextro-isomers of opioids (e.g. dextromethorphan), compounds which have no analgesic activity.
o Pupillary Constriction
 Stimulation of Edinger-Westphal (parasympathetic) nucleus of the oculomotor nerve to produce
miosis.
 Pinpoint pupil is a pathognomonic sign of opioid overdose.
 Antagonized by naloxone, atropine or ganglionic blockers.
o Nausea and Vomiting
 Complex effects on vomiting centers in the medulla.
 Direct stimulation of the chemoreceptor trigger zone (CTZ) in the area postrema on the floor of the
fourth ventricle. This activates the vomiting center proper
 Emetic effects markedly potentiated by stimulation of the vestibular apparatus, so ambulatory
patients are much more likely to vomit than those lying quietly.
 In animals (and man?), very high doses can depress the vomiting center
o Muscle Rigidity
 Large i.v. doses can cause generalized stiffness of skeletal muscle. Thought due to μ-mediated
increase in striatal dopamine synthesis and inhibition of striatal GABA release.
 Most common with fentanyl and congeners.
 May play a role in some overdose fatalities.
b. Cardiovascular Effects
o Decrease in central sympathetic tone causes vasodilation and orthostatic hypotension.
o Effects on both capacitance and resistance vessels.
o Bradycardia by stimulating central vagal nuclei
o Little or no myocardial depression.
o Histamine Release
o Morphine, codeine, meperidine cause non-immunologic displacement of histamine from tissue mast cells.
o Occasionally redness, hives, itching near injection site. Rarely, hypotension, generalized flushing.
o Not an allergy—true allergic responses to opioids are very rare.
o Facial itching and warmth are common after opioids—probably a dysesthesia which has nothing to do with
histamine.
o Smooth Muscle Effects
o Intestine and Stomach
 Spasm of smooth muscle all along the GI tract. Both small and large bowel become hypertonic, but
rhythmic propulsive activity is diminished. Delay in intestinal transit time and spasm of the anal sphincter cause
constipation.
 Delayed gastric emptying. Important because it may slow absorption of oral medications.
 Mechanism involves both CNS effects and peripheral actions on opioid receptors in the enteric plexus.
Smooth muscle effects of morphine > meperidine > agonist-antagonist opioids.
 Chronic administration of opioids frequently necessitates the administration of laxatives and stool
softeners to treat constipation. Recent evidence that poorly-absorbed quaternary opioid antagonists are also effective in
reversing this local effect.
 Constipating effect is used therapeutically for treatment of diarrhea. Diphenoxylate (in Lomotil) and
loperamide (Imodium) are poorly-absorbed opioids that do not produce central effects.
o Biliary System
 Contraction of smooth muscle along the biliary tree and spasm of the sphincter of Oddi.
 Can precipitate biliary colic on rare occasions.
 Effect antagonized by naloxone and partially reversed by glucagon, nitroglycerin, or atropine.
o Urinary Tract
 Increase contractions of the ureter and tone of the urinary sphincter, but decrease force of detrusor
muscle contraction. Decreased attention to full bladder. Can cause urinary retention.
 Probably both central and peripheral mechanisms involved.
b. Effects on Pregnancy and the Neonate
o All cross the placenta.
o No teratogenic effects, but chronic use may cause physical dependence in utero. Neonatal withdrawal after
delivery can be life-threatening.
o Opioids given during labor can cause respiratory depression in baby.
o Tolerance
o Reduction in effect with repeated dosing (or higher dose to produce same effect). First indication usually
decreased duration of analgesia, then decreased intensity. Can be profound.
o Cross-tolerance to other opioids.
o Mechanism not known precisely. Involves adaptive response of adenylyl cyclase and/or G protein coupling. Not
a pharmacokinetic effect.
o Develops most rapidly to depressant effects like analgesia, respiratory depression, euphoria, but much less
tolerance to stimulatory effects like constipation or miosis. This has some important clinical consequences:
 Heroin addicts or methadone maintenance patients may have little euphoria from high doses but
continue to experience constipation and miosis.
 Terminal cancer patients and others requiring high doses for analgesia are also tolerant to respiratory
depression (cf. p. 6), but they frequently require treatment for constipation.
o Physical Dependence
1. Adaptation which produces stereotyped withdrawal syndrome (abstinence) when drug is stopped. Symptoms
stop when small dose of opioid is given.
2. Giving antagonist (naloxone) to physically dependent person causes rapid onset of more severe precipitated
abstinence.
3. Withdrawal symptoms include runny nose, vomiting, diarrhea, gooseflesh, mydriasis, shaking chills, drug
seeking behavior.
4. Physical dependence not the same as psychological dependence or addiction. Mild physical dependence may be
common.
5. Addiction produced by appropriate medical treatment is a very unusual event. Irrational fear of addicting
patients cited as a frequent cause for inadequate pain treatment.
o Use of Methadone in Opioid Physical Dependence:
1. Opioid Detoxification—patient switched from short-acting opioid to methadone (T1⁄2 = 35 hr) and tapered
slowly. Withdrawal symptoms protracted, though mild. Adjuvants like clonidine and sedatives may be helpful.
2. Maintenance—chronic methadone to maintain a state of tolerance and physical dependence. Several putative
benefits:
 ↓ withdrawal symptoms, so drug seeking (& illegal activity) decreased.
  Tolerance develops to opioid euphoria, so injection of illegal heroin is not reinforcing. (Behavior may
or may not decrease.)
 Methadone given orally, so risk of needles reduced.
 Obtaining methadone requires regular contact with caregivers and access to counseling and other
treatment.

Opioid Agonists – Pharmacokinetics

Onset and duration most often the basis for selection of an opioid. Huge variation in physicochemical properties and therefore
absorption and distribution throughout the body.

Physicochemical Properties of Some Opioid Agonists

 A. Pharmacokinetics of Morphine
1. Rapid absorption, wide distribution, and rapid clearance from plasma.
2. Clearance mainly by hepatic biotransformation (70% first pass).
 Primarily 3-glucuronide (inactive)
 6-glucuronide. A highly active metabolite, but role in clinical effects is uncertain. May account for
opioid depression reported in renal failure. May also be important with chronic dosing.
 N-demethylation to normorphine
3. Polar metabolites cleared by kidney.
4. Relatively hydrophilic drug, so CNS penetration and exit are slow. This accounts for slow onset and long
duration. Effects lag behind changes in plasma concentrations.
B. Pharmacokinetics of Meperidine
1. Rapid absorption, wide distribution, and rapid clearance from plasma.
2. Clearance mainly by hepatic biotransformation (48-56% first pass).
 N-demethylation to normeperidine, oxidation to meperidinic acid or normeperidinic acid.
 Normeperidine is a CNS stimulant and can produce convulsions in man. Metabolite has T1⁄2 of 8-12
hr so significant amounts may accumulate. Toxicity most likely with high doses in renal failure.
C. Pharmacokinetics of Fentanyl
1. Rapid absorption, wide distribution, moderately rapid hepatic clearance
2. More than 60% first-pass metabolism to inactive metabolites.
3. Extremely lipophilic. Rapidly crosses BBB and other membrane barriers so effects parallel changes in plasma
concentrations.
4. Fat solubility means that drug may be administered by multiple routes: useful analgesic effects by transdermal
patch, intranasal spray, and buccal mucosa (fentanyl “lollipop”).

Opioid Agonists – Individualization of Dosage

1. Analgesic requirements are enormously variable. Usual adult morphine dose (10 mg) only 70% effective in acute pain.
2. Range of effective concentrations (the “therapeutic window”) is narrow for each patient but varies widely between
patients. Implication: “cookbook” analgesia likely to be inadequate or excessive much of the time.
3. Lower starting doses for elderly, hypovolemic, debilitated, hypothyroid or those given other CNS depressants.
4. Do not be afraid to give adequate treatment to patients who have become highly tolerant.
5. Watch for accumulation of parent drug and/or metabolites in hepatic or renal failure.

Opioid Antagonists
1. Naloxone
o Pure, competitive antagonist at μ, κ, and δ receptors (highest affinity at μ)
o Given alone, almost no effect. Some behavioral effects in animals.
o Rapidly reverses opioid overdose, but effect short due to redistribution. Patient may become renarcotized.
2. Naltrexone
o Used orally in high doses to treat detoxified heroin addicts (blocks euphoria from injected heroin).
o Effects primarily from active metabolite, 6-β-naltrexol.

Opioid Agonist-Antagonists
1. Developed in search for less abusable potent analgesics.
2. All have analgesic (agonist) properties as well as ability to antagonize morphine effects.
3. Two basic mechanisms:
 Partial agonists at μ receptor. Buprenorphine has high affinity, but limited efficacy at μ receptor. Given alone, it has
morphine-like effects. Competes effectively with agonists like morphine and may reduce effect.
 Agonists/Partial agonists at κ receptor. Nalorphine, pentazocine, nalbuphine, butorphanol act as κ agonists (probably κ3)
to produce analgesia. Also act as competitive antagonists at μ receptors (high affinity but no efficacy at this receptor).
1. Clinical properties:
 Potent analgesics effective in moderate to severe pain.
 Relatively limited toxicity (respiratory dep., smooth muscle)
 Decreased abuse potential, but also decreased patient acceptance (mood elevation may be clinically important!).
 Occasional dysphoria or hallucination with κ agonists
 Antagonist properties mean they can precipitate withdrawal in patients already receiving chronic treatment with opioid
agonists.
1. Neither agonist vs. antagonist potency nor μ/κ selectivity seem to predict clinical utility or patient acceptance.