5-Hydroxytryptamine & Its Antagonists: Autocoids and Related Drugs

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Autocoids and Related Drugs

Amine autacoids

5-Hydroxytryptamine &
its Antagonists

by:
Mr. Shivsharan B. Dhadde
5-HYDROXYTRYPTAMINE (5-HT)

Two types of 5-HT are:

1.Serotonin: The vasoconstrictor substance appeared in the serum when blood clotted

2. Enteramine: The smooth muscle contracting substance present in enterochromaffin cells of


gut mucosa.

• About 90% of body’s content of 5-HT is localized in the intestines; most of the rest is in
platelets and brain.

• It is also found in plants (banana, pear, pineapple, tomato, stinging nettle, cowhage).

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SYNTHESIS, STORAGE AND DESTRUCTION

• 5-HT is synthesized from amino acid tryptophan & degraded primarily by MAO and
to a small extent by a dehydrogenase.
• Decarboxylase acts on 5-hydroxytryptophan to produce 5-HT.
• 5-HT is actively taken up by an amine pump serotonin transporter (SERT), of platelets
& serotonergic nerve endings.
• Platelets do not synthesize but acquire 5-HT by uptake during passage through
intestinal blood vessels.
• 5-HT is stored within storage vesicles & its uptake at vesicular membrane by
vesicular monoamine transporter (VMAT-2)

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SYNTHESIS AND DESTRUCTION

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SEROTONERGIC (5-HT) RECEPTORS

• Four families of 5-HT receptors (5-HT1, 5-HT2, 5-HT3, 5-HT4-7) comprising of 14


receptor subtypes have so far been recognized.
• 5-HT3 is a ligand gated cation (Na+,K+) channel & all other 5-HT are G protein
coupled receptors.
• These G protein coupled receptors function through:
✓ decreasing cAMP production (5-HT1) or
✓ increasing cAMP production (5-HT4, 5-HT6, 5-HT7) or
✓ by generating IP3/DAG as second messengers (5-HT2) .
• 5-HT3 is a ligand gated cation (Na+,K+) channel on activation elicits fast
depolarization.

IP3 — Inositol trisphosphate; DAG Diacylglycerols 5


Important 5-HT receptor subtypes

5-HT1: Autoreceptors; inhibit serotonergic neural activity in brain.


5-HT1A—present in raphe nuclei and hippocampus
5-HT1B/1D—Constricts cranial blood vessels & inhibits inflammatory neuropeptides

5-HT2A: Most important postjunctional receptor mediating direct actions of 5-HT like:
✓ vascular & visceral smooth muscle contraction,
✓ platelet aggregation,
✓ neuronal activation in brain.
5-HT3 : Depolarizes neurones by gating cation channels; elicits reflex effects of 5-HT—emesis, gut
peristalsis, bradycardia, transient hypotension, apnoea, pain, itch.

5-HT4 : Mediate intestinal secretion, augmentation of peristalsis.


ACTIONS of 5-HT

1. CVS
• Arteries are constricted (smooth muscle action ) as well as dilated (through EDRF
release) by direct action of 5-HT
• 5-HT 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 5-HT dilates arterioles and constricts venules: capillary
pressure rises and fluid escapes.
• The direct action to increase capillary permeability is feeble.
ACTIONS of 5-HT

2. Smooth muscles

• 5-HT is a potent stimulator of g.i.t., by direct action as well as through enteric plexuses.

• 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.


ACTIONS of 5-HT
ACTIONS of 5-HT

3. Glands
• 5-HT 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.
4. 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.
• 5-HT is less potent than histamine in releasing CAs from adrenal medulla.
ACTIONS of 5-HT

5. Respiration

•A brief stimulation of respiration and hyperventilation are the usual response, but large
doses can cause transient apnoea through coronary chemoreflex.

6. Platelets

•5-HT causes changes in shape of platelets and is a weak aggregator through 5-HT2A
receptors.

•However, it does not induce the release reaction.


ACTIONS of 5-HT

7. CNS

•Injected i.v., 5-HT 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
• 5-HT is a confirmed neurotransmitter in the brain; brain 5-HT has a fast turnover rate.
• Cells containing 5-HT are present in the raphe nuclei of brainstem, substantia nigra and
few other sites.
• 5-HT is probably involved in sleep, temperature regulation, thought, cognitive function,
behaviour & mood, vomiting & 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.
PATHOPHYSIOLOGICAL ROLES

3. Neuroendocrine function
• 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 5-HT.
5. Migraine
• 5-HT is said to initiate the vasoconstrictor phase of migraine & to participate in
neurogenic inflammation of affected blood vessels.
• Methysergide (5-HT antagonist) is an effective prophylactic and sumatriptan (5-HT1B/1D
agonist) can control an attack.
PATHOPHYSIOLOGICAL ROLES

6. Haemostasis
• Platelets release 5-HT during aggregation at the site of injury to blood vessel & accelerates
platelet aggregation and clot formation.
• 5-HT promote retraction of the injured vessel.
• Both the above actions contribute to haemostasis.
7. Variant angina
• Along with thromboxane A2, 5-HT released from platelets has been implicated in causing
coronary spasm and variant angina.
8. Hypertension
• Increased responsiveness to 5-HT as well as its reduced uptake and clearance by platelets
has been demonstrated in hypertensive patients.
PATHOPHYSIOLOGICAL ROLES

9. Intestinal motility
• Enterochromaffin cells and 5-HT 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 5-HT.
• Bowel hyper-motility and bronchoconstriction in carcinoid is due to 5-HT but flushing and
hypotension are probably due to other mediators.
• Pellagra may occur due to diversion of tryptophan for synthesizing 5-HT.
DRUGS AFFECTING 5-HT SYSTEM

1. 5-HT precursor: Tryptophan increases brain 5-HT and produces behavioural effects because
tryptophan hydroxylase in brain is not saturated by the amount of tryptophan available
physiologically.
2. Synthesis inhibitor: p-Chlorophenylalanine selectively inhibits tryptophan hydroxylase & reduces
5-HT level in tissues. It is not used clinically (toxicity)
3. Uptake inhibitor: Tricyclic antidepressants inhibit 5-HT uptake. Selective serotonin reuptake
inhibitors (SSRI): fluoxetine, sertraline
4. Storage inhibitor: Reserpine blocks 5-HT uptake into storage granules and its causes depletion.
5. Degradation inhibitor: Nonselective MAO inhibitor (tranylcypromine) & selective MAO-A inhibitor
(chlorgyline) increase 5-HT content by preventing its degradation.
6. Neuronal degeneration: 5, 6 dihydroxytryptamine selectively destroys 5-HT neurones.
7. 5-HT receptor agonists: A diverse range of compounds producing a variety of actions have been
found to activate subtypes of 5-HT receptors.
5-HT ANTAGONISTS

• A variety of drugs block serotonergic receptors; many are nonselective, but some newer
ones are highly subtype selective.
• The ability to antagonize at least some actions of 5-HT is found in many classes of drugs, e.g.
▪ Ergot derivatives -ergotamine, LSD, 2-bromo LSD, methysergide
▪ Adrenergic α blockers - phenoxybenzamine
▪ Antihistaminics -cyproheptadine, cinnarizine
▪ Other - chlorpromazine, morphine, etc.,
• These are nonselective & interact with several other receptors as well
• Many are partial agonists or antagonize certain actions of 5-HT but mimic others.
Cyproheptadine
• It primarily blocks 5-HT2A receptors and has additional H1 antihistaminic, anticholinergic
and sedative properties.
• Like other antihistaminics, it has been used in allergies and is a good antipruritic, but the
anti 5-HT 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.
• Anti 5-HT activity is utilized in controlling intestinal manifestations of carcinoid &
postgastrectomy dumping syndromes, antagonizing priapism/orgasmic delay caused by 5-HT
uptake nhibitors like fluoxetine and trazodone.
• Side effects drowsiness, dry mouth, confusion, ataxia, weight gain.
Clozapine

• In addition to being a dopaminergic antagonist, this atypical antipsychotic is a 5-


HT2A/2C blocker.

• Clozapine may also exert inverse agonist activity at cerebral 5-HT2A/2C receptors which
may account for its efficacy in resistant cases of schizophrenia.

Ondansetron

• It is the prototype of the new class of selective 5-HT3 antagonists that have shown
remarkable efficacy in controlling nausea and vomiting following administration of
highly emetic anticancer drugs and radiotherapy.
Risperidone

• This atypical antipsychotic is a combined 5-HT2A + dopamine D2 antagonist, similar to


clozapine.
• 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 5-HT
and DA antagonists, but interact with other neurotransmitter receptors as well.
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.
• Dry gangrene of hands & feet is the most prominent feature.
• Miscarriages occur in women and cattle.
• Ergot contains a host of pharmacologically active substances—alkaloids,
histamine, ACh, tyramine & 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: they are vasoconstrictor and
α -adrenergic blocker.
Other semisynthetic derivatives

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


cerebroactive.

(b) 2-Bromo-α-ergocryptine (Bromocriptine): is a dopaminergic agonist.

(c) Methysergide: it is mainly anti 5-HT.

• Ergot alkaloid related compounds have diverse pharmacological properties

• They act as agonists, partial agonists & antagonists on certain subtypes of α adrenergic,
serotonergic & dopaminergic receptors in a tissue specific manner.
Actions of ergot alkaloids

Ergotamine
•It acts as a partial agonist & antagonist at α adrenergic & all subtypes of 5-HT1 & 5-HT2
receptors, but does not interact with 5-HT3 receptors:
-produces sustained vasoconstriction, visceral smooth muscle contraction, vasomotor
centre depression & antagonizes action of NA &5-HT 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 & gangrene.
Actions of ergot alkaloids

Dihydroergotamine (DHE)

• Hydrogenation of ergotamine reduces serotonergic and α-adrenergic agonistic


actions, but enhances α-receptor 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.
Actions of ergot alkaloids

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 5-HT receptors,


metabolic and vascular effects and enhancement of Ach release in cerebral cortex have
been demonstrated.

• It has been advocated for treatment of dementia.


Actions of ergot alkaloids

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 5-HT or α blocking actions and is not an oxytocic.
Actions of ergot alkaloids

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 5-HT receptors has been demonstrated in uterus, placental
and umbilical blood vessels and in certain brain areas.
• It is a moderately potent 5-HT2 antagonist in g.i. smooth muscle and a weak
dopaminergic agonist on the 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 first pass 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 blood-brain 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.

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