5HT Pharmacology and Therapeutics

8/8/2019 5HT Pharmacology and Therapeutics

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5 HT in Pharmacology &

Therapeutics

Dr Arif Hashmi JR II


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Protein receptors that mediate the effect

of 5HT have existed in the membrane of a

variety of cell types of animals for millions

of years, their ancestry being as old as or

older than some of that of adrenoreceptors

and receptors for some peptides.


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During such a long period there has been ample

opportunity for mutations and as a consequent a

multitude of different but related receptors today

form the 5 HT family, the largest known

neurotransmitter family


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As long ago as 1868 it was known that the

blood contained a vasoconstrictive

substance


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In Italy, Erspamerhad, since the late 1930s,

been investigating a constituent of gastric and

enteric mucosa of mammals, and salivary

glands of octopus

He had named the compound enteramine and

this substance was finally demonstrated also to

be 5-HT


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Irvine Page Arda Green and Maurice

Rapport, isolated and characterised this

substance, and named it for its

vasoconstrictor properties Serotonin


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Gaddum demonstrated the presence of

this newly isolated chemical in the brain

He also demonstrated that the action of5HT in the gut was antagonised by

LSD, a hallucinogenic substance that

had just been synthesized back then


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Measuring 5HT Early attempts

Bioassay using an isolated oestrus uterus

Amin (1954)

Rat stomach strip John Vane (1957)

Spectophotoflourimeter Robert Bowman

HPLC


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5-HT synthesised from tryptophan

Sequence of steps -

hydroxylation & decarboxylation

Synthesis & Metabolism of 5HT


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Receptor Identification & Naming

The first definitive identification of 5-HT

receptor subtypes was by Gaddum & Picarelli(1957)


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Gaddums classification was the D- and M-

receptor, named because of the sensitivity of

the receptor subtypes to dibenzyline and

morphine as blockers


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5HT Receptor subtypes and their

Ligands


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The 5-HT1 receptor class is comprised of

five receptor subtypes - 5-HT1A

, 5-HT1B

, 5-

HT1D

, 5-ht1E

and 5-ht1F


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5-HT1A receptors

5-HT1A receptors are present widely in theCNS, especially raphe nucleus


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Implicated in -

Neuro-endocrine regulation of ACTH

but not Prolactin secretion

Anxiety, 5HT 1A KO mice demonstrate

increased anxiety

Hyperphagia pre-synaptic 5HT 1Aautoreceptor activation


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Peculiar Lab response - Spontaneous tail-flick response attributed

to post-synaptic 5HT1A

receptor activation


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5-HT1B

receptors

Expressed in the CNS, basal ganglia,

striatum and frontal cortexand are

thought to serve as terminal

autoreceptors

also found in Cerebral arteries and other

vascular tissues


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Interest in 5-HT1B

receptor agonists has been

enhanced by the antimigraine properties of

Sumatriptan, a non-selective 5HT1B/1D

agonist


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Donitriptan - mixed activity at both 5-HT1D

and 5-HT1B

receptors, displays uniquely high

selectivity towards cranial versus peripheral

tissues, thereby leading to drug candidate

with minimal cardiovascular effects

It has completes Phase I trial or migraine

and is currently in Phase II


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The putative 5-HT1B receptor agonist,

anpirtoline, has analgesic and

antidepressant-like properties in rodents

5-HT1B

receptor KO mice were reported

to be both highly aggressive and have an

increased preference for alcohol


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5-HT1D

receptors

The 5HT1D

receptor possesses 63%

overall structural homology with the 5HT1B

receptor. Its level of expression is very

lowcompared with 5HT1B

receptors

- dorsal raphe nucleus & human heart


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5-ht1E

receptors

The putative 5-ht1E

receptor was first

identified in binding studies in homogenates

of humanfrontal cortex, but it was not

possible to readily determine its overalldistribution and pharmacology


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5-ht1F

receptors

The 5-ht1F

receptor consists of a 366-amino

acid protein, negatively linked to adenylyl

cyclase in recombinant cell systems. This

receptor is most closely related to the 5-ht1E

receptor with >70% sequence homology


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The 5-HT2 receptor class is comprised of

the 5-HT2A

, 5-HT2B

and 5-HT2C

receptor

subtypes

couple preferentially to Gq/11

to increase

the hydrolysis of inositol phosphates and

elevate cytosolic Ca2+


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5-HT2A

receptors

distributed in the CNS, serotonergic terminal

areas

high densities of 5-HT2A

receptors are found

in prefrontal, parietal, and somatosensorycortex, claustrum, and inplatelets


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5-HT2A

receptors in the GI tract are thought

to correspond to the D subtype of 5-HTreceptor originally described by Gaddum

and Picarelli


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5-HT2A

receptors mediate contractile

responses in a series of vascular smooth

muscle preparations

Platelet aggregation and increased

capillary permeability following exposure

to 5-HT have been attributed to 5-HT2A

receptor-mediated functions


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5-HT2B

receptors

originally were described in stomach fundus

5-HT2B

receptor are also seen in cerebellum,

hypothalamus and amygdala


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This sub-type has been implicated in -

Hyperphagia

Anxiolysis

Endothelium-dependent relaxation in

vein

Small intestine smooth muscle

contraction


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5HT2C

receptors

Due to lack of selective ligands, current

knowledge is limited

receptor has been implicated in feeding

behaviorand susceptibility to seizure


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The 5-HT3 receptor class: an

intrinsic ligand-gated channel

5-HT3 receptors are found on neurones, of

both central and peripheral origin(GI tract,

including vagal and splanchnic afferents),

area postrema


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trigger rapid depolarisation due to a transient

inward current, subsequent to the opening ofnonselective cation channels (Na+, Ca2+

influx, K+ efflux).


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5-HT4 Receptor

Widely distributed throughout the body

- CNS- GI tract 5-HT4 receptors are located on

neurons of the myenteric plexus and on

smooth muscle and secretory cells.


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Evoke secretion in the alimentary tract

facilitate theperistaltic reflex

Couple to Gs to activate adenylyl cyclase,

leading to a rise in intracellular levels of

cyclic AMP (cAMP) - asprokinetic

benzamides in gastrointestinal disorders


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5-ht5 receptors

No evidence has been obtained toconfirm that the recombinant 5-ht5

receptor is expressed in an endogenous

setting.

Two subtypes of the 5-ht5 receptor (5-

ht5A and 5-ht5B)


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5-ht6 Receptors

- highly expressed in limbic and extrapyramidal

brain areas

- Atypical anti-psychotics


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5-HT7 receptor

- extensive vascular distribution

- responsible for the prominent persistent

vasodilator response to 5-HT in

anaesthetised animals- also expressed in nonvascular smooth

muscle and the CNS.


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Atypical anti-psychotics, e.g. clozapine

have high affinity for the 5-HT7 receptor

Down-regulation occurs after chronic anti-

depressant use


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5-HT in Therapeutics

1. Migraine

2. Anti-emetic

3. Anxiolytic

4. Schizophrenia

5. Depression


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Migraine

1. Triptans 5-HT1 agonist

2. Ergot derivatives


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Triptans are indole derivatives, withsubstituents on the 3 and 5 positionsSumatriptan, Zolmitriptan, Naratriptan,

Rizatriptan

Sumatriptan is an example of planneddrug discovery


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interact potently with 5-HT1D and 5-HT1Breceptors and have a low or no affinity forother subtypes of 5-HT receptors.


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Two hypotheses have been proposed

explaining the causation of Migraine

1. Opening of AV anastomoses aroundthe carotid

2. Release of pro-inflammatory neuro-peptides from thr axonal terminals


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Triptans MOA can explain both these

hypotheses -

1. causing vasoconstriction

2. pre-synaptic auto-receptor preventing

release of neuropeptides


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PK parameters -1. oral absorption ranges from 14

70%2. peak plasma concentrations arereached in 1-3 hrs3. average half life in plasma is 1-2.5 hrs, maximum being forNaratriptan -6 hrs4. protein binding ranges from 14-

30%5. metabolism oxidativedeamination6. excretion urinary


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Adverse Effects -

Cardiac

Orally administered triptans can cause

paresthesias; asthenia and fatigue;

flushing; feelings of pressure, tightness, or

pain in the chest, neck, and jaw;

drowsiness; dizziness; nausea; andsweating

On inj mild pain, stinging, or burning


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Contraindications -

1)h/o vessel disease

2)patients with uncontrolled hypertension

3) Naratriptan c/i severe renal or hepatic

impairment

4) Sumatriptan, rizatriptan, and

zolmitriptan c/i with MAOI

treatment of acute attacks of Migraine


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treatment of acute attacks of Migraineand not intended for prophylactic use.

taken at the earliest possible

Parenteral administration if vomiting

Cumulative dose has to be within

defined limitsnot be used concurrently with Ergot

derivatives and MAOI


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Ergot and its derivatives

An age old drugIts abortifacienteffect has been knownfor ages.

Consumption of bread contaminatedwith the fungus leads to dramatic effects hallucinations, delusions,

posturing. St. Anthony's fire, Salemwitch trials


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Numerous semisynthetic derivatives of

the ergot alkaloids have been preparedby catalytic hydrogenation of the natural

alkaloids, e.g., dihydroergotamine.

Other products of this series include

lysergic acid diethylamide (LSD), a potent

hallucinogenic drug, and methysergide,

a serotonin antagonist.


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Adverse effects assoc. with Ergot use

1. Cardiac side effects

2. Prolonged vasospasm,gangrene

3.Abortifacient

4. Nausea & Vomiting

5. Leg cramps, numbness, localized

edema, itching


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5-HT-Receptor Antagonists


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Ketanserin

potently blocks 5-HT2A

, >5-HT2C

no significant effect on 5-HT3, 5-HT4,5-HT1-receptor family

high affinity for adrenergic receptors

and histamine H1 receptors


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lowers blood pressure causing a reductioncomparable adrenergic-receptor

antagonists or diuretics

Reduces the tone of both capacitance andresistance vessels

effect relates to blockade of 1 adrenergicreceptors, not its blockade of 5-HT

2A

receptors

inhibits 5-HT-induced platelet aggregation,but it does not greatly reduce the capacity ofother agents to cause aggregation.

Atypical Antipsychotic Drugs


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Atypical Antipsychotic Drugs

Clozapine

5-HT2A/2C

-receptor antagonist

reduced incidence of extrapyramidal side

effects

greater efficacy for reducing negative

symptoms of schizophrenia

Clozapine also has a high affinity for subtypes

of do amine rece tors.

Methysergide


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Methysergide

blocks 5-HT2A

, 5-HT2C

receptors

inhibits vasoconstrictor and pressor effects

of 5-HT, actions of 5-HT on various types ofextravascular smooth muscle

although methysergide is an ergot

derivative, it has onlyweak vasoconstrictor

and oxytocic activity


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used for the prophylactic treatment of migraine

and other vascular headaches

without benefit when given during an acute

migraine attack the protective effect takes 1 to 2

days to develop and disappears slowly whentreatment is terminated

might be due to the accumulation of an active

metabolite of methysergide, methylergometrine,

which is more potent than the parent drug


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Side effects of methysergide are usually

mild and transient

Common side effects include gastro-

intestinal disturbances

symptoms related to vasospasm-induced

ischemia (numbness and tingling of

extremities, pain in the extremities, and

low back and abdominal pain)


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CNS -psychosis, anxiety, insomnia

inflammatory fibrosis

fibrosis regresses after drug

withdrawal

if methysergide is used

chronically, treatment should beinterrupted for 3 weeks or more

every 6 months


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Cyproheptadine

structure resembles that of the phenothiazine

histamine H1-receptor antagonists it is an

effective H1-receptor antagonist

prominent 5-HT blocking activityon smooth

muscle by virtue of its binding to 5-HT2A

receptors.

weak anticholinergic activity and possesses

mild CNS depressantproperties


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effective in controlling skin allergies, pruritus.

to counteract the sexual side effects ofselective 5-HT-reuptake inhibitors such as

fluoxetine and sertraline

weight gain and increased growth in children

have been observed and attributed to

impaired regulation of growth-hormonesecretion


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References

1. Green R. Neuropharmacology of 5 HydroxyTryptamine. British Journal of Pharmacology (2006)147, S145S152

2. Hoyer et al. International Union of Pharmacology

Classification of Receptors for 5-Hydroxytryptamine. Pharmacological Reviews (1994)46(2).

3.Brunton et al. Goodman & Gilman's ThePharmacological Basis of Therapeutics, 11e

4. Katzung et al. Basic & Clinical Pharmacology, 11e


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5HT Pharmacology and Therapeutics