Histamine, Serotonin and Ergot Alkaloids

Chapter 16

Histamine, Serotonin, &

the Ergot Alkaloids

Section IV: Drugs With Important

Actions On Smooth Muscle



Histamine



Serotonin



Autacoid Groups



_{Prostaglandins}



Endogenous peptides



Leukotrienes

HISTAMINE

Chemistry & Pharmacokinetics



2-(4-imidazolyl)ethylamine



Formed by decarboxylation of the

amino acid L-histidine



found in plant and animal tissue

and released from mast cells/

basophils as part of an allergic

reaction



Its bound form are biologically

inactive

Pharmacokinetics



_{Plays a role chemotaxis of white}

blood cells



Mast cells are especially numerous

at sites of potential injury such as

the nose, mouth, and feet, internal

body surfaces and blood vessels.



_{Non-mast cell histamine is found in}

several tissues, including the brain,

where it functions as a

neurotransmitter.



Histamine storage and release is the

enterochromaffin-like (ECL) cell of

the stomach.

Storage & Release of Histamines

A. IMMUNOLOGIC RELEASE



IgE attachment to receptor



Degranulation

Release of histamine, ATP, & other mediators

_{Type 1 allegic reactions: hayfever} & acute urticaria



Negative Feedback Control

Mechanism

Mediated by H2 receptor

Histamine mediate its own release Exhibited by mast cells and basophils

in skin of humans

limit the allergic reaction in the skin and blood

Storage & Release of Histamines

B. CHEMICAL AND MECHANICAL RELEASE



HISTAMINE DISPLACERS (BOUND TO UNBOUND FORM)

 _{morphines & tubocurine (Does not require energy to be released)}  Loss of granules from mast cells, since Na displaces amines

 _{Chemical & mast cells injuries}

Pharmacodyanamics

HISTAMINE RECEPTOR SUBTYPES

Receptor

Subtype Location Post receptor Mechanism Selective Agonist Partially Inverse Agonist

H1 SM, endothelium, _brain Gq, IP3, DAG Histaprofiden Mepyramine, triprolidine, cetirizine

H2 Gastric mucosa, cardiac muscle, mast

cells, brain Gs, cAMP Amthamine

Cimetidine, ranitidine, tiotidine H3 Presynaptic autoreceptors & herereceptors; brain, myenteric plexus

Gi, cAMp R-α-Methylhistamine, imetit,, immepip Thioperamide, iodoprenpropit, clobenpropit,, tiprolisant H4 Eosinophils, neutrophils, CD4 T

cells Gi, cAMP

Clobenpropit,

imetit, clozapine Thioperamide

Pharmacodynamics of Histamine

B. TISSUE AND ORGAN EFFECTS

1. Nervous system



Powerful stimulant of sensory nerve endings ( pain & itching)



Local high concentration depolarize efferent (axonal) nerve endings



H1 receptors: modulates respiratory neuron signaling (inspiration &

expiration)



H3 receptors: modulates release of several transmitters i.e.

acetylcholine, amine and peptide transmitters in the brain

Pharmacodynamics of Histamine

B. TISSUE AND ORGAN EFFECTS

2. Cardiovascular system

•_{Injection or infusion: decrease}

systolic & diastolic pressure-increase heart rate

•H1 receptor activation:

Vasodilator action of histamine •Mediated by release of

nitric oxide from the endothelium

•_{Stimulatory action to the heart} & reflex tachycardia

•H2 mediated cAMP

•Histamine induced edema

•_{Urticaria (hives) signals the}

release of histamine in the skin

•Direct cardiac effects

1. H1: decreased contractility 2. H2: increased contractility

Pharmacodynamics of Histamine

B. TISSUE AND ORGAN EFFECTS

3. Brionchiolar smooth muscles

 _{Asthma patients: hyper-reactive neural response}

 Response to histamine is blocked by autonomic blocking drugs (ganglion blocking agents; H1 receptor antagonist)

 _{Small doses of inhaled histamine: bronchial hyper-reactivity i.e. asthma} & cystic fibrosis

Pharmacodynamics of Histamine

B. TISSUE AND ORGAN EFFECTS

4. Gastrointestinal tract smooth muscles

 _{Contraction of smooth muscles in gut}  H1 receptor mediated

 _{Guinea pigs ileum: standard bioassay for this amine}

5. Other smooth muscle organs

 No effect on eye

 _{pregnant woman suffering from anaphylactic shock may end up} aborting

Pharmacodynamics of Histamine

B. TISSUE AND ORGAN EFFECTS

6. Secretory tissue

 _{Activation of H2 receptors on gastric parietal cells: increase cAMP &} Ca+2

 _{Powerful stimulant of gastric acid secretion}  _{Acetylcholine & gastrin do not increase cAMP}

Pharmacodynamics of Histamine

B. TISSUE AND ORGAN EFFECTS

8. Triple response

- Redspot, edema & flare response



Effects on 3 separate cell types

① _{Smooth muscle in the microcirculation} ② _{Capillary or the venular endothelium} ③ _{Sensory nerve endings}

Clinical Pharmacology of

Histamine

Clinical Uses

- Provocative test or bronchial hyper reactivity

Toxicity and Contraindications

- Flushing, hypotension, tachycardia, wheals,

bronchoconstriction, & gastrointestinal upset

- Should not be administered to patients w/ asthma, ulcer

disease, and gastrointestinal bleeding

Histamine Antagonist



_{Physiologic antagonist}



Injection of epinephrine can be life saving in systemic

anaphylaxis



Release inhibitors



Reduce the degranulation of mast cells that result from

immunologic triggering of antigen IgE



Cromolyn & nedocromyl



Receptor antagonist



H2 receptor antagonist

o _{burimamide: inhibit gastric stimulating activity of histamine} o Therapy for peptic disease



H3 & H4

Histamine Receptor Antagonists



Distinguished by relatively strong sedative

effects:

 1st _Generation

- More likely to block autonomic receptors - Stable amines

- Enter CNS rapidly

- Rapidly absorbed orally

 2nd _Generation

- Less sedating; less bioavailability in the CNS - Rapidly absorbed orally

- Metabolized by CYP3A4

- 4-6 hours duration of action after single dose - Meclizine &others: longer acting 12-24hrs - Less lipid soluble

- Substrates of P-glycoprotein transporter in the blood brain barrier

H1 Receptor Antagonist

Histamine Receptor Antagonists

- Both neutral H1 antagonist & inverse H1 agonist reduce/ block

the action of histamine by reversible competitive binding

- Have negligible potency to H2 receptor and little at H3

- Result from similarity to structure of drugs that effect

muscarinic cholinoreceptor, α-adrenoreceptor,, serotonin &

other local anesthetic receptor site

H1 Receptor Antagonist: PHARMACODYNAMICS

Histamine Receptor Antagonists

1. Sedation

- Resemble that of antimuscarinic drugs - “sleep aids”

- Ordinary dosage: children manifest excitation rather than sedation - Marked stimulation, agitation, convulsion at very high toxic levels

2. Antinausea and antiemetic actions

- Motion sickness

- doxylamine (in bendectin) as treatment in the past

3. Antiparkinsonism effect

- diphenhyramine

4. Anticholinoreceptor actions

- Fist generation agents i.e. ethonalamine & ethyldiamine - Reported benefits for nonallergic rhinorrhea

- Causes urinary retention and blurred vision

H1 Receptor Antagonist: PHARMACODYNAMICS

Histamine Receptor Antagonists

5. Adrenoceptor-blocking actions

- Phenothiazine subgroup i.e. promethazine - Cause orthostatic hypotension

6. Serotonin blocking action

- Observed in 1st generation H1 antagonist *cyproheptadine - Its structure resembles that of phenothiazine anhistamines - Potent H1 blocking agent

7. Local anesthesia

- Blocked Na channels in excitable membranes - Dipenhydramine & promethazine

- Alternative to those allergic to conventional anesthetics

H1 Receptor Antagonist: PHARMACODYNAMICS

Histamine Receptor Antagonists

1. Allergic reactions H1 ANTIHISTAMINES

2. Motion sickness & Vestibular disturbance

 Scopalamine, fist generation H1 antagonist: dipenhydramine, piperazines (cyclizine & meclizine)

 Synergism w/ ephedrine & amphetamine more effective  Menieres syndrome

3. Nausea and vomitting of pregnancy

 Piperazine derivatives (teratogenic effects), doxylamine (in Bectin) contains pyridoxine

H1 Receptor Antagonist: CLINICAL PHARMACOLOGY

CLINICAL USES

1st _{Generation 2nd generation}

Rhinitis (hay

fever) Allergic rhinitis

urticaria Chronic urticaria

Histamine Receptor Antagonists



Excitation and convulsions in children



Postural hypotension



Allergic responses



Lethal venticular arrhythmias

- Early administration of 2nd generation agents (tetrafenadine or aztemizole

H1 Receptor Antagonist: CLINICAL PHARMACOLOGY

Histamine Receptor Antagonists

H1 antihistaminic drugs in clinical use

FIRST- GENERATION ANTIHISTAMINES

ETHANOLAMINES Carbinoxamine (Clistin) Dimenhydrinate

Diphenhydramine

PIPERAZINE DERIVATIVES Hydroxyzine

Cyclizine Meclizine

ALKLAMINES Brompheniramine Chlorpheniramine PHENOTHIAZINE Promethazine

MISCELLANEOUSSECOND- GENERATION ANTIHISTAMINESCyproheptadine

PIPERIDINE Fexofenadine

MISCELLANEOUS Loratidine

Histamine Receptor Antagonists



Blocked gastric acid secretion with low toxicity



Has no H1 agonist or antagonist effect



Displays constitutive property; and are inverse agonists



Over the counter drugs

H2 Receptor Antagonists

H3 & H4 Receptor Antagonists

 No selective drugs are presently available

 H3 ligands: may be of value in sleep disorders, narcolepsy, obesity & cognitive & psychiatric disorders

 Tiprolisant

 H4 blockers: have potential in chronic inflammatory

Serotonin and Enteramine

Serotonin

- a vasoconstrictor (tonic) substance released from

blood clot into the serum

Enteramine

- smooth muscle stimulant in intestinal mucosa

Identification of serotonin and enteramine in 1951 led

to the synthesis of

5-hydroxytryptamine

.

Serotonin

 Local hormone in the gut  _{Platelet clothing process}

 Migraine headache and several conditions (eg. Carcinoid syndrome)  _{Found in:}

*enterochromaffin cells in GIT (mammals), *platelets in the blood

*raphe nuclei of the brainstem

Biosynthesis of Serotonin

and Melatonin

Rate-limiting step:

Hydroxylation at C5 by tryptophan hydrolase 1 This can be blocked by

p-chlorophenylalanine (PCPA; fenclonine) and by p-chloroamphetamine

Melatonin

Serotonin receptor subtypes

Receptor

subtypes Distribution selective Partially agonists

Partially selective antagonists

5-HT 1A Raphe nuclei,

hippocampus 8-OH-DPAT,repinotan WAY100635 5-HT 1B Substantia nigra, globus pallidus, basal ganglia Sumatrapin, L694247 5-HT 1D Brain Sumatrapin, elitriptan 5-HT 1E Cortex, putamen 5-HT 1F Cortex, hippocampus LY3344864 5-HT 1P Enteric nervous system 5-Hydroxyindal apine Renzapride 5-HT 2A Platelets, smooth muscle, cerebral cortex a- methyl-5-HT, DOI Kentaserin 5-HT 2B Stomach

fundus a- methyl-5-HT, DOI RS127445 5-HT 2C Choroid,

hippocampus a- methyl-5-HT, DOI, Lorcaserin Mesulergine 5-HT 3 Area postrema, sensory and enteric nerves 2-methyl-5-HT, m-chlorophenylbi guanide Granisetron, ondansetron 5-HT4 CNS and myenteric neurons, smooth muscle BIMU8, renzapride, metaclopramid e GR1138080 5-HT 5A,B Brain 5-HT 6,7 Brain Clozapine(%-HT7)

Tissue and Organ system

effects

Receptor subtype Effects

Repitonan (5-HT _{1A, agonist}) Antinociceptive action

5-HT ₃ Vomiting reflex, chemoreceptive

reflex

5-HT _1P and 5-HT₄ Enteric nervous system function

5-HT _2A Effect on bronchiolar smooth

muscle

5-HT ₂ Contraction of vascular smooth

Receptor subtype Effects

5-HT _1A and 5-HT ₇ Complex action

5-HT₄ Prokinetic effect

Serotonin syndrome

- condition associated with skeletal muscle contractions and

precipitated when MAO inhibitors are given with serotonin

agonist

5-HT _1A, 5-HT ₂, 5-HT₄ Normal cardiac development in

fetus 5-HT _{2B (agonist)}

Clinical Pharmacology of

Serotonin

 Buspirone (5-HT _1Aagonist) – effective nonbenzodiazepine anxiolytic

 Dexfenfluramine– selective 5HT agonist; appetite suppressant

 Triptans (e.g sumtripan) – used for migraine headache

 Valproic acid and topiramate- anticonvulsant

 Propranolol, amitriptyline – for prophylaxis of migraine

 Flunarizine– calcium channel blocker, prevent recurrences of migraine

 Verapamil – modest efficacy as prophylaxis against migraine

 Cisapride– 5-HT4 agonist, for gastroesophageal reflux and motility disorders

 Tegaserod– 5-HT4 partial agonist, for irritable bowel syndromewith constipation

Serotonin antagonist

 Phenoxybenzamine

has a long lasting blocking action at 5-HT2 receptors.

 Cyproheptadine

resembles the phenothiazine antihistaminic agents

 Ketanserin

blocks 5-HT2 receptors on smooth muscle and other tissue

 Ritanserin

5-HT2 antagonist has no or little alpha-blocking

 Ondasentron

Ergot Alkaloids



Produced by

Claviceps purpurea

, fungus that

infects grasses and grains



Epidemics of ergot poisoning 

ergotism



St. Anthony’s fire



ergot poisoning in medieval

times named after the saint whose help was sought

in relieving the burning pain of vasospastic

Chemistry and

Pharmacokinetics



2 major families of compounds that incorporate

nucleus



_{Amine alkaloids}



_{Peptide alkaloids}

Ergot alkaloids are absorbed from GIT

Amine alkaloids are absorbed in rectum and buccal

cavity by administration with aerosol inhaler

Organ System effects



Lysergic acid diethylamide (LSD)

is synthetic ergot

compounds; powerful hallucinogens.



_{Bromocriptine, cabergoline and pergolide}



have the highest selectivity for pituitary

dopamine receptors. Supresses prolactin secretion

from pituitary cells.

Clinical Pharmacology of

Ergot Alkaloids

Subclass Mechanism of action

Effects Clinical Applications Pharmacokine-tics, Toxicities, Interactions

Vasoselective:

Ergotamine agonist effects at 5-Mixed partial HT2 and alpha

adrenoceptors

Causes marked smooth muscle contraction but blocks

alpha agonist vasoconstriction

Migraine and cluster

headache Duration 12-24hOral parenteral-Toxicity- Prolonged

vasospasm causing angina, gangrene,

uterine spasm Uteroselective:

Ergonovine agonist effects at 5-Mixed partial HT2 and alpha

adrenoceptors

Same as ergotamine Some selectivity for uterine smooth muscle

Postpartum bleeding

Migraine headache (methylyergonovine)Oral, parenteral Duration 2-4 h Toxicity- same as ergotamine CNS selective: Lysergic acid diethylamide Central nervous system (CNS) 5-HT2 and dopamine agonist 5-HT2 agonist in periphery Hallucinations

Psychotomimetic None widely abused Duration several hOral Toxicity- Prolonged

psychotic state, flashbacks