Histamine, Serotonin and Ergot Alkaloids

Chapter 16Histamine, 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 theamino acid L-histidine

found in plant and animal tissueand released from mast cells/basophils as part of an allergicreaction

Its bound form are biologicallyinactive

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 basophilsin skin of humans

limit the allergic reaction in the skin and blood


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

Compound 48/80 (exocytotic degranulation/ requires energy & Ca+2)

Pharmacodyanamics

HISTAMINE RECEPTOR SUBTYPES

ReceptorSubtype

LocationPost receptor Mechanism

PartiallySelective Agonist

Inverse Agonist

H1SM, endothelium, brain

Gq, IP3, DAG HistaprofidenMepyramine, triprolidine, cetirizine

H2Gastric mucosa, cardiac muscle, mast cells, brain

Gs, cAMP AmthamineCimetidine, ranitidine, tiotidine

H3

Presynapticautoreceptors & herereceptors; brain, myenteric plexus

Gi, cAMpR-α-Methylhistamine,imetit,, immepip

Thioperamide, iodoprenpropit,clobenpropit,, tiprolisant

H4Eosinophils,neutrophils, CD4 T cells

Gi, cAMPClobenpropit,imetit, clozapine

Thioperamide

A. MECHANISM OF ACTION

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



2. Cardiovascular system

•Injection or infusion: decreasesystolic & diastolic pressure-increase heart rate

•H1 receptor activation:Vasodilator action of histamine

•Mediated by release ofnitric oxide from theendothelium

•Stimulatory action to the heart& reflex tachycardia

•H2 mediated cAMP•Histamine induced edema

•Urticaria (hives) signals therelease of histamine in the skin

•Direct cardiac effects1. H1: decreased contractility2. H2: increased contractility

and pacemaker rate



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

metacholine provocation



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



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

7. Metabolic 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 & H4o Not yet available for clinical use

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

Figure. General structure of H1 antagonist drug


- 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

Other actions of H1 receptor antagonist aside from blocking histamine


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




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




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 (hayfever)

Allergic rhinitis

urticaria Chronic urticaria

Bronchial asthma


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

CLINICAL USES: TOXICITY

Histamine Receptor AntagonistsH1 antihistaminic drugs in clinical use

FIRST- GENERATION ANTIHISTAMINES

ETHANOLAMINES Carbinoxamine (Clistin)DimenhydrinateDiphenhydramine

PIPERAZINE DERIVATIVES HydroxyzineCyclizineMeclizine

ALKLAMINES BrompheniramineChlorpheniramine

PHENOTHIAZINE Promethazine

MISCELLANEOUS CyproheptadineSECOND- GENERATION ANTIHISTAMINES

PIPERIDINE Fexofenadine

MISCELLANEOUS LoratidineCetirizine


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 conditions: asthma; pruritus, allergic rhinitis, & pain conditions

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

Neurotransmitter

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

Stored serotonins are depleted by reserpine

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- a melanocyte-stimulating

hormone

Serotonin receptor subtypes

Receptorsubtypes

Distribution Partiallyselective agonists

Partially selective

antagonists

5-HT 1A Raphe nuclei, hippocampus

8-OH-DPAT,repinotan

WAY100635

5-HT 1B Substantianigra, globuspallidus, 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 nervoussystem

5-Hydroxyindalapine

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-chlorophenylbiguanide

Granisetron, ondansetron

5-HT 4 CNS and myentericneurons,smooth muscle

BIMU8,renzapride, metaclopramide

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, chemoreceptivereflex

5-HT 1P and 5-HT 4 Enteric nervous system function

5-HT 2A Effect on bronchiolar smooth muscle

5-HT 2 Contraction of vascular smooth muscle

Receptor subtype Effects

5-HT 1A and 5-HT 7 Complex action

5-HT 4 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-HT 4 Normal cardiac development in fetus

5-HT 2B (agonist)

5-HT 2B (antagonist)

Associated with valvulopathyPrevent pulmonary hypertension

Clinical Pharmacology of Serotonin

Buspirone (5-HT 1A agonist) – 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

Fluoxentine – modulate serotogenic transmission

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

prototypical 5-HT3 antagonist

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 vasospasticischema.

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 buccalcavity by administration with aerosol inhaler

Primary metabolites- A ring, and peptide alkaloids

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

Mixed partial agonist effects at 5-

HT2 and alpha adrenoceptors

Causes marked smooth muscle

contraction but blocks alpha agonist

vasoconstriction

Migraine and cluster headache

Oral parenteral-Duration 12-24h

Toxicity- Prolonged vasospasm causing angina, gangrene,

uterine spasm

Uteroselective:Ergonovine

Mixed partial agonist effects at 5-

HT2 and alpha adrenoceptors

Same as ergotamineSome selectivity for

uterine smooth muscle

Postpartum bleedingMigraine headache

Oral, parenteral (methylyergonovine)

Duration 2-4 hToxicity- same as

ergotamine

CNS selective:Lysergic acid diethylamide

Central nervous system (CNS) 5-

HT2 and dopamine agonist5-HT2 agonist in

periphery

HallucinationsPsychotomimetic

None widely abused OralDuration several h

Toxicity- Prolonged psychotic state,

flashbacks

Documents

Histamine, Serotonin and Ergot Alkaloids