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

Storage & Release of Histamines

A. IMMUNOLOGIC RELEASE IgE attachment to receptor Degranulation
Release of histamine, ATP, & other mediators

Negative Feedback Control Mechanism

Mediated by H2 receptor Histamine mediate its own release Exhibited by mast cells and basophils in skin of humans

Type 1 allegic reactions: hayfever & acute urticaria

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

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

Pharmacodyanamics
A. MECHANISM OF ACTION
HISTAMINE RECEPTOR SUBTYPES
Receptor Subtype
H1

Location

Post receptor Mechanism

Gq, IP3, DAG

Partially Selective Agonist

Histaprofiden

Inverse Agonist
Mepyramine, triprolidine, cetirizine Cimetidine, ranitidine, tiotidine Thioperamide, iodoprenpropit, clobenpropit,, tiprolisant Thioperamide

SM, endothelium, brain

H2

Gastric mucosa, cardiac muscle, mast cells, brain

Presynaptic autoreceptors & herereceptors; brain, myenteric plexus Eosinophils, neutrophils, CD4 T cells

Gs,

cAMP

Amthamine

H3

Gi,

cAMp

R-Methylhistamine, imetit,, immepip Clobenpropit, imetit, clozapine

H4

Gi,

cAMP

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 pressureincrease 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 and pacemaker rate

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 metacholine provocation

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

7.

Metabolic Effects

Pharmacodynamics of Histamine
B. TISSUE AND ORGAN EFFECTS 8. Triple response
- Redspot, edema & flare response Effects on 3 separate cell types
Smooth muscle in the microcirculation

Capillary or the venular endothelium

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
o Not yet available for clinical use

Histamine Receptor Antagonists

H1 Receptor Antagonist
Distinguished by relatively strong sedative effects:
1st Generation
More likely to block autonomic receptors Stable amines Enter CNS rapidly Rapidly absorbed orally 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
Figure. General structure of H1 antagonist drug

2nd Generation

Histamine Receptor Antagonists

H1 Receptor Antagonist: PHARMACODYNAMICS
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

Other actions of H1 receptor antagonist aside from blocking histamine

Result from similarity to structure of drugs that effect muscarinic cholinoreceptor, -adrenoreceptor,, serotonin & other local anesthetic receptor site

Histamine Receptor Antagonists

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 Motion sickness doxylamine (in bendectin) as treatment in the past

2.
-

Antinausea and antiemetic actions

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

Histamine Receptor Antagonists

H1 Receptor Antagonist: PHARMACODYNAMICS
Other actions of H1 receptor antagonist aside from blocking histamine

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

Histamine Receptor Antagonists

H1 Receptor Antagonist: CLINICAL PHARMACOLOGY
CLINICAL USES

1. Allergic reactions H1 ANTIHISTAMINES

1st Generation Rhinitis (hay fever) urticaria Bronchial asthma 2nd generation Allergic rhinitis Chronic urticaria

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

Histamine Receptor Antagonists

H1 Receptor Antagonist: CLINICAL PHARMACOLOGY
CLINICAL USES: TOXICITY

Excitation and convulsions in children Postural hypotension Allergic responses Lethal venticular arrhythmias
- Early administration of 2nd generation agents (tetrafenadine or aztemizole

Histamine Receptor Antagonists

H1 antihistaminic drugs in clinical use
FIRST- GENERATION ANTIHISTAMINES
ETHANOLAMINES Carbinoxamine (Clistin) Dimenhydrinate Diphenhydramine Hydroxyzine Cyclizine Meclizine Brompheniramine Chlorpheniramine Promethazine

PIPERAZINE DERIVATIVES

ALKLAMINES PHENOTHIAZINE

MISCELLANEOUS SECOND- GENERATION ANTIHISTAMINES Cyproheptadine

PIPERIDINE MISCELLANEOUS

Fexofenadine Loratidine Cetirizine

Histamine Receptor Antagonists

H2 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

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 pchlorophenylalanine (PCPA; fenclonine) and by pchloroamphetamine

Melatonin
- a melanocyte-stimulating hormone

Serotonin receptor subtypes

Receptor subtypes
5-HT 1A 5-HT 1B

Distribution

Partially selective agonists

8-OH-DPAT, repinotan Sumatrapin, L694247

Partially selective antagonists

WAY100635

5-HT 2A

Platelets, smooth muscle, cerebral cortex Stomach fundus Choroid, hippocampus Area postrema, sensory and enteric nerves CNS and myenteric neurons, smooth muscle Brain Brain

a- methyl-5HT, DOI a- methyl-5-HT, DOI a- methyl-5-HT, DOI, Lorcaserin 2-methyl-5-HT, mchlorophenylbi guanide BIMU8, renzapride, metaclopramid e

Kentaserin

Raphe nuclei, hippocampus Substantia nigra, globus pallidus, basal ganglia Brain

5-HT 2B 5-HT 2C 5-HT 3

RS127445 Mesulergine Granisetron, ondansetron

5-HT 1D

Sumatrapin, elitriptan 5-HT 4 LY3344864 5Hydroxyindal apine Renzapride 5-HT 5A,B 5-HT 6,7

5-HT 1E
5-HT 1F 5-HT 1P

Cortex, putamen
Cortex, hippocampus Enteric nervous system

GR1138080

Clozapine(%HT7)

Tissue and Organ system effects

Receptor subtype Repitonan (5-HT 1A, agonist) 5-HT 3 5-HT 1P and 5-HT 4 5-HT 2A 5-HT 2 Effects Antinociceptive action Vomiting reflex, chemoreceptive reflex Enteric nervous system function Effect on bronchiolar smooth muscle Contraction of vascular smooth muscle

Receptor subtype 5-HT 1A and 5-HT 7 5-HT 4 5-HT 1A, 5-HT 2, 5-HT 4 5-HT 2B (agonist) 5-HT 2B (antagonist)

Effects Complex action Prokinetic effect Normal cardiac development in fetus Associated with valvulopathy Prevent pulmonary hypertension

Serotonin syndrome - condition associated with skeletal muscle contractions and precipitated when MAO inhibitors are given with serotonin agonist

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. Anthonys fire ergot poisoning in medieval times named after the saint whose help was sought in relieving the burning pain of vasospastic ischema.

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 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 5HT2 and alpha adrenoceptors

Causes marked smooth muscle contraction but blocks alpha agonist vasoconstriction Same as ergotamine Some selectivity for uterine smooth muscle

Migraine and cluster headache

Oral parenteralDuration 12-24h Toxicity- Prolonged vasospasm causing angina, gangrene, uterine spasm Oral, parenteral (methylyergonovine) Duration 2-4 h Toxicity- same as ergotamine Oral Duration several h Toxicity- Prolonged psychotic state, flashbacks

Uteroselective: Ergonovine

Mixed partial agonist effects at 5HT2 and alpha adrenoceptors

Postpartum bleeding Migraine headache

CNS selective: Lysergic acid diethylamide

Central nervous system (CNS) 5HT2 and dopamine agonist 5-HT2 agonist in periphery

Hallucinations Psychotomimetic

None widely abused