histamine, serotonin and ergot alkaloids
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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
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
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
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
Pharmacodynamics of Histamine
B. TISSUE AND ORGAN EFFECTS
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
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
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
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
Other actions of H1 receptor antagonist aside from blocking histamine
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
Other actions of H1 receptor antagonist aside from blocking histamine
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
Other actions of H1 receptor antagonist aside from blocking histamine
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 (hayfever)
Allergic rhinitis
urticaria Chronic urticaria
Bronchial asthma
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
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
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 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
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