Download Histamine and Serotonin

Histamine and Serotonin
By
S.Bohlooli, PhD
Ardabil University of Medical Sciences
Basic pharmacology of
histamine
Chemistry
Pharmacokinetics
Pharmacodynamics
Ardabil University of Medical Sciences
Distribution
Histamine is widely, if unevenly,
distributed throughout the animal
kingdom and is present in many
venoms, bacteria, and plants.
Ardabil University of Medical Sciences
Chemistry and pharmacokinetics
Ardabil University of Medical Sciences
Metabolism
Ardabil University of Medical Sciences
Storage and release

Immunologic release



histamine plays a central role in immediate
hypersensitivity and allergic responses
The release of histamine only partially
explains the biological effects that ensue
from immediate hypersensitivity reactions
Chemical and mechanical release

Tubocurarine, succinylcholine, morphine
Ardabil University of Medical Sciences
Pharmacodynamics


Mechanism of action
Tissue and organ system effect









Nervous system
Cardiovascular system
Bronchial smooth muscle
Gastrointestinal tract smooth muscle
Other smooth muscle organs
Secretary tissue
Metabolic effects
The triple response
Other effects possibly mediated by histamine
Ardabil University of Medical Sciences
Receptor
Subtype
Distribution
Postreceptor
Mechanism
Partially Selective
Agonists
H1
Smooth muscle, endothelium,
brain
Gq, IP3, DAG
Histaprodifen
H2
Gastric mucosa, cardiac muscle,
mast cells, brain
Gs, cAMP
Amthamine
Cimetidine,1 ran
itidine,1
tiotidine
H3
Presynaptic: brain, myenteric
plexus, other neurons
Gi, cAMP
R--Methylhistamine,
Thioperamide,
iodophenpropit,
clobenpropit,1
tiprolisant1
H4
Eosinophils, neutrophils, CD4 T
cells
Gi, cAMP
Clobenpropit, imetit,
clozapine
Thioperamide
imetit, immepip
Ardabil University of Medical Sciences
Partially
Selective
Antagonists
Mepyramine,
triprolidine,
cetirizine
Nervous system






regulation of drinking
body temperature
secretion of antidiuretic hormone
control of blood pressure
perception of pain
wakefulness
Ardabil University of Medical Sciences
Cardiovascular System





Vasodilation
Increased "Capillary" Permeability
Triple Response of Lewis
Heart
Histamine Shock
Ardabil University of Medical Sciences
Extravascular Smooth Muscle


Contraction is due to activation of H1
receptors
relaxation (for the most part) is due to
activation of H2 receptors
Ardabil University of Medical Sciences
Exocrine Glands

regulator of gastric acid secretion
Ardabil University of Medical Sciences
Peripheral Nerve Endings


Pain
Itch
Ardabil University of Medical Sciences
Clinical pharmacology of
histamine

Clinical use




a diagnostic agent
to assess nonspecific bronchial hyperreactivity in
asthmatics
as a positive control injection during allergy skin
testing
Toxicity and contraindications

Flushing, hypotension,tachycardia, headache
wheals, brochoconstriction, gastrointestinal upset
Ardabil University of Medical Sciences
Histamine antagonists


H1 receptor antagonists
H2 receptor antagonists
Ardabil University of Medical Sciences
Basic Pharmacology of H1
Receptor Antagonists
Chemistry
Pharmacokinetics
Pharmacodynamics

Ardabil University of Medical Sciences
Chemistry

Structure-activity
Relationship


reversible
competitive inhibitors
contain a substituted
ethylamine moiety
Ardabil University of Medical Sciences
Ardabil University of Medical Sciences
Pharmacokinetics


Absorption, distribution
Metabolism:

Astemizole and Terfenadine
Ardabil University of Medical Sciences
Pharmacological Properties





Smooth Muscle
Capillary Permeability
Flare and Itch
Immediate Hypersensitivity Reactions
Central Nervous System

Can both stimulate and depress the CNS
Ardabil University of Medical Sciences
Pharmacodynamics


Histamine receptor blockade
Other actions







Sedation
Antinausea and antiemetic actions
Antiparkinsonism effects
Antichlinoceptor effect: Promethazine
Adrenoceptor blocking action
Serotonin blocking action
Local anesthesia: Promethazine
Ardabil University of Medical Sciences
Clinical pharmacology of H1
receptor antagonists

Clinical use




Allergic reaction
Motion sickness and vestibular disturbance
Nausea and vomiting of pregnancy?
Toxicity




Sedation, antimuscarninc action,
Drug allergy
Drug interaction
Teratogenic effects
Ardabil University of Medical Sciences
Table 24-2. Preparations and Dosage of Representative H1-Receptor Antagonists*
CLASS AND
NONPROPRIETARY
NAME
TRADE NAME
DURATI
ON OF
ACTION,
HOURS
PREPARATI
ONSa
SINGLE DOSE
(ADULT)
SINEQUAN
6-24
O, L, T
10-150 mg
Carbinoxamine maleate
RONDEC,d
others
3-6
O, L
4-8 mg
Clemastine fumarate
TAVIST, others
12
O, L
1.34-2.68 mg
Diphenhydramine HCl
BENADRYL;
others
12
O, L, I, T
25-50 mg
Dimenhydrinate
DRAMAMINE;
others
4-6
O, L, I
50-100 mg
Pyrilamine maleate
POLYHISTINE-D d
4-6
O, L, T
25-50 mg
Tripelennamine HCl
PBZ
4-6
O
25-50 mg, 100
mg (sustained
release)
First-Generation Agents
Tricyclic Dibenzoxepins
Doxepin hydrochloride
Ethanolamines
Ethylenediamines
Ardabil University of Medical Sciences
Piperazines
Hydroxyzine HCl
ATARAX;
others
6-24
O, L, I
25-100 mg
Hydroxyzine pamoate
VISTARIL
6-24
O, L
25-100 mg
Cyclizine HCl
MAREZINE
4-6
O
50 mg
Cyclizine lactate
MAREZINE
4-6
I
50 mg
Meclizine HCl
ANTIVERT;
others
12-24
O
12.5-50 mg
PHENERGAN;
others
4-6
O, L, I, S
12.5-50 mg
Cyproheptadine HClc
PERIACTIN
4-6
O, L
4 mg
Phenindamine tartrate
NOLAHIST
4-6
O
25 mg
SEMPREX-Dd
6-8
O
8 mg
ZYRTEC
12-24
O
5-10 mg
Phenothiazines
Promethazine HCl
Piperidines
Second-Generation Agents
Alkylamines
Acrivastineb
Piperazines
Cetirizine hydrochlorideb
Phthalazinones
Azelastine hydrochlorideb
ASTELIN
Ardabil University of Medical Sciences
12-24
T
2 sprays per
Piperidines
Levocabastine hydrochloride
LIVOSTIN
6-12
T
One drop
Loratadine
CLARITIN
24
O, L
10 mg
Desloratadine
CLARINEX,
AERIUS
24
O
5 mg
Ebastine
EBASTEL
24
O
10-20 mg
Mizolastine
MIZOLLEN
24
O
10 mg
Fexofenadine
ALLEGRA,
TELFAST
12-24
O
60 mg
HCl, hydrochloride.
*For a discussion of phenothiazines, see Chapter 18.
aPreparations are designated as follows: O, oral solids; L, oral liquids; I, Injection; S, suppository; T,
topical. Many H1-receptor antagonists also are available in preparations that contain multiple drugs.
bHas mild sedating effects.
cAlso has antiserotonin properties.
dTrade name drug also contains other medications.
Ardabil University of Medical Sciences
Application:Common Cold?

Despite persistent popular belief, H1
antagonists are without value in
combating the common cold.
Ardabil University of Medical Sciences
Basic pharmacology of
serotonin
Chemistry
Pharmacokinetics
Pharmacodynamics

Ardabil University of Medical Sciences
Chemistry &
pharmacokinetics
Ardabil University of Medical Sciences
Ardabil University of Medical Sciences
Pharmacodynamics

Mechanism of action

Tissue and organ
system effect





Nervous system
Airways
Cardiovascular
system
Gastrointestinal tract
Skeletal muscle
Ardabil University of Medical Sciences
Ardabil University of Medical Sciences
Ardabil University of Medical Sciences
Clinical pharmacology of
Serotonin


Serotonin agonists
Serotonin antagonists
Ardabil University of Medical Sciences
Table 11-4. Serotonergic Drugs: Primary Actions and Clinical Uses
RECEPTOR
ACTION
DRUG
EXAMPLES
CLINICAL DISORDER
5-HT1A
Partial
agonist
Buspirone,
ipsaperone
Anxiety, depression
5-HT1D
Agonist
Sumatriptan
Migraine
5-HT2A/2C
Antagonist
Methysergide,
trazodone,
risperidone,
ketanserin
Migraine, depression,
schizophrenia
5-HT3
Antagonist
Ondansetron
Chemotherapy-induced emesis
5-HT4
Agonist
Cisapride
Gastrointestinal disorders
5-HT
transporter
Inhibitor
Fluoxetine,
sertraline
Depression, obsessive-compulsive
disorder, panic disorder, social
phobia, posttraumatic stress
disorder
Ardabil University of Medical Sciences
Serotonin antagonists




Phenoxybenzamine (5HT2)
Cyproheptadine (5HT2)
Ketanserin (5HT1C)
Odansetrone (5HT3)
Ardabil University of Medical Sciences
Appetite control through
serotonin?


Sertonin related to sleep, emotion, sex, and
appetite
Could reduce food intake

Fenfluramine, dexfenfluramine


Cause serotonin release and inhibition of food uptake
Toxicity:


fatal and nonfatal pulmonary hypertension
Valvular lesions
Ardabil University of Medical Sciences