HISTAMINE AND ANTI

HISTAMINE
Dr. Huda
CIMS MULTAN
HISTAMINE
 Biogenic amine present in many animal and
plant tissues (hence the name Histos:
tissue)
 Also present in venoms and stinging
secretions
FUNCTIONS
 Autacoid: endogenous subs with complex
physiologic and pathophysiologic
functions that have potent nonautonomic
pharmacologic efects when administered as
drugs
 Include histamine, serotonin,
prostaglandins, vip
 Neurotransmitter

 Stimulate gastric secretion

SYNTHESIS
 By decarboxylation of aminoacid Histidine
and stored in vesicles in mast cells, EC
cells, neurons and few other cell types
METABOLISM
 By enzymes Monoamine oxidase, Diamine
oxidase

 Excess production measured by conc. Of

Imidazole acetic acid in urine.
DISTRIBUTION
 Widely distributed skin, GIT mucosa,
lungs,brain, CSF and bone marrow
 Mast cells are predominated site of
histamine storage
RECEPTORS
 4 histamine receptors
 Histamine receptors are GPCR

 H1 mediate effects on smooth muscles leading

to vasodilation, increased vascular
permeability and contraction of nonvascular
S/M, bronchoconstriction, pain and itching in
skin, local edema due to endothelial cell
retraction
 H2 mediate histamine stimulation of gastric
acid secretion and maybe involved in cardiac
stimulation
 feedback inhibtion of histamine release from
mast cells due to inc. intracellular cAMP
 H4 Receptors located on leukocytes and
mast cells, involved in chemotactic
responses
MOA
ANAPHYLAXIS
 Type I allergic response(immediate
hypersensitivity reaction)
 Mediated by IgE antibodies

 IgE binds to receptors on mast cells

and basophils
 Fab portion of antibody binds antigen
and causes (moderate to massive)
release of:
histamine
leukotrienes
prostaglandins
etc., etc.
 COMMON CAUSES OF ANAPHYLACTIC AND
ANAPHYLACTOID REACTIONS
  Non-IgE-mediated
IgE-mediated
Anaphylactoid
Anaphylaxis

  NMJ blockers, opioids,

Peanuts, seafood, plasma expanders
eggs, milk, grains  Aminoglycosides
 Venoms  Protamine
 Radiocontrast media
 Foreign proteins
 Urticaria of cold,
 Some exercise-induced
heat, sun
bronchospasm  Some exercised-induced
bronchospasm
 ANAPHYLAXIS: EFFECTS AND TREATMENT
(MAY INVOLVE RELEASE OF MEDIATORS IN ADDITION TO HISTAMINE)

 Decreased blood pressure

 Decreased cardiac output
 Bronchoconstriction and increased pulmonary
secretions
 Pruritis

 Treatment:Epinephrine - not initially

antihistamines
(epinephrine is a physiological antagonist of
histamine, not a pharmacological antagonist)

(alpha-1 vasoconstriction, beta-1 increased HR,

beta-2 bronchodilation)
EFFECTS OF HISTAMINE
 CVS
 Triple response of Wilis on terminal
vasculature (itching and pain)
Intradermal histamine injection causes:
 Red spot (few mm) in seconds: direct
vasodilation effect , H1 receptor
mediated
 Flare (1cm beyond site): axonal reflexes,
indirect vasodilation, and itching, H1
receptor mediated
 Wheal (1-2 min) same area as original
spot, edema due to increased capillary
permeability, H1 receptor mediated
 IV histamine: fall in bp, cutaneous
flushing over face and upper trunk, rise
in body temp, intense headache

CLINICAL USE
 No clinical use

 Diagnostic agent
 THREE MECHANISTICALLY DIFFERENT
APPROACHES TO MINIMIZE HISTAMINE REACTIONS
 Physiological antagonism (e.g.,
epinephrine)

 Inhibitthe release of histamine

(e.g., cromolyn, nedocromil)

 Pharmacologicalantagonism
(antihistamines)_ H1 & H2 Receptor
antagonists
H1 RECEPTOR ANTAGONIST
 CLASSIFICATION
 First generation

 Competitive pharmacological antagonist at H1

receptors
 Neutral at phy. Ph

 Lipid solube

 Cross bbb

 Block action of histaminergic neurons in CNS

 Sedative

 Autonomic receptor blocking effect(anti

cholingeric side efects) also block serotonin
receptors
 Anti motion sickness efects
SECOND GENERATION
 Ionized at phy Ph
 Donot cross bbb

 Less sedative

 Don’t impair psychomotor performance

 Less sedative/ hypnotic

FIRST GENERATION
AGENTS
Uses:
 Adjunctive in anaphylaxis and other cases where
histamine release can occur (H2 antagonist, and
epinephrine must also be used in anaphylaxis)

 Antiallergy (allergic rhinitis, allergic

dermatoses, contact dermatitis, uriticaria. )

 Sedative/sleep aid

 To prevent motion sickness (meclizine, cyclizine)

FIRST GENERATION
AGENTS
Uses (cont’d)
 Antiemetic: prophylactic for motion sickness
(promethazine)
 Antivertigo (meclizine)
 Local anesthetic: (diphenhydramine)
 Antitussive (diphenhydramine)
 Management of chemotherapy induced vomiting
(diphenhydramine)
ADVERSE EFFECTS
 1ST GEN
SEDATION, DROWSINESS
headache, nausea & vomiting
cough
constipation, diarrhea
dry mouth, blurred vision
urinaRYretention
2ND GEN
 Less adverse effects

 Torsade de points by prolonging QT

interval
TOXICITY
 Sedation
 Fever

 Excitement

 Dry mouth

 Blurred vision

 Pupillary dilatation

 Hallucinations

 Convulsions

 Orthostatic hypotension
INTERACTION
 Between anti histamine and other drugs
with sedative properties e.g
brnzodiazepines, alcohol

 Drugs that inhibit hepatic metabolism

cause high levels of anti histamines
e,.g azole anti fungal and CYP3A4
inhibitors interfere with met. Of 2nd gen,
drugs and precipitate arrhythmias
H2 RECEPETOR ANTAGONIST
 Prototype: cimetidine
 Other include:

 Ranitidine, famotidine, nizatidine

 Orally active

 Realtively nontoxic

 Half life 1-3 hrs

 DOA of single dose 12-24hrs

MECHANISM AND EFFECTS

 Selective Pharmacological blockade of H2
receptors
 Dec gastric acid secretion
CLINICAL USE
 Peptic ulcer, duodenal ulcer: reduce
nocturnal acid secretion, accelerate
healing and prevent recurrance
 Acute ulcer 2 or more doses per day

 Prophylaxis; single bedtime dose

 I/V in preventing gastric erosin and

hemorrhage in streesed pts in ICU
 Zollinger Ellison syndrome

 GERD