anti-histaminics

1. DR ZIKRULLAH

2.  INTRODUCTION
 Histamine is a low –molecular weight naturally
occurring hydrophilic endogenous amine that
produces a variety of physiolgic and pathologic
responses in different tissues and cells through G-
protien coupled membrane receptors.
 It is an important chemical mediator of inflammation
in allergic disease.

3.  Mast cells located in the skin,lungs,and G.I tract as
well as circulating basophils contains large amounts of
histamine.
 Histamine does not easily cross the blood brain barrier
and CNS effects are usually not evident.

4.  SYNTHESIS
 Synthesis of Histamine in tissues is by decarboxylation
of histidine.Histamine is stored in vesicles in a
complex with Heparin,
 Stored histamine is subsequently released in response
to An-Ab reaction or in response to certain drugs.

5.  METABOLISM
 There are two pathways of metbolism in humans.The
most important pathway involves methylation
catalyzed by histamine-N-methytransferase,which is
further degraded by monoamine oxidase.
 The other pathway involves oxidative deamination
catalyzed by histaminase.

6.  RECEPTORS
 There are three subtypes of Histamine receptors
 H1 Receptors are found in conductive tissue of the AV
node and slow heart rate by decreasing AV nodal
conduction.
 Histamine induces vascular endothelium to release
NO causing vasodilatation.

7.  Acting through H1 and H2 receptors it causes increase
capillary permeability,hypotension,tachycardia,
headache and flushing.
 Cardiac H1 receptors mediate coronary
vasoconstriction.

8.  H2 receptors are widely distributed through the
myocardium and nodal tissue , where they exert
positive inotropic and chronotropic effects as well as
vasodilatation of coronary vessels.
 Activation of H2 receptors by histamine results in
stimulation of gastric hydrogen ion secretion.

9.  H3 receptors are found in the heart are localized to
presynaptic postganglionic sympathethic nervous
fibers where they act as autoinhibitory to presynaptic
norepinephrine release.
 H3 receptors when stimulated causes the inhibition of
the synthesis and release of histamine.

10. MOA of Histamine on H1 RECEPTOR
Histamine binds with H1 Receptor
PIP2 Hydrolysis
Activation of IP3/DAG Pathway
Realease of Ca from intracellular stores
Activation of Protein kinase C

11. MOA of Histamine on H2 Receptor
Histamine binds with H2 Receptor
Activation of Adenylyl Cyclase
Increase Camp
Phosphorylation of specific protein

12. MOA of Histamine on H3 Receptor
Histamine binds with H3 Receptor
Restrict Ca ion influx
K channel activation
Decrease cAMP

13.  EFFECTS ON ORGAN SYSTEM
 CVS
 It reduces arterial blood pressure but increases HR and
myocardial contractility.H1 receptor stimulation
increases capillary permeability and enhance
ventricular irritability,whereas H2 receptor stimulation
increases HR and contractility.
 Both receptors mediate peripheral arteriolar dilatation
and some coronary vasodilatation.

14.  RESPIRATORY
 H1 receptors causes bronchial smooth muscle
constriction whereas H2 receptors causes
bronchodilatation.
 H1 receptors causes pulmonary vasodilatation whereas
H2 receptors causes vasoconstriction.

15.  GASTROINTESTINAL
 Activation of H2 receptors in parietal cells increases
gastric acid secretion.
 Stimulation of H1 receptors leads to contraction of
intestinal smooth muscles.

16.  DERMAL
 The classic wheal and flare response of the skin to
histamine results from increased capillary
permeability and vasodilatation and is primarily via H1
receptor activation

17.  IMMUNOLOGICAL
 Histamine is a major mediator of Type 1
hypersensitivity reaction.
 H1 receptor stimulation attracts leucocytes and induce
synthesis of PG
 H2 receptor activates suppressor T lymphocytes

18.  CLASSIFICATION OF H RECEPTOR ANTAGONIST
 H1 ANTAGONIST ( FIRST GENERATION)
Diphenhydramine
Pyrilamine
Chlorpheniramine
Promethazine
Hydroxyzine
Dimenhydrinate

19.  H1 ANTAGONIST (SECOND GENERATION)
 Fexofenadine
 Loratidine
 Levocabastine
 Cetirizine
 Levocetirizine
 Azelastine
 Mizolastine
 Desloratidine
 Ebastine

20.  H2 ANTAGONISTS
Cimetidine
Ranitidine
Famotidine
Nizatidine

21.  H3 Antagonist
a. Thioperamide
b. Impromidine
c. Clobenpropit

22. MOA of H1 Antagonist
Binds competitively with H1 Receptor
Blocks PIP2 Hydrolysis
Prevents activation of IP3/DAG pathway
Prevents Ca release & Protein kinase C activation

23. MOA of H2 Antagonist
Binds competitively with H2 Receptors
Prevents Adenylyl Cyclase activation
Decrease cAMP level
Prevents Phosphorylation of proteins

24. Pharmacokinetics of H1 Antagonist
 Well absorbed from oral as well as parenteral route.
 Metabolized in the liver.
 Excreted in the urine.
 Widely distributed in the body & enter the brain.
 Newer compounds penetrate the brain poorly.
 Duration of action of most agents are 4-6 hours.
 Newer agents like cetirizine,loratidine etc have
prolonged duration of action.(12-24 hours)

25.  ANTIHISTAMINES OF IMPORTANCE IN
ANAESTHETHIC PRACTICE
 PROMETHAZINE(phenergan)
 To treat anaphylactic reaction(Type 1 hypersensitivity)
 Sometimes in the ICU as a sedative agent.
 Dose
 Oral : 25-50mg
 IM : 1mg/kg
 IV : 0.5 mg/kg

26.  CHLORPHENIRAMINE(AVIL)
 This is used for anaphylactic reactions along with
Adrenaline and Hydrocortisone in anticipated
surgeries such as orthopedics for BCIS.
 Dose :
 Oral : 2-4 mg
 IV/IM : 0.1 mg/kg

27. DIPHENHYDRAMINE
 It is first generation antihistaminics.
 It has also anticholinergic, antitussive, antiemetics
and sedative effect.
 Uses
 Allergic symtoms
 Common cold
 Insomnia
 Motion sickness
 Bronchial astma and COPD

28. CETRIZINE
 It is metabolites of hydroxyzine
 Having marked affinity for H1 receptor.
 It penetrate blood brain barrier poorly
 MOA-
 It act by inhibiting release of histamine and cytotoxic
mediators from platelets as well as eosinophill
 DOSE-
 Oral- 10 mg

29.  RANITIDINE
 This is administered as a premedication, for
chemoprophylaxis against aspiration pneumonitis, to
increase the Ph of the gastric fluid ,should aspiration
occur during the perioperative period.
 Dose :
 In premedication : 50 mg im, slow iv infusion

30. Pharmacokinetics
 Orally absorbed.
 Bioavailability 60-80%.
 Absorption not interfered by food in stomach.
 Cant cross BBB.
 Lesser permeability in placenta and milk.
 T1/2: 2-3 hours.
 Excreted unchanged through urine as well as bile.

31.  ADVERSE EFFECTS OF H1 ANTAGONISTS
 The first generation drugs have adverse effects on the
CNS including somnolence,diminished alertness ,
slow reaction time ,and impairment of cognitive
function.
 Anticholinergic effects such as dry mouth,blurred
vision,urinary retention,impotence ,tachycardia are
seen.

32.  Second generation antihistamines are unlikely to
produce CNS effects such as somnolence unless the
recommended doses are exceeded.

33.  ADVERSE EFFECTS OF H2 ANTAGONIST
Headache,somnolence,confusion
Bradycardia,hypotension,heart block
Hyperprolactinemia
Acute pancreatitis
Thrombocytopenia
Agranulocytosis
Interstitial nephritis

34. THANK YOU