Autocrine & Paracrine Pharmacology (Part II) Prof. Alhaider Department of Pharmacology College of Medicine

OBJECTIVES At the end of lecture the Students should be able to: 1- Specify storage sites of histamine 2- Explain the synthesis, release & inactivation of histamine 3-List histamine receptors regarding: Type, major location, major biologic effects 4-Explain the clinical uses of histamine receptors antagonists.

Continue 5- Describe the synthesis of Eicosanoids 6- Classify drugs that inhibit synthesis of eicosanoids 7- Enumerate the pharmacological actions of eicosanoids 8-Enumerate the clinical uses of PGs analogs

H istamine Neurotransmitter Allergic & Inflammatory reactions Gastric acid secretion

Highest amounts in mast cells Storage Sites Highest amounts in mast cells Basophils Skin Lung Intestinal mucosa Stomach Brain

Biosynthesis

Inactivation Histamine Imidazole N-methyltransferase Methyl histamine (Oxidation) Methyl imidazole acetic acid Imidazole N-methyltransferase Diamine oxidase

-ve presynaptic autoregulation H 1 H 1 + H 2 + H 3 + H 3 -ve presynaptic autoregulation

RELEASE Primary mechanism, during allergic reactions on sensitizing [ IgE antibody interacts with antigen on the surface of mast cells ] Mast cells are degranulated and release histamine and leads to allergic reactions. It also has some role in acute inflammation ,on injury it causes local vasodialtion and leakage of plasma, anti bodies and inflammatory cells. Its release is modulated by binding to H3 presynaptic receptors

Continue Enzymes as trypsin or drugs as morphine or other chemicals can liberate histamine Tissue injury by trauma or burn

acute allergic responses secretion of gastric acid Histamine receptors Receptor Type Major Tissue Locations Major Biologic Effects H1 smooth muscle, endothelial cells acute allergic responses H2 gastric parietal cells secretion of gastric acid H3 central nervous system neurotransmission H4 mast cells, eosinophils, T cells regulating immune responses

Effects Of Histamine Pain, itching, hives الطفح الجلدي Hypotension, tachycardia, flushing and bronchoconstriction تحصل في حالات فرط الحساسية Headache, visual disturbances, increase skin temperature Excessive secretion of gastric acids and diarrhea Bronchoconstriction, dyspnea,

Histamine receptors antagonists

Physiologic antagonists: Histamine effects can be reduced by physiologic antagonism such as epinephrine which acts on different receptors but produces effects opposite to histamine especially in anaphylaxis. Therefoe, Epinephrine is the drug of choice for Anaphylaxis (فرط الحساسية) Specific receptor blockage: Of Blocking of histamine receptors. But in most of the cases these blockers specific in their binding and blocking activity.

First generation H1 receptor Blockers (CNS) First generation H1 receptor Blockers (CNS). Diphenhydramine , cyclizine , promathazine Second generation H1 receptor blockers (Pero Loratidine Citrizine

Has a Sedating effect Clinical uses : Diphenhydramin (First generation) H1 antagonists ( Blockers ) Has a Sedating effect Clinical uses : Insomnia Motion sickness Cold medication Allergy

Loratadine (Second generation) H1 antagonists Non-sedating effect Clinical uses Allergic conditions as : allergic rhinitis Conjunctivitis Urticaria

Inhibitor of gastric acid secretion Used in the treatment of Cimetidine H2 antagonists Inhibitor of gastric acid secretion Used in the treatment of peptic ulcers

BETAHISTINE H3 antagonists Used in treatment of vertigo in middle ear

Eicosanoids

INHIBITORS OF EICOSANOIDS

Drugs Corticosteroids Zileuton NSAIDs Phospholipids Arachidonic Acid Phospholipase A2 Arachidonic Acid Prostaglandins Thromboxane (TXA2) Prostacyclin Cyclooxygenase Leukotrienes Lipoxygenase Corticosteroids Zileuton NSAIDs

Actions of prostaglandins (Very Important) Causes vasodilatation of vascular smooth muscle cells Causes inhibition of platelets aggregation Sensitize neurons to cause pain Induce labor Decrease intraocular pressure Acts on thermoregulatory center of hypothalamus Acts on kidney to increase glomerular filtration Acts on parital cells of stomach to prevent gastric mucosa

Comparison in actions between Prostaglandins Thromboxane A2

Vascular smooth muscles: Prostaglandins Thromboxane A2 Potent vasoconstrictor. Potent vasodilators .

Blood: TXA2 inhibit platelet aggregation a potent inducer of platelet aggregation. Prostaglandins inhibit platelet aggregation

Inflammation: Both play important role in inflammatory reactions.

Bronchial smooth muscle: -Prostaglandins ( bronchorelaxation ) -Thromboxane (bronchoconstriction)

Uterine smooth muscle: Prostaglandins increase uterine contractions → Menstruation/ Dysmenorrhea آلام الطمث/ Labor contractions

GIT smooth muscle: - Prostaglandins GIT motility

GIT secretions: Prostaglandins ↓acid secretion  Mucin secretion

Kideny Prostaglandins increase renal blood flow and diuresis.

Central and peripheral nervous systems Fever

Clinical uses of prostaglandins analogs ( Synthetic prostaglandins )

Carboprost Abortion Induce abortion in first trimester.

Carboprost cont. PGF “less used nowadays “ 2) Treatment of postpartum haemorrhage ( vasoconstriction + uterine muscle contraction)

Latanoprost (↓ IOP by enhancing outflow of the aqueous humar) eye drops /in treatment of open angle glaucoma. (↓ IOP by enhancing outflow of the aqueous humar)

Misoprostol Treatment of Peptic ulcer

Prostaglandin Antagonists have very important clinical uses e Prostaglandin Antagonists have very important clinical uses e.g: NSADS (Aspirin; Paracetamol; Brufen). Also, Leukotriene antagonists have an important value for treating asthma الربو

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