AUTOCOIDS

HISTAMINE INHIBITORS

B2 agonists Cromolyn Epinephrine Glucocorticoids Theophylline

HISTAMINE

Binds H1 – H4 (all G-protein coupled) receptors H1 receptor: SM, brain

Activates IP3/DAG H2 receptor: gastric mucosa, cardiac muscle, mast

cells, brain Increases cAMP

H3 receptor: presynaptic membranes in brain, myenteric plexus, other neurons Inhibits cAMP production and Ca2+ influx

Decreases release of Nepi, serotonin, histamine, etc H4 receptor: leukocytes in BM and blood

Exerts chemotactic effects on eosinophils and mast cells

HISTAMINE

Neurons Mediation of pain and itching (H1) Urticarial response to insect stings (H1) Inspiratory/expiratory centers (H1) Release of nt (H3)

Female Reproductive system Contraction of uterus (H1) abortion in woman w/ anaphylactic rxn

Respiratory System Bronchoconstriction (H1)

Stomach Gastric acid secretion (H2)

Intestines SM contraction (H1) diarrhea

Heart Increase HR, contractility, and pacemaker rate (H2)

Metabolic (H3) CV system

Decrease systolic and diastolic bp due to vasodilation of arterioles and precapillary sphincters (H1 and H2)

H1- Receptor Antagonists

1st Generation Cyproheptadine Diphenhydramin

e Meclizine Promethazine

2nd Generation Cetirizine

H1-Receptor Antagonists

1st gen: strong sedative effects, enter CNS 2nd gen: much less sedating MoA: Reversible competitive inhibition of H1 Effects: - inhibition of edema and itching

Antinausea and antiemetic Inhibition of bronchiolar and GI SM contraction

Therapeutic Uses: DOC in allergic rhinitis (Hay fever) and urticaria

Diphenydramine & Cetirizine 1st gen are good for prevention of motion sickness Second choice for parkinsonism due to their

central antimuscarinic effect

Question

DOC for Hay fever or urticaria?

DOC for prevention of motion sickness?

Diphenhydramine (Benadryl) Reduces histamine effects on SM,

immune cells, and blocks muscarine and alpha-adrenoreceptors; highly sedative

Uses: IgE immediate allergies, hay fever, urticaria, antiemetic, anti-motionsickness

1st gen H1 antagonist

Cetirizine (Zyrtec)

Reduces histamine effects on SM and immune cells

IgE immediate allergies, hay fever, urticaria

2nd generation H1 antagonist

H2 – Receptor Antagonists

Cemitidine Famotidine Ranitidine

H2 – Receptor Antagonists

MoA: - Competitive inhibitors of H2-receptors in gut parietal cells inhibits cAMP production inhibits gastric acid secretion

Therapeutic uses: GERD, upset stomach (use prophylactically

before meals) Toxicity

Gynecomastia, galactorrhea, loss of libido, impotence

Leukopenia, thrombocytopenia

Serotonin binds 5-HT receptors

Involved in migraines, gut, blood clotting, carcinoid syndrome

90% stored in EC cells of GI Complex with ATP inside granules, released

w/stimulus – thrombin, TXA2, reserpine (neurons)

In blood, stored in platelets Mediates inhibitory effects on

behaviours: mood, sleep, appetite, temp regulation, pain perception, bp, vomiting

Serotonin

Chemoreceptor reflex and vomiting reflex mediated by 5-HT3

Neurons: stimulates pain and itching No major effects on respiratory system CV: - vascular SM contraction,

vasoconstrictor of systemic vessels, induces platelet aggregation 5-HT2 Vasodilator in skeletal muscle and coronary

muscles (NO-mediated) GI: increased tone and peristalsis (5-HT2)

Carcinoid Syndrome Secondary to carcinoid tumors

Discrete, yellow, well-circumscribed tumors that occur anywhere along the GI and lung

Neuroendocrine origin overproduction of serotonin

Clinical presentation: flushing of skin (head, upper thorax), nausea, vomiting, 50% have cardiac abnormalities caused by 5-HT induced fibrosis of the tricuspid and pulmonary valves

TIPS = Tricuspid Insufficiency, Pulmonary Stenosis Affects right side of heart

Urine: 5 – HIAA (degradation product of 5-HT)

5-HT Agonists

Buspirone Ergonovine Ergotamine LSD Metoclopramide

5-HT1B/1D Agonists

Eletriptan Sumatriptan Zolmitriptan

5-HT Antagonists

Butyrophenones Cyproheptadine Ketanserin Ondasetron Phenoxybenzamine

5-HT Agonists Triptans – orally administered

5-HT1B/1D (found in cerebral and meningeal vessels) mediates vasoconstriction

Inhibit vasodilator release from trigeminal nerve endings

Therapeutic uses DOC for severe acute migrane Treatment for cluster headache

Toxicity: cardiac arrhythmias, MI, paresthesias, dizziness, coronary vasoconstriction

Question

What are the DOC for SEVERE ACUTE MIGRAINE?

Treatment of CLUSTER HEADACHE?

Triptans, Sumatriptan

Ergot Alkaloids

5-HT, dopamine, and alpha-receptor agonists

Oral bio of Ergotamine is little; Ergonovine is high

Induce mood changes, perceptual disorders, hallucinations

Increased vasoconstriction due to alpha and 5-HT receptor in the CV, GI, and Uterus

Toxicity: prolonged vasospasm causing gangrene

Question

Drug for FIRST SIGN of migraine attack? Ergonovine/Ergotamine

Drug for hyperprolactinemia? bromocriptine (D2 receptor agonist) &

cabergolide (ergot alkaloid) Drug for postpartum bleeding?

Ergonovine

Eicosanoids COX-1: - constitutively expressed;

inhibited by NSAIDS COX-2: - inducible expression, inhibited

by NSAIDS, glucocorticoids, and selective inhibitors

Arachidonic Acid PGG2 PGH2 other PGs, TXA2, tec

MoA: IP3/DAG & Rho GTPase pathways, GPCR

Effects of Eicosanoids Vascular:

PGE2 and PGI2 are potent arteriolar vasodilators

TXA2 potent vasoconstrictor LTs strongly increase venule permeability

GI: SM contraction by LTs and PGs PGE2 and PGI2 have cytoprotective effects

(secrete mucus/bicarbonate) Respiratory:

Bronchial SM is relaxed by PGE2 and PGI2 LTs are powerful bronchoconstrictors

Effects of Eicosanoids Blood:

TXA2 is powerful inducer of platelet aggregation

PGI2 inhibits platelet aggregation LTB4 is a chemotactic agent

Lipid – Derived Autocoids

Prostaglandins Alprostadil Carboprost

Tromethamine Dinoprostone Epoprostenol Latanoprost Misoprostol

Lipid – Autocoid Inhibitors

Glucocorticoids – inhibit PLA2 and COX-2

Cromolyn Montelukast NSAIDS – inhibit COX-1 and COX-2 Zafirlukast – blocks selective

leukotriene rcpt Zileuton – inhibits 5-Lipoxygenase

Alprostadil

PGE1 analog 2nd line of defence against erectile

dysfunction Toxicity: penile pain, prolonged erection,

and priaprism (persistant erection) “The permanent boner” drug

Carboprost Tromethamine

PGF2alpha analog 2nd trimester abortion

Dinoprostone

PGE2 analog Vaginal adiministration 2nd trimester abortion, benign

hydatidiform mole, ripening of cervix to induce labor

MoA: induction of uterine contractions and effects on cervical collagenase

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