Post on 07-May-2015
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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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