L10- Autacoids Overview

Question 1

list and define the Autacoids

Answer 1

-histamine, serotonin, eicosanoids

• diverse physiological and pharmacological activities
• brief lifetime, act near site of synthesis (autocrine, paracrine activity)

Question 2

Histamine has (1) number of (2) type receptors all (with/without) constitutive activity. (4) are the clinically important receptors.

Answer 2

1- 4: H1/2/3/4
2- G protein
3- with constitutive activity
4- H1, H2

Question 3

H1 are G(s/q/i) receptors found on the following, (2)

Answer 3

1- Gq (PLC activation)

2- endothelium, smooth muscle cells, nerve endings

Question 4

H2 are G(s/q/i) receptors found on the following, (2)

Answer 4

1- Gs (adenylyl cyclase activation)

2- gastric mucosa, cardiac muscle cells, some immune cells

Question 5

His causes vaso-(constriction/dilation) due to H(1/2) receptors found on (3) cells

Answer 5

1- vasodilation
2- both H1, H2
3- H2 vascular smooth muscle, H1 endothelial cells (NO formation)

Question 6

His causes (increased/decreased) heart contractility and (increases/decreases) heart rate due to H(1/2) receptors

Answer 6

1- inc contractility
2- inc pacemaker rate
3- H2 receptors

Question 7

His causes (increased/decreased) capillary permeability causing (2) due to H(1/2) receptors on (4).

Answer 7

1- inc permeability (separation of endothelial cells)
2- edema (fluid and molecules in perivascular space)
3- H1
4- BVs - endothelium

=> urticaria (His release in skin)

Question 8

His will cause (constriction/relaxation) of GI tract smooth muscle via H(1/2)

His will cause (constriction/relaxation) of bronchiolar smooth muscle via H(1/2)

Answer 8

1- contraction (inc motility)
2- H1

3- bronchoconstriction
4- H1

Question 9

His is responsible for mediating (1) signals at nerve endings in the CNS via H(1/2)

Answer 9

1- pain, itching

2- H1

Question 10

His promotes secretion of (1) in the (2) via H(1/2)

Answer 10

1- gastric acid
2- parietal cells
3- H2

Question 11

(1) are histamine releasing inhibitors by reducing (2). (3) are other drugs that can reduce His release.

Answer 11

1- cromolyn, nedocromil
2- mast cell degranulation
3- β2 agonists

Question 12

compare 1st and 2nd generation H1 receptor antagonists

Answer 12

1st- sedative effects, more likely to block ANS receptors (more liposoluble); also has cholinergic, α-adrenergic, serotonin, Na channel antagonist effects

2nd- less sedating (less liposoluble) b/c less CNS effects + substrates of P-glycoprotein in BBB

Question 13

H1 blockers MOA

Answer 13

inverse agonists (although still called H1 receptor antagonists)

Question 14

what are the 3 uses for H1 receptor antagonists

Answer 14

• allergies: allergic rhinitis, urticaria
• motion sickness, nausea (1st gen. block H1, M1 since they have CNS effects)
• somnifacents (1st gen., insomnia Tx due to CNS effects)

Question 15

list the adverse effects of H1 receptor antagonists

Answer 15

• sedation (more for 1st gen.)

- dry mouth (mostly 1st gen. –> anti-cholinergic effects)

Question 16

H2 receptor blockers are mainly used to inhibit (1) in the treatment of (2) via (3) mechanism

Answer 16

1- gastric acid secretion
2- peptic ulcer, acute ulcer, GERD
3- competitive antagonism

Question 17

list the adverse effects of H2 receptor antagonists

Answer 17

(generally extremely safe- <3% have adverse effects)
-HA, dizziness, diarrhea, muscular pain, constipation

-Given IV: confusion, hallucinations, agitation –> ICU patients that are elderly or have renal/hepatic dysfunction

Question 18

Cimetidine is a (1) type drug used for (2) and has (3) and (4) as the main adverse effects.

Answer 18

1- H2 receptor antagonist
2- GERD (dec gastric acid secretion)
3- inhibits cytochrome P450 –> slows metabolism of other drugs
4- binds androgen receptors (antiandrogenic effects) => gynecomastia, reduced sperm count in men / galactorrhea in women

Question 19

briefly describe the types of serotonin receptors

Answer 19

• 6 G-coupled protein receptors

- 1 ligand gated ion channel = 5-HT-3*****

Question 20

what are the two types of serotonin agonists used

Answer 20

• 5-HT-1d/1b receptor agonist

- 5-HT-4 receptor agonist

Question 21

(1) are the 5-HT-1d/1b receptor agonists used to treat (2). The main adverse effect is (3), therefore it is contraindicated in patients with (4).

Answer 21

1- sumatriptan / triptans
2- migraines (acute, severe)
3- coronary vasospasm
4- CAD, angina

Question 22

describe the MOA of 5-HT-1d/1b agonists for treating migraines

Answer 22

Migraines: trigeminal nerve releases CGRP (calcitonin G-related peptide) on vasculature (CGRP receptor) causing vasodilation => migraine

-Triptans: i) binds 5-HT-1d on Trigeminal nerve to prevent CGRP release; ii) binds 5-HT-1b on vasculature –> vasoconstriction => migraine relief

Question 23

describe the adverse effects for each 5-HT-4 receptor agonists

Answer 23

-Metoclopramide: somnolence, nervousness, dystonic rxns + rare extrapyramidal effects and tardive dykinesia

Cisapride: long QT interval => cardiac effects

Question 24

list the types of serotonin antagonists

Answer 24

• 5-HT-2 antagonists
• 5-HT-3 antagonists
• Ergot Alkaloids

Question 25

what is the general MOA of Ergot Alkaloids

Answer 25

• agonist, partial agonist, antagonist for α-adrenonergic and 5-HT receptors
• agonist, partial agonist for CNS DA receptors

-some are more selective for presynaptic receptors, some for postsynaptic

Question 26

The main adverse effect of Ergot Alkaloids is (1). It should not be used in (2) patients, patients with (3), or patients taking (4). This effect can be useful for in the diagnosis of (5) using (6) ergot.

Answer 26

1- vasospasm
2- pregnant (–> fetal distress, miscarriage)
3- peripheral vascular disease, CAD, HTN, impaired renal/hepatic function
4- other vasoconstriction drugs
5- variant angina
6- ergonovine (IV) (–> coronary artery spasm)

Question 27

the main source of eicosanoids is (1- describe structure) which is usually found in (2) part of the cell and will undergo either the (3) or (4) pathway

Answer 27

1- arachidonic acid (20C unsaturated FA with 4 double bonds)
2- phospholipids (2nd position)
3- COX (cyclo-oxygenase: PGs/PCs, TXs)
4- lipoxygenase (LTs)

Question 28

describe the 2 forms COX

Answer 28

(cyclo-oxygenase)

• COX-1: constitutive enzyme, produces PGs involved in homeostasis
• COX-2: inflammatory cells, induced by inflammatory stimuli

Question 29

LTs are associated with the following disorders/events: (1). (2) and (3) are the types mainly involved in (1) (explain mechanism).

Answer 29

1- asthma, anaphylactic shock, CVD

2/3- LT-C4, LT-D4: potent bronchoconstrictors (secreted in asthma, anaphylaxis)

Question 30

describe the general mechanism of action for eicosanoids

Answer 30

• autocrine, paracrine
• G-protein coupled receptors: Gs, Gq, Gi
• Smooth muscle contraction via Ca2+ (Gq)
• Smooth muscle relaxation via cAMP (Gs)