L10- Autacoids Overview Flashcards
list and define the Autacoids
-histamine, serotonin, eicosanoids
- diverse physiological and pharmacological activities
- brief lifetime, act near site of synthesis (autocrine, paracrine activity)
Histamine has (1) number of (2) type receptors all (with/without) constitutive activity. (4) are the clinically important receptors.
1- 4: H1/2/3/4
2- G protein
3- with constitutive activity
4- H1, H2
H1 are G(s/q/i) receptors found on the following, (2)
1- Gq (PLC activation)
2- endothelium, smooth muscle cells, nerve endings
H2 are G(s/q/i) receptors found on the following, (2)
1- Gs (adenylyl cyclase activation)
2- gastric mucosa, cardiac muscle cells, some immune cells
His causes vaso-(constriction/dilation) due to H(1/2) receptors found on (3) cells
1- vasodilation
2- both H1, H2
3- H2 vascular smooth muscle, H1 endothelial cells (NO formation)
His causes (increased/decreased) heart contractility and (increases/decreases) heart rate due to H(1/2) receptors
1- inc contractility
2- inc pacemaker rate
3- H2 receptors
His causes (increased/decreased) capillary permeability causing (2) due to H(1/2) receptors on (4).
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)
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)
1- contraction (inc motility)
2- H1
3- bronchoconstriction
4- H1
His is responsible for mediating (1) signals at nerve endings in the CNS via H(1/2)
1- pain, itching
2- H1
His promotes secretion of (1) in the (2) via H(1/2)
1- gastric acid
2- parietal cells
3- H2
(1) are histamine releasing inhibitors by reducing (2). (3) are other drugs that can reduce His release.
1- cromolyn, nedocromil
2- mast cell degranulation
3- β2 agonists
compare 1st and 2nd generation H1 receptor antagonists
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
H1 blockers MOA
inverse agonists (although still called H1 receptor antagonists)
what are the 3 uses for H1 receptor antagonists
- 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)
list the adverse effects of H1 receptor antagonists
- sedation (more for 1st gen.)
- dry mouth (mostly 1st gen. –> anti-cholinergic effects)
H2 receptor blockers are mainly used to inhibit (1) in the treatment of (2) via (3) mechanism
1- gastric acid secretion
2- peptic ulcer, acute ulcer, GERD
3- competitive antagonism
list the adverse effects of H2 receptor antagonists
(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
Cimetidine is a (1) type drug used for (2) and has (3) and (4) as the main adverse effects.
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
briefly describe the types of serotonin receptors
- 6 G-coupled protein receptors
- 1 ligand gated ion channel = 5-HT-3*****
what are the two types of serotonin agonists used
- 5-HT-1d/1b receptor agonist
- 5-HT-4 receptor agonist
(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).
1- sumatriptan / triptans
2- migraines (acute, severe)
3- coronary vasospasm
4- CAD, angina
describe the MOA of 5-HT-1d/1b agonists for treating migraines
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
describe the adverse effects for each 5-HT-4 receptor agonists
-Metoclopramide: somnolence, nervousness, dystonic rxns + rare extrapyramidal effects and tardive dykinesia
Cisapride: long QT interval => cardiac effects
list the types of serotonin antagonists
- 5-HT-2 antagonists
- 5-HT-3 antagonists
- Ergot Alkaloids
what is the general MOA of Ergot Alkaloids
- 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
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.
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)
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
1- arachidonic acid (20C unsaturated FA with 4 double bonds)
2- phospholipids (2nd position)
3- COX (cyclo-oxygenase: PGs/PCs, TXs)
4- lipoxygenase (LTs)
describe the 2 forms COX
(cyclo-oxygenase)
- COX-1: constitutive enzyme, produces PGs involved in homeostasis
- COX-2: inflammatory cells, induced by inflammatory stimuli
LTs are associated with the following disorders/events: (1). (2) and (3) are the types mainly involved in (1) (explain mechanism).
1- asthma, anaphylactic shock, CVD
2/3- LT-C4, LT-D4: potent bronchoconstrictors (secreted in asthma, anaphylaxis)
describe the general mechanism of action for eicosanoids
- autocrine, paracrine
- G-protein coupled receptors: Gs, Gq, Gi
- Smooth muscle contraction via Ca2+ (Gq)
- Smooth muscle relaxation via cAMP (Gs)
