Sertonin, Antihistamine, Endothelial Receptor Agonists and Antagonists

Tryptophan (in diet; in 2 steps)

They don't synthesize it, but take it up from blood (active uptake process in platelets and nerve terminals)

90% in GI enterochromaffin cells; rest is in platelets and brain

tryptophan hydroxylase

Inhibit breakdown/metabolism of 5HT to 5-OH Indole Acetaldehyde (promote serotonin syndrome)

other amino acids

p-chlorophenylalanine (irreversible)

cocaine, SSRA (fluoxetine), TCA (imipramine)

reserpine

MAO inhibitors

p-chloroamphetamine, which then depletes overall 5HT levels

at least 15, with multiple transduction mechanisms

role in anxiety/depression

role in migraine

role in CNS behaviors; places more emphasis on cardiovascular role

role in nausea and vomiting (esp due to chemo)

Central NT
Melatonin precursor
Inc GI motility*
carcinoid tumor (inc 5HT): diarrhea, bronchoconstriction, edema
Platelets: 5HT-2 receptors-->aggregation, vasoconstriction

Respiratory: bronchoconstriction (contraindicated in asthma); stim aortic, carotid chemoreceptors and inc RR
GI: intense rhythmic contractions due to direct and indirect effects (sm intestine very 5HT sensitive)
Vagal: 5HT-3 receptors on afferents --> stim vomiting

1. direct (immediate) large artery vasoconstriction, indirect (NO and PGI2, prolonged) vasodilation
2. Heart: direct ionotrope, chronotrope
3. Reflex mech due to change in BP
4. Stim sensory nerve endings in baroreceptors, vagal afferents --> bradycardia, hypotension (with overdose)

1. pain perception
2. sleep/wakefulness
3. behaviors (depression, schizophrenia, OCD etc)
4. neuroendocrine regulation (control hypothalamic cells involved in ant pituitary hormones)

sumatriptan
fluoxetine
buspirone
cisapride
LSD
ergot alkaloids

5HT1-D agonist; contraindicated in angina; used for migraine

SSR; depression

5HT1-A agonist; for anxiety

5HT4 agonist; inc GI motility, dec G-E reflux (taken off market for fatal arrhythmias*)

5HT1-A; hallucinogen

5HT1, 2 agonist

methylsergide, cyproheptadine
ketanserin
ondansetron
clozapine

5HT2 antagonists; used for carcinoid, migraines

5HT2, alpha antagonist; antihypertensive

5HT3 antagonist; for chemotherapy induced n/v

5HT2A/2C antagonist; for schizophrenia

Bronchoconstriction***
(rhinitis, conjunctivitis, urticaria, dermatitis, anaphylaxis)

synth by decarboxylation of histidine; released from mast cells when stim by IgE due to foregin Ag in body

sm muscle, endothelium, CNS;
vasodilation, bronchoconstriction, sm muscle activation, separation of endothelial cells

parietal cells;
regulate gastric acid secretion

CNS;
regulate release of other NTs

recently discovered, widespread (organs of digestive tract, basophils, bone marrow), unknown fxn

small, lipophilic (cross BBB), not specific to H1; highest sedation among antihistamines

more specific to peripheral H1 receptor; less sedation than 1st gen (but when given in higher dose, will still cause sedation)

metabolite derivatives or active enantiomers of prior antihistamines; safer, faster, more potent than 2nd gen (will still give sedation if given in higher dose, but less sedation than 2nd or 1st)

rapid onset, half lives= loratidine 24 hrs, fexofenedine 14 hrs, cetirizine 8 hours (kids metabolize cetirizine faster; rates similar for others)

Be aware that multiple classes (PGs, TXA, PGI, LT) that do opposite things (vasoconstriction vs vasodilation)

generic name for PGE-2, relax uterine sm muscle when labor is induced; to terminate pregnancy in early stages

analogue of PGE-1, prevent gastric ulcers

serotonin (5HT), endothelin-1 (ET)

potent vasoconstrictor; plasma levels are increased in pulm HTN

sulphonamide based ET-A & ET-B receptor blocker; contraindicated in pregnancy for teratogenic effects**; induces CYP2C9, CYP3A4

sulphonamide based selective ET-A antagonist (ET-A:ET-B 6500:1); CYP2C9 metabolism-->interacts with warfarin

headache, constipation, dizziness, insomnia

non-sulphonamide ET-A moderately selective (260:1) antagonist; no interaxn w coumarin based anticoagulants