Autacoid Histamine and Seratonin Pharmacology

Question 1

1. What is an autocoid, give 5 examples?

Answer 1

an endogenous substance that mediates inflammation; the are seldom used as therapeutic agents themselves but antagonists

histamine, serotonin, lipid-derived eicosanoids (prostaglandins, leukotrienes), bradykinins, cytokines

Question 2

1. Discuss the biosynthesis, and storage of histamine.

Answer 2

biosynthesized from histadine

stored in mast cells, basophils, enterochromaffin-like cells and neurons

Question 3

1. Discuss the 4 histamine receptor subtypes, their location and associated G protein-coupled receptor.

Answer 3

H1 Gq coupled in CNS, smooth muscle
H2 Gs coupled in gastric mucosa, heart, mast cells and CNS
H3 Gi coupled auto receptors on histaminergic neurons
H4 Gi coupled eosinophils, neutrophils, CD4 T-cells

Question 4

1. List the enzymes in converting histadine to histamine and histamine to its metabolites.

Answer 4

dine –> mine is histadine decarboxylase

histamine phase I rxn metabolism by diamine oxidase or metabolism by histamine-N-methyltransferase

Question 5

2. When is histamine released as part of an immune reaction?

Answer 5

mast cells and basophils can release if sensitized by IgE and stimulated by antigen

substances of IgG or IgM mediated responses cause histamine release

certain drugs (NMJ blockers, opiods and succinylcholine) can displace histamine from storage cells

Question 6

1. Name 3 ways to antagonize histamine.

Answer 6

physiological antagonism (ie. epi)
block degranulation (cromolyn sodium or nedocromil)
histamine receptor antagonists

Question 7

3. Effects of peripheral histamine H1 receptor activation include (5).

Answer 7

vasodilation of small blood vessels (decreased bp)
increased capillary permeability (edema, urticaria)
bronchoconstriction and bronchospasm
activation of nerve endings- pain and itch
contraction of intestinal smooth muscle

Question 8

Diphenhydramine (Benadryl or Sominex)

Answer 8

1st generation antihistamine

acts as a H1 receptor inverse agonist for receptor in the GI tract, large blood vessels, bronchial muscle and CNS

has significant antimuscarinic activity (associated with nausea/vomitting, motion sickness

primary metabolism by 2D6

adverse runs: CNS impairment and anitmuscarinic effects

Question 9

Cetirizine (Zyrtec)

Answer 9

2nd generation antihistamine, less sedating

H1 receptor inverse agonist; minimal antimuscarinic activity

metabolism by 3A4

few adverse reactions, sedation and dry mouth; care with low renal clearance

Question 10

Fexofenadine (Allegra)

Answer 10

2nd generation antihistamine (active metabolite terfenadine)

H1 receptor inverse agonist, virtually no antimuscarinic activity

most excretion through feces, effluxes from CNS via the P-glycoprotein pump

few adverse reactions, care with decreased renal function and avoid taking fruit juices

Question 11

Loratadine (Claratin, Tavist ND)

Answer 11

2nd generation antihistamine

H1 receptor inverse agonist, little or no antimuscarinic activity

extensive 3A4, opportunity for drug interactions

few adverse reactions, caution to hepatic disease

Question 12

4. What are the effects of peripheral histamine H2 receptor activation?

Answer 12

vasodilation of small blood vessels

increased heart rate (due to reflex and direct stimulation)

gastric acid secretion

Question 13

Cimetidine (Tagamet)

Answer 13

tx. for GERD, peptic ulcer disease, intermittent dyspepsia

acts as an inverse agonist reducing constitutive activation of H2 on parietal cells

nonselective inhibitor of CYP enzymes (newer have less interactions)

runs, moderate to severe headaches, rare blood dyscrasias; caution with renal insufficiency or hepatic disease

Question 14

5. What molecule is serotonin produced from and where is it stored? What is the general class of receptors?

Answer 14

biosynthesized from tryptophan, stored in enterochromaffin cells of CI epith.; in platelet vesicles and in brain synaptic vesicles

14 receptor subtypes, most are G protein coupled, one is a ligand-gated ion channel

Question 15

1. What two enzymes are required to reach the active form on seratonin?

Answer 15

tryptophan hydroxylase then aromatic amino acid decarboxylase

Question 16

1. Name two enzymes in the metabolism of seratonin in both inactivation and in production of melatonin.

Answer 16

to produce melatonin: arylalkylamine-N-acetyltransferase and N-acetylserotinin-O methyltransferase

to inactivate: monoamine oxidase and aldehyde dehydrogenase

Question 17

Erotamine (Ergomar)

Answer 17

ergot alkaloid used to relieve migraines

mechanism of action is complex, with some opposing and unrelated actions; partial agonist or antagonist at 5-HT, DA and a-adrenergic receptors causing vasoconstriction; also an oxytocic agent

primarily metabolized by 3A4; adverse rxns include ergotism with vasoconstriction; contraindicated with vascular disease, renal or hepatic malfunction; pregnancy risk X

Question 18

Sumatriptan (imitrex)

Answer 18

tx of acute migraine with or without aura

agonist at presynaptic 5HT1D and vascular 5-HT1B receptors causing vasoconstriction (acting on peripheral neuron or vessel directly_

metabolism mostly by MAO-A in liver

potentially fatal vasospactic effects: coronary artery- MI and arrhythmias, bowel ischemia; precaution with CV concerns, ischemic bowel disease, hepatic or renal insufficiency

Question 19

6. Describe serotonin syndrome and its clinical presentation.

Answer 19

serotonin syndrome is caused by excessive serotonin concentrations at its receptors, symptoms developing within the first 12 hrs: agitation, hyperthemia, flushing, GI disturbances, myoclonus, rhabdomyolysis, tremor (greater in lower extremities)and seizures

Question 20

6. What are treatment objectives when a patient has serotonin syndrome?

Answer 20

remove precipitating drugs, monitor vitals and support with IV fluids, control agitation (benzodiazepines), antagonize 5-HT actions, control hypertension and tachycardia, control hyperthermia (no role for antipyretic as it is caused peripherally)