14) Histamine 5HT Ergot Alkaloids Flashcards
Histamine synthesis and storage
- Synthesized from istidine
- Stored in mast cells (enterochromaffin cells in the gut)
Histamine is metabolized by
- Monoamine oxidase (MAO)
- Diamine oxidase
Excess production of histamine in the body (eg, in systemic mastocytosis) can be detected by
- Measurement of its major metabolite (imidazole acetic acid) in the urine
Hitamine is released from mast cells in response to
- IgE-mediated (immediate) allergic reactions
- Plays a pathophysiologic role in seasonal rhinitis (hay fever), urticaria, and angioneurotic edema
Histamine also plays a physiologic role in the control of
- Acid secretion in the stomach
- As a neurotransmitter
Two receptors for histamine
- H1 and H2
- Mediate most of the peripheral actions
- 2 others (H3, H4) have also been identified
The triple response
- Demonstration of histamine effect on the skin
- Mediated mainly by H1 and H2 receptors
- This response involves a small red spot, an edematous wheal, which is surrounded by a red flare
H1 receptor distribution
- Smooth muscle
- Endothelium
- Brain
H2 receptor distribution
- Stomach
- Heart
- Mast cells
- Brain
H3 receptor distribution
- Nerve endings
- CNS
H4 receptor distribution
- Leukocytes
- CD4 T-cells
5-HT1D/1B receptor distribution
- Brain
5-HT2 receptor distribution
- Smooth muscle
- Platelets
- Brain
5-HT3 receptor distribution
- CNS
- Sensory and enteric nerves
5-HT4 receptor distribution
- Gastro-intestinal tract
H1 and 5-HT2 post-receptor mechanisms
- Gq; ↑ IP3 and DAG
H2 and 5-HT4 post-receptor mechanisms
- Gs; ↑cAMP
H3, H4, and 5-HT1D/1B post-receptor mechanisms
- Gi; ↓cAMP
5-HT3 post-receptor mechanism
- Ligand-gated Na+/K+ channel
First generation H1 antagonists (blockers)
- Very sedating
- New subgroup prototyped by chlorpheniramine and cyclizine is less sedating
- Half lives = 4–12 h
Second generation H1 antagonists (blockers)
- Prototyped by loratadine
- Great reduced sedation and autonomic effects
- Half lives = 12–24 h
H1 blockers MOA
- Competitive antagonists at the H1 receptor
- No effect on histamine release from storage sites
- More effective if given before histamine release occurs
Some (but not all) first-generation agents have
- Anti-motion sickness effects (diphenhydramine, dimenhydrinate, cyclizine, meclizine….)
First generation H1 antagonists selectivity
- Less selectivity to histamine receptors
- Anti-cholinergic activity
Second generation H1 antagonists selectivity
- More selective to the peripheral histamine receptors
- Don’t cross the blood brain barrier (BBB) so they have less sedation side effects and less anticholinergic effects
H2 blocker prototype
- Dimetidine
- Single dose DOA may be 12–24 h
H2 antagonist (cimetidine) MOA
- Pharmacologic blockade of histamine H2 receptors
- Relatively selective
- No significant blocking actions at H1 or autonomic receptors
The only therapeutic effect of clinical importance (H2 receptor antagonist)
- Reduction of gastric acid secretion
Cimetidine
- Potent inhibitor of hepatic drug-metabolizing enzymes
- May also reduce hepatic blood flow
- Significant antiandrogen effects in patients receiving high doses (others don’t have this side effect)
H2 blockers (names)
- Ranitidine
- Famotidine
- Nizatidine
- Cimetidine
Serotonin production/storage
- Produced from tryptophan
- Stored in vesicles in cells of the gut and neurons of the CNS and enteric nervous system
After release, serotonin is metabolized by
- Monoamine oxidase (MAO)
Excess serotonin production in the body can be detected by
- Measuring its major metabolite in the urine
- 5-hydroxyindole acetic acid (5-HIAA)
After release from neurons, serotonin
- Partially taken back up into the nerve ending by a serotonin reuptake transporter (SERT)
Serotonin agonists in clinical use act at these receptors
- 5-HT1D/1B
- 5-HT2
- 5-HT4
Antidepressants
- Selective serotonin reuptake inhibitors (SSRI)
H1 receptor clinical outcome
- Itching
- Pain
- Bronchoconstriction
- Vasodilation, local edema
H2 receptor clinical outcome
- Gastric acid secretions
H3 receptor clinical outcome
- Appetite suppressant investigation
5-HT2 receptor clinical outcome
- In the CNS, mediate a reduction in appetite that has been used in the treatment of obesity
5-HT3 receptor clinical outcome
- Sspecially in the chemoreceptive area and vomiting center
- Antagonists have anti-emetic effects
5-HT4 receptor clinical outcome
- Intestinal motility
Prototypic H1 antagonists
- Diphenhydramine
- Loratadine
Prototypic H3 antagonists
- Clobenpropit
Prototypic H4 antagonists
- Thioperamide
Prototypic 5-HT1D/1B agonists
- Triptans: Sumatriptan,….
5-HT2 prototypic agonists
- Loracserin
5-HT2 prototypic antagonists
- Ketanserin
5-HT3 prototypic antagonists
- Ondansetron
5-HT4 prototypic agonists
- Tegaserod (partial agonist)
5-HT4 prototypic antagonists
- Tegaserod (partial agonist)
5-HT1D/1B agonists (names)
- Sumatriptan
- Almotriptan
- Eletriptan
- Frovatriptan
- Naratriptan
- Rizatriptan
- Zolmitriptan
5-HT1D/1B agonists indication
- Acute migraine
- Cluster headache
5-HT1D/1B agonists side effects
- Paresthesias
- Pain
- Dizziness
- Coronary vasospasm
5-HT2 agonists indication
- Treatment of obesity
5-HT3 agonists indication
- Especially in the chemoreceptive area and vomiting center
- Antagonists have anti-emetic effects
5-HT4 agonists indication
- Chronic constipation
5-HT4 agonists side effects
- Cardiovascular toxicity
5-HT2 antagonist names/MOA
- Ketanserin, cyproheptadine are competitive antagonists
- Phenoxybenzamine is an irreversible blocker
5-HT2 antagonist indication
- Treatment of carcinoid tumor (neoplasm that secretes large amounts of serotonin and peptides)
- Causes diarrhea, bronchoconstriction, and flushing
5-HT2 antagonist side effects
- Ketanserin, phenoxybenzamine: cause α-blockade thus have α-blockade SE
- Cyproheptadine: causes H1-blockade thus has H1-blockade SE
5-HT3 antagonists (names)
- Ondansetron
- Granisetron
- Dolasetron
- Alosetron
5-HT3 antiemetic actions
- Vomiting associated with cancer chemotherapy and postoperative vomiting
Alosetron (5-HT3 antagonist) is used in the treatment of
- Women with irritable bowel syndrome associated with diarrhea
5-HT3 antagonist side effects
- Diarrhea
- Headache
Dolasetron (5-HT3 antagonist) side effects
- Has been associated with QRS and QTc prolongation in the ECG
Alosetron (5-HT3 antagonist) side effects
- Causes significant constipation
associated with fatal bowel complications
Serotonin and drugs with 5-HT agonist effects are associated with
- Hyperthermia (high fever)
- Hyperreflexia and tremors (skeletal muscle effects)
- Cardiovascular abnormalities (hypertension)
- Hyperactive bowel syndrome; diarrhea
- Mydriasis
- Agitation and coma that can be life-threatening
Precipitating drugs
- SSRI
- Sumatriptan
- Ondansetron
- Not sure how and if true
Mild Serotonin Syndrome symptoms
- Mydriasis
- Shivering
- Sweating
- Tachycardia (mild)
Moderate Serotonin Syndrome symptoms
- Altered mental status
- Autonomic hyperactivity
- Neuromuscular abnormalities
Life threatening Serotonin Syndrome symptoms
- Delirium
- Hypertension
- Hyperthermia
- Muscle rigidity
- Tachycardia
Ergot alkaloid clinical effects on vessels
- Migraine treatment
- α-adrenoceptor–mediated vasoconstriction
- Overdose can cause ischemia and gangrene of the limbs or bowel
Ergot alkaloid clinical effects on uterus
- Reduce post-partum bleeding
- Powerful and long-lasting contraction that reduces bleeding
- Contract the uterus especially near term (delivery) - Ergonovine is the prototype
- In pregnancy, the uterine contraction is sufficient to cause abortion or miscarriage
Ergot alkaloid clinical effects on the brain
- Bromocriptine has been used to reduce prolactin secretion (dopamine is the physiologic prolactin release inhibitor) in Hyperprolactinemia and parkinsonism
Hallucinations may be prominent with
- Naturally occurring ergots
- Lysergic acid diethylamide (LSD)
- Uncommon with the therapeutic ergot derivatives
In the pituitary, some ergot alkaloids are
- Potent dopamine-like agonists and inhibit prolactin secretion
- Bromocriptine are among the most potent semisynthetic ergot derivatives
