In the previous article we talked about a part of the autacoid parts, which is a decarboxylated amino acid, and we said that it is divided into two types.
- Histamine
- serotonin
We talked about histamine in all its details, and today we will talk about serotonin with all its agonist and antagonist drugs.
serotonin
- Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine NTs, a local hormone in the gut.
- It is formed by decarboxylation of L-tryptophan.
- It is metabolized by MAO to 5-Hydraxyindoleacetic acid (5-HIAA) (normal level 2-7 mg/day in urine), Increase 5-HIAA level in patient with carcinoid tumors.
- Triphasic blood pressure response of serotonin
- Injection of serotonin in experimental animal; cause:
- decrease HR, CO and BP due to chemoreceptor response.
- increase in BP due to VC.
- decrease in BP due to VD in skeletal muscle blood vessels.
Serotonin Syndrome
- a condition associated skeletal muscle contraction, appear when MAO inhibitors are given with serotonin increase agents. Main symptoms: Hypertension, agitation, hyperthermia, muscle rigidity.
Serotonin Receptor Agonists
- Buspirone
Is a selective 5-HT1A agonist, is an antianxlety agent.
Used to treat generalized anxiety disorder.
Side effects:
- dizziness
- headache
- nervousness.
Triptans Family:-
- Sumatriptan
Absorption
Bioavailability: 15% (PO); 97% (SC)
Onset: 10 min (SC); 30 min (PO)
Duration: 9-24 hr (SC)
Peak plasma time: 0.5-3 hr (PO); 5-20 minutes (SC)
Peak plasma concentration: 18-51 ng/mL (PO); 55-108 ng/mL (SC, 6 mg dose)
Distribution
Protein bound: 14-21%
Vd: 2.4 L/kg
Metabolism
Metabolized via hepatic MAO-A isoenzyme
Elimination
Half-life: 2-2.5 hr (PO); 115 min (IV)
Renal clearance: 264 mL/min
Total body clearance: 1176-1200 mL/min
Excretion: Urine (60%); feces (40%)
- Zolmitriptan
Pharmacokinetics
Half-Life elimination: 2.8-3.7 hr
Peak Plasma Time: 1.5 hr; 3 hr (ZMT)
Bioavailability: 40%
Onset of action: 0.5-1 hr
Protein Bound: 25%
Vd: 7.0 L/kg
Metabolism: liver
Metabolites: N-desmethyl zolmitriptan
Excretion: Urine (65%); Feces (30%)
- Rizatriptan
Absorption
Bioavailability: 45-50%
Onset of action: Within 2 hr
Peak plasma time: 1-1.5 hr
AUC: 30% higher in females than in males
Distribution
Protein bound: 14%
Vd: 110 L (female); 140 L (male)
Metabolism
Metabolized by MAO-O
Metabolites: N-monodesmethyl-rizatriptan
Elimination
Half-life elimination: 2-3 hr
Excretion: Urine (82%); feces (12%)
- Naratriptan
Absorption
Bioavailability: 70%
Peak Plasma Time: 3-4 hr
Peak Plasma Concentration: 50-1,000 ng/ml; 50% higher in women
Distribution
Protein Bound: 28-31%
Vd: 170 L
Metabolism
Via hepatic CYP450 enzymes
Elimination
Half-Life: 6 hr
Excretion: Urine 50%
- Eletriptan
Pharmacokinetics
Half-Life elimination: 4 hr
Peak Plasma Time: 1.5-2 hr
Bioavailability: 50%
Protein bound: 85%
Vd: 138 L
Metabolism: hepatic CYP3A4
Metabolites: N-demethylated eletriptan (10-20%)
Renal Clearance: 3.9 L/hr
Excretion: 90% Non-renal
- Almotriptan
Pharmacokinetics
Half-Life: 3-4 hr
Peak Plasma Time: 1-3 hr
Bioavailability: 70%
Protein bound: 35%
Vd: 180-200 L
Absorption: Well absorbed
Metabolism: CYP3A4, CYP2D6
Excretion: Urine (75%)
- Frovatriptan
Pharmacokinetics
Half-life: 26 hr
Peak plasma time: 2-4 hr
Metabolism: CYP1A2
Distribution: 4.2 L/kg (male); 3 L/kg (female)
Protein binding: 15%
Bioavailability: 20% (male); 30% (female)
Excretion: Feces (62%); urine (32%)
- Triptans Family used in treatment of migraines and cluster headaches
- Mechanism of action:
Triptans are selective agonists for 5-HT1B and 5-HT1D:
- Inhibit the release of vasodilating peptides (especially calcitonin gene-related peptide; CGRP).
- Vasoconstriction effect on intracranial blood vessels.
- Contraindication:
patients at risk for coronary artery disease due to, coronary artery vasospasm.
- Adverse effect
- Dizziness
- Dry mouth
- Feeling heavy in your face, arms, legs, and chest
- Feeling sleepy
- Flushing
- Muscle weakness
- Nausea
- Skin reaction (if you take the triptan as a shot)
- Tightness in your throat
- Tingling sensations
- Tegaserod
It is a 5-HT4 partial agonist in the GIT, stim. Gl motility.
It is used in irritable bowel syndrome with constipation (IBS-C).
It is removed from the market.
- Cisapride
It is a gastroprokinetic agent (enhance GI motility).
It acts directly as 5-HT4 receptor agonist and Indirectly as a parasympathomimetic.
Used in gastroesophageal reflux disease (GERD).
It is voluntary withdrawal due to long QT interval
- Mosapride
It is a gastroprokinetic agent.
Used in gastritis, GERD, functional dyspepsia and IBS.
Drug Interaction: with LMEls QT interval prolong
Serotonin Receptor Antagonists
- Pizotifen or Pizotyline
It is a 5-HT2A and 5-HT2c receptors antagonist.
Used for prevention of migraine (Prophylaxis).
Off-label used as appetite stimulant.
- Ketanserin
Is a 5-HT2 antagonist on smooth muscle and platelet, it also block a-receptor, it used as antihypertensive.
- Ondansetron
Mechanism of Action
Mechanism not fully characterized; selective 5-HT3 receptor antagonist; binds to 5-HT3 receptors both in periphery and in CNS, with primary effects in GI tract
Has no effect on dopamine receptors and therefore does not cause extrapyramidal symptoms
Absorption
Bioavailability: 56-71% (PO); food increases extent of absorption (17%)
Onset: 30 min
Peak plasma time: IV, end of infusion; IM, 30 min; PO, 2 hr (tablet) or 1 hr (soluble film)
Distribution
Protein bound: 70-76%
Vd: Children, 1.7-3.7 L/kg; adults, 2.2-2.5 L/kg
Metabolism
Extensive hepatic metabolism, with hydroxylation followed by glucuronide (indole ring) or sulfate conjugation; metabolized by CYP2D6 and partly by CYP1A2 and CYP3A4
Metabolites: Glucuronide conjugate, sulfate conjugate (inactive)
Elimination
Half-life: 2-7 hr (children <15 years); 3-7 hr (adults); patients with mild to moderate hepatic impairment, 12 hr; patients with severe hepatic impairment (Child-Pugh class C), 20 hr
Renal Clearance: 0.26-0.38 L/hr/kg
Total body clearance: 600-700 mL/min
Excretion: Primarily urine (30-70%); feces (25%)
- Granisetron
Mechanism of Action
Selective 5-HT3 receptor antagonist; granisetron binds to 5-HT3 receptors both in the peripheral and central nervous system with primary effects in GI tract
Pharmacokinetics
Half-life: 3-14 hr
Onset: 4-10 min (IV)
Duration: 24 hr (IV)
Bioavailability: 60% (PO)
Release rate (patch): 3.1 mg/24 hr
Protein bound: 65%
Vd: 2-4 L/kg
Metabolism: Extensively metabolized in liver via N-demethylation, oxidation, conjugation, and CYP3A subfamily
Metabolites: Inactive
Total body clearance: 0.2-0.79 L/hr/kg
Excretion
Feces: 38%
Urine: 60%
- Palonosetron
Mechanism of Action
Selective 5-HT3 receptor antagonist; palonosetron binds to 5-HT3 receptors both in peripheral and central nervous system with primary effects in GI tract
Pharmacokinetics
Half-life: 40 hr
Peak plasma: 5.6±5.5 ng/mL (dose-proportional)
AUC: 35.8±20.9 ng.hr/mL (dose-proportional)
Protein bound: 62%
Vd: 8.3±2.5 L/kg
Metabolism: CYP2D6, CYP3A and CYP1A2
Metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron (<1% parent activity)
Excretion: Urine (80-93%); feces (5-8%)
Clearance: 160±35 mL/hr/kg (total)
- Dolasetron
Mechanism of Action
Selective 5-HT3 receptor antagonist this drug is binds to 5-HT3 receptors located on vagal neurons in GI tract, blocking signal to vomiting center in the brain, thus preventing N/V
Pharmacokinetics
Half-life: parent compound <10 min, hydrodolasetron (active) 4-9 hr
Peak plasma time: IV: 0.6 hr, PO: 1-1.5 hr
Bioavailability: 59-80% (PO)
Vd: 5.8-10 L/kg
Protein binding: 69-77%
Metabolism: dolasetron is metabolized to hydrodolasetron (active) by carbonyl reductase; hydrodolasetron is subsequently metabolized by CYP2D6 and CYP3A
Metabolites: hydrodolasetron (active)
Total body clearance: 9.4-13.4 mL/min/kg
Renal clearance: 2.6-3.4 mg/kg
Excretion: urine (53-61%); feces (25-33%)
- Tropisetron
Mechanism of action
Tropisetron competitively binds to and blocks the action of serotonin at 5HT3 receptors peripherally on vagus nerve terminals located in the gastrointestinal (GI) tract as well as centrally in the chemoreceptor trigger zone (CTZ) of the area postrema of the central nervous system (CNS). This results in the suppression of chemotherapy- and radiotherapy-induced nausea and vomiting.
Absorption
The absorption of tropisetron from the gastrointestinal tract is rapid (mean half-life of about 20 minutes) and nearly complete (more than 95%). Due to first-pass metabolism in the liver, the absolute bioavailability of a 5 mg oral dose is 60%. The peak plasma concentration is attained within three hours.
Volume of distribution
400-600 L.
Protein binding
71% bound to plasma protein in a non-specific manner.
Metabolism
The metabolism of tropisetron occurs by hydroxylation at the 5, 6 or 7 positions of its indole ring, followed by a conjugation reaction to the glucuronide or sulphate with excretion in the urine or bile (urine to faeces ratio 5:1). The metabolites have a greatly reduced potency for the 5-HT3 receptor and do not contribute to the pharmacological action of the drug.
Route of elimination
About 8% of tropisetron is excreted in the urine as unchanged drug, 70% as metabolites; 15% is excreted in the feces.
Half-life: 5.7 h.
Clearance: 1800 ml/min.
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