Tadalafil gehört zur Gruppe der PDE5-Hemmer und wirkt über eine hochselektive Blockade des Enzyms Phosphodiesterase Typ 5. Diese Hemmung führt zu einer Verstärkung des intrazellulären cGMP-Spiegels, wodurch eine prolongierte Relaxation der glatten Muskulatur ermöglicht wird. Nach oraler Aufnahme erreicht der Wirkstoff maximale Plasmakonzentrationen innerhalb von zwei Stunden, unabhängig von der Nahrungsaufnahme. Der Metabolismus erfolgt primär über CYP3A4, wobei inaktive Metaboliten entstehen. Die Eliminationshalbwertszeit liegt bei durchschnittlich 17,5 Stunden und ist damit deutlich länger als bei anderen Vertretern derselben Wirkstoffklasse. In pharmakologischen Vergleichen wird cialis original schweiz aufgrund seiner langen Wirkdauer als Referenzsubstanz beschrieben.

Serotonİn

SEROTONIN
Biosynthesis and Metabolism
L-Tryptophan

Tryptophan-5-hydroxylase X p-chlorophenilalanine
p-chloroamphetamine
5-Hydroxy tryptophan
(5-HTP)

Dopa decarboxylase
5-Hydroxytryptamine
(5-HT) 5-HT N-acetylase
MAOA-B N-acethyl-5-HT
Hydroxyindol
O-methyltransferase
5-hydroxyindole acetaldehyde
Melatonin
Aldehyde dehydrogenase Aldehyde reductase
5-HIAA 5-Hydroxytryptophol
Kidney
Distribution and Storage
• Found in plant (eg. bananas), animal tissues, • Enterochromaffin cells in the gastrointestinal tract • Serotonergic neurons in the enteric nervous system • Raphe nuclei of the brain stem, brain serotonergic neurons (involved in deppression, anxiety, migraine, mood, sleep, appetite, temperature regulation, pain, blood pressure and vomiting) • Pineal gland (Serotonin → Melatonin) • Carcinoid tumor
Pharmacological Effects

SEROTONIN RECEPTORS

Recepto
Distribution Postreceptor
Partially selective Partially selective
mechanism
agonists
antagonists
5-HT5A,B Brain Unknown

Cardiovascular System
• A powerful vasoconstrictor except in skeletal muscle
• Dimetoxyiodophenylaminopropan → 5-HT ↑→ • Sumatriptan → 5-HT1D → vasoconstraction • Ergot alkaloids → 5-HT1 → vasoconstraction • Serotonin → Angiotensin II, norepinephrine, PGF2α↑→ 1. Bezold-Jarich reflex → blood pressure ↓ 2. Vasoconstraction → blood pressure ↑ 3. Vasodilation in vessels in skeletal muscle, NO ↑→ Airways
bronchial sensory nerve ending → hyperventilation • Bronchospasm in asthmatic patients
Gastrointestinal tract
• The stimulatory response
→ direct effects of 5-HT in smooth muscle cells (5-
in intestine and 5-HT2B in stomach fundus) → stimulation of enteric ganglia (5-HT ↑ → stimulation of nevre endings on longitudinal and • Relaxation or contraction in esophagus (5-HT ↑ • Enteric 5-HT → intraluminal pressure↑, pH ↓, intraluminal pressure↑, pH ↓, peristaltic contraction ↑ (5-HT ↑
Nervous System
• present in raphe nuclei of the brain stem, brain
in vomiting center and GI tract → vomiting reflex X Ondansetron, granisetron. • A potent stimulant pain and itch sensory nerve ending chemoreceptor reflex (Bezold-Jarich reflex) → bradycardia and hypotention
Pathophysiologic effects
Carcinoid tumors
Enterochromaffin cell tumors → secretion of 5-HT↑→
serotonin crysis X octreotide
Migrain
• Plasma and platelet 5-HT concentrations vary with the
• Urinary concentrasions of 5-HT and its metabolites↑
Dumping sendrome
Postgastrectomy sendrome (flushing, dizziness,
weakness, vasomotor collapse, pain and headache)
Pulmonary embolism
Thromboemboli → Serotonin ve TXA ↑→
(5-HT2 X Ketanserin)
Anxiety and depression
Serotonin→5-HT →
(Buspirone)

Serotonin Agonists

• Acute treatment of migraine attacks with or without
• Cont: Ischemic heart disease, peripheral and cerebral
vascular syndromes, uncontrolled hypertension, use within 24 hours of ergotamine derivatives, another 5-HT1 agonists; use within 72 hrs CYP3A4 inhibitors, hemiplegic or basilar migraine, prophylactic treatment of migraine, severe hepatic impairment, in patients <18 years of age • Adverse reactions: Chest pain, palpitation, dizziness,
headache, chills, pain, vertigo, nausea, vomiting, dyspepsia, abdominal pain/discomfort, weakness, paresthesia, back pain, hypertonia, pharyngitis • Pregnancy Risk Factor C

Eletriptan (Relpax)
• It is the latest addition to this group
• Ketoconazole, erytromycin, fluconazole & verapamik
Naratriptan (Naramig)
• Is the one of the most potent 5-HT agonist
• The active metabolite, N-desmethyl rizatriptan has
Rizatriptan (Maxalt RPD)
• Absorption and elimination are rapid
• Metabolise by MAO-A to inactive metabolites • Competitive inhibitor of CYP2D6

Sumatriptan (Imigran, Sumatran)
• 5-HT1B and 5-HT1D ↑→ Acute migraine and Cluster
• Contraindicated in coronary artery disease and angina • Naratriptan is contraindicated in severe hepatic or renal impairment, peripheral vascular syndromes
Zolmitriptan (Zomig)
• The dose should be reduced in moderate to severe

Ergotamine (Avmigran, Cafergot, Ergafein),
dihydroergotamine (Neomigran)
• Some of their properties are similar to those of
Additional effects: adrenergic receptors block, vasoconstriction directly
Buspirone (Buspon), gepirone, ipsapirone
• 5-HT ↑


Fenfluramine, deksfenfluramine
• 5-HT res↑, serotonin release↑, serotonin re-uptake↓

Sibudramin (Reductil)
• serotonin re-uptake↓ →anorexigenic

Cisapride
• 5-HT ↑→

Serotonin- selective reuptake inhibitors
(SSRIs)

Fluoxetine, paroxetine, sertraline
• Antidepressants
• +MAO inhibitors → Serotonin syndromes
Serotonin antagonists

Methysergide (5-HT1 and 5-HT2 block)
strong competitive serotonin antagonist, partial serotonin agonist (vasoconstrictor) • used in the prophylaxis of migraine and Horton • antidiaretic in carcinoid syndrome and Dumping • contraindicates in peripheral vascular diseases and
Cyproheptadine (5-HT2A ve H1 block)
• Antidiaretic in carcinoid syndrome and Dumping • side effects: weight gain, drowsiness and increased
Ketanserin (5-HT1C, 5-HT2 and α1 block)
• used in the treatment of hypertension, vasospastic conditions and Raynaud syndrome
Ritanserin (5-HT2 block)
• platelet agregation ↓, vasoconstriction↓,
Granisetron >Ondansetron (5-HT3 block)
• used in the prevention of nausea and vomiting
Tropisetron (5-HT3 block)
• used in the prevention of nausea and vomiting
Pizotifen (Antiserotonerjik, antihistaminik)
• used in the prophylaxis of migraine

Source: http://www.dapenra.co.id/downloads/Serotonin.pdf