Serotonin

5-Hydroxytryptamine

• Widely distributed amine
• Present in animals and plants
• Present in GI enterochromaffin cells (90%), platelets, and brain
• Synthesized from tryptophan in diet in two steps (mechanism in later card)
• Platelets do not synthesize but take up serotonin from the blood in an active process. 
• Nerve terminals also take serotonin up from the blood via an active process
• Cell storage in granules similar to catecholamines

Tryptophan → 5-Hydroxytryptophan

Enzyme: Tryptophan hydroxylase

Rate Limiting

5-Hydroxytryptophan → 5-Hydroxytryptamine (Serotonin)

Enzyme: 5-OH Tryptophan decarboxylase

5-Hydroxytryptamine → 5-OH Indole Acetaldehyde

Enzyme: MAO

MAOI can lead to excess Serotonin

5-OH Indole Acetaldehyde → 5-Hydroxy Indole Acetic Acid

Enzyme: Aldehyde Dehydrogenase

• Other amino acids inhibit uptake into CNS
• p-chlorophenylalanine inhibits serotonin synthesis and promotes serotonin release
• Irreversible
• fenfluramine to decrease appetite
• Cocaine, SSRA (fluoxetine), TCA (imipramine) inhibit neuronal re-uptake
• Reserpine inhibits storage and causes depletion
• MAO inhibitors inhibit serotonin metabolism

• At least 15 types and subtypes
• Multiple transduction mechanisms
• 5HT-1A: Role in anxiety/depression
• 5HT-1D: Role in migraine
• 5HT-2: Role in CNS various behaviors and in cardiovascular system
• 5HT-3: Role in nausea and vomiting esp due to chemotherapy

• Central Neurotransmitter
• Precursor of melatonin
• GI tract- motility
• In carcinoid tumors: large amounts released leading to diarrhea, bronchoconstriction, and edema
• Plateletes: 5HT-2 receptors → aggregation and vasoconstriction

• Respiratory System:
• Bronchoconstriction if asthmatic
• Stimulation of aortic and carotid chemoreceptors
• Increased respiratory rates
• GI Tract:
• Small intestine very sensitive to serotonin
• Intense rhythmic contractions due to direct and indirect (ganglia in wall) effects
• Stimulates vomiting
• 5-HT 3 receptors on vagal afferents and centrally
• Cardiovascular System
• Direct vasoconstriction or large arteries and coronary arteries and indirect vasodialtion (NO and PGI₂ mediated
• Indirect vasodilation occurs after long term treatment
• Heart: direct inotropic and chronotropic effects
• Reflex mechanisms due to change in BP
• Stimulation of sensory nerve endings in baroreceptors and in vagal afferents in coronary circulation → bradycardia and hypotension
• Occurs at high overodose situations of Serotonin
• CNS effects
• Pain perception
• Sleep/Wakefulness - induces sleep
• Various behaviors normal/abnormal: depression, schizophrenia, obsessive compulsive behavior
• Neuroendocrine regulation-controls hypothalamic cells involved in release of several anterior pituitary hormones

• Sumatriptan: 5-HT1D agonist
• Contraindicated in patients with angina
• Fluoxetine: Selective serotonin uptake inhibitor for depression and other indications
• Buspirone: 5-HT1A agonist for anxiety
• Cisapride: 5-HT4 agonist for increase GI motility and decrease GE reflux
• Removed from US market due to fatal arrhythmias
• LSD: 5-HT1A- Hallucinogen
• Ergot Alkaloids: 5-HT1 and 5-HT2 and other receptors

• Methysergide and Cyproheptadine: 5-HT2 antagonists
• Used for treatmetn of carcinoid and migraines
• Ketanserin: 5-HT2 antagonist used as an anti-hypertensive
• Ondansetron: 5-HT3 antagonist for chemotherapy induced nausea and vomiting
• Clozapine: 5-HT2A/2C antagonist for schizophrenia

• Signal involved in local immune response, also a neurotransmitter
• Synthesized by the decarbozylation of histidine
• Either stored or quickly inactivated by histamine-N-methyltransferase and diamine oxidase
• Release of histamine from mast cells is stimulated by IgE antibodies which respond to forgein antigens in the body

• H1: Found on smooth muscle, endothelium, and CNS tissue
• Activation results in vasodilation, bronchoconstriction, smooth muscle activation and separation of endothelial cells
• H2: Found on parietal cells
• Regulates gastric acid secretion
• H3: Found in the CNS
• Regulates the release of other neurotransmitters
• H4: Recently discovered in different parts of the body including organs of the digestive tract, basophils, and bone marrow cells
• Function is not known

• Small, lipophilic, cross BBB
• Not specific to H1 receptor
• Groups:
• Ethylenediamines
• Ethanolamines
• Alkylamines
• Piperazines
• Tricyclics
• Common Structural Features:
• 2 aromatic rings
• Connected to a central carbon, nirtogen, or CO
• Spacer between the central X and amine
• Usually 2-3 carbons in length
• Linear, ring, branched, saturated or unsaturated
• Amine is substituted with small alkyl groups
• Cause severe sedation

• Modifications of first generation
• Less side effects
• More selective for peripheral H1 receptors
• Examples
• Terfenadine
• Loratadine
• Cetirizine
• Mizolastine
• Astemizole

• Metabolic derivatives or active enantimers of existing drugs
• Safer, faster acting, or more potent than second generation drugs
• Examples:
• Fexofenadine
• Desloratadine
• Levocetirizine
• More polar in nature so less side effects (less sedation)

• Relatively rapid onset
• Elimination Half-lives:
• Loratadine-up to 28 hrs
• Fexofenadine- 14 hrs (3rd Gen but listed under this heading in notes)
• Cetirizine- 8 hrs
• Children metabolize faster

• First Gen Drugs:
• Anticholinergic CNS interactions
• Gastrointestinal reactions
• Sedation, Dizziness, Tinnitus, Blurred vision, Euphoria, Lack or coordination, Anxiety, Insomnia, Tremor, Nausea and Vomiting, Constipation, Diarrhea, Dry Mouth, and Dry Cough
• 2nd Gen Drugs:
• Common side effects: drowsiness, fatigue, headache, nausea, and dry mouth
• Less common in second generation drugs  

• Group of potent biologically active cmpds containing 20 carbon atoms derived from arachidonic acid
• Prostaglandins, leukotrienes, thromboxanes, and prostacyclins
• Each eicosanoids is associated with a specific type of activity, in some cases these effects oppose one another
• Local mediators

• Lower BP
• Inhibit platelet aggregation
• Control inflammation
• Lower Gastric secretions
• Stimulate uterine contractions
• Relax smooth smuxles of the uterus
• Half life of only mins
• Dinoprostone
• Used to induce labor
• PGE₂
• Relax smooth muscles of the uterus
• Terminate pregnancies in early stages
• Misoprostol-
• Analogue of PGE₁
• Used to prevent gastric ulcers in patients who have a high risk of developing them
• Also used to treat Barrets esophagus

• Constrict blood vessels
• Trigger blood platelet aggregration

• Dilate Blood Vessels
• Inhibit blood platelet aggregration

• Constrict smooth muscles especially in the lungs

• Prostacycline
• Thromboxane A2
• Endothelin-1
• Serotonin
• Adrenomedulline
• Vasoactive Intestinal Peptide (VIP)
• Vascular Endothelial Growth Factor (VEGF)

• Potent vasoconstrictor
• Plasma levels increased in pulmonary hypertension

• Sulphonamide based endothelial receptors (ET_A ET_B) receptor blocker
• Contraindicated in pregnancy: teratogenicity esp in 1st trimester
• Inducer of
• CYP2C9
• CYP3A4
• Half life of 5.6 hrs +/- 1.6 hrs

• Sulphonamide based selective ET_A antagonist
• Half life: 5-7 hrs
• ET_A: ET_B 6500:1
• CYP 2C9 metabolized
• Interaction with warfarin
• Adverse Effects:
• Liver enzyme abnormalities
• Headache
• Edema
• Constipation
• Nasal Congestion
• URT infection
• Dizziness
• Insomnia
• Flushing

• Non-sulphonamide ET_A moderately selective (260:1) antagonist
• No significant interaction with coumarin based anticoagulants