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51 Cards in this Set

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Serotonin synth and metabolism? (aka 5-HT or enteramine)
1. synth from dietary tryptophan by the enzymes tryptophan hydroxylase and L-aromatic acid decarboxylase

2. stored in intracellular vesicles and released by a Ca dependent process

3.circulating serotonin is elim from the plasma by pulmonary uptake and hepatic metabolism

4. metab by MAO to an inactive metabolite (5-HIAA) which is excreted by the kidneys; urinary 5-HIAA conc is elevated in pts w/ carcinoid tumor
Distribution of serotonin?
1. central serotonergic neurons (primarily in the raphe nucle)

2. neuronal cells of the myenteric and submucosal plexuses and the mucosal enterochromaffin cells of the GI tract (pylorus and upper small intestine)
-- GI tract contains 90% of the serotonin in the body

3. platelets DO NOT synth serotonin – high affinity uptake system captures and stores serotonin in platelets as they pass through GI circulation

4. Mast cells DO NOT contain serotonin

5. Found in plants (stinging nettle) and venoms (wasps)
Physiological fxns of serotonin?
1. Neurotransmitter (CNS and GI tract)

2. The precursor for melatonin in the pineal gland

3. An autacoid (vasoconstriction and increased platelet aggregation)

4. Circulating serotonin does not enter the CNS, but can act on the chemoreceptor trigger zone (CTZ) and the cerebral blood vessels
Serotonin receptors are subdivided into four major groups…
1. 5-HT1
2. 5-HT2
3. 5-HT3
4. 5-HT4
5-HT1 receptors do what?
1. Vascular 5-HT1 receptors mediate vasodilation via:
-- direct stim of vascular smooth muscle
-- stim of endothelial cells which produce NO
-- prejxnal inhibition of NE release from sympth fibers

2. Stim of vascular 5-HT1B receptors constricts large extracerebral arteries and arteriovenous anastomoses
-- and unfortunately, the coronary arteries in pts w/ CAD

3. Stim of presynap 5-HT1B and 5-HT1D receptor inhibits release of proinflamm peptides from trigeminal nerve endings into the perivascular space

4. 5-HT1 receptros in the CNS
-- subdivided into at least 4 subtypes, but only one is of pharm importance for this course
-- 5-HT1A – involved in behavior (largest conc in the hippocampus); inhib neuronal activity by hyperpol cells (opens K channels)
-- the antianxiety drug bispirone is a partial agonist at 5-HT1A receptors
What drugs are selective agonists at 5-HT1B/D receptors

5-HT2 receptors do what?
1. Periph 5-HT2 receptors mediate:
-- vasoconstriction
-- stim of PHI2 synth by vascular endothelial cells
-- platelet aggregation – 5-HT is a weak platelet agonist, but it amplifies aggregation caused by TXA2, EPI, thrombin, etc
-- bronchoconstriction
-- increasedintestinal motility and secretion

2. central 5-HT2 receptors are the major 5-HT receptor involved in depression (large conc in cerebral cortex)
What drug is an antagonist at 5-HT1 and 5-HT2 receptors?
5-HT3 receptors do what?
1. Motor effects
-- stimulation of prejxnal 5-HT3 receptors increases ACh release from intramural neurons of the GI tract

2. Sensory effects
-- the Bexold-Jarisch chemoreceptor refles
-- stim of dermal sensory fibers (afferent pain fibers)
-- stim of visceral sensory fibers (afferent vagal to the CTZ)
-- emesis by direct stim of the CTZ
What drugs are antagonists at 5-HT3 receptors?


5-HT4 receptors do what?

stim of prejxnal 5-HT4 receptors increases ACh release from intramural cholinergic neurons of the GI tract
What drugs are agonists at 5-HT4 receptors?


Serotonin effects on the CNS?
Involved in regulation of sleep, affect (mood), body temp, sexual behavior, the perception of pain and BP
Serotonin effects on the blood vessels?
-- potent constrictor (5-HT2) of all vessels except those in skeletal muscle and heart which are dilated (5-HT1)
-- pulm blood vessels are very sensitive: constriction lowers venous return and thus CO
-- afferent arteriolar constriction lowers GFR and reduces urine flow
-- causes greater constriction of venules than arterioles: blood pools in caps causing flushing of the skin which gradually takes on a bluish hue. No effect on cap permeability
-- constricts coronary arteries via 5-HT1B receptors in pts w/ CAD

-- constricts large extracerebral arteries and arteriovenous anastomoses via stim of 5-HT1B receptors
Serotonin effects on heart and blood pressure?
-- changes in rate and dp/dt occur secondary to CV reflexes

Response to an i.v. injection of serotonin is triphasic
1. initial transitory decrease results from stim of 5-HT3 receptors in the coronary vascular bed (Bezold-Jarisch reflex = vagally mediated bradycardia and vasodilation from central inhibition of sympathetic tone)

2. secondary rise in BP is results from direct constriction of resistance vessels (5-HT2 receptors)

3. secondary rise is followed by a prolonged fall in BP produced by the dilation of arterioles (5-HT1 receptors) in the skeletal m.
Serotonin effects on hemostasis?
-- during repair of damaged blood vessels, platelets release serotonin which accelerated further platelet aggregation and causes local vasoconstriction (both via 5-HT2)

-- platelet aggregation elicited by serotonin does NOT produce a platelet “release rxn”
Serotonin effects on the lungs?
Bronchoconstriction (5-HT2) in asthmatic pts
Serotonin effects on the GI system?
1. bowel is very sensitive to small amts of 5-HT

2. Vagal stim releases 5-HT from cells in the GI tract

3. rise in intraluminal pressure elicits the discharge of 5-HT (from enterochromaffin cells) into the intestinal lumen

4. This 5-HT:
-- acts directly (5-HT2) to increase tone and motility of smooth m. and indirectly to lower the threshold of intraluminal pressure required to activate the peristaltic reflex (a local reflex involving the intrinsic nerves)
-- enhances the release of ACh (via 5-HT3 and 5-HT4 receptors) which also increase GI motility, tone, and secretion
-- 5-HT is not important in the normal regulation of GI motility
Serotonin effects on the uterus?
Mild contraction of the pregnant uterus
Pathophysiologic effects of serotonin?
1. DEPRESSION – abnormalities of central serotonin release appear to be involved in endogenous depression

2. NAUSEA AND VOMITING – 5-HT produces n/v by stim of 5-HT3 receptors at the CTZ and/or visceral sensory afferent fibers carried in the vagus

3. CARDIOVASCULAR DISEASE – 5-HT constricts coronary arteries in pts w/ CAD


Serotonin and carcinoid syndrome
-- tumors or the enterochromaffin cells secrete serotonin autonomously or in response to stimuli (eg. alcohol)
-- massive elevation of circulating serotonin causes:
1. bronchospasm
2. intestinal cramping and diarrhea
3. steatorrhea
4. unusual flusing of skin of trung and neck
-- histamine and PGs may also be involved in producing these effects
-- large tumors may use so much tryptophan for 5-HT synth that niacin suffers enough to produce pellagra
Treatment of carcinoid syndrome?
Treat w/ CYPROHEPTADINE (blocks 5-HT1 or 5-HT2 receptors) or OCTREOTIDE (a somatostatin agonist)

OCTREOTIDE inhibits the release of serotonin from the tumor cells
Explain post-gastrectomy dumping syndrome.
-- may occur after surgical trtmt of a peptic ulcer

Within 30min of eating, patients experience:
1. tachycardia
3. postural hypotension
4. sweating
5. abdominal pain
6. diarrhea
7. vomiting

-- syndrome believed to result from rapid dumping of hyperosmolar gastric contents into the intestines which results in:
1. rapid shift of water from vascular compartment into the gut, producing hypovolemia, which in turn elicits a baroreflexly-mediated increase in sympth activity (tachy and diaphoresis)
2. stimulation of the 5-HT release into the intestinal lumen
3. a direct/indirect increase in intestinal tone and motility (cramping), activation of the peristaltic reflex (diarrhea) and stim of afferent vagal fibers (vomiting)
Which drugs are 5-HT4 serotonin agonists?
Cisapride and tegaserod general properties and MOA?
5-HT4 receptor agonists

MOA: enhance ACh release in the GI tract
Pharm effects of cisapride and tegaserod?
-- enhanced esoph clearance of gastric acid

-- elevated LES pressure

-- accelerated gastric emptying

-- decreased small bowel transit time
Therapeutic uses of cisapride and tegaserod?
1. increase LES pressure in pts w/ GERD

2. Accelerate gastric emptying and increase LES pressure prior to surgery

3. clear stomach and duodenum of food prior to endoscopic examination

4. enhance gastric emptying in pts w/ diabetic gastroparesis
Adverse S/Es of cisapride and tegaserod?
Abdominal cramping
What is a migraine headache?
Attack of intense headache, often unilateral, and often exacerbated by normal physical activity
-- assoc anorexia, nausea, vomiting, and photo- or phonophobia
-- headache may last 4-72h
-- Several theories on etiology
Theories on migraine headache etiology?
1. Something (?) causes an initial cerebral vasoconstriction, and the resulting oligemia produces the visual aura
-- vasoconstriction is followed by excessive dilation of extracerebral (meningeal and dural) arteries and A-V anastomoses
-- vasodilation causes headache

2. Release of neuropeptides (VIP, CGRP, etc) from the trigeminal nerve endings causes a sterile inflamm rxn around sensory nerves and the extravasation of fluid into the meningeal mbrns
Presentation of cluster headache?
-- named for tendency to occur in clusters of time
-- charac by deep non-throbbing pain usually involving one eye and the adjacent temple, cheel or forehead
-- same part of face or head involved in every headache
-- affected eye is watery and red w/ partial ptosis (and even miosis)
-- ipsilateral nostril is congested or hypersecretory; n/v rare
-- typically occur during sleep, lasting .5-2h
Patient response to a cluster headache? Epidemiology?
-- unlike pts w/ migraines who prefer to lie quietly, pts w/ cluster headaches pace the floor in search of relief
-- remission of headache is followed by an exhausted sleep, only to be followed by reappearance of another attack some time later
-- pts usually have 1-4 headaches/day for several weeks/months before the headaches cease, only to reappear some months later
-- begins in 3rd and 4th decade and usually occurs in males
-- may occur in daylight hours, especially in pts who imbibe alcohol, a particularly powerful trigger for these headaches
Cluster headache treatment?
-- respond poorly to ergotamine cmpds

-- inhalation of oxygen is effective and is used for home therapy
What are the 5-HT1B/1D agonists?
Index cmpd is SUMATRIPTAN
Sumatriptan and almotriptan MOA?
Hypothesized to involve three actions:
1. cranial vasoconstriction

2. peripheral inhib of the release in inflamm peptides from the trigeminal nerve

3. central inhib of second-order neurons in the trigemino-cervical cmpls
Pharm effects of sumatriptan and almotriptan?
-- constricts large extracerebral arteries and A-V anastomoses
-- these effects may have nothing to do w/ efficacy of these drugs in trtmt of migraine headache

-- inhibits release of proinflamm neuropeptides which stim sensory pain receptors and cause vasodilaiton and beurogenic extravasation of plasma

-- NO peripheral dilation or constriction of normal blood vessels
Therapeutic uses of sumatriptan and almotriptan?
1. rapidly relieves headache and other symptoms of migraine attacks, regardless of type or duration of attack prior to therapy
2. SUMATRIPTAN has short half-life (~2h), so headache may occur after single-dose therapy
3. If pts does not respond well to initial dose, subsequent doses are not likely to produce additional benefit

1. sumatriptan (s.c.) signif decreases the severity of pain
2. sumatriptan also decreases the fxnal disability and ipsilateral conjunctival injection
Toxicity and S/Es of sumatriptan and almotriptan?
-- rebound headache
-- “atypical” sensations – tingling, warm/hot sensation
-- dizziness, vertigo
-- severe coronary vasospasm in pts w. signs/symptoms CAD or MI
-- do not use w/ ergot-type drugs (dihydroergotamine) or w/in 24h of use of an egot-type drug
Name the serotonin agonist and antagonist?
General properties of metoclopramide?
1. AGONIST at 5-HT4 receptors

2. ANTAGONIST at 5-HT3 receptors

3. ANTAGONIST at D2 receptors
MOA of metoclopramide?
1. GI STIM – stim of 5-HT4 receptor enhances ACh release from cholinergic neurons innervating the LES and stomach

2. ANTIEMETIC EFFECTS – blockade of 5-HT3 receptors (vagal afferents and CTZ) and D2-dopamine receptors
Pharm effects of metoclopramide?
1. Enhances esoph clearance of gastric acid

2. Elevates LES pressure

3. Accelerates gastric emptying

4. Decreases small bowel transit time
Therapeutic uses of metoclopramide?
1. increase LES pressure in pts w/ GERD

2. empty stomach and increase LES pressure prior to surgery

3. clear the stomach/duodenum of food prior to endoscopy

4. enhance gastric emptying in pts w/ diabetic gastroparesis

5. prevent nausea and vomiting in pts w/ peptic ulcer, ulcerative colitis, and gastric cancer

6. prevent n/v in pts receiving chemo or radiation for cancer
Adverse S/Es of metoclopramide?
-- sedation and fatigue

-- altered GI absorption of other drugs

-- Blockade of central D2-dopamine receptors
-- increased plasma prolactin can cause galactorrhea and amenorrhea (females) and gynecomastia (males)
-- dystonias, Parkinson’s or tardive dyskinesia, akathisia
Serotonin receptor antagonists?


General properties of ondansetron and dolasetron?
Ondansetron (p.o. or i.v.) – 5-HT3 receptor antagonist which has NO EFFECT on dopa receptors or 5-HT4 receptors
MOA of ondansetron and dolasetron?
-- chemo and radiation for cancer releases 5-HT from the 5-HT containing cells of the GI tract

-- this 5-HT stims the 5-HT3 receptors at vagal nerve endings and/or CTZ to produce n/v

-- ondansetron blocks 5-HT2 receptors at both these sites
Therapeutic uses of ondansetron and dolastetron?
1. NAUSEA/VOMITING caused by chemo/radiation
-- ondansetron is more efficacious than metoclopramide and does not cause acute dystonic rxns or akathisia like metoclopramide
-- well-suited for use in younger adults and children (groups more likely to develop dystonia w/ metoclopramide)
-- Dexamethosone and ondansetron are EQUALLY efficacious in treating n/v caused by chemo, and their combo in pts receiving high doses is more effective than either agent given alone
-- dexamethasone mech of blocking n/v is unknown, although it is the GOLDSTANDARD for trtmt n/v


3. N/V assoc w. “morning sickness” during pregnancy
Gen properties, MOA, and pharm effects of cyproheptadine?
-- structurally related to the phenthiazines. Enters the CNS

Cyproheptadine blocks:
1. 5-HT1 and 5-HT2 receptors
2. H1 histamine receptors
3. muscarinic receptors – causes most of the adverse S/Es
Therapeutic uses of cyproheptadine?
ALLERGIC DISEASES (primarily from antihist effects)
-- allergic rhinitis
-- conjunctivitis
-- pruritic dermatoses
-- prophylaxis of cold urticaria (urticaria, angioedema, and occasionally hypotension develops after exposure to cold air or water)

-- stims food intake in children and adults
-- produces variable weight gain/linear growth in infants/children
-- effective in some pts w/ anorexia nervosa

MIGRAINE HEADACHE (5-HT1 receptors??)
-- prophylaxis reduces frequency, intensity

CARCINOID SYNDROME (5-HT1 and 2 receptors)
-- decreases GI hypermotility and hypersecretion and diarrhea

-- partially relieves the GI symptoms

-- used as soporific agent to prevent nightmares
S/Es from cyproheptadine?
Primarily caused by muscarinic receptor blockade:
1. exacerbation of angle-closure glaucoma, BPH, and GI or GU obstruction
2. CNS depression which is additive w/ other drugs
3. drowsiness and sedation
4. paradoxical restlessness and excitation in children
5. dry mouth, nose and throat