Smooth Muscle (pt 3/4) Serotonin & Prostaglandins

Question 1

What is Serotonin?

Answer 1

-Neurotransmitter
-Local hormone in the gut
-Component of the platelet clotting process – serotonin is found in platelets in the blood
-Found in plant & animal tissues, venoms & stings
-After synthesis, it is either stored or inactivated (by MAO)
-In the pineal gland – serotonin is a precursor to Melatonin

Question 2

What functions are Serotonin involved in?

Answer 2

Mood
Sleep
Appetite
Temp regulation
Pain perception
Regulation of BP
Vomiting

Question 3

Serotonin plays a role in what clinical conditions?

Answer 3

Depression
Anxiety
Migraines

Question 4

Where is Serotonin predominantly located?

Answer 4

90% of the serotonin of the body is found in the enterochromaffin cells of the GI tract.
-Synthesize Serotonin
-Store it with ATP (granules)
-Released in response to mechanical or neuronal stimuli
-Paracrine action (local)

Question 5

Where is the remaining 10% of Serotonin located?

Answer 5

Serotonergic neurons are located in the Raphe Nuclei of the brain stem.
-Also around blood vessels
-synthesize, store, and release serotonin as a neurotransmitter

Question 6

What do you need to know about the different Serotonin receptor subtypes?

Answer 6

5-HT receptor Subgroups – 7 different subgroups
-5-HT3 = ligand gated ion channel
-5-HT3 = excitatory, ionotropic, Zofran
-All others are GPCR (metabotropic)

Question 7

What are the Nervous System Effects of Serotonin (5-HT3)?

Answer 7

-GI tract & Medulla: Vomiting reflex due to chemical triggers
-Potent stimulator of pain and itching: Insect & plant stings
-Coronary Vascular Beds: Bezold-Jarisch Reflex (bradycardia and hypotension)

Question 8

What are the Respiratory Effects of Serotonin?

Answer 8

-Small direct stimulant effect on bronchial smooth muscle
-Facilitates Ach release from bronchial vagal nerve endings
-May cause hyperventilation due to chemoreceptor reflex OR stimulation of bronchial sensory nerve endings

Question 9

What are the CV Effects of Serotonin?

Answer 9

-Constriction of vascular smooth muscle: Powerful vasoconstrictor (reflex bradycardia). Pulmonary & renal vessels very sensitive

EXCEPT: Skeletal muscle & heart
-Dilates blood vessels
-If the endothelium is damaged, the coronary vessels will constrict

⬆Platelet aggregation

Question 10

What are the GI Effects of Serotonin?

Answer 10

-Strong stimulant of GI Smooth Muscle
-Increases tone
-Facilitates peristalsis: Prokinetic
-No effect on secretions: ? Inhibitory effect; Non-conclusive research

Question 11

What causes Serotonin Syndrome? (3 drugs)

Answer 11

Excess of serotonergic activity in the CNS.
-SSRIs
-2nd Gen Anti-Depressants
-MAOIs

Question 12

What are the symptoms of Serotonin Syndrome?

Answer 12

-HTN
-Hyperreflexia, tremor, clonus
-Hyperthermia
-Hyperactive bowel sounds, diarrhea
-Mydriasis
-Agitation
-Coma

Question 13

What is the treatment for Serotonin Syndrome?

Answer 13

-5-HT2 Antagonist
-Benzos (sedation)
-Muscle relaxants
-Intubation
-Ventilator

Question 14

What drugs are the Serotonin Receptor Agonists?

Answer 14

-Buspirone (5-HT1A): Non-benzo anxiolytic
-Dexfenfluramine: Appetite suppressant (withdrawn cardiotoxicity)
-Sumatriptan (5HT1D/1B): Migraine HAs
-Cisapride: Treatment of reflux & motility disorders. Highly toxic – for compassionate use only
-Tegaserod: Irritable bowel syndrome
-Fluoxetine: SSRI for depression

Question 15

What is a Carcinoid Tumor?

Answer 15

-Slow growing neuroendocrine tumor (emits NT like substances)
-Most commonly located in the intestine
-Usually begin in the digestive tract or the lung
-10% secrete excess levels of hormone especially Serotonin
-Potential for malignancy

Question 16

What are the Serotonin Antagonists that are too toxic for general use?

Answer 16

p-Chlorophenylalanine & p-Chloroamphetamine

Question 17

What is Reserpine?

Answer 17

A Serotonin Antagonist.
-Blocks aminergic transmitter vesicles from uptake and storage of serotonin, norepinephrine & dopamine (Blocks storage)
-Treatment of HTN
-Adverse Effects: sedation, fatigue, nightmares, depression, EPS, diarrhea, GI cramps

Question 18

What are other misc Serotonin Receptor Antagonist Drugs?

Answer 18

-Phenoxybenzamine (5-HT2): Irreversible α-blocker (tx of Pheo)
-Ergot Alkaloids (can be agonist or antagonist depending on type of Ergot)
-Cryoheptadine (5-HT2 & H1)
-Ondansetron

Question 19

Describe Cryoheptadine (5-HT2 & H1)

Answer 19

-Prevents smooth muscle actions of both receptors
-No effect on gastric secretion
-Antimuscarinic effects & sedation
-Tx: Carcinoid Tumor & Cold Induced Urticaria

Question 20

What is Ondansetron used for?

Answer 20

-Prototypical 5-HT3
-Prevention of N/V due to surgery or Chemo Tx
-Can be used during Pregnancy

Question 21

What are Prostaglandins?

Answer 21

-Chemical mediators found in most body tissues (systemic actions)
-Regulate cell functions
-Promote the inflammatory response

Question 22

Where are PGD2 located?

Answer 22

Airways, brain, mast cells

Question 23

What are the effects of PGD2?

Answer 23

Bronchoconstriction

Question 24

Where are PGE2 located?

Answer 24

Brain, Kidneys, Platelets
Vascular Sm. Muscle

Question 25

What are the effects of PGE2?

Answer 25

-Bronchodilation
-Gastroprotection
-↑Activity of GI Sm. Muscle
-↑Sensitivity to pain
-↑Body temperature
-Vasodilation

Question 26

Where are PGF2 located?

Answer 26

Airways, Eyes, Uterus
Vascular Sm Muscle

Question 27

What are the effects of PGF2?

Answer 27

-↑Activity of GI Sm. Muscle
-Bronchoconstriction
-↑Uterine contraction

Question 28

Where are I2 located? (Prostacyclin)

Answer 28

Brain, Endothelium, Kidneys, Platelets

Question 29

What are the effects of I2? (Prostacyclin)

Answer 29

-↓Platelet aggregation
-Gastroprotection
-Vasodilation

Question 30

Where is Thromboxane A2 located?

Answer 30

Kidneys, Macrophages, Platelets, Vascular Sm. Muscle

Question 31

What are the effects of Thromboxane A2?

Answer 31

-↑Platelet aggregation
-Vasoconstriction

Question 32

The constrictive effects on smooth muscle are mediated by______, and the dilation is mediated by______.

Answer 32

Constriction: mediated by the release of Ca (effected by CCBs)
Dilation: mediated by increased cAMP

Question 33

Arachidonic Acid can become Prostaglandins via ____ or ____.

Answer 33

COX-1 or COX-2

Question 34

Describe COX-1?

Answer 34

-Synthesized continuously
-Physiologic PGs
-Present in all tissues/cells (platelets, endothelial cells, GI tract, kidneys)
-Essential in synthesis of TXA2 (plt aggregation). Inhibition of COX1 inhibits Thromboxane A2, inhibiting plt aggregation for the lifetime of the platelet (8-10 days)

Question 35

Describe COX-2.

Answer 35

Pathologic PGs.
-Present in several tissues (not all): brain, bone, kidneys, GI tract, female reproductive system
-Inactive until stimulated by pain & inflammation
-Inducible pain and inflammatory.

Question 36

Traditional NSAIDs block _____, while Celecoxib is safer because it only takes out_____.

Answer 36

NSAIDs block COX-1 and COX-2 enzymes
Celecoxib blocks just COX-2.

Question 37

What are the clinical uses of Prostaglandins?

Answer 37

-Female Reproductive Sys: Induction of labor and Dysmenorrhea
-Male Reproductive Sys: Erectile dysfunction
-Pulmonary HTN: I2 ↓peripheral, pulmonary & coronary vascular resistance
-Patent ductus arteriosus (↓E2 = closure)
-Organ transplant rejection
-Osteoarthritis
-Rheumatoid Arthritis
-Glaucoma
-MI/Stroke prevention

Question 38

What is the MOA of NSAIDs (Aspirin, Ibuprofen)?

Answer 38

Inhibit COX-1 & COX-2.
-Analgesic: Inhibiting prostaglandins that promote pain
-Antipyretic: Inhibiting pyrogenic (fever inducing) prostaglandins
-Anti-inflammatory Effects: Inhibiting prostaglandins that promote edema

Question 39

T/F: NSAIDs treat symptoms, but do not cure the underlying disorder.

Answer 39

True. Just symptom mgmt.

Question 40

What are the anti-platelet effects of Aspirin?

Answer 40

-ASA binds irreversibly to platelet COX-1
-Prevents the synthesis of Thromboxane A2
-Inhibits platelet aggregation
-Irreversible: Effect lasts for the lifetime of the platelet (7-10 days)

-Use has declined due to the adverse effects of the GI tract and the advent of newer drugs
-Low-dose ASA still in use for MI and stroke (anti-platelet effect – decreased clot formation)

Question 41

Aspirin and ALL NSAIDS except for Acetaminophen and COX-2 Specific do what?

Answer 41

-Inhibit platelet aggregation
-Interfere with blood coagulation
-Increase the risk of bleeding

Question 42

What are the antiplatelet effects of NSAIDs (non-Aspirin)?

Answer 42

-NSAIDS bind reversibly with platelet COX-1
-Anti-platelet effects lasts only while the drug is present in the blood
-Platelet function returns after 4 half-lives of the drug

Question 43

What are the normal Kidney effects of Prostaglandins?

Answer 43

-Increase bloodflow via vasodilation at times of decreased bloodflow
-Counters the vasoconstrictive effects of Angiotensin II, Norepinephrine & other constricting substances

Question 44

What is aspirin effective in treating?

Answer 44

-Prototype
-Effective in mild to moderate pain
Skin, muscles, joints and other connective tissue
-Ex. Arthritis
-PO: plain, enteric coated (can irritate lining of GI tract if uncoated), chewable tablets
-Unstable in liquid
-PR: suppositories
-Nephrotoxic at high doses

Question 45

How can aspirin therapy become nephrotoxic?

Answer 45

-Aspirin therapy inhibits prostaglandins that dilate the renal blood vessels
-Constriction of renal arteries and arterioles
-Decreases the bloodflow to the kidneys
-Decreases GFR
-Increases the retention of salt and water

Question 46

How does Ibuprofen compare to Aspirin?

Answer 46

-Ibuprofen is a Propionic acid derivative
-Better tolerated than aspirin, but more money.
-Both cause all the same adverse effects/
-Has decreased GI irritation/GI upset compared to aspirin.

Question 47

What do you have to be careful of with the administration of ibuprofen?

Answer 47

-Beware of accidental OD: combined use of prescription and non-prescription forms of NSAIDS
-Monitor BUN/Creatinine due to potential for renal damage
-Use lower doses in patients with liver or renal impairment

Question 48

What are the benefits of Celecoxib (Celebrex)?

Answer 48

-Selective COX-2 Inhibitor
-Less gastric irritation
-No antiplatelet effects
-Potentiate pre-existing HTN
-Highly protein bound
-Half-life 11 hours
-Often given PO pre-op

Question 49

Describe Acetaminophen (Tylenol).

Answer 49

-Commonly used Aspirin supplement
-Does not cause N/V, GI bleeding or disrupt coagulation
-Equal to Aspirin in analgesia & antipyrexia
-Lacks anti-inflammatory effects
-OD = fatal liver damage
-Tablet, liquid, rectal suppository, & IV
-Marketed OTC in many analgesics & cold remedies
-Prescribed with codeine, hydrocodone, or oxycodone
-Enhance analgesic effects

Question 50

What are contraindications to the use of NSAIDs?

Answer 50

-Peptic ulcer disease
-GI or other bleeding disorders (Drinkers, eso varices)
-Hypersensitivity reaction
-Cross-sensitivity between ASA & NSAIDS
-Impaired renal function
-ASA is C/I in children with influenza/chickenpox (Reye’s syndrome)
-Alcoholics (NO TYLENOL)
-Asthma

ASA irritates GI lining (bleeding)

ASA and NSAIDs can induce bronchospasm; use caution in asthmatics.

Question 51

What is Reye’s Syndrome?

Answer 51

Confusion, swelling of brain, and liver damage. Occurs in children recovering from some viral infection or with a metabolic disorder who are given ASA.

Question 52

What are the considerations for NSAID use in pediatrics?

Answer 52

-Acetaminophen for fever and/or pain
-Ibuprofen for fever
-No Aspirin (Reye’s Syndrome: Rapidly progressive encephalopathy after acute viral illness)

Question 53

What are the considerations for NSAID use in geriatrics?

Answer 53

-Acetaminophen: safe in recommended doses. Caution in liver damage and alcohol use/abuse
-Aspirin: safe in small doses for prevention of MI & Stroke (81 mg)
-ASA/NSAIDS: safe in PRN dosing for pain or pyrexia. Monitor GI effects, Take with food, Monitor renal function