Smooth Muscle (pt 3/4) Serotonin & Prostaglandins Flashcards
What is Serotonin?
-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
What functions are Serotonin involved in?
Mood
Sleep
Appetite
Temp regulation
Pain perception
Regulation of BP
Vomiting
Serotonin plays a role in what clinical conditions?
Depression
Anxiety
Migraines
Where is Serotonin predominantly located?
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)
Where is the remaining 10% of Serotonin located?
Serotonergic neurons are located in the Raphe Nuclei of the brain stem.
-Also around blood vessels
-synthesize, store, and release serotonin as a neurotransmitter
What do you need to know about the different Serotonin receptor subtypes?
5-HT receptor Subgroups – 7 different subgroups
-5-HT3 = ligand gated ion channel
-5-HT3 = excitatory, ionotropic, Zofran
-All others are GPCR (metabotropic)
What are the Nervous System Effects of Serotonin (5-HT3)?
-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)
What are the Respiratory Effects of Serotonin?
-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
What are the CV Effects of Serotonin?
-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
What are the GI Effects of Serotonin?
-Strong stimulant of GI Smooth Muscle
-Increases tone
-Facilitates peristalsis: Prokinetic
-No effect on secretions: ? Inhibitory effect; Non-conclusive research
What causes Serotonin Syndrome? (3 drugs)
Excess of serotonergic activity in the CNS.
-SSRIs
-2nd Gen Anti-Depressants
-MAOIs
What are the symptoms of Serotonin Syndrome?
-HTN
-Hyperreflexia, tremor, clonus
-Hyperthermia
-Hyperactive bowel sounds, diarrhea
-Mydriasis
-Agitation
-Coma
What is the treatment for Serotonin Syndrome?
-5-HT2 Antagonist
-Benzos (sedation)
-Muscle relaxants
-Intubation
-Ventilator
What drugs are the Serotonin Receptor Agonists?
-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
What is a Carcinoid Tumor?
-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
What are the Serotonin Antagonists that are too toxic for general use?
p-Chlorophenylalanine & p-Chloroamphetamine
What is Reserpine?
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
What are other misc Serotonin Receptor Antagonist Drugs?
-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
Describe Cryoheptadine (5-HT2 & H1)
-Prevents smooth muscle actions of both receptors
-No effect on gastric secretion
-Antimuscarinic effects & sedation
-Tx: Carcinoid Tumor & Cold Induced Urticaria
What is Ondansetron used for?
-Prototypical 5-HT3
-Prevention of N/V due to surgery or Chemo Tx
-Can be used during Pregnancy
What are Prostaglandins?
-Chemical mediators found in most body tissues (systemic actions)
-Regulate cell functions
-Promote the inflammatory response
Where are PGD2 located?
Airways, brain, mast cells
What are the effects of PGD2?
Bronchoconstriction
Where are PGE2 located?
Brain, Kidneys, Platelets
Vascular Sm. Muscle
What are the effects of PGE2?
-Bronchodilation
-Gastroprotection
-↑Activity of GI Sm. Muscle
-↑Sensitivity to pain
-↑Body temperature
-Vasodilation
Where are PGF2 located?
Airways, Eyes, Uterus
Vascular Sm Muscle
What are the effects of PGF2?
-↑Activity of GI Sm. Muscle
-Bronchoconstriction
-↑Uterine contraction
Where are I2 located? (Prostacyclin)
Brain, Endothelium, Kidneys, Platelets
What are the effects of I2? (Prostacyclin)
-↓Platelet aggregation
-Gastroprotection
-Vasodilation
Where is Thromboxane A2 located?
Kidneys, Macrophages, Platelets, Vascular Sm. Muscle
What are the effects of Thromboxane A2?
-↑Platelet aggregation
-Vasoconstriction
The constrictive effects on smooth muscle are mediated by______, and the dilation is mediated by______.
Constriction: mediated by the release of Ca (effected by CCBs)
Dilation: mediated by increased cAMP
Arachidonic Acid can become Prostaglandins via ____ or ____.
COX-1 or COX-2
Describe COX-1?
-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)
Describe COX-2.
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.
Traditional NSAIDs block _____, while Celecoxib is safer because it only takes out_____.
NSAIDs block COX-1 and COX-2 enzymes
Celecoxib blocks just COX-2.
What are the clinical uses of Prostaglandins?
-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
What is the MOA of NSAIDs (Aspirin, Ibuprofen)?
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
T/F: NSAIDs treat symptoms, but do not cure the underlying disorder.
True. Just symptom mgmt.
What are the anti-platelet effects of Aspirin?
-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)
Aspirin and ALL NSAIDS except for Acetaminophen and COX-2 Specific do what?
-Inhibit platelet aggregation
-Interfere with blood coagulation
-Increase the risk of bleeding
What are the antiplatelet effects of NSAIDs (non-Aspirin)?
-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
What are the normal Kidney effects of Prostaglandins?
-Increase bloodflow via vasodilation at times of decreased bloodflow
-Counters the vasoconstrictive effects of Angiotensin II, Norepinephrine & other constricting substances
What is aspirin effective in treating?
-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
How can aspirin therapy become nephrotoxic?
-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
How does Ibuprofen compare to Aspirin?
-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.
What do you have to be careful of with the administration of ibuprofen?
-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
What are the benefits of Celecoxib (Celebrex)?
-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
Describe Acetaminophen (Tylenol).
-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
What are contraindications to the use of NSAIDs?
-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.
What is Reye’s Syndrome?
Confusion, swelling of brain, and liver damage. Occurs in children recovering from some viral infection or with a metabolic disorder who are given ASA.
What are the considerations for NSAID use in pediatrics?
-Acetaminophen for fever and/or pain
-Ibuprofen for fever
-No Aspirin (Reye’s Syndrome: Rapidly progressive encephalopathy after acute viral illness)
What are the considerations for NSAID use in geriatrics?
-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
