Pharm 3:

Question 1

Nausea

Answer 1

• unpleasant feeling
• Decreased Gastric Motility
• Increased Intestinal Tone

Question 2

Retching

Answer 2

• Spasmodic respiratory contractions
• closed glottis

Question 3

Emesis means

Answer 3

Vomiting

Question 4

Vomiting Results when

Answer 4

1. Deep breath
2. Larynx raised to open esophageal sphincter
3. soft palate raise to close nares
4. Diaphragm contracts down
   
   1. negative thorax pressure
   2. facilitates esophagus opening
5. Abdominal muscles contract expelling stomach contents
   
   1. w/pyloris closed only way is out

Controlled by THE CNS

Question 5

Emesis Center

Answer 5

• aka Vomiting Center
• Medullary
• receives afferent input from periphery
  
  • pharyxn

Question 6

Chemoreceptor Trigger zone (CTZ)

Answer 6

• in area postrema
• projects to Emesis center

Question 7

Afferent input to EC

Answer 7

• CTZ
• GI Tract
  
  • vagal and sympathetic
  • mucosal irritatioin
  • GI distention
• Non-GI visceral input
  
  • bile ducts
  • peritoneum
  • heart
• Vestibular system
• Forebrain input
  
  • psychological factors

Question 8

Emesis: Treatment

Answer 8

• Depends on etiology
  
  • peripheral
    
    • inflammation
    • toxins
    • CTX and other drugs
  • motion sickness
  • Psychological factors

Question 9

Classes of Antiemetic Drugs

Answer 9

• 5-HT3 antagonists
• NK1 (Neurokinin 1) receptor antagonist (anti-substance P)
• Phenothiazines and butyrophenones
  
  • anti-dopaminergic antipsychotics
• Substituted benamides
  
  • anti-dopainergic
• Benzodiazepines
  
  • effective against psychologically-induced emesis
• H1 antagonists
• anti-cholinergics
• Cannabinoids
• Corticosteroids

Question 10

5-HT3 Antagonists

Answer 10

• Receptors present on visceral afferents in CZ and EC
  
  • GOOD TARGET
• Setron Family
  
  • Graniseetron
  • Dolasetron
  • Ondansetron (zofran)
• Good efficacy against chemotherapy-induced N&V (CINV)
  
  • interfere w/vagal afferents
  • less effective against motion sickness and psychologicall-induced emesis
• Long Half-lives
  
  • QD or BID dosing
• Extensive Liver metabolism
  
  • Hepatic impairment=dose reduction
• Good toxicity profile
  
  • headache, dizziness, constipation
  • some prolonged QT
    
    • Dolasetron

Question 11

NK1 Antagonists

Answer 11

• AKA substace P and Tachykiniin receptor antagonists
• Receptors present in GI, CTZ and NTS (Vomitng center)
  
  • GOOD TARGET
• -Pitant
  
  • Aprepitant (FDA Approved)
  • Fosaprepitant (IV aprepitant)
  • Rolapitant (FDA approved)
  • Casopitant (Close to EU approval)
  • Vestipitant (In clinical Trials)
• Long duration of action
• More effective than 5HT3 antagonists against the second phase of CINV
• Evidence:
  
  • anxiolytic and antidepressant
• Problems:well tolerated
  
  • decreased appetite
  • dizziness
  • indigestion

Question 12

Phenothiazines

Answer 12

• Antagonist of dopamine receptors
  
  • especiallly in CTZ
  • good antihistamines also
• Phenothiazines
  
  • Prochlorperazine
  • Promethazine
  • Thiethylperazine
• Butyrophenone
  
  • Droperidol
• Black box warning due to prolonged QT
  
  • only at high antipsychotic dose
• effective against post-op N&V (PONV)
• Adverse Effects:
  
  • Extrapyramidal
    
    • tardive dyskinesia
  • Prolonged QT, Torsades w/droperidol

Question 13

Substituted Benzamides

Answer 13

• Metoclopramide and trimethobenzamide
  
  • dopamine receptor antagonists
    
    • (other effects also)
  • Mechanism unclear
• Adverse events:
  
  • Extrapyramidal
    
    • tardive dyskinesia
      
      • treatment sould be short term
      • Class action law suits-patients tx longer than 12 weeks

Question 14

H1 Antihisatmines

Answer 14

• first generaiton antihistamines
  
  • Diphenhydramine and Dimenhydrinate
  • Effective against motion sickness
  • Problems: Sedation and Anticholinergic effects
    
    • or a benefit
• Newer generation
  
  • Meclizine
  • Fewer Anticholinergic effects

Question 15

Scopolamine

Answer 15

• Muscarinic Antagonist
• very effect against motion sickness
  
  • Problems: anticholinergic effects
  • Transdermal patch localizes effects
    
    • to some extent

Question 16

Benzodiazepines

Answer 16

• Effective against anxiety-related emesis (Memory, Fear, Anticipation)
  
  • important in cancer chemotherapy
  • Sedation may be problematic
    
    • short acting compounds minimize
      
      • lorazepam
    • Risk of dependence

Question 17

Cannabinoids

Answer 17

• PPrincipal constituent of marijuana is Delta9-THC
• Effective against all forms of N&V
• Derivatives approved for use in US
  
  • Dornabinol and nabilone
  • against N&V w/cancer chemotherapy (CINV)
  • AIDS-related chachexia
• Adverse effects limit usefulness
  
  • psychoactivity

Question 18

Inflammatory Bowel Disease (IBD): etiology

Answer 18

• Etiology unclear
  
  • envioromental factors
  • Lifestyle
  • autoimmune involvement

Question 19

Inflammatory Bowel Disease (IBD): Treatment

Answer 19

• Aminosalicylates
• Glucocorticoids
• Antimetabolites
  
  • purine analogs
  • Methotrexate
• Anti-TNF-Alpha Antibody
• Anti-a4-integrin

Question 20

Aminosalicylates

Answer 20

• Long history of successful Treatment of IBD
• contain 5-ASA
• anti-inflammatory via cyclooxygenase inhibition
• Localized, topical effects
• low systemic exposure
• Problems:
  
  • Renal Toxicity
    
    • contraindication w/renal disease
  • Alergic Rxns to Aspirin
  • Common less serious side effects
    
    • headache
    • flatulence
    • abdominal pain
    • diarrhea

Question 21

IBD stand approach

Answer 21

Bottom up

1. Antibiotics/ Aminosalicylates
2. Immunomodulartors/Corticosteroids
3. Surgery/Biologics

Question 22

Azo compounds

Answer 22

• -salazine
  
  • sulfsalazine
  • olsalazine
  • balsalazine
• prodrugs are poorly absorbed from intestine
• Azo bonds are cleaved by colonic flora release 5-ASA
• 5-ASA poorly absorbed from colon but acetylated by flora
• Ac-5ASA
  
  • inactive but absorbable
• Sulfapyradine carrier is absorbed and produces systemic effects
  
  • N&V
  • Headache
  • achy malaise

Question 23

Mesalamine Formulations

Answer 23

• Deliver 5-ASA to targeted portions of the GI
  
  • -asa
    
    • Pentasa
      
      • targets entire GI
    • Asacol
      
      • targets ileum and colon
    • Rowasa
      
      • enema formulation targets colon
    • Canasa
      
      • suppository formulation

Question 24

Glucocorticoids

Answer 24

• adrenocorticosteroid anti-inflammatory drugs
• Reduce expression of pro-inflammatory gene products
  
  • NF-kB
  • AP-1
  • Myriad
• Prednisone, Prenisolone, Dexamethasone, Hydrocortisone
  
  • intermediate half life allow infrequent oral dosing
  • best use-short term flare ups
• Administered by:
  
  • Injection
  • Oral
  • Targeted preparations
    
    • Suppositories and enemas target bowel
• Adverse Effects
  
  • significant bc of wide-spread activity
    
    • receptors expressed in most tissues
  • Cushings-type effects
    
    • metaboilc changes
    • redistribution of fat
    • hair growth
  • Adrenal Insufficiency
  • Infection
  • CNS effects
  • Electrolyte imbalance