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Flashcards in Pharm 3: Deck (24)
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1

Nausea

  • unpleasant feeling
  • Decreased Gastric Motility
  • Increased Intestinal Tone

2

Retching

  • Spasmodic respiratory contractions
  • closed glottis

3

Emesis means

Vomiting

4

Vomiting Results when

  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

5

Emesis Center

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

6

Chemoreceptor Trigger zone (CTZ)

  • in area postrema
  • projects to Emesis center

7

Afferent input to EC

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

8

Emesis: Treatment 

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

9

Classes of Antiemetic Drugs

  • 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 

10

5-HT3 Antagonists

  • 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

11

NK1 Antagonists

  • 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

12

Phenothiazines

  • 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

13

Substituted Benzamides

  • 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

14

H1 Antihisatmines

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

15

Scopolamine

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

16

Benzodiazepines

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

17

Cannabinoids

  • 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

18

Inflammatory Bowel Disease (IBD): etiology

  • Etiology unclear
    • envioromental factors
    • Lifestyle
    • autoimmune involvement 

19

Inflammatory Bowel Disease (IBD): Treatment

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

20

Aminosalicylates

  • 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

21

IBD stand approach

Bottom up

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

22

Azo compounds

  • -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

23

Mesalamine Formulations

  • 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

24

Glucocorticoids

  • 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