GI Pharm Flashcards
PONV Risk Factors
- Patient
- Surgical
- Anesthetic
PONV Risk Factors:
Patient
- Patient:
- female
- age <50
- non-smokers
- hx PONV/motion sickness
PONV Risk Factors:
Surgical
- Surgical:
- length of surgery
- laparotomies
- laparoscopic procedures
- ENT
- breast
- OBGYN
- plastic surgeries
PONV Risk Factors:
Anesthetic
- Anesthetic:
- inhalational agents
- N2O
- neostigmine
- etomidate
- opioids
PONV is associated with…
- increased morbidity
- dehydration
- electrolyte imbalances
- wound dehiscence
- bleeding
- esophageal rupture
- airway compromise
- low pt satisfaction
Areas that our Antiemetics focus on
- Emesis is a complex reflex involving multiple NT’s triggered by activating the vomiting center in the medulla oblongata
- Direct stimuli—noxious odors, pain, motion sickness
-
Indirect—first activate chemoreceptor trigger zone (CTZ) in area postrema/floor of 4th ventricle which then activates vomiting center
- CTZ is stimulated by signals in stomach/small intestine or by direct stimulation (ex. opioids, chemotherapy)
Emesis Treatment
- Multimodal approach is best
- Modulate activity in vomiting center and CRTZ
- Treatment Options not discussed in detail in this lecture:
- Midazolam (benzo) → may work to decrease synthesis and release of DA in CRTZ and decrease anxiety related signaling to vomiting center
- Dexamethasone (corticosteroid) → discussed in steroids lecture; unclear antiemetic mechanism; typically given post induction for antiemetic effect. 4-8 mg
- synergistic with zofran
Scopolamine:
MOA/Dose
- “antimuscarinic of choice”
- Anticholinergic at muscarinic receptor
- Competitively and reversibly binds to muscarinic receptors to inhibit binding of Ach
- Tertiary amine = crosses BBB
- Most often used transdermal
- 5 mcg/hr for 72 hrs
- Best when placed at least 4 hrs prior to noxious stimuli for prophylaxis
Scopolamine:
Side Effects
- Pupillary dilation, ↑ IOP → avoid in glaucoma (esp narrow angle)
- Bronchodilation
- Antisialogogue, Dry mouth
- Sedation
- Moderate ↑ HR/CO
-
Anticholinergic syndrome: restlessness, hallucinations, somnolence, unconsciousness
- Tx: physostigmine
Metoclopramide (Reglan)
MOA
- Benzamide (PABA derivative); prokinetic
- DA-2 receptor antagonist acting centrally on CRTZ (crosses BBB) and peripherally to ↑ mobility of esophagus, stomach, and intestine
- ↑Ach release via 5-HT4 receptor stimulation = ↑GI tract mobility
- Contraction of LES and gastric fundus, ↑ gastric and small intestine motility, ↓ muscle activity in pylorus and duodenum
- 5HT-4 agonist to ↑cAMP to ↑peristaltic activity
- Weak 5-HT3 receptor antagonist (at high doses might enhance anti-emetic effects)
- Kinetic only NO change in gastric pH
Metoclopramide (Reglan)
Pk
- PB = 30%
- Onset = 1-3 min
- DOA = 1-2 hrs
- E½t = 2-4 hrs
- Renal excretion, 40% unchanged (“not goof for renal failure and dialysis pts”)
Metoclopramide (Reglan)
Side Effects
- Extrapyramidal effects (contraindicated in Parkinson’s, caution in restless leg syndrome or other movement dxs)
- Restlessness/Akathesia
- Cramping → give slowly over 3-5 min
- ↑ lactation
- ↑ HR / ↓BP
- Dysrhythmias if used in conjunction w/ ondansetron (case reports)
- CONTRAINDICATED IN BOWEL OBSTRUCTION
Metoclopramide (Reglan)
Dosage
- Dose 10-20 mg IV slowly; 15-30 min before induction (for pro-kinetic benefit)
- 0.15 mg/kg to children post T&A to reduce PONV in PACU
**Droperidol** and Haloperidol
MOA/Pk/Dose
- Butyrophenone; DA-2 receptor antagonists at CRTZ (antiemetic properties)
- Pk:
- Highly PB
- Peak = 30 min
- DOA = 12 hrs (“long half life good for post op”)
- Antiemetic dose = droperidol 0.625 mg – 1.25 mg IV
**Droperidol** and Haloperidol
Side Effects
- Extrapyramidal symptoms (avoid in Parkinson’s)… DO NOT give w/ metoclopramide
- Additive w/ CNS depressants
- Drowsiness (higher doses)
- Hallucinations
- Slow HR
- QT prolongation and torsades (black box warning)
-
Malignant neuroleptic syndrome (tachycardia, alterations BP, fluctuating LOC, muscle rigidity, hyperthermia, rhabdomyolysis, autonomic instability = mirror MH)
- Tx: Amantadine- DA-agonist w/ mild anticholinergic effects
Amisulpride (Barhemsys®)
-
Dopamine (D2/D3) antagonist FDA approved 2020 for PONV
- Replacement for droperidol in multimodal PONV mgt.
- Dose-dependent QT prolongation warning on insert
- Avoid doses >10mg. Avoid in known prolonged QT. Avoid w/ other drugs w/ prolonged QT as SE.
-
Minimal drug interactions
- neither inhibits nor promotes liver enzyme activity
- exhibits limited protein binding (25-30%)
- AVOID w/ Parkinson’s pts
- Adverse effects similar to placebo group
- Well-tolerated in elderly pts
Amisulpride (Barhemsys®)
Pk
- Vd in surgical pts: 127-144 L
- Rapid onset (1-2 min)
- E½t: 4-5 hrs
- Minimal metabolism/no CYP450 metabolism (excreted unchanged in urine 58%/feces 23%)
- Avoid in renal failure (OK in mild to mod renal dz GFR >30 mL/min)
Amisulpride (Barhemsys®)
Use
-
Prevention of PONV (either alone or in combination):
- 5 mg as single IV dose infused over 1-2 min at anesthesia induction.
-
Treatment of PONV
- 10 mg as single IV dose infused over 1-2 min post-op.
- Photodegradation an issue: administer w/in 12 hrs of removal from protective carton.
- Infusion site pain reported
Ondansetron (Zofran)
- 5-HT3 Receptor antagonist, antiemetic
- Primarily works at CRTZ centrally and vagal nerve terminals peripherally
- Not effective in motion sickness or PONV caused by vestibular stimulation
Ondansetron (Zofran)
Pk
- PB 70%
- Vd: 2 L/kg
- Onset: 30 min
- DOA: 4-8 hrs
- E½t: 3-4 hrs
- Liver metabolism
- Cross BBB
Ondansetron (Zofran)
Dose
- Dose: 4- 8 mg IV over 2 min
- Pediatric 0.05-0.15 mg/kg IV
- Debate over beginning of surgery vs. end of surgery
Ondansetron (Zofran)
Side Effects
- Headache w/ rapid admin
- Sedation
- Constipation
- Slight QT prolongation
- AV block (w/ co-admin of metoclopramide)
- Caution in liver dz
Additional 5-HT3 Antagonists
Dolasetron
Grainsetron
Palonosetron
Ramosetron
Tropisetron
Aprepitant (emend):
MOA/dose
-
Neurokinin- 1(NK1) antagonist
- Serves to antagonize substance P
- Little/no affinity for serotonin, DA, and corticosteroid receptors
- PONV and N/V r/t CA chemo (typically combo w/ other antiemetics)
- Moderate effectiveness- usually part of multimodal approach
- Dose PONV: 40 mg IV prior to induction
Aprepitant (emend):
Pk
- PB >95%
- Vd = 70 L
- E½t = 9-13 hrs
- Primary metabolism by liver, CYP3A4
Antiemetics: NK1 Antagonists
Side Effects
- Neutropenia, Anemia, Leukopenia (concern in CA pts)
- Fatigue
- Peripheral neuropathy
- Dyspepsia
- Diarrhea
- UTI
- Injection site pain
- CYP3A4 metabolism inhibition: many drug interactions including many chemo drugs and corticosteroids… adjusted doses important).
- CYP2D6 inducer: warfarin, oral contraceptives (“r/f unwanted pregnancy”), codeine (“r/f overdose”)
Promethazine, Chlorpromazine, Prochlorperazine
Action/Use/Pk/Dose
- Phenothiazines
- Exert antiemetic effects by interaction w/ DA receptors in CRTZ
- H1 antagonist- to be covered later
- Use: blood transfusion reaction, allergic reaction, sedation, PONV
- Following IV admin, clinical effects in 5 min
- DOA 4-6 hrs
- E½t = 9-16 hrs
- Liver metabolism
- Contraindicated under 2 yrs old (fatal resp depression)/comatose state
- Sedation common concern
- Dose: Promethazine 6.25-12 mg IV, up to 25 mg
Antiemetics: Cannabinoids
- Agents: Dronabinol [Marinol], Nabilone [Cesamet] both chemically related to active ingredient in marijuana
- Unknown MOA: activation of cannabinoid receptors adjacent and within vomiting center
- Improves chemotherapy induced nausea
- Improves appetite in HIV pts
- NOT currently FDA approved PONV use