GI Pharm/Diuretics Flashcards
Patient risk factors of PONV
- female
- age < 50
- nonsmokers
- hx of PONV/motion sickness
Surgical risk factors of PONV.
- length of surgery
- laparotomies
- laparoscopic procedures
- ENT
- breast
- OBGYN
- plastic surgeries
anesthetic risk factors of PONV
- use of inhalational agents
- N2O
- neostigmine
- etomidate
- opioids
PONV is assicated with what complications?
- increased morbidity
- dehydration
- electrolyte imbalances
- wound dehiscence
- bleeding
- esophageal rupture
- airway compromise
- low patient satisfaction
What is the vomitting center and where is It located?
- nucleus of neurons in the medulla oblongota
What are some direct stimuli of nausea?
- noxious odors
- pain
- motion sickness
What are some indirect stimuli of nausea?
- first activate the chemoreceptor trigger zone (CTZ) in area postrema/floor of 4th ventricle which then activates the vomitting center
- CTZ is stimulated by signals in the stomach/small intestine or by direct stimulation (ex. opioids, chemotherapy)
What are the 5 receptor types targeted by our antiemetic drugs?
- 5HT3 = serotonin3
- DA2 = dopamine2
- M = muscarinic cholinergic
- H1 = histamine1
- NK1 = neurokinin1
Explain the antiemetic effect of midazolam.
- may work to decrease synthesis and release of dopamine in the CRTZ and decrease anxiety related to signaling in the vomitting center
What class of drug is dexamethasone?
Explain the antiemetic effect.
When is typically given?
What is the dose?
- corticosteroid
- antiemetic mechanism unclear
- typically given post induction for antiemetic effect - needs to be given at the beginning of a case
- works synergistically with ondansetron
- 4 - 8 mg
Scopolamine: Class, structure, MOA, dosing, SE
- Class
- Anticholinergic at muscarinic receptor
- structure
- Tertiary amine = crosses the BBB
- MOA
- Competitively and reversibly binds to muscarinic receptors to inhibit binding of Ach
- dose
- Most often used transdermal
- 5 mcg/hour for 72 hours
- Best when placed at least 4 hours prior to noxious stimuli for prophylaxis
- Most often used transdermal
- Side Effects:
- Pupillary dilation, increased IOP → avoid in glaucoma (especially narrow angle)
- Bronchodilation
- Antisialogogue
- Anticholinergic syndrome (restlessness, hallucinations, somnolence and unconsciousness. Tx: Physostigmine)
- Sedation
- Dry mouth
- Moderate increase in HR/CO - not as much as atropine and glyco
amisulpride (barhemsys): class + use
- class
- dopamine (D2/D3) antagonist approved by FDA in 2020 for PONV
- use
- proposed as a replacement for droperidol in multimodal PONV mgt.
amisulpride (barhemsys): PK
- Rapid onset of action (1-2 minutes) - give slowly over 1 -2 min
- E1/2 life – 4-5 hours (less than droperidol)
- Vd in surgical patients: 127 to 144 L
- Minimal metabolism/no cytochrome P450 metabolism (excreted unchanged in urine 58%/feces 23%)
- avoid in renal failure (OK in mild to moderate renal disease GFR>30 ml/min
amisulpride (barhemsys): SE (chart with drug vs placebo)
- dose dependent QT prolongation
amisulpride (barhemsys): cautions/contraindications/drug interactions
- Dose dependent QT prolongation warning in package insert
- Avoid doses >10mg
- Avoid in known prolonged QT
- Avoid with other drugs with prolonged QT as SE.
- Minimal drug interactions
- neither inhibits nor promotes liver enzyme activity
- exhibits limited plasma protein binding (25-30%)
- AVOID with Parkinson’s patients
- Adverse effects similar to placebo group
- Well-tolerated in elderly patients
- Avoid in renal failure (OK in mild to moderate renal disease GFR>30 ml/min)
amisulpride (barhemsys): dose + misc notes
- Prevention of PONV (either alone or in combination):
- 5 mg as a single intravenous dose infused over 1-2 minutes at anesthesia induction
- treatment of PONV
- 10 mg as a single intravenous dose infused over 1-2 minutes post-operatively
- Photodegradation an issue: administer within 12 hours of removal from the protective carton.
List some additional 5HT3 antagonists besides zofran.
- Dolasetron
- Grainsetron
- Palonosetron
- Ramosetron
- Tropisetron
aprepitant (emend): class, MOA, use, Vd, PB, Metabolism, 1/2 life, dose
- class
- Neurokinin- 1 (NK1) antagonist
- MOA
- Serves to antagonize substance P
- Little to no affinity for serotonin, dopamine, and corticosteroid receptors
- use
- PONV and nausea/vomiting related to cancer chemotherapy (typically in combination with other antiemetics)
- Moderate effectiveness- usually as part of multi-modal approach
- PONV and nausea/vomiting related to cancer chemotherapy (typically in combination with other antiemetics)
- Vd: 70L
- PB: >95%
- Primary metabolism by liver: CYP3A4
- Half-life 9-13 hours
- Dose PONV: 40 mg IV prior to induction (better if given prior to exposure of “offending agents”)
List potential side effects of NK1 antagonists
- diarrhea
- neutropenia, anemia, leukopenia (concern in CA population)
- peripheral neuropathy
- dyspepsia
- UTI
- injection site pain
**remember these SE may be more notable with chronic use and not so much with single time use**
What are the potential drug interactions of NK1 antagonists?
- CYP3A4 metabolism inhibition:
- metabolized by CYP3A4, but also inhibits CYP3A4
- many drug interactions including many chemotherapeutic drugs and corticosteroids… adjusted doses important).
- CYP2D6 inducer
- warfarin (would be subtherapeutic)
- oral contraceptives (would be subtherapeutic)
- codeine (more of drug metabolized to morphine – resp depression and OD)
List two cannabionoid agents that a patient might be taking.
- Dronabinol [Marinol]
- Nabilone [Cesamet]
- both chemically related to the active ingredient in marijuana
What is the use and MOA of cannabionoids?
- Unknown MOA: activation of cannabinoid receptors adjacent and within vomiting center
- Improves chemotherapy induced nausea and improves appetite in HIV patients
- NOT currently FDA approved for use in PONV
What are adverse effects of cannabinoids?
- same as marijuana
- sedation (additive with other sedatives)
- temporal disintegration
- dysphoria
- personality changes
- tachycardia and hypotension
- Abuse potential (*Schedule III DEA controlled substance)*
What is the occurence of aspiration in the perioperative period?
- 1/3 with laryngoscopy
- 1/3 w/ extubation
- 1/3 during the procedure
What are the primary determinants of pulmonary complications regarding aspiration?
- volume and acidity of apsirated gastric contents
What are some foods/factors that precipitate effects of GERD? Lifestyle modifications to treat GERD?
- smoking
- alcohol
- fatty meals
- caffeine
- acidic foods
- citrus
- chocolate
- eat smaller meals throughout day
- sleep with HOB elevated
Briefly describe pharmacologic management of GERD.
- PPIs - ↓ acid secretion
- H2 blockers - ↓ acid secretion
- Antacids - ↑ gastric pH
- Metoclopramide - prokinetic functions, encourgage gastric emptying, increase tone of LES
- Sucralfate / misoprostol – cytoprotective (not used in aspiration prophylaxis)
What is the MOA of antacids?
- Neutralize hydrogen ions in gastric contents or decrease the secretion of hydrogen chloride into the stomach
- Aluminum, calcium and magnesium salts
- Hydrogen ions in the stomach acid react with the base, forming a stable compound- consuming the hydrogen ions and increase pH >5.
- Relieves symptoms of gastritis, improves rate of gastric ulcer healing and duodenal ulcer pain relief, increases gastric motility (neutralized pH increases gastrin release and gastric motility).
What are some considerations for long term use and potential drug interactions of antacids?
- If pH too high, impaired food digestion
- Electrolyte abnormalities
- Drug interactions: increase rate of absorption for salicylates, indomethacin and naproxen; decreased bioavailability of PO cimetidine
Sodium bicarbonate: MOA, cautions
- Prompt rapid neuralization of stomach pH, may result in acid rebound
- Pts with HTN, heart disease may not tolerate sodium load
Magnesium hydroxide (milk of magnesia): MOA, cautions
- Prominent laxative, osmotic diarrhea
- Caution in renal impairment- results in metabolic alkalosis, neurologic, neuromuscular and cardiovascular impairments
Calcium carbonate: MOA, cautions
- Metabolic alkalosis with chronic therapy
- Symptomatic hypercalcemia in renal disease, hypophosphatemia, acid rebound
Aluminum hydroxide: MOA, cautions
•Renal disease, excessive aluminum concentration → encephalopathy
•SLOWS gastric emptying → (could increase aspiration risk), constipation
•Phosphorous depletion leading to anorexia, muscle weakness, osteoporosis
What is histamine?
Where is It synthesized and stored?
Why is It relased?
What does It cause upon release?
Which receptors mediate effects?
- Naturally occurring endogenous amine
- Synthesized in tissues –decarboxylation of histadine
- Stored in vesicles- mast cells (skin, lung, gastric mucosa) & circulating basophils
- Released in response to antigen-antibody reaction/ certain drugs
- Induces contraction of smooth muscle in the airways, increases secretion of acid in the stomach, and stimulates release of neurotransmitters in CNS
- Effects mediated by H1, H2 and H3 receptors
Where are H1 receptors expressed?
What effects do they exhibit?
- smooth muscle-contraction lung & GI, vascular endothelium- release of NO, sensory nerve stimulation
- Lungs - bronchoconstriction – asthma/bronchitis → increased airway resistance
- Vascular smooth muscle – predominant effect of histamine= dilation – hypotension/erythema
- Vascular endothelium – increased capillary permeability - edema
- Peripheral nerves - sensitization - itching, pain, sneezing
- Heart-found in A-V node-slow HR by slowing conduction
Where are H2 receptors expressed?
What effects do they exhibit?
- gastric parietal cells, cardiac muscle, mast cells
-
Heart – Positive inotropic and chronotropic effects → increase in heart rate and contractility
- Coronary vasculature- vasodilation (offsets H1 constriction)
- Airways - relaxes bronchial smooth muscle
-
Stomach
- Activation of cAMP → activates proton pump of parietal cells to secrete hydrogen ions
- Effects due to direct stimulation of gastric parietal cells- increases gastric acid secretion – increased risk of PUD, GERD
Where are H3 receptors expressed?
What effects do they exhibit?
- sort of analagous to alpha 2 receptors with negative feedback mechanisms
- Location- Heart & Presynaptic postganglionic SNS fibers
- Stimulation causes Inhibition of synthesis and release of histamine
- Activity impaired by H2 antagonists → enhanced histamine release. AVOID rapid administration of these agents esp when in combo with a histamine releaser (eg. Atracurium)
- should coadminister an H1 blocker because of the impaired inhibition of histamine release by H2 antagonists
How do H1 and H2 antagonists work?
- H1 or H2 antagonists- Competitive and reversible inhibition.
- The drugs occupy receptors on effector cell membranes.
- Histamine receptors are seven-transmembrane G protein-coupled receptors
- H1 antagonists- Allergic rhinitis treatment
- H2 antagonists-inhibit acid gastric fluid secretion
- H1 and H2 antagonists do not inhibit the release of histamine- they block the response to histamine!
H1 antagonists are classically known as _________ and are used to treat what conditions?
- anithistamines
- mild allergy
- rhinitis, conjunctivitis, uticaria, pruritis
- motion sickness
- chemotherapy induced NV
- PONV
- insomnia
H1 antagonists block which actions of histamine at H1 receptors?
- vasodilation
- increased capillary permeability
- bronchoconstriction
- CNS effects
- Itching
- pain
- do not block H2 receptors
- some bind to muscarinic receptors
List first generation H1 antagonists and their characteristics.
- diphenhydramine
- hydroxizine
- chlorpheniramine
- promethazine (phenergan)
- doxepin
- sedation
- less specific for H1 receptors
- active at muscarinic, serotonin and alpha receptors
- lipophilic
- nonionized
- cross BBB
List second generation H1 antagonists and their characteristics.
- loratidine
- desloratidine
- acrivastine
- fexofenadine
- non drowsy
- more selective for H1
- less crosses BBB → decreases CNS toxicity
- ionized at physioloic pH
Name an anitcholinergic used for PUD/GERD.
What is the MOA and primary use?
Adverse Effects?
-
Dicyclomine
- Muscarinic ACh receptor antagonist
- Decreases acid secretion
- Primarily used to treat irritable bowel syndrome
- Less effective than H2 antagonists and PPIs
- Adverse effects
- •Dry mouth, constipation, blurred vision, cardiac arrhythmia, urinary retention
- doesn’t have sedative issue like scopolamine so good for daily use
PUD TX: chart
Misoprostol: Class + use
- Methyl analog of prostaglandin E1
- In US, only indicated in the prevention of NSAID-induced ulcers
misoprostol: MOA
- Inhibits gastric acid secretion by inhibiting histamine-stimulated cAMP production
- Mucosa-protective; binds to prostaglandin E receptors, facilitates production of mucus and bicarbonate
misoprostol: Pregnancy category, adverse effects
-
Pregnancy category X
- Stimulates uterine contraction
- Used in combination with mifepristone to induce pregnancy termination
- ADE
- Diarrhea (up to 40%)
- Abdominal cramps (7 – 20%)
sucralfate: class, use, MOA
- Aluminum salt of a sulfated disaccharide
- Used for acute/maintenance tx of duodenal ulcers
- MOA
- In acidic environment (pH < 4), forms a gel-like substance that selectively binds to mucosa; forms protective barrier against acid, pepsin etc…
- No acid-neutralizing activity
- Does not treat cause of ulcer, just coats/protects it
sucralfate: PK, adverse effects, administration considerations
- Minimal systemic absorption; >90% excreted in feces
- ADE:
- Constipation (2%)
- Aluminum toxicity
- Separate administration of other drugs by 2 hours before or 4 hours after
- This prevents 1) changes in pH 2) inhibition of absorption of other drugs (common with co-administration)
- Pills are difficult to swallow for many patients
Triamterene: class and MOA, cautions
-
potassium sparing diuretic
- CB says this is a weak diuretic - often used in bombo with a thiazide or loop diuretic
- Site of action: Collecting duct
- Action: Na+ channel blockade (luminal membrane; independent of aldosterone)
- precautions: can cause hyperkalemia
spironolactone: class, use
- class
- synthetic 17-lactone drug
- competitive aldosterone antagonist
- ***aldosterone is a hormone that increases the reabsorption of Na and H2O & seceretion of poatssium → increases volume and BP
- use
- primarily to treat heart failure, ascites, hypertension, hypokalemia, and Conn’s syndrome
- spironolactone is a weak diuretic, and is usually combined with other diuretics (HCTZ)
Acetazolamide (diamox): class, use, MOA
- class
- carbonic anhydrase inhibitor
- Carbonic Anhydrase catalyzes H+ and HCO3- released from CO2 and H2O. H+ is then excreted in exchange for Na+ on the renal luminal membrane & HCO3- is reabsorbed with Na+
- Use
- Glaucoma, altitude sickness, ICP
- MOA
- blocks the action of carbonic anhydrase therefore increasing amounts of Na+, and H2O in the urine (and decreasing bicarb reabsorption)
Dopaminergic agents, low dose dopamine: dose, uses and considerations
- dose: 1 - 3 mcg/kg/min
- Renal vasodilation
- Inhibition Na-K-ATPase pump/decreases renal O2 consumption
- Effect diminished after 48 hours-down-regulation of dopaminergic receptors/contraction intravascular volume
- No evidence dopamine has a renal protective effect despite increased urine output
Dopaminergic agents, fenoldopam: class, MOA, PK
- Selective for D1 receptor with moderate action at alpha 2
- arterial/arteriolar dilation leading to a decrease in BP via activation of peripheral D1 receptors
- Increases renal perfusion and urine output
- Rapid onset, short half-life (10 minutes)
- Short term treatment of severe HTN
