Boothe GI Flashcards
1
Q
Leptin
A
- Produced by white adipose tissue
- Inhibits food intake, increases energy expenditure and increases insulin sensitivity (AMP kinase)
- Influences thermogensis, increase hematopoiesis, angiogenesis, wound repair
- Glucocorticoids stimulate leptin expression
- Leptin may inhibit insulin secretion, peripherally competes with it; other reports - no effect
2
Q
Acetylation-stimulating protein (ASP)
A
- Produced from complement factor C
- Increased glucose uptake and diacylglycerol acyltransferase activity, decreased hormone-sensitive lipase
- Concentrations increase with increased lipids, in proportion to body fat in obese humans; decrease in states of fasting
- Adipocyte triglyceride synthesis and storage increase after eating, inc FFA and TriG clearance
- Reduces hepatic glucose production
3
Q
Adiponectin
A
- Secreted by adipocytes, necessary for normal insulin activity
- Decrease circulating glucose independent of fat content, & without affecting insulin - decreased hepatic glucose formation, increased tissue use by decreasing insulin resistance
- Concentration negatively correlated wiht body fat (esp visceral fat) content
- Dec by catecholamines, cytokines, glucorticoids - insulin resistance
4
Q
Ghrelin
A
- Located in peripheral tissues, release by empty stomach
- Oppose leptin action in hypothalamus, increase food intake/decrease energy expenditure
5
Q
Mirtazapine
A
- Piperazino-azepine antidepressant
- 5HT-1 agonist - inhibits serotonin reuptake
- Sympathetic (norepi) actions reflect antagonism of a2 auto-receptors
6
Q
Benzodiazepines (diazepam, oxazepam)
A
- Induce appetite through gabaminergic effects and central inhibition of satiety center in hypothalamus
- Do not stimulate appetite as well in dogs as in cats
- Hepatotoxicity (appears idiosyncratic) with use of diazepam for app stimulation in cats
7
Q
Cyproheptadine
A
- Antihistamine with antiserotonin properties
- MOA - inhibition of serotonergic receptors that control appetite
8
Q
Megestrol Acetate
A
- Synthetic derivative of progesterone
- Targets cachexia via direct and indirect stimulation of appetite and antagonizing catabolic effects of cytokines
- Increased basal insulin conc, inc response to carb load, inc lipoprotein lipase, modulation body temp
- Inhibits formation TNF-a, IL-1, IL-6; modulate central neuroT that regulate appetite (NPY)
9
Q
Dirlotapide
A
- Selective microsomal triglyceride transfer protein inhibitor - blocks assembly and release of lipoprotein into bloodstream
- Weight control mechanism unclear - decreases GI fat absorption, increased lipid filling of enterocytes (satiety signal)
- Orally bioavailable in dog but nonlinear kinetics (hepatic metabolism)
- May affect absorption of fat soluble vitamins (A & E); possible ophthalmic side effects
10
Q
Propofol
A
-Anecdotally stimulate appetite through GABA-A and NYP stimulation, serotonin inhibition
11
Q
Emesis
A
- Different afferent pathways all coordinated by emetic center (lateral reticular formation) coordinates afferent peripheral and central neural signals (substance P - tachykinin neuropeptid)
- Emetic center close to CTZ (adjacent to area postrema bottom of lateral ventrcile - not protected by BBB)
- CTZ coordinates vomiting associated with blood-borne chemicals
- Psychogenic vomiting (cerebral cortex), head trauma/inc ICP (limbic system)
- Solitarius nucleus - receptors for enkephalin, histamine(H1), 5HT-3, ACh - ACh major afferent at higher centers, H1 secondary transmitter
- Substance P (tachykinin neuropeptide) - key neurotransmitted associated with emetic center, targets NK1 (neurokinin) receptors throughout emetic center
- CTZ stimualted by bloodborne compounds - mediated by D2, 5HT-3, H1, NK1 receptors; numerous opioid receptors in CTZ
- Vestibular apparatus -> CN VIII -> vestibular nuclei - CTZ via H1 receptors
- Peripheral impulses from pharynx via CN IX to emetic center; also via visceral organ irritatation/stretch (sympathetic or vagal afferents) from heart, stomach, SI, liver, GB, kidney, UB, uterus, etc. - primarily mediated by ACh (muscarinic receptors to emetic center via CN X)
12
Q
Peripheral emetics
A
- Distention of pharynx/esophagus/GI with warm water or saline
- Irritation of GI or pharynx with warm NaCl solution, NaCl directly in pharynx
- Oral H2O2 (3%) rapid emesis in dogs and cats (potential fatal aspiration)
- Ipecac - alkaloid emetine - increases lacrimation, salivation, bronchial secretions +/- vomit (peripheral & central); may kill cats, not recommended
13
Q
Central Emetics
A
- Drugs (esp opiates) that stimulate CTZ
- Apomorphine - only marginal depressant activity, stimulates D2 receptors more than other opioid actions; stimulates vomiting in CTZ but depressed emetic center - subsequent doses won’t work if 1st doesn’t
- Xylazine (cats) - A2 stimulation at lower doses than sedation
14
Q
Maropitant Citrate
A
- NK1 receptor antagonist - blocks substance P in area postrema and nucleus solitarius
- High 1st pass metabolism, better availability SQ than oral
- Bone marrow hypoplasia in puppies less than 11 weeks
- Specificity for NK1 makes safe and effective (better than chlorpromazine, metoclopromide; not better than ondansetron) for central and peripheral causes of emesis
15
Q
Vestibular emesis
A
- Vomiting caused my vestibular apparatus can be controlled by antihistamines (cyzlizine, meclizine)
- Can cross BBB and may directly effect emetic center in addition to histaminic effects
16
Q
Phenothiazines (chlorpromazine, mepazine, prochlorperazine, triflupromazine, etc.)
A
- Broad spectrum antiemetics effective for central causes except labyrinthine stimulation
- Block emesis at CTZ at low doses due to antidopaminergic (D2) and antihistaminergic effects. Some weak antiserotinergic effects too.
- Primary adverse effects are sedation and hypotension (alpha blockade)
17
Q
Butyrophenone derivatives
A
- Haloperidol & droperidol
- Potent antiemetics due to anti-dopaminergic activity.
- Rarely used due to side effects (similar to phenos but more profound)
18
Q
Metoclopromide
A
- Blocks emesis at CTZ - D2 antagonist, 20 times as potent as phenos
- Mixed 5HT3 antagonist/5HT4 agonist - anti-emesis at high doses due to 5HT3
- Peripheral anti-emetic effects d/t prokinetic
19
Q
Serotonin antagonists
A
- Ondansetron potent antiserotonergic (5HT3) effects, no effects at other receptors
- Active metabolite (dolasetron)
- Cyproheptadine (anti-H2 and anti-5HT3) used for vomiting and diarrhea
20
Q
Miscellaneous antiemetics
A
- Sedatives (barbituates & benzos) can control pyschogenic/behavioral vomiting
- Glucocorticoids (dexamethasone esp) have unknown antiemetic effects
- Cannaboids inhibit vomiting, likely via CB1 receptor stimulation
21
Q
Peripheral antiemetics
A
- GI protectants: protect epithelium from irritation and prevent vomiting - demulcents, antacids, kaolin/pectin/bismuth salts
- Anticholinergics: block muscarinic receptors in emetic center & inhibit peripheral cholinergic transmission (glyco only peripheral - no BBB). Inhibition of vagal afferents, relaxtion of GI smooth muscle spasm; delayed gastric emptying - do not use >3d; do not use with drugs that depend on cholinergic activity (opioids, cisapride, metoclopromide)
- Prokinetics: (reglan) - inc esophageal sphincter tone, duodenal pyloric relaxation, antegrade antrum contraction
22
Q
H-2 receptor antagonists
A
- Reversible, competitive inhibitors that reduce H ion content of gastric secretions and amount of pepsin
- Famotidine (9x)> Ranitidine (5-12x) > Cimetidine
- Oral Bioavailability opposite (cemitidne 70%, ranitidne 50%, famotidine 37%)
- Impair oral absorption of some drugs; dec hepatic metabolism of other drugs (CYP - cimetidine>ranitidine>famotidine); famotidine preferred d/t inc potency, fewer drug interactions
- Potential for rebound gastric acid hypersecretion
23
Q
Proton Pump Inhibitors (PPI - omeprazole/pantoprazole)
A
- Most potent anti-secretory drugs, reducing gastric acid secretion 80-95%
- Potent, irreversible antagonist of H+K+/ATPase proton pump (prodrug, protonated to be transformed into active inhibitor)
- Lag time of 3-5 days before maximal effect
- Partial inhibition of drugs eliminated by selected cytochrome P450 enzymes have been reported for omeprazole
- The potential for inhibition of drug metabolism because of drugs or disease may result in longer drug half-lives of other drugs
- Diarrhea and transient fluctuations in liver enzymes have been reported
- Rebound hypersecretion of gastric acid as described for antihistaminergic drugs should be anticipated, and discontinuation of proton pump inhibitors should occur gradually
- Only famotidine, pantoprazole, and omeprazole suppressed gastric acid secretion, compared with placebo.
24
Q
Prostaglandin analgoues
A
- Misoprostol is a methyl ester analog of prostaglandin E1
- actions appear to be mediated by interaction with a basolateral membrane receptor. Intracellular concentrations of cAMP decrease, which in turn decreases protein kinase activity and hydrogen ion concentration
- Oral, onset 30 mins, half life 20-40 mins
- Basal, nocturnal, and food-induced gastric acid secretion is inhibited
- Can cause diarrhea, can induce uterine contractions and is contraindicated in pregnancy
- primary indication for misoprostol is prevention or treatment of NSAID-induced ulceration
25
Sucralfate
-disaccharide (octasulfate of sucrose) aluminum hydroxide product that binds to and protects damaged epithelial cells from acid, bile, and pepsin activity
-sucrose is freed from aluminum hydroxide, cross-polymerizes, and binds to exposed (damaged) anions of GI epithelial cell membranes
-administered at least 30 minutes before antacids and on an empty stomach, 1 hour before feeding (needs acidic env <4 to work)
-binds to and inactivates bile acids, thus promoting its use in biliary disorders, and inhibits pepsin-mediated hydrolysis of mucosal proteins.
last up to 6 hours
-Sucralfate appears to stimulate production of local mediators that protect the gastric mucosa. These include prostaglandins sulfhydryl ions or other oxygen radical scavengers, and epidermal growth factor
-Sucralfate also increases mucosal blood flow either by inducing local nitric oxide or prostaglandin production or by directly stimulating mucosal angiogenesis
-Sucralfate binds to a number of drugs, with the prototypic example being cimetidine
-minimally absorbed after oral administration and is associated with few, if any, side effects.
-does not prevent the formation of the ulcer; rather, protects damaged tissue once it occurs
26
Bethanecol
- Ester derivative of choline, acts as cholinergic agonist at M2 receptors
- Enhance amplitude of contractions throughout GIU including LES
- Coordination of SI contraction minimal - not considered prokinetic
- Side effects: enhanced parasympathomimetic stimulation - cramps, diarrhea, salivation, bradycardia
27
Metoclopromide (prokinetic)
- Lipid soluble derivative of para-aminobenzoic acid; structurally related to procainamide
- Central anti-dopaminergic effects (antiemetic)
- Peripherally anti-dopaminergic & indirect stimulation of cholinergic receptors: enhanced release of ACh from intrinsic cholinergic neurons (inhibited by pretreatment with anticholinergic)
- Prokinetic activity: muscarinic activity, D2 receptor antagonist, 5HT4 agonist activity.
- Effects limited to LES (tightens), stomach (antegrade contraction in fundus), and pylorus (relaxation) - but also says promotes peristalsis in SI (???)
- Oral bioavailibility 50-70% (1st pass effect)
- Dose dependent CNS effects: nervousness, restlessness, depression, disorientation; tremors, motor restlessnes.
- Opioids and atropine antagonize action
28
Domperidone
- Dopamine antagonist, prokinetic properties similar to metoclopromide but not cholinergic activity, not inhibited by atropine
- Dose not cross BBB easily - can have some central antidopaminergic effects
29
Cisapride
- Broadest spectrum of all prokinetics: dose-dependent activity increase from esophagus (less so in cat) through colon
- Appear to be mediated by indirect stimulation of cholinergic nerves, mediated by serotonin through 5HT4 receptors
- Colonic contraction via 5HT2a
- Stimulation probably occurs at myenteric plexus (GI secretion not enhanced)
- Prolonged elimination in hepatic disease
- No central dopamine receptor activity, no extrapyramidal effects
- Stimulation of 5HT4 by cisapride (or others) can cause blockade of rapid K+ influx through delayed rectifier potassium channel: QT prolongation -> torsades de pointes -> +/- fatal arrhythmia (no cardiac side effects reported in veterinary species) - increased risk with other drugs that inhibit CYP450
30
Erythromycin
- Stimulates GI motility as sub-antimicrobial doses
- Effects mimic motilin: enhances LES pressure, incoordinated stomach contraction
- Rapid tolerance d/t downregulation of motilin receptors
- Other macrolides have similar effects to variable degrees (may explain GI side effects in dogs on for antibiotic use)
31
H2 (ranitidine) - prokinetic
-Inhibit anticholinesterase activity - prokinetic at antisecretory doses
