What are the SYM and PARA receptors on GI tract smooth muscle? Actions (table)?
- SYM beta-2: probably through pre-synaptic INH of PARA activity
What is the predominant autonomic tone in the GI tract? Ganglionic blockade?
- Ganglionic blockade:
1. Reduced tone and motility
3. DEC gastric and pancreatic secretions
What are the consequences of cholinergic excess (table)?
- PARA agonists
- AchE inhibitors
What are the consequences of cholinergic deficit (table)?
What is the enteric nervous system?
- Involved in sensorimotor control; afferent sensory neurons, motor nerves, and interneurons organized into 2 nerve plexuses:
1. Myenteric (auerbach's): b/t longitudinal and circular muscle layers -> contraction/relaxation of GI smooth muscle
2. Submucosal (meissner's): secretory and absorptive functions of GI epithelium, local blood flow, and neuroimmune activities
What is the role of Ach in the ENS?
- Primary excitatory transmitter to smooth muscle and secretory cells
- Probably also the major neuron-to-neuron ganglionic transmitter
What are the roles of dopamine and serotonin in the ENS? Metoclopramide?
- DOPAMINE: modulatory transmitter
- SEROTONIN (5-HT): transmitter or co-transmitter at excitatory neuron-to-neuron junctions
- Metoclopramide: tx for N/V and gastroparesis -> 5-HT4 agonism, vagal and central 5-HT3 antagonism, possible sensitization of muscarinic receptors on sm m + D1, D2 (INH sm m contraction) antagonism
1. Pro-kinetic agent: coordinated contractions that enhance transit (largely confied to upper GI tract -> INC lower esophageal sphincter tone and stimulates antral/small intestinal contractions)
What is the role of enkephalin in the ENS?
- In some secretomotor and interneurons
- INH Ach release and peristalsis -> may stimulate secretion
- Related to opioid peptides
What is IBD? Drug target?
- Range of diseases: mostly Crohn's, ulcerative colitis
- Dysbiosis of normal intestinal homeostatic relationship b/t intestinal mucosa and normal microbiome, leading to inflammatory rxn
1. Genetic predisposition
2. Disruption of physical barrier (mainly UC)
3. Microbe sensing dysfunction (Crohn's)
4. Adaptive immune response dysregulation (both)
- TNF-alpha INH: block interaction b/t TNF-alpha and receptor types 1, 2, and soluble receptors, neutralizing pro-inflam cell signaling and INH expression of inflam genes (ex: Infliximab)
When should TNF-alpha INH be used in Crohn's disease mgmt?
- Moderate-severe Crohn's pts who have not had a response to adequate therapy with CCS or an immunomodulator
- Alternative to CCS
When can Infliximab be used to treat UC?
- Mild-moderate disease that is refractory to CCS tx
- CCS-intolerant pts due to adverse effects
- Severe disease where standard tx has failed:
1. Adalimumab/Golimumab approval post-date this recommendation
2. Cetolizumab NOT approved for this indication
What is the treatment algorithm for the tx of IBD (flow chart)?
- 5-ASA is Mesalazine, a salicylate that works only in the gut, minimizing side effects
- Topical CCS: enema, cream, or injections around fissure for localized delivery
- TNF-alpha AE’s: reactivation of latent TB, secondary malignancy, rashes, opportunistic infections; don’t use live vaccines while on these
What opioid drug targets are implicated in GI physiology? How?
- B-endorphin is the preferred ligand for mu receptors
1. Morphine and Loperamide are agonists -> if used as anti-diarrheals, may cause constipation
2. Naloxone, etc. are antagonists
3. Responsible for analgesia, but can also cause respiratory depression (COD from OD)
4. Give laxatives to pts on opiates
- Dynorphin ligand at kappa receptors in myenteric plexus = delayed transit, visceral antinociception (DEC sensitivity to pain)
- Enkephalin at delta receptors in myenteric plexus = delayed transit
What are the clinical effects of the opiates in the GI tract?
- Focus on clinical effects and widespread distribution:
1. Gallbladder: biliary pain, delayed digestion
2. Gastroduodenum: anorexia, N/V
3. Small bowel: constipation, delayed digestion, hard/dry stool
4. Colon: bloating, distenstion, cramps, pain, spasm
5. Anorectum: incomplete evacuation and straining constipation
What are some ways that drugs can induce diarrhea?
- Osmotic: meds draw water into the GI tract
- Secretory: Na+ absorption impaired, and Cl- and HCO3- ions secreted into the lumen
- Disordered motility: drugs affecting cholinergic tone
- Inflammatory: disruption of colonic flora, leading to C. diff or direct damage to gastric mucosa -> may occur after brief exposure, but risk INC w/duration, >1, repeated AB's, or NG tube
- C. diff by disrupting acid-base envo/epi homeostasis: PPI's, H2 antags, immunosuppressants, NSAIDs (direct epi damage + changes in Na+ permeability -> reduced bicarb, mucous, and inflammatory protection; PG INH, preventing repair mechs)
- Fatty diarrhea: mal-digestion or absorption
1. Orlistat, cholestyramine: hypercholesterolemia
2. Octreotide: paradoxical (stops absorption of fat) -> tx of secretory diarrhea in pts w/carcinoid tumors, HIV-assoc
3. Metformin: 50% of pts; osmotic diarrhea via glu + a symptom of lactic acidosis
How can you treat drug-induced diarrhea?
- Selection of alternative agent
- Addition of specific meds, like Metronidazole or Vancomycin for tx of C. diff diarrhea
1. Drugs to treat C. diff have poor bioavailability, keeping everything in the gut -> Vanc can be given orally for this (even though it is usually given IV due to its poor bioavailability)
2. Be suspicious of anti-microbial drugs as cause
What are the risk factors and potential consequences of pill-induced esophagitis? How can this be avoided?
- Damage usually heals in a few days, but can lead to esophageal perforation, hemorrhage, and death if left unresolved (ex: bisphosphonates)
- Risk factors: old age, institutionalization, pre-existing esophageal/swallowing disorders, recumbent position
1. PMH: Parkinson, neuro impairment, cerebro-vascular accidents, myasthenia gravis, stricture, reflux disease, hiatal hernia
2. Drug features: gelatin capsules, ER
- Avoid by giving liquid formulations, remaining upright, and avoiding anti-cholinergics
What are 2 key features of the intestinal wall that modulate bioavailability of MANY drugs?
- P-gp/MDR-1: counteracting active transport of drugs back to the lumen after passive absorption may re-present substrates to CYP3A again and again
1. Grapefruit juice INH P-gp, INC bioavailability of some drugs -> AE’s may appear (more likely if CV, CNS effects) if small therapeutic window
- Overlapping substrate specificities and tissue distribution
How are antacids implicated in gastric drug interactions?
- Some 24 drugs found to have their bioavailability (AUC) reduced by >50% w/concurrent antacids
- Chelation: antimicrobials (Doxy, Tetra, most Floros)
1. Administer 4 hours before or 2 hrs after AB
- May cause constipation/diarrhea, and can alkalinize urine
- May alter pH of the stomach, affecting bioavailability of drugs that rely on gastric acidity to be absorbed (H2 antagonists can also do this)
What are some neurotransmitters drug targets for anti-emesis?
- Serotonin: 5-HT3, 5-HT4
- Dopamine: D1, D2
- Ach: primarily involved via the vestibular N (motion sickness)
- Traditional prior to chemo to prophylactically treat someone with a serotonin antagonist; CTZ = chemo trigger zone
1. OndanSETRON: anti-serotinergic anti-emetic
What are some problems with laxatives?
- Electrolyte imbalances
- Older populations may actually become dependent on these
- Metamucil: can get stuck in the throat (bulk-forming laxative)
What is the first thing you should rule out in a patient with a new symptom on a new drug?
- If patient is taking a medication, ALWAYS rule out drugs as a precipitating factor
- Consider the potential for additive effects with multiple-drug regimens, esp. in the elderly
How is the ENS involved in peristalsis? What neurotransmitters are involved?
- ENS receives input from PARA and SYM, but largely self-functioning
1. Food-sensing: enterochromaffin cells release 5-HT (serotonin)
2. Intrinsic primary afferents activated
3. Behind bolus: Ach, Substance P, NPY stimulate circular muscle contraction (constricting lumen), and INH longitudinal muscle
4. In front of bolus: VIP, NO relax circular muscle tone while excitatory pathways are activated in longitudinal pathways, shortening the segment