Module 2.1 (Pharmacology of GI drugs)

What are the indications for n/v agents?

- simple n/v

- motion sickness

- post operative n/v (PONV)

- chemotherapy induced n/v (CINV)

- radiation induced n/v (RINV)

Vomiting center contains the emetic center as well as the _________________

solitary tract nucleus

What are the various sources that the vomiting center can receive input from?

- GI tract

- Chemoreceptor Trigger Zone

- Vestibular Apparatus

- Cerebral cortex and associated structures in the limbic system

Vomiting signal from the GI tract:

- cytotoxic drugs (cisplatin) cause damage to ____________ found in stomach and small intestine which release serotonin into GI tract

- ___________ stimulates vomiting center and CTZ

- ECL cells

- serotonin

Vomiting signal from the GI tract:

- ________________ in the GI mucosa can stimulate vomiting in response to _______ as well as __________ pathogens via vagal and sympathetic afferents

- chemoreceptors

- bacterial

- viral

Vomiting signal from the GI tract:

- _______________ in the pharynx can stimulate vomiting in response to stress via the ______________ and ___________ afferents

- mechanoreceptors

- glossopharyngeal

- trigeminal

Vomiting signal from the CTZ:

- located in the area postrema of the 4th ventricle of the brain

- lack of ______________ at CTZ permits monitoring of blood and CSF for toxic substances

- if toxic substances are detected, signal sent to _________, to induce vomiting

- the CTZ contains high concentrations of receptors for __________, _________, ____________, ____________

- blood brain barrier

- vomiting center

- serotonin

- dopamine

- acetylcholine

- cannabinoids

Vomiting signal from vestibular apparatus:

- peripheral portion of vestibular apparatus located within _____________

- ___________ inputs feed into the vomiting center and are associated with things like motion/sea sickness, or inner ear diseases like _____________

- stimulation of vestibular apparatus is mediated through __________ and __________ receptors

- inner ear

- afferent

- Meniere's disease

- histamine

- acetylcholine

Vomiting signal from the cerebral cortex and associated structures in the limbic system:

- modulate experiences such as taste, sight, smell, and memory which is involved in ____________________

anticipatory nausea

Neuromediators in N/V:

What are the receptors in the GI tract?

- serotonin (5HT3)

Neuromediators in N/V:

What are the receptors in the CTZ?

- serotonin (5HT3)

- dopamine (D2)

- cannabinoid (CB1)

- acetylcholine (M)

Acetylcholine can bind to both nicotinic and muscarinic receptors, but drugs that bind to the _____________ receptor are the ones that are useful against n/v?

muscarinic

Neuromediators in N/V:

What are the receptors in the vestibular apparatus?

- histamine (H1)

- acetylcholine (M)

Neuromediators in N/V:

What are the receptors in the solitary tract nucleus?

- dopamine (D2)

- serotonin (5HT3)

- cannabinoid (CB1)

- substance P (NK1)

- histamine (H1)

- acetylcholine (M)

Anti-emetic medications are all antagonists except for drugs that bind to which receptor?

- cannabinoid

note: drugs that bind to cannabinoid receptor (CB1) are agonists

What are the classes of anti-emetic medications?

- 5HT3 receptor antagonists

- NK1 receptor antagonists

- dopamine receptor antagonists

- cannabinoid receptor agonists

- antihistamines

- anticholinergics

- misc

What drug class:

- antagonizes 5HT3 receptors in GI tract, CTZ, NTS

- 5HT3 receptor antagonists

What drug class:

- indications: CINV, PONV, RINV

- equally efficacious when used at equivalent doses

A. 5HT3 RA

B. NK1 RA

C. DA receptor antagonists

D. Cannabinoids

A. 5HT3 RA

What drug class:

- dolasetron

- granisetron

- ondansetron

- palonosetron

A. 5HT3 RA

B. NK1 RA

C. DA receptor antagonists

D. Cannabinoids

A. 5HT3 RA

What drug class:

- used off label for hyperemesis gravidarum

- 1st gen can be used for general n/v

- effective in CINV because serotonin plays a key role in the acute phase of CINV

A. 5HT3 RA

B. NK1 RA

C. DA receptor antagonists

D. Cannabinoids

A. 5HT3 RA

5HT3RAs are ineffective for motion sickness and anticipatory and delayed n/v with the exception of ___________ which is FDA approved for acute or delayed n/v but is given in combination with netupitant

palonosetron

Which 5HT3RA?

- highest affinity for the 5HT3 receptor

- metabolized by CYP2D6

- half life 40 hours

palonosetron

Which 5HT3RA?

- metabolized by CYP1A2, CYP2D6, CYP3A4

- dose reduction required in severe hepatic impairment

- half life 3-9 hours

ondansetron

Which 5HT3RA?

- metabolized by CYP3A4

- half life 3-9 hours

granisetron

Which 5HT3RA?

- metabolized by CYP2D6, CYP3A4

- half life 3-9 hours

dolasetron

These are the common adverse effects of what drug class?

- constipation/diarrhea

- headache

- lightheadedness

A. 5HT3 RA

B. NK1 RA

C. DA receptor antagonists

D. Cannabinoids

A. 5HT3 RA

What 5HT3RAs can cause QT prolongation?

- dolasetron

- ondansetron

- granisetron

What drug class:

- most effective for acute phase of n/v

- drug interactions: QT prolongating drugs, drugs that can cause serotonin syndrome

A. 5HT3 RA

B. NK1 RA

C. DA receptor antagonists

D. Cannabinoids

A. 5HT3 RA

These are symptoms of ______________________

- agitation

- hallucinations

- tachycardia

- fever

- excessive sweating

- shivering/shaking

- muscle twitching/stiffness

- trouble with coordination

- n/v, diarrhea

- pt MUST REPORT symptoms immediately

- usually issue if pt is on 3+ agents affecting this

serotonin syndrome

NK1RAs are antagonists of the NK1 receptors in the ___________

NTS

These agents are all:

- aprepitant

- fosaprepitant (prodrug used for injection)

- rolapitant

- netupitant (formulated with palonosetron)

NK1RAs

These are the indications for what drug class:

- CINV

- PONV

- particularly useful for delayed emesis

NK1RAs

NK1RAs have a large volume of distribution; crosses ________

BBB

Which NK1RA?

- half life 9-13 hours

- CYP3A4 substrate, inhibitor, inducer

- CYP2C9 inducer

aprepitant (fosaprepitant)

Which NK1RA?

- half life 7 days; allows for one time dosing

- metabolized CYP3A4

- CYP2D6 inhibitor

- when used for CINV dose is repeated at 2 week intervals

rolapitant

Which NK1RA?

- half life 80 hours

- metabolized by CYP3A4

netupitant

Aprepitant Drug interactions:

- __________ (CYP3A4): increased risk of adverse effects (alprazolam has increased levels)

- _____________ (CYP3A4): increased drug exposure (have to reduce dose by 50%)

- ________________ (CYP3A4 induction): decreased efficacy; can last 28 days

- _________ (CYP2C9 induction): decreased INR

- cisapride, pimozide, astemizole are all __________ because of life threatening QT prolongation

- benzodiazepines

- dexamethasone

- oral contraceptives

- warfarin

- CONTRAINDICATED

Rolapitant Drug interactions:

- _________________ (CYP3A4): caution/contraindicated; can reduce effects of rolapitant

- _________/______________ (CYP2D6 inhibitor): increased effects

- ____________(CYP2D6 inhibitor): increased INR

- thioridazine, pimozide- ____________ because of life threatening QT prolongation

- St. Johns wort

- codeine/dextromethorphan

- warfarin

- CONTRAINDICATED

These are the adverse effects of what drug class?

- fatigue

- diarrhea

- constipation

- dyspepsia

- hiccups

- dizziness

- headache

NK1RAs

____________ are not used for treatment once n/v has started

NK1RAs

NK1RAs are usually given in combination with _____________ and/or a ______________

5HT3RAs and/or a corticosteroid

DA receptor antagonists antagonize D2 receptors in the ____________

CTZ

____________ can also be used for motion sickness because of ___________ and _______________ properties

- DA receptor antagonists

- antihistamine

- anticholinergic

note: histamine and muscarinic receptors are involved in activation of vestibular apparatus

These are the indications for what drug class:

- simple n/v

- motion sickness

- prn for CINV or PONV

DA receptor antagonists

These agents are all:

- chlorpromazine

- prochlorperazine

- promethazine

DA receptor antagonists

These are the adverse effects of what drug class:

- drowsiness

- dizziness

- dry mouth, constipation

- QT prolongation

- extrapyramidal symptoms

- neuroleptic malignant syndrome

- DA receptor antagonists

- note: drowsiness most prominent with promethazine

- note: extrapyramidal symptoms most prominent with prochlorperazine

What are extrapyramidal symptoms?

- dystonia

- Parkinsons like symptoms

- tardive dyskinesia

What is neuroleptic malignant syndrome?

characterized by:

- hyperpyrexia

- severe extrapyramidal dysfunction

- altercations in consciousness, mental status

- autonomic instability: increase/decrease in BP, tachycardia, sweating

- increased CPK, acute renal failure, leukocytosis

Cannabinoids are agonists of CB1 receptor in the _______ and ________

- CTZ

- NTS

This is the only indication for this drug class:

- CINV

cannabinoids

These agents are:

- dronabinol

- nabilone

cannabinoids

____________ are very lipophilic and readily absorbed

- peak concentrations in 30 mins to 2 hours

cannabinoids

These are the adverse effects of what drug class:

- euphoria

- drowsiness

- hallucinations

- appetite stimulation

- sympathomimetic activity (palpitations, tachycardia, hypotension, flushing, bloodshot eyes)

-these drugs are schedule 2 or 3 substances

cannabinoids

- histamine receptor antagonists antagonize H1 receptors at the _______________, and __________

- HRAs also have __________ properties

- vestibular apparatus

- NTS

- anticholinergic

These agents are:

- diphenhydramine

- dimenhydrinate

- hydroxyzine

- meclizine

histamine receptor antagonists

These are the indications for what drug class:

- motion sickness

- vertigo

- simple n/v

- PONV

histamine receptor antagonists

These are the adverse effects of what drug class?

- drowsiness

- dry mouth

- blurred vision

- constipation

- urinary retention

- confusion

- dizziness

- tremors

histamine receptor antagonists

anticholinergics antagonize muscarinic recptors in _______________

vestibular apparatus

What is the only available anticholinergic? This drug is DOC for motion sickness

scopalamine

These are the indications for what drug class?

- motion sickness

- PONV

anticholinergics

These are the adverse effects of what drug class?

- anticholinergic effects

- dry mouth (xerostomia)

- urinary retention

- blurred vision

- constipation

anticholinergics

What drug is an antagonist of D2 receptors in the CTZ but also has mixed activity as a 5HT3 receptor antagonist/5HT4 receptor agonist

metoclopramide

What drug:

- prokinetic agent

- increases GI motility and LES tone

metoclopramide

These are the indications for what drug?

- diabetic gastroparesis associated with n/v

- CINV or PONV

- GERD (with gastroparesis)

metoclopramide

This is the PK of what drug?

- half life 4-6 hours

- duration of action 1-2 hours

metoclopramide

These are the adverse effects of what drug?

- drowsiness, anxiety, depression, QT prolongation

- extrapyramidal effects

- increased prolactin (infrequent); can cause gynecomastia

- avoid in patients taking antipsychotics

- avoid high doses

- limit use <12 weeks

metoclopramide

What drug:

- may block D2 receptors in CTZ

- actions similar to metoclopramide

- indications: simple n/v, PONV

- rarely used

trimethobenzamide

What drug is this describing:

- mixture of glucose, fructose, phosphoric acid

- acts by decreasing smooth muscle contraction and delaying gastric emptying

phosphorated carbohydrate (emetrol)

What drug indication:

- n/v associated with food or drink

phosphorated carbohydrate (emetrol)

What drug adverse effects:

- abdominal pain or diarrhea

- caution in patients with diabetes or those with hereditary fructose intolerance

phosphorated carbohydrate (emetrol)

What drug is a combination product of a vitamin and antihistamine. Good for pregnant patients

pyridoxine +/- doxylamine

These are the adverse effects of what drug:

- drowsiness

- headache

- lightheadedness

- constipation

- dry mouth

pyridoxine +/- doxylamine

Disorder of intestinal water and electrolyte absorption resulting from:

- increased osmotic load within the lumen

- excessive secretion of electrolytes and water into the intestinal lumen

- exudation of protein and fluid from the mucosa

- altered intestinal motility resulting in rapid transit

diarrhea

What are the two ways in which anti-diarrheal agents work?

- enhancing water absorption

- decreasing intestinal motility

anti-diarrheal agents are best used in patients with ___________ or __________ symptoms

- significant

- persistent

What type of anti-diarrheal agent is this:

- act on peripheral u opioid receptors in the myenteric plexus to decrease motility

anti-motility agents

These drugs are all:

- loperamide (penetrates the least, lacks abuse potential, best for diarrhea)

- diphenoxylate/atropine

- difenoxin/atropine

anti-motility agents

What anti-motility agent is this:

- 40-50x more potent than morphine as an anti-diarrheal

- acts peripherally

- does not penetrate CNS well

- available OTC or Rx

loperamide

adverse effects of what drug?

- constipation

- dizziness

- drowsiness

- headache

- risk of cardiac adverse effects with high doses (QT prolongation, TDP)

- loperamide

These are the drug interactions for what drug:

- pgp inhibitors: quinidine, ketoconazole, ritonavire (can increase concentrations)

- CYP3A4 inhibitors: clarithromycin, nefazodone, ketoconazole, atazanavir (can increase concentrations)

- CYP2C8 inhibitors: gemfibrozil (can increase concentrations)

- SJW, valerian: (can decrease concentrations)

drug interactions for loperamide

What drug:

- atropine added to discourage abuse

- adverse effects: CNS, anticholinergic

- only indicated for diarrhea; not for severe infectious diarrhea or severe inflammatory bowel disease

- diphenoxylate/difenoxin

What drug:

- anti-secretory and anti-inflammatory effects

- antimicrobial effects: H. pylori

bismuth subsalicylate

What drug AE:

- black discoloration of tongue and stool

- CNS effects

- hearing loss

- avoid in salicylate allergy

- avoid in children <12

- avoid in those at risk of bleeding

- avoid in those already taking salicylates

- avoid in immunocompromised

bismuth subsalicylate

These are the drug interactions for what drug:

- warfarin

- valproic acid

- methotrexate

- probenecid

- quinolones

- tetracyclines

bismuth subsalicylate

What drug:

- synthetic analog of somatostatin

- works by inhibiting gastric secretions and decreasing the rate of gastric emptying

- injectable product

octreotide

What drug AE:

- nausea

- diarrhea

- abdominal pain

- injection site pain

- caution: can cause cholelithiasis, steatorrhea

octreotide

What is the daily challenge for the gut?

- extract water, minerals, and nutrients from the small intestine but leaving behind a pool of manageable fluid for proper expulsion of waste

definition:

- decreased stool frequency or volume

- difficult stool passage

- incomplete evacuation

constipation

definition:

- evacuation of formed fecal material from the rectum

laxation

definition:

- evacuation of unformed, watery fecal material

- usually from the entire colon

catharsis

Laxatives _________ intestinal absorption of water and electrolytes

- decrease

- note: increased absorption of water and electrolytes can lead to constipation

laxatives __________ retention of fluid in the colon

- enhance

- note: decreased water retention can lead to constipation

What drug class:

- draw water into the small or large intestine or colon via osmosis

- contain Mg cations or phosphate anions

- produce effect in 1-3 hours

saline laxatives

These agents are:

- magnesium citrate

- magnesium sulfate

- magnesium hydroxide

- sodium phosphate

saline laxatives

What saline laxative is this:

- may cause electrolyte imbalances

- drug interactions: FQ, TCNs, ketoconazole, itraconazole, levothyroxine, bisphosphonates, iron

magnesium

What saline laxative is this:

- avoided for constipation, used for catharsis

- can cause hyperphosphatemia, hypocalcemia, hypernatremia, renal impairment, acute phosphate neuropathy

- caution: renal impairment, sodium restricted diet, taking diuretics; megacolon, GI obstruction, colostomy (rectal administration)

- contraindicated in heart failure

phophate salts

What osmotic laxative is this:

- can be combined with electrolytes to produce catharsis

- without electrolytes can be used for the treatment of short term and chronic constipation

- adverse effects: abdominal discomfort, cramping, bloating, flatulence

- monitor K+: may cause electrolyte imbalances

PEG

What osmotic laxative:

- lactulose, sorbitol, mannitol

- MOA: hydrolyzed in the colon to short chain fatty acids which osmotically draw water into the lumen

- AE: bloating, abdominal pain, flatulence, nausea, diarrhea, electrolyte imbalances

nondigestible sugars and alcohols

________ and ________ are equally efficacious for:

- constipation due to opioids or vincristine

- constipation in the elderly

- idiopathic chronic constipation

- sorbitol

- lactulose

What type of laxative is this:

- fiber that is non-digestible; increases stool water and bulk

- produce bowel movement in 72 hours

bulk forming laxative