GI

Question 1

Bevacizumab

Answer 1

An anti-VEGF-A humanized monoclonal antibody which serves to reverse the “leakiness” induced by VEGF. This “leakiness” prevents adequate drug delivery to tumors. It traps VEGF so that it can’t interact with VEGFR-2 receptor

When combined with carboplatin and paclitaxel increases survival in non-small cell lung cancer by 2 months (also for colorectal cancer, renal cell carcinoma)

Given IV

Contraindicated in patients with a history of hemoptysis, brain metastasis, or a bleeding diathesis. It also makes surgery more risky, and can cause severe hypertension and proteinuria. Can occosionally cause strokes, MIs, and gastric perforation. Risk of colonic perforation increasees with intact primary colonic tumors, peritoneal carcinomatosis, PUD, diverticulitis, or prior radiation treatment. Less infusion reactions. CNS hemorrhage

Contraindicated in patients with squamous cell tumors due to unacceptably high rates of life-threatening hemoptysis in early phase clinical trials

Question 2

Erlotinib

Answer 2

HER1/EGFR tyrosine kinase Inhibitor

Binds to the ATP binding site of kinase domain and reversibly blocks enzymatic funtion of EGFR, killing EGFR cell lines (does not block binding of EGF)

Monitor warfarin (INR) while on these drugs

Orally administered (should not be taken with food).

First-line treatment of locally advanced or metastatic pancreatic cancer in combination with gemcitabine (Thomas says colon cancer though). Approved for second-line treatment of patients with locally advanced or metastatic non-small cell lung cancer. Side effects similar to Gefitinib, along with hepatic toxicity

Side effects: diarrhea, acneform rash, anorexia, fatigue, serious or fatal interstitial lung disease, and Steven Johnson syndrome

Resistance: secondary mutations that change binding site. Amplification of met oncogene which amplifies downstream of EGFR, also KRAS mutations.

Question 3

Cetuximab

Answer 3

Monoclonal chimeric (mouse/human) antibody that binds to the extra-cellular surface of EGFR to block receptor dimerization.

Also: antibody dependent cellular cytotoxicity (panitumumab does not have this mechanism)

Given IV

Used for squamous cell carcinomas of the head and neck (along with cisplatin based chemotherapy), metastatic colon cancer (used in patients who cannot tolerate irinotecan-based therapy, or on top of irinotecan-based therapy)

Side effects: infusion reactions: acneform rash in majority of patients, along with pruritis, nail changes, headache and diarrhea. May cause anaphylactoid reactions during infusion, especially among patients in southern US.

Question 4

Panitumumab

Answer 4

Recombinant, fully humanized IgG against the extracellular EGFR domain.

Unlike cetuximab, it does not mediate antibody dependent cell-mediated cytotoxicity

Used in metastatic colon cancer

Leads to rash, infusion reactions, pulmonary fibrosis, and electrolyte abnormalities (same as cetuximab)

Question 5

Irinotecan

Answer 5

Targets topoisomerase I

Converted to active form SN-38 by carboxylesterases in the liver.

Has a longer half-life than topotecan, but hepatic metabolism is significant (through glucuronidation).

Dose limiting toxicity is delayed diarrhea (polymorphism for UDG glucoronidation)(treat with loperamide). The second most common toxicity is myelosuppression. Can also lead to an anticholinergic syndrome with diarrhea, hypersalivation, lacrimation, et c.

No longer used to treat non-small cell lung cancer due to difficulty in achieving proper blood levels.

Usually used in combination with 5-FU and Leucovorin to treat late stage colon cancer. Cells can gain resistance by shifting to topoisomerase II reaction

Question 6

5-Fluorouracil

Answer 6

A pyrimidine analog that inhibits RNA and DNA function.

Used against metastatic colon carcinomas, upper GI tract carcinomas, and breast carcinomas, but rarely used as a single agent.

Usually given IV

Used in combination with cisplatin for HNSCC, irinotecan or oxaliplatin in colon cancer. Also serves to sensitize neoplastic cells for radiation therapy

5-FU can be used in combination with methotrexate. It directly inhibits thymidylate synthase. It can also be given with leucovorin, which binds to thymidilate synthase as well to facilitate inhibition. It can also inhibit RNA processing and be incorporated into DNA

Its dose limiting toxicity is leukopenia. It can lead to mucosal ulcerations throughout the GI tract and lead to fulminant diarrhea, shock and death

Combinations: Leucovorin can be a cofactor for thimidylate synthase almost always given together

Methotrexate: inhibits purine synthesis and gathers more PRPP so 5-FU anabolism enhanced

Question 7

Capecitabine

Answer 7

An orally administered pro-drug of 5-FU approved for the treatment of metastatic breast cancer and metastatic colorectal cancer

Causes similar toxicities as 5-FU, but with more hand-foot syndrome (erythema, desquamation, pain, and sensitivity to touch of the palms and soles), mucositis, myelosuppression

Has a polar group that provides water solubility (the sugar), a lipophilic group that allows absorption through the gut, and is stable in stomach acid. This is why it is a good oral agent

Question 8

Streptozotocin

Answer 8

An antibiotic that is broken down to an alkylating intermediate, 2-chloroethyl diazonium, capable of alklating guanine, cytidine, and adenine bases and causing inter- and intra-strand cross-links. Better than other nitrosourea containing anti-cancers, doesn’t form a carbamoylating agent

Used in treatmnet of human pancreatic islet cell carcinoma (has a glucose attached that attracts it to islets) and malignant carcinoid tumors (often occur in small intestine, stomach).

Nausea, mild renal/hepatotoxicity occurs in two-thirds of patients (do not give with other nephrotoxic drugs). Can also cause anemia, leukopenia, or thrombocytopenia.

Resistance can be due to MGMT repair enzymes

Like most alkylating agents, it is dependent on an intact apoptotic response (p53).

Question 9

Mitomycin

Answer 9

An antibiotic that is curative in treating anal cancers (in combination with cisplatin and 5-FU) and via direct instillation to treat superficial bladder carcinomas.

It serves as a bi- or trifunctional alkylating agent.

Given IV

Major toxicity is myelosuppression along with nausea, vomiting, diarrhea, stomatitis, rash, fever, and malaise. HUS can also occur. It can also lead to renal failure and interstitial pulmonary fibrosis, and potentiate the cardiac toxicity of doxorubicin when used in combination

Resistance is through deficient activation and P-glycoprotein mediated efflux

Question 10

Doxorubicin

Answer 10

Anthracycline

Intercalater of DNA, Topo II inhibitior, free radical generator.

Used to treat Kaposi sarcoma, ovarian cancer, multiple myeloma, and malignant lymphomas

Can be given with an iron chelator to prevent as much free radical formation to protect against dilated cardiomyopathy.

p53 or caspase dependent

Resistance: mdr-1, decreased activity/mutated Topo II, enhanced ability to repair strand breaks

Given IV (if you miss the vein, it causes severe local vesicant action and tissue necrosis), does not cross the BBB

Can turn urine red

Myelosuppression is dose limiting toxicity, along with ST- and T-wave alterations and dilated cardiomyopathy

Question 11

Epirubicin

Answer 11

Anthracycline indicated for treatment of breast cancer and gastric carcinoma

Same side effect profile as doxorubicin

Question 12

Paclitaxel and Docetaxel

Answer 12

Taxanes (docetaxel is synthetic congener of pacitaxel)

Central components of regimens for treating metastatic esophageal, ovarian, breast, lung, GI, genitourinary, and head and neck cancers

albumin-bound nanoparticle solutions that bind to a different B-tubulin site as the vinca alkaloids and inhibit disassembly of microtublues (very limited water solubility, but docetaxel is more soluble)

Resistance: mdr-1, B-tubulin mutations, an increase in survivin, alpha aurora kinase.

Does not depend on p53

Dose limiting toxicity of paclitaxel is neutropenia (treat with filgrastim). Also causes hypersensivity reactions (avoid by pre-treating with dexamethasone, diphenhydramine) and peripheral neuropathy

Docetaxel causes more neutropenia but less neuropathy. Fluid retention is a problem here (treat with dexamethasone)

Question 13

Vinorelbine

Answer 13

Microtubule binding vinca alkaloid (like vincristine)

Administered in normal saline IV. Used with cisplatin for treatment of small cell lung cancer.

Primary toxicity is granulocytopenia (with less neurotoxicity as other vinca alkaloids)

An oral formulation is active in small cell carcinoma

Question 14

Cisplatin

Answer 14

Cisplatin penetrates CNS poorly, most is covalently bound to plasma proteins (in contrast to carboplatin).

It is inactivated by aluminum, so must avoid contact with aluminum needles.

Side effects: can cause nephrotoxicity if not treated with chloride diuresis. Causes ototoxicity that is not helped by chloride treatment (more pronounced in children). Nausea and vomitting occur in almost all patients. Also causes myelosuppression, peripheral motor and sensory neuropathy.

Associated with development of AML

Often used following surgical resection of Stage I and II non-small cell lung cancer. It produces responses against cancers of the head and neck, anal and rectal carcinomas, and sensitizes cells to radiation (especially with HNSCC)

Question 15

Oxaliplatin

Answer 15

A platinum cooordination complex that is used against colorectal and gastric cancer. Leaving group is an oxalate instead of a chloride, like in cisplatin

MOA: exhibits a cytotoxicity that does not depend on the MMR system or the HMG proteins that are required by other platinum containing compounds, which may explain its greater role in colorectal cancer. It also supresses expression of thymidylate synthase, and is therefore often used with 5-FU (synergy), which actually up-regulates TS expression.

Dose limiting toxicity is peripheral neuropathy. An acute form is triggered by cold liquids, while a chronic form is more dose related

Overexpression of glutathione and NER mechanism can lead to resistance

Question 16

Gemcitabine

Answer 16

Pyrimidine Analog

Inhibits DNA synthesis by inhibition of DNA polymerase and ribonucleotide reductase, cell cycle-specific for the S-phase of the cycle (also blocks cellular progression at G1/S-phase). It can also hit non-proliferating cells via inducing apoptosis

Gemcitabine is phosphorylated intracellularly by deoxycytidine kinase to gemcitabine monophosphate, which is further phosphorylated to active metabolites gemcitabine diphosphate and gemcitabine triphosphate. Gemcitabine diphosphate inhibits DNA synthesis by inhibiting ribonucleotide reductase; gemcitabine triphosphate incorporates into DNA and inhibits DNA polymerase (chain terminator).

Used against rapidly dividing and non-dividing cells

Can be used to treat non-small cell lung, metastatic pancreatic (best if tumors express hENT and low expression of RNR), ovarian, esophageal, and bladder cancer.

Activity greatly enhanced by combination with cisplatin/carboplatin

Myelosuppression is generally the dose-limiting toxicity, can cause HUS, can’t use with radiation therapy

Resistance is through increased deactivation by deoxycytidine deaminase or decreased activation by deoxycytidine kinase

Question 17

GI tract acidity/ treatment of peptic ulcers

Answer 17

Through muscarrinic blockade, gastric secretion is blocked: volume and amount of acid, pepsin, mucin are all reduced

Pirenzepine: muscarinic antagonist, like atropine, reduces gastric acid secretion but with fewer side effects.

Telenzepine: similar to pirenzepine except it is more potent analog

These drugs are investigational in the US

Drugs used in acid-peptic diseases: diseases include GERD, peptic ulcer, stress-related mucosal injury. All of these involve erosion or ulceration due to acid, pepsin, bile overwhelming the defensive barriers of the GI mucosa (mucus, bicarb, PGE2, blood flow)

Question 18

Antacids

Answer 18

Treatment of dyspepsia and acid-peptic disorders

Weak bases that react with HCL forming salt and water

Sodium Bicarbonate (baking soda, alka seltzer): reacts with HCL to form CO2 and NaCl, resulting in gastric distention and belching. Can cause metabolic alkalosis. Na -fluid retention

Calcium carbonate (Tums, os-cal): less soluble. Reacts with HCL to form CO2 and CaCl2. Belching and metabolic alkalosis. Milk-alkali syndrome (hypercalcemia, renal insufficiency, metabolic alkalosis)

Excessive doses of both of these can result in hypercalcemia, renal insufficiency.

Magnesium Hydroxide/ Aluminum Hydroxide: With HCL it forms magnesium chloride or aluminum chloride and water. No gas is made, no belching. met alkalosis is uncommon. Can cause osmotic diarrhea so given with Maalox. Dont give these long term to patients with renal insufficiency.

From ppt (Magnesium Hyrdroxide-osmotic diarrhea; Aluminum Hydroxide- constipation)

Adverse: diarrhea, constipation, acid-base balance, milk-alkali syndrome. All of these affect the absorption of other meds by binding the drug, so don’t give within two hours of tetracyclines, fluoroquinolones, itraconazole, and iron

Question 19

Proton Pump Inhibitors

Answer 19

Omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole

Esomeprazole and pantoprazole are also IV

MOA: All are lipophilic weak bases that become protonated in the parietal cell canaliculus (active form) and forms a thiophilic sulfenamide cation, which forms a disulfide bond with the H/K ATPase, irreversibly inactivating it.

pharmacokinetics: Ideal: short serum half life, activated near site of action, long duration of action. Omeprazole is available as powder formulation that containes sodium bicarb. Administered as inactive prodrugs. capsule dissolves in alkaline intestine. Omeprazole has fastest onset of action. 50% bioavail. 3-4 days of usage before full inactivation of enzyme. Rapid first-pass metabolism

In contrast to H2 blockers, they inhibit both fasting and meal stimulated secretion.

Uses: GERD- most effective agent in this disease, and Peptic Ulcer Disease- heals more than 90% of duodenal ulcers within 4 weeks and gastric ulcers in 6-8 weeks, NSAID ulcers, gastrinoma

*H. pylori: heal the ulcer and kill the organism. 2 antibiotics and a proton pump inhibitor

Adverse: very safe. low B12 levels, respiratory and enteric infections (C. difficile), increased gastrin (no acidic feedback inh)

CI: decreased acid alters absorption of ketoconazole, itraconazole, digoxin, atazanavir.

Question 20

H2-receptor antagonists

Answer 20

Use has declined since proton pump inhibitors were made

Cimetidine, ranitidine, famotidine, nizatidine

Cimetidine, ranitidine, famotidine: all undergo first pass metabolism- 50% bioavailability. serum half life of 1.1-4 hrs. In elderly, decline of 50% drug clearance

MOA: competitive inhibition at parietal cell H2 receptor and suppress acid secretion in linear dose dep manner. Highly selective. Reduces acid secretion stimulated by histamine, gastrin, and cholinomimetic agents through 2 mech:

1) Histamine released from ECL cells by gastrin or vagal is blocked.
2) with H2 blockade, gastrin and vagal stimulation on parietal cells is less effective.

Especially effective at inhibition of nocturnal acid secretion

Treatment of GERD, peptic ulcer disease (Usesless in H. pylori associated ulcers), nonulcer dyspepsia, prevention of bleeding from stress-related gastritis

Adverse: cimetidine is associated with mental status change and can cause gynecomastia or impotence. Don’t use in pregnancy. Can cause blood dyscrasias

CI: cimetidine interferes with CYP. No interactions with nizatidine and famotidine.

Question 21

Sucralfate

Answer 21

viscous tenacious paste that binds to ulcers or erosions for 6 hours.

less than 3% of drug is absorbed, the rest is eliminated in feces.

Used in critically ill to prevent stress ulcers

MOA: negative charge sucrose sulfate binds to positive charged proteins in the base of ulcer

Adverse: constipationi in 2% due to aluminum salt

Question 22

Misoprostol

Answer 22

Prostaglandin analog of PGE1

oral absorption, then metabolized to a free acid. less than 30 min half life

acid inhibitory and mucosal protective properties. Stimulates bicarb and enhances blood flow at mucosa. Binds to PG receptor on parietal cells, reducing histamine stimulated cAMP production causing acid inh.

Uses: peptic ulcers from NSAIDS and termination of pregnancies in conjunction with mifepristone

Adverse: diarrhea and cramping, uterine contractions so dont use in pregnancy

Question 23

Latanoprost

Answer 23

Topically active PGF_2alpha derivative used for treatment of open angle glaucoma

Question 24

Prostacyclin

Answer 24

AKA: PGI₂, epoprostenol

Synthesized by the vascular endothelium and is a powerful vasodilator and inhibitor of platelet aggregation.

Used clinically to treat pulmonary hypertension and portopulmonary hypertension

Question 25

Alprostadil

Answer 25

PGE₁

used for its smooth muscle relazing effects to maintain the ductus arteriosus patency in some neonates awaiting cadiac surgery and in treatment of impotence

Question 26

Aspirin

Answer 26

AKA acetylsalicylic acid

Rapidly absorbed from stomach and upper small intestine, bound to albumin

Irreverisbly inhibits COX1 and 2 (antiplatelet effect lasts 8-10 days, the life of the anuclear platelet)

Used against TIAs, unstable angina, coronary artery thrombosis with MI, and thrombosis after coronary artery bypass grafting

Side effects include gastric upset, gastric and duodenal ulcers. Rarely, hepatotoxicity, asthma, rashes, GI bleeding, and renal toxicity occur

Don’t use in hemopheliacs (duh)

Not effective in treating ankylosing spondylitis (unlike all other NSAIDs)

Question 27

Celecoxib

Answer 27

Selective COX-2 inhibitor.

Cox-2 inhibitors have the same analgesic, antipyretic, and anti-inflammatory effects but half of the GI adverse effects. Associated with a higher incidence of cardiovascular thrombotic events

Associated with fewer endoscopic ulcers than most other NSAIDs

May cause rashes, does not effect platelet aggregation at usual doses, and may also interact with warfarin. Can also cause renal toxicity

Question 28

Meloxicam

Answer 28

A COX-2 inhibitor that is not as selective as celecoxib.

It is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen.

Does not effect TXA2 in appreciable levels in vivo

Question 29

Diclofenac

Answer 29

Nonselective COX inhibitor

GI ulceration may occur less frequently than with some other NSAIDs.

Often paired with misoprostol to prevent GI effects, but this may lead to diarrhea.

Impairs renal blood flow and glomerular filtration rate. Elevation of serum aminotransferases is more common with this drug than other NSAIDs.

Used for postoperative opthalmic inflammation, solar keratoses, and has a rectal suppository for preemptive analgesia and postoperative nausea

Question 30

Diflunisal

Answer 30

Nonselective COX inhibitor

Subject to capacity limited metabolism

Claimed to be particularly effective for cancer pain due to bone metastases and for pain control in dental surgery

Limit dosage with renal impairment

Question 31

Etodolac

Answer 31

Nonselective COX inhibitor

Can be given 3-4 times a day (not many specifics on this one)

Question 32

Flurbiprofen

Answer 32

Nonselective COX inhibitor

Complex MOA: Its S enantiomer inhibits COX, but may also interact with TNF alpha and nitric oxide synthesis

Available in topical opthalmic formulation for inhibition of intraoperative miosis, used in ear, neck, and nose surgery

Rarely associate with cogwheel rigidity, ataxia, tremor, and myoclonus

Question 33

Ibuprofen

Answer 33

Nonselective COX inhibitor

derivative of phenylproprionic acid

More potent than aspirin in anti-inflammatory effect

Effective in closing PDAs in preterm infants just like indomethacin

Decreases urine output les than indomethacin

Contraindicated in patients with nasal polymps, angioedema, and bronchospastic reactivity to aspirin

Use with aspirin decreases both the protective cardiac effects of aspirin and the anti-inflammatory effect of both drugs

Question 34

Indomethacin

Answer 34

Potent Nonselective COX inhibitor

May also inhibit phospholipase A and C, inhibit neutrophil migration, and decrease T and B-cell proliferation

Used to close PDAs and as pain reliever in numerous conditions

Can be given as an epidural injection

GI effects include pancreatitits. Headaches can occur along with renal papillary necrosis

Probenecid prolongs its half life

Question 35

Ketoprofen

Answer 35

Nonselective COX and lipoxygenase inhibitor

Probenicid prolongs its half life

Not superior to other NSAIDs in clinical efficacy

Question 36

Ketorlac

Answer 36

Nonselective COX inhibitor

Used as an analgesic, not as an anti-inflammatory (although it has anti-inflammatory properties)

Is often used in conjunction with or to replace morphine for pain control

Question 37

Nabumetone

Answer 37

Only nonacid nonselective COX inhibitor in current use

Given as a ketone prodrug that is converted to an acid in the body.

Does not undergo enterohepatic circulation; cleared by kidneys

May be less damaging to stomach than other NSAIDs

Associated with a pseudoporphyria and photosensitivity in some patients

Very expensive

Question 38

Naproxen

Answer 38

Nonselective COX inhibitor

Only NSAID marketed as a single enantiomer

Used for usual rheumatologic indications

Incidence of GI bleeding is low but double that of ibuprofen

Rare cases of allergic pneumonitits, leukocytoclastic vasculitits, and pseudoporphyria have been noted

Question 39

Oxaprozin

Answer 39

Another propionic acid nonselective COX inhibitor

Main difference is very long half life (50-60 hours)

Mild uricosuric, meaning it may be useful in gout patients

Question 40

Piroxicam

Answer 40

Nonselective COX inhibitor

at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function.

Used for usual rheumatic indications

Has increased incidence of peptic ulcer and bleeding compared to other NSAIDs

Question 41

Sulindac

Answer 41

A sulfoxide prodrug nonselective COX inhibitor

Used for rheumatic diseases, familial intestinal polyposis, and may inhibit development of colon, breast, and prostate cancer.

Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia, agranuloctyosis, and nephrotic syndrome have all been observed. It can also elevate serum aminotransferases like diclofenac

Question 42

Tolmetic

Answer 42

Nonselective COX inhibitor

Short half-life; not often used

ineffective at treating gout, and may cause thrombocytopenic purpura

Question 43

Choice of NSAIDs

Answer 43

For renal insufficiency, choose nonacetylated salicylates

Use celecoxib plus omeprazole or misoprostol for those patients with the highest risk of a GI bleed.

Choice requires a balance of efficacy, cost-effectiveness, safety, and personal factors

Question 44

Acetominophen

Answer 44

Analgesic, not an anti-inflammatory

Weak COX-1 and COX-2 inhibitor

Highly reactive metabolite (N-acetyl-p-benzoquinone) is toxic to both liver and kidneys

Does not affect uric acid levels and lacks platelet modifying effects

Use in people that can’t handle aspirin and children with viral infections

Fatal with large doses, antidote is acetylcysteine

GI bleeding does not occur

Question 45

Aminosalicylates

Answer 45

Drugs containing a 5-aminosalicylic acid that are used in the treatment of inflammatory bowel diseases (especially ulcerative colitis).

Include sulfasalazine, olsalazine, balsalazide, and mesalamine

Thought to work topically, not systemically, in areas of diseased GI mucosa. MOA is potentially through modulation of inflammatory mediators derived both from COX and lipoxygenase pathways. It also inhibits the activity of NF-kB.

Azo compounds (S,O, and B) are bound to an inert compound. This bond is broken by bacteria in the terminal ileum and colon, activating drug here

Mesalamine compounds are bascially different ways of packaging the 5-ASA to get it to the colon. Includes Pentasa (contains timed release microgranules), Asacol and Apriso, Lialda (all three are pH sensitive). You can also get it there via an enema (Rowasa) or suppositories (Canasa)

Sulfasalazine has the highest incidence of adverse effects (especially in slow acetylators) including nausea, GI upset, headaches, arthralgias, bone marrow suppression, and malaise. Hypersensitivity to sulfapyridine (metabolite) can also occur. It also impairs folate absorption, so supplement with folate

The rest are well tolerated, but osalazine may induce a secretory diarrhea (different than inflammatory diarrhea)

Question 46

Glucocorticoids Used In Inflammatory Bowel Disease

Answer 46

MOA: inhibit production of inflammatory cytokines and chemokines, reduce expression of inflammatory cell adhesion molecules, and inhibit gene transcription of NO synthase, PLA₂, and NF-kB

Used to treat patients with moderate to severe active inflammatory bowel disease. They are not useful in maintaining remission

Prednisone and prednisolone are the most commonly used oral glucocorticoids in GI practice

Hyrdocortisone enemas, foam, or suppositories are used to treat inflammatory bowel disease (of rectum and sigmoid colon) topically and avoid systemic administration

Budesonide is a potent synthetic analog of prednisolone that has a huge first pass effect, but is formulated to be released in the distal ileum and colon (site of action)

If systemic administration can be avoided, do so, as there are lots of adverse effects to glucocorticoids

Question 47

Purine Analogs (Azathioprine and 6-Mercaptopurine)

Answer 47

Purine antimetabolites that have immunosuppressive properties used in the treatment of inflammatory bowel diseases

Azathioprine is a precursor to 6-MP and has a greater bioavailability than does 6-MP. Active metabolite is 6-thioguanine, which has a significantly greater half life than the parent drug due to concentration within cells.

Important for both induction and maintenance of remission (80% effective) of ulcerative colitis and Crohn’s disease

Dose-related toxicities include nausea, vomiting, bone marrow depression, and hepatic toxicity. Leukopenia may respond to GSF. TPMT is what catabolizes 6-MP, which can lead to more bone marrow suppression if low levels are present in the patient. May predispose to lymphoma

Avoid allopurinol, as both drugs interact with xanthine oxidase (this can lead to severe leukopenia)

Question 48

Methotrexate

Answer 48

Antimetabolite that can induce and maintain remission in patients with Chrohn’s disease (effect on ulcerative colitis is uncertain)

Principal MOA is inhibition of DHFR leading to decreased thymidine and purine production. It may also interfere with inflammatory actions of IL-1, stimulate the release of adenosine (endogenous anti-inflammatory), and stimulate apoptosis and death of activated T-lymphocytes

At high doses, causes bone marrow depression, megaolblastic anemia, alopecia, and mucositis. Supplement with folate. Risk of hepatic damage is lower in these patients that those being treated for psoriasis

Question 49

Anti-TNF_alpha Therapy

Answer 49

Used for moderate to severe Chron’s disease in patients who have not responded to conventional therapies (Infliximab is also used for ulceratice colitis). Used in both induction and maintenance, but eventually they may lose effect due to antibody formation against the antibodies.

Infliximab (chimeric) and Adalimumab (recombinant) are IgG’s against TNFalpha that both neutralize soluble/insoluble TNF as well as induce cell death. This second action is due to presence of Fc region of the antibody

Certolizumab is 95% human and is a pegylated Fab portion of an antibody that still neutralizes TNF but cannot induce cell death

Effects are due to suppression of TH1 response (TB, hepB, fungal organisms, bacterial sepsis, et c.). Serum sickness and rare acute hepatic failure, demyelinating disorders, hematologic reactions, and new or worsened congestive heart failure may occur. They are also associated with psoriatic skin rashes that resolve after drug discontinuation.

Question 50

Eicosanoid effects on GI

Answer 50

PGE₂ and PGF_2alpha cause longitudinal smooth muscle contraction, circular smooth muscle contraction is caused by PGF_2apha and PGE₁ and is relaxed by PGE₂. Administraction of PGE₂ or PGF_2alpha results in colicky cramps

LTB₄ is synthesized by human colonic epithelial cells and is substantially increased in patients with inflammatory bowel disease

Question 51

Interferons for Hepatitis

Answer 51

Current treatment of hepatitis C is peginterferon alfa and ribaviran (for 48 weeks). Also used in treatment of chronic hepatitis B. Only about 15% effective when used alone. 40% effective in combination with ribavirin

Works by activating JAK-STAT signal-transduction pathways which leads to viral resistance via inhibition of protein synthesis, cleavage of cellular and viral RNAs, and inactivation of eIF-2

HCV resistance is through inhibition of the IFN-induced protein kinase

Must be given IV

Can be pegylated to prolong action (once per week dosing)

Adverse Effects: can lead to a terrible flu-like feeling following initial injection. Dose limiting toxicities are depression, myelosuppression, cardiotoxicity, neurotoxicity manifested by somnolence, confusion, seizures,

Question 52

Ribavirin

Answer 52

Purine nucleoside analog with a modified base and D-ribose sugar. Used on a wide range of RNA and DNA viruses (HCV).

MOA: incompletely understood but relates to alteration of cellular nucleotide pools and inhibition of viral mRNA synthesis

Resistance has only occurred in Sinbis and HCV

Orally available; taken up in the proximal small bowel

Can cause a dose-related anemia owing to extravascular hemolysis and suppression of bone marrow; fatigue, cough, rash, et c. Very teratogenic

Question 53

Adefovir

Answer 53

diester prodrug of adefovir, an acyclic phosphonate nucleotide analog of AMP

Clinical use is limited to HBV infections. Used in combination with other anti-HBV nucleosides

Can serve as a comptetitive inhibitor of viral DNA polymerases and reverse transcriptases and as a chain terminator

Causes a dose-related nephrotoxicity and tubular dysfunction (hypophosphatemia, acidosis, glycosuria, and proteinuria)

Question 54

Entecavir

Answer 54

Guanosine nucleoside analog with selective activity against HBV polymerase used in treating chronic HBV

Requires intracellular phosphorylation. It inhibits base priming, reverse transcription, and synthesis of the positive strand of HBV DNA all by hitting the reverse transcriptase

Severe acute exacerbations of Hepatitis B have been reported in people that discontinued therapy. Monitor liver function test following discontinuation.

Question 55

Lamivudine

Answer 55

A nucleoside analog that inhibits HIV reverse transcriptase and the HBV DNA polymerase.

Needs cellular enzymes to convert it to triphosphate form which competitively inhibits polymerases and causes chain termination.

Point mutations in the YMDD motif of HBV DNA leads to resistance, but this could be overcome by adefovir

Well-tolerated; occasional rise in aminotransferase levels following therapy

Question 56

Telbivudine

Answer 56

Synthetic thymidine nucleoside analog with activity against HBV DNA polymerase

It is phosphorylated by cellular kinases to active triphophate form (competitive inhibitor and chain terminator, like the others)

Generally well-tolerated. Discontinuation can cause increased creatine kinase, nausea, diarrhea, fatigue, myalgia, and myopathy

Given orally

Question 57

Tenofovir

Answer 57

nucleotide analog with activity against both HIV-1 and HBV. It is administered orally as the disoproxil prodrug.

Will likely supersede most adefovir use due to its safety, efficacy, and resistance profile

Question 58

Treatment of Chronic Hepatitis B

Answer 58

Chronic disease: positive HBsAg for 20+ weeks

Stages: 1. rep stage with immune tolerance 2. replicative stage with immune clearance 3. non rep stage, HBeAg disappears but HBsAg may remain

can progress to cirrhosis and hepatic failure

Treatment:

1. multiple antiviral agents: emtricitabine, entecavir, clevudine, telbivudine, tenofovir
2. interferon alpha reserved for patients w/ persistent HBeAg and elevated transmaminase

Question 59

Treatment of Hepatitis C

Answer 59

Hep C seldom clears on its own. It can lead to cirrhosis, hepatic failure, HPC

Treatment with pegylated interferon alpha and oral ribavirin

Question 60

Benzodiazepines

Answer 60

Diazepam, Chlordiazepoxide, lorazepam

Used in acute ethanol withdrawal

binds GABA_A receptor

Question 61

Disulfuram

Answer 61

Inhibits the oxidation of acetaldehyde to acetate (Aldehyde dehydrogenase)

Deters drinking from those with alchol abuse

Causes facial flushing, nausea, vomiting, dizziness, and headache (hangover)

Other drugs (metronidazole, cefotetan, trimethoprim) inhibit ALDH as well

Question 62

Naltrexone

Answer 62

opioid antagonist, blocks the mu receptors. studies have found that small doses of opioids increase the appetite for alcohol. Do the math

Reduces the rate of relapse and reduces cravings especially when used in combination with behavioral counseling.

oral dose but can be given IM for extended release

dose-dep hepatotoxicity

Question 63

Acamprosate

Answer 63

Acts on GABA, glutamate, serotonergic, NE, DA receptors

weak NMDA antagonist and GABA activator are best effects

Adverse: nausea, vomiting, diarrhea, rash. Do not use in patients with renal impairment.

Question 64

Odansetron, Topiramate

Answer 64

Odansetron: serotonin 5-HT3 receptor antagonist

Topiramate: drug used for seizures

These drugs have shown efficacy in maintaining abstinence and reducing cravings in chronic alcoholism

Question 65

Ethanol

Answer 65

90% of alcohol is oxidized in liver; remainder is excreted through lungs and urine. Zero-order kinetics

MEOS: used NADPH as cofactor. During chronic alcohol consumption, this enzyme in induced and alcohol is better cleared; however, so are other drugs that use CYP450. Toxins and free radicals are also produced

Effects on liver and GI tract: Liver disease in 15-30%, alcoholic fatty liver can progress to hepatitis and cirrhosis, chronic pancreatitis, gastritis, anemia and protein malnutrition (water-soluble vitamins)

Drug interactions: enhances metabolism of other drugs, esp important for acetaminophen. In contrast, acute alcohol ingestion can inhibit metabolism of drugs (reduced blood flow) like TCA, phenothiazine, sedative-hypnotics

Question 66

Methanol

Answer 66

used in industrial production of organic compounds and solvents

absorbed through skin, GI tract, lungs. Eliminated by ox to formaldehye, formic acid, CO2

Early symptoms: gastritis and inebriation. Most characteristic- visual disturbance “like being in a snowstorm” and can progress to blindness.

Treatment:

1. support of respiration
2. suppression of metabolism by alcohol dehydrogenase, hemodialysis to remove methanol and toxic products, and alkalinization to balance metabolic acidosis.

Fomeprizole, ADH inhibitor, is used to treat methanol and ethylene glycol poisioning. Adverse: burning at infusion site, headache, nausea, dizziness

Ethanol has higher affinity for ADH so can also be used

Question 67

Ethylene Glycol

Answer 67

Polyhydric alcohol in antifreeze and solvents

Sweet taste

metabolized to toxic aldehydes and oxalate

Stages:

1. excitation followed by CNS depression
2. metabolic acidosis from lactate
3. renal insufficiency due to oxalate in renal tubules

Fomepizole in standard of treatment

Question 68

GI system autonomics

Answer 68

Muscarinic agonists increases secretory and motor activity of the gut. Salivary and gastric glands are strongly stimulated. Peristaltic activity is increased and most sphincters are relaxed. M3 required for smooth muscle contraction

**Acetylcholine: ** binds M3

**Methacholine: ** synthetic choline ester that acts as a non-selective muscarinic receptor agonist in the parasympathetic nervous system. methacholine challenge test in asthma

Carbachol: cholinergic agonist

**Pilocarpine: ** Like bethanechol, M3 agonist. Treat xerostomia in Sjogren’s and glaucoma

**Bethanechol: ** stimulates muscarinic receptors without any effect on nicotinic receptors. Unlike acetylcholine, bethanechol is not hydrolyzed by cholinesterase and will therefore have a long duration of action. Treat post op and neuro ileus. Hits M3 on muscle cells and at myenteric plexus synapses

Neostigmine: intermediate duration cholinesterase inhibitor. IV for treatment of acute large bowel distention

Question 69

Anticholinergic Drugs

Answer 69

GI tract: blockade of muscarinic receptors has dramatic effects on motility and secretory functions. Dry mouth, gastric secretions is blocked (less acid, pepsin, mucin). Paralysis of motility is temporary; 1-3 days later, enteric nervous system will reestablish some peristalsis.

Atropine: muscarinic antagonist

Pirenzepine: Reduce gastric acid secretion with fewer adverse effects than atropine due to selective blockade of M1 innervating the stomach

Telenzepine: more potent analog of Pirenzepine

Dicyclomine: antagonistt at M3. Reduces smooth muscle and secretory activity of gut. Treatment of IBS, minor diarrhea. Toxicity: tachycardia, confusion, urinary retention

Question 70

Metoclopramide and Domperidone

Answer 70

D2 receptor antagonists

inhibits cholinergic smooth muscle stimulation

Increase esophageal peristaltic amplitude, increase LES pressure, and enhance gastric emptying. Also block area postrema (CTZ of medulla)- antiemetic and antinausea

Treatment of GERD, impaired gastric emptying, nonulcer dyspepsia, prevention of vomiting, postpartum lactation stimulation

Adverse: Metoclopramide has CNS effects: restlessness, drowsiness, insomnia, anxiety, EPS, tardive dyskinesia (main reason you don’t give long term), elevated prolactin levels (associated with galactorrhea, gyneocomastia, impotence, and menstrual disorders). Domperidone is well tolerated b/c it does not cross BBB very well.

Question 71

Bulk-Forming Laxatives

Answer 71

indigestible, hydrophilic colloids that absorb water and distend the colon, promoting peristalsis

Psyllium, Methylcellulose: natural plant products

Polycarbophil: synthetic fibers

Adverse: bacterial digestion leads to bloating and flatus

Question 72

Stool Surfactant Agents (softeners)

Answer 72

Permit water and lipids to permeate

Oral or rectal

Docusate and glycerin suppository

Docusate common in hospital to minimize straining and constipation

Mineral oil lubricates fecal material, retarding water reabsorption. Prevents and treats fecal impaction in young children and debilitated adults. Aspiration results in lipid penumonitis

Long term use can impair absorption of fat soluble vitamines K,A,D,E

Question 73

Osmotic Laxatives

Answer 73

Soluble but nonabsorbable compounds that results in increased stool liquidity due to increase in fecal fluid

Nonabsorbable sugars or salts:

For acute constipation or prevention of chronic constipation

Magnesium hydroxide (milk of magnesia) should not be used for prolonged periods in those with renal insufficiency- hypermagnesemia

Sorbitol and Lactulose are sugars that prevent chronic constipation- causes flatus and cramps

High doses cause prompt bowel evacuation (purgation) in 1-3 hours. Most commonly used purgatives are magnesium citrate and sodium phosphate. Important to maintain hydration to compensate for fecal loss

Sodium phosphate causes hyperphosphatemia, hypocalcemia, hypernatremia, hypokalemia and can lead to cardiac arrhythmias and renal failure

Balanced Polyethylene Glycol

PEG is used for colon cleansing before GI endocscope procedures (colonostocopy). No cramps or flatus produced. Isotonic solutions contain inert nonabsorbable sugar (PEG) and no electrolyte shift occurs.

Question 74

Stimulant Laxatives

Answer 74

Carthartics

Induce bowel movements. MOA unclear but stimulates enteric nervous system and colonic electrolyte and fluid secretion

Anthraquinone Derivatives

Aloe, senna, cascara occur in plants. poorly absorbed and produce bowel movement in 2 hours. Chronic use gives rise to melanosis coli(brown pigment in colon)

Diphenylmethane Derivatives

Bisacodyl- bowel movement in 6-10 hours (oral) or 30-60 min (rectal) used for acute and chronic constipation

Question 75

Lubiprostone

Answer 75

chloride channel activator laxative

Used for chronic constipation and IBS with predominant constipation

stimulates type 2 chloride channel in small intestine, increasing chloride rich secretion shortening transit time

CI in pregancy

Nausea in 30% due to delayed gastric emptying

Question 76

Opioid Receptor Antagonist

Answer 76

These agents dont cross BBB, so don’t diminish pain blocking effects of opioids.

Methylnaltrexone bromide: treatment of opioid induced constipation. Subcutaneous administration

Alvimopan: short term use for those in the hospital who have undergone small or large bowel resection. orally and shouldnt be taken more than week. Cardiovascular toxicity

Question 77

Antidiarrheal agents

Answer 77

For mild to moderate acute diarrhea and IBS and IBD. Not for bloody diarrhea, high fever

Opioid Agonists

Loperamide doesnt cross BBB and no analgesics (no addictive potential)

Diphenoxylate opioid agonist that does have analgesic effects at high doses. commercial preps add atropine to prevent overdosage

Bile Salt-Binding Resins

Cholestyramine, Colestipol, Colesevelam may decrease diarrhea caused by excess fecal bile acids. Diseases of the terminal ileum lead to malabsorption of bile salts

Colsevelam doesnt affect the absorption of other drugs

Adverse: bloating, flatulence, constipation, fecal impaction

Octreotide

Octreotide has similar actions to somatostatin (inhibits gastrin, CCK, slows motility, reduces blood flow)

Useful for treating carcinoid and VIPomas diarrhea; pancreatic fistula b/c it inhibits pancreated secretion

Octreotide increases motility at low doses but at high doses it does the opposite

Adverse: steatorrhea (with KADE deficiencies), gallstones in 50%, blood glucose imbalances, bradycardia.

Kaolin, Pectin, Subsalicylate, Bismuth are also used for treatment of diarrhea

Question 78

Pancreatic Enzyme Supplements

Answer 78

Exocrine pancreatic insufficiency - cystic fibrosis, pancreatitis, pancreatic resection and leads to steatorrhea, vitamin malabsorption and weight loss

supplements contain amylase, lipase, and protease

Pancreatin: alochol derived extract of hog pancreas with low conc. of lipase and proteolytic enzymes

Pancrelipase: enriched preparation. 12 times lipolytic activity and 4 times proteolytic activity of pancreatin.

Pancrelipase rapidly inactivated by gastric acids. Enteric-coated preparations dont need to be given with an acid inhibitor

Well tolerated; capsules should not be chewed b/c it can cause oropharyngeal mucositis. diarrhea and abdominal pain

Question 79

Ursodiol

Answer 79

Bile acid therapy for gallstones

oral administration. After conjugation in liver and excretion in bile, it undergoes hepatic recirculation with a 100 hour half life

Decreases cholesterol content by reducing hepatic cholesterol secretion

Used for dissolution of small cholesterol gallstones in patients with gallbladder disease who refuse surgery or are poor surgical candiates.

Adverse: Bile salt induced diarrhea (unlike chenodeoxycholate, it is not associated with hepatotoxicity)

Question 80

Antiemetic Agents

Answer 80

Vomiting center in lateral medullary reticular formation. Acts through CN VIII and X and nucleus tractus solitarius

Area postrema is outside BBB and rich in D2 receptors

Vestibular system is rich in M1 and H1

Vagal and spinal afferents rich in 5-HT3 are stimulated by radiation, chemotherapy, distention

Question 81

Serotonin 5-HT3 Antagonists

Answer 81

Antiemetic by blockade of receptors on extrinsic vagal and spinal afferents

Ondansetron, Granisetron, Dolasetron, Palonsetron

Palonsetron is a newer IV with greater affinity and longer half life

Used for Chemotherapy induced nausea and vomiting (effect enhanced by combination with glucocorticoids like dexamethasone or methylprednisolone) and postoperative and postradiation nausea and vomiting

Alosetron– IBS w diarrhea (AE – constipation)

Adverse: headache, dizziness, QT prolongation (mainly dolasetron)

metabolized by P450

Question 82

Aprepitant and Fosaprepitant

Answer 82

Neurokinin receptor antagonist

Antiemetic

NK1 antagonism at area postrema

Aprepitant (oral) is highly selective and crosses BBB

Fosaprepitant is IV and converted to aprepitant in 30 minutes after infused

Aprepitant is metabolized by CYP3A4

– Increased aprepitant plasma level by ketoconazole,
ciprofloxacin, clarithromycin, nefazodone, ritonavir,
nelfinavir, verapamil, quinidine)
– Decreases the INR in patients taking warfarin

with corticosteroids for prevention of acute and delayed nausea and vomiting from chemotherapy

Adverse: fatigue, dizziness,diarrhea, and drug interactions all from Aprepitant

Question 83

Phenothiazines and Butyrophenones (antiemetics)

Answer 83

Antipyschotic agents that are used for their inhibition of dopamine and muscarinic receptors to prevent emesis

Sedation through anti Histamine action

Prochlorperazine, Promethazine, Thiethylperazine

Droperidol (IM or IV) extremely sedating and EPS occurs, QT prolonged

Question 84

Metoclopradmide and Trimethobenzamide

Answer 84

Antiemetic via dopamine receptor blockade

Trimethobenzamide has antihistmaine activity

Used for prevention and treatment of nausea and vomiting, metoclopramide may be given in high doses

EPS effects: restlessness, dystonia, parkinsonian symptoms.

Question 85

H1 antihistamines/ anticholinergics for antiemesis

Answer 85

Diphenhydramine and Dimenhydrinate are first generation H1 antagonists that have anticholinergic properties.

Meclizine is H1 antihistamine and causes less sedation used for motion sickness and vertigo due to labyrinth dysfunction

Scopolamine (Hyoscine) muscarinic antagonist used for preventing motion sickness High incidence of anticholinergic effects orally, better tolerated as a transdermal patch

Question 86

Dronabinol

Answer 86

Cannabinoid to reduce vomiting

THC from marijuana

Oral

appetite stimulant and antiemetic

Adverse: euphoria, dysphoria, dry mouth, hallucinations, hungry, tachycardia

Nabilone is a closely related THC analog

Question 87

Prokinetic Drugs

Answer 87

Prokinetic agents are drugs that can selectively stimulate gut motor function

Drugs that increase LES are useful for GERD; drugs that improve gastric emptying may be useful for gastroparesis and postsurgical gastric emptying delay; stimulate small intestine to treat ileus and intestinal pseudo-obstruction; enhance transit for constipation

Bethanechol: stimulates M3; treat GERD and gastroparesis

Erythromycin: macrolide that stimulates motilin receptors on smooth muscle and promotes the migrating motor complex. Useful in those with gastroparesis and acute upper GI hemorrhage to promote emptying of blood (cisapride was increased with QT prolongation, as is erythromycin)

Metoclopramide: D2 antagonist. Dopamine normally inhibits cholinergic smooth muscle stimulation

Domperidone: D2 antagonist like Metoclopramide

Neostigmine: acute large bowel distention treatment

Octreotide: somatostatin analog that inhibits pancreatic secretion among other effects

Tegaserod: serotonin 5-HT4 partial agonist which binds the receptors on the presynpatic terminal of submucosal intrinsic primary afferent nerves. Ultimately this promotes peristaltic reflex and proximal bowel contractions and distal bowel relaxation.

Used to treat chronic constipation and IBS

Pulled from market b/c of cardiovascular adverse effects

Lubiprostone: activates type 2 chloride channel

Guanylate cyclase C agonist: ** Linaclotide** – activates CFTR

Question 88

Metronidazole

Answer 88

Nitroimidazole compound used in the treatment of E. histolytica infections, Giardia lamblia infections. Also has antibacterial activity against all anaerobic cocci and anaerobic Gram-negative bacilli, including Bacteroides, Clostridium, H.pylori, and Campylobacter

It is a pro-drug that is activated by susceptible organisms via their ferredoxins that are capable of donating electrons to metronidazole. PFOR’s keep the ferrodoxins reduced. Oxygen is inhibitory. Degrades DNA

Resistance is due to decreased oxygen scavenging (higher O₂) and lowered levels of PFORs. Resistance can also occur via a reducing reaction in Bacteroides and via multiple pathways by H. pylori

Well absorbed in the gut, so therapeutic levels may not be reached in the colon; it is also not as effective against the cyst form of E. histolytica. Metabolized by liver; can be excreted by kidneys and can cause a reddish brown urine

Toxicities: Well-tolerated, but can cause headache, nausea, dry mouth, metallic taste, and diarrhea. Furry tongue, glossitis, and stomatitis can be associated with exacerbation of candidiasis. Can cause peripheral neuropathies and Steven-Johnson syndrome. Acts like disulfuram upon consumption of ethanol

Often combined with a luminal agent such as paromomycin or iodoquinol for treatment of E. histolytica infections

Tinidazole is an analog used for the same purposes, and is more effective than metronidazole in the treatment of Giardia lamblia infections. Has less GI toxicity, hence its use in treating diarrheal Giardiasis

Question 89

Nitazoxanide

Answer 89

Used for treatment of trophozoites of E. histolytica infections and giardiasis; and oocytes of C. parvum. Can also treat helminths such as T. trichiura, A. lumbricoides, E. vermicularis, A. duodenale, and S. stercoralis

Interferes with PFOR enxyme-dependent electron-transfer reaction (essential to anaerobic metabolism in protozoan and bacterial species)

Main treatment for cryptosporidiosis, especially in immune competent children

Toxicities are rare, but include a greenish tint to the urine

Question 90

Paromomycin

Answer 90

An aminoglycoside used as a luminal agent in treatment of E. histolytica infections in combination with metronidazole for liver abscesses or amebic colitis, or as a solo drug for asymptomatic patients

Binds to 30S subunit of rRNA. Does not seem to be absorbed (100% fecal recovery). Parenteral administration carries same risks of ototoxicity and nephrotoxicity as the other aminoglycosides.

Also used in pregnant women for treatment of giardiasis

Another luminal agent is iodoquinol

Question 91

Pyrimethamine-sulfadiazine

Answer 91

An antimalarial that works on DHFR (pyramethamine) and also hits the incorporation of PABA into synthesis of dihydropteroic acid (sulfadiazine)

Slowly but completely absorbed orally

Adverse Effects: occasional skin rashes and reduced hematopoiesis. Excessive doses can mimic a folate deficiency. It is teratogenic

Question 92

Iodoquinol

Answer 92

A halogenated 8-hydroxyquinoline that is used as a luminal agent to eliminate intestinal colonization with E. histolytica.

At high doses over long periods of time can lead to subacute myelo-optic neuropathy (can also lead to milder peripheral neuropathy)

Can be used in combination with metronidazole to treat amebic colitis or amebic liver abscesses and can be used alone to treat asymptomatic colonization

Question 93

Benzimidazoles

Answer 93

Anti-helminthics used in treatment of STH infections (ascariasis, enterobiasis, trichuriasis, and hookworm)

Includes thiabendazole, mebendazole, and albendazole

MOA: inhibits microtubule polymerization by binding to parasitic B-tubulin

Resistance can occur through site-directed mutagenesis of the B-tubulin gene

Especially effective at treating GI nematodes, where absorption is not necessary.

None are recommended for use during pregnancy

Albendazole: More effective than Mebendazole at curing hookworm, strongyloidiasis, tissue-dwelling helminths, and trichuriasis infections in children. Treatment of choice for Echinococcus granulosus and neurocysticercosis of Taenia solium. Like mebendazole, it is poorly water soluble. Fatty foods increase absorption. Can cause mild GI symptoms; causes liver dysfunction in long term use. Also have to watch out for inflammatory reactions brought about by dying cysts of neurocysticercosis.

Thiabendazole: Not used as often due to less toxic effects of mebendazole and albendazole, but is still used topically for cutaneous larva migrans (creeping eruption). Toxicities include anorexia, nausea, vomiting, and dizziness.

Mebendazole: Seems like its not used as often as albendazole. No significant systemic toxicity due to low systemic bioavailabitily

Question 94

Diethylcarbamazine

Answer 94

Used mostly for treatment of lymphatic filariasis caused by Wuchereria bancrofti and Burgia malayi

MOA not well characterized

Does not fix lymphatic damage, only prevents future lymphatic damage

Do not use for onchocerciasis or loiasis because of severe reactions related to microfilarial destruction

Toxicities include anorexia, nausea, headache, and vomiting. Major adverse effects relate to host response to dead parasites

Not sure why this is a drug for this phase?

Question 95

Ivermectin

Answer 95

An anti-helminth that immobilizes affected organisms by inducing a tonic paralysis of the musculature via activation of a family of glutamate-gated chloride channels that are found only in invertebrates.

Resistance can occur via pumping out the drug via and ATP-dependent P-glycoprotein or by changing the drug target

Metabolized by liver

Used to treat onchocerciasis, lymphatic filariasis, strongyloidiasis, and other intestinal nematodes including ascariasis, enterobiasis, trichuriasis, and hookworm infections.

Well tolerated by uninfected humans, but can cause a big inflammatory reaction due to dying parasites

Question 96

Praziquantel

Answer 96

A pyrazinoisoquinoline derivative use to treat schistosomiasis, liver and lung fluke infections, and tape worm infections

Causes increased muscular activity and spastic paralysis of affected worms as well as damaging tegument leading to more exposed antigens.

Causes direct toxicities of nausea, diarrhea, headache, dizziness, and drowsiness. Causes indirect effects of fever, pruritus, uricaria, rashes, et c. that are tied to dying organisms

Contraindicated in ocular cysticercosis

Question 97

Metrifonate

Answer 97

An organophosphate used initially as an insecticide, now as an anthelmintic

Works on cholinesterases of Schistosoma mansoni and S. haematobium

Question 98

Oxamniquine

Answer 98

Used as second line to treat Schistosoma mansoni infections (second to praziquantel)

Not really used in US

Question 99

Niclosamide

Answer 99

Second-choice drug to praziquantel for treatment of tape worms (Taenia saginata, Diphyllobothrium latum, Hymenolepis nana)

Contraindicated in Taenia solium infections because it can lead to cysticercosis.

No longer approved for use in the US

Question 100

Piperazine

Answer 100

Not really used much, as it was replaced by the benzimidazoles

It can treat Ascaris lumbricoides and Enterobius vermicularis

Works on a GABA-receptor to paralize worms

Question 101

Pyrantel Pamoate

Answer 101

Open nonselective cation channels and induce persistent activation of nicotinic acetylcholine receptors and spastic paralysis of worm.

Used against hookworm, pinworm, and roundworm, but is ineffective against Trichuris triciura

Poorly absorbed, hence its use in only intralumenal GI nematodes

Its an alternative to mebendazole or albendazole in treatment of ascariasis and enterobiasis

Do not use with piperazine

Question 102

Penicillins

Answer 102

highly active Beta lactam antibiotic that works against gram positive organisms

MOA: the last step in peptidoglycan synthesis is inhibited (in both beta lactam and vancomycin) where transpeptidase unites two glycopeptides

Resistance: 1. structural differences in PBP (target of the drugs) 2. inability of agent to penetrate to site of action 3. active efflux pumps

*High yield: Penicillins with good oral absorption: Penicillin V (phenoxymethyl ether group), Oxacillin, Amoxicillin, Cloxacillin, Dicloxacillin, Ampicillin, Carbenicillin

S. aureus has penicillinase so penicillin G and V are inactivated. Penicillinase resistant are oxacillin, cloxacillin, dicloxacillin

Question 103

Vancomycin

Answer 103

Antibiotic against broad spectrum of gram-positive bacteria

MOA: Inhibits the synthesis of cell wall by binding with high affinity to the D-alanyl-D-alanyl terminus of cell wall precursor units (inihbits transglycosylase)

Used to treat osteomyelitis, endocarditis, and other infections like C. difficile that cause pseudomembranous colitis

Resistance: Enterococcus faecium and faecalis via plasmid transposon. Organisms can alter D-ala D-ala target to D-ala D-lactate or D-ala D-serine

poor oral absorption, IV injection only. Not highly protein bound, unlike teicoplanin. 90% excreted by renal filtration

Adverse: hypersensitivity, flushing can cause red-man syndrome, auditory impairment

Question 104

Teicoplanin

Answer 104

Similar to vancomycin in its structure (has different R groups), MOA, spectrum of activity, route of elimination (renal)

Active against methicillin susceptible and resistant staph

IM and IV, not orally active

Question 105

Bacitracin

Answer 105

MOA: Inhibits the synthesis of bacterial cell wall by inhibiting the dephosphorylation of a lipid transport molecle of cell wall peptidoglycan subunits

Active orally only for antibiotic associated diarrhea due to C. difficile because it is not absorbed by the gut (has been replaced by oral vancomycin)

Toxicity: serious nephrotoxicity from parental use, hypersensitivity from topical use

Question 106

Tetracycline

Answer 106

Bacteriostatic antibiotic active against broad range of aerobic and anaerobic (Bacteroides) gram positive and negative

MOA: binds 30S subunit and inhibits protein synthesis. Prevents access of aminoacyl tRNA to A site on mRNA ribosome

Uses: doxycycline eradicates Vibrio cholerae within 48 hours

Enterohepatic circulation in the bile so they are around for a long time (weeks)

Incomplete oral absorption ranging from 30-95% High absorption for minocycline and doxycycline on empty stomach. Absorption mainly takes place in the stomach and upper small intestine. Absorption impaired by dairy and bases; chelated by di/trivalent cations (antacids)

Toxicity: toxic metabolite gets into the kidney and causes nephrotoxicity (but not with doxycycline). GI irritation (administer with food), pseudomembranous colitis, hepatic toxicity,

Renal excretion except for Minocycline, which has hepatic clearance

Question 107

Tigecycline

Answer 107

Not appreciably absorbed from GI tract. Parenteral use only with wide and rapid distribution into tissues

Glycycline, derivative of tetracycline

Effective against tetracycline resistant bacteria (no resistance due to efflux pumps or ribosomal alterations)

Little nephrotoxicity

Question 108

Chloramphenicol

Answer 108

MOA: inhibits protein synthesis by binding to 50S subunit. Prevents tRNA to bind to A site. Also inhibits mitochondrial protein synthesis in human cells. Erythropoietic cells are particularly sensitive

Mostly used to treat pregnant women with Rocky Mountain Spotted fever (they cant take doxycycline). It is also used for bacterial meningitis

Resistance: plasmid encoded acetyltransferase inactivates the drug; decreased permeability; ribosome mutation

Inhibits the action of clindamycin; inhibits CYP

Rapidly absorbed from the GI tract

Dose related anemia, and potentially fatal idiopathic aplastic anemia. Can also cause a “gray baby syndrome.”because they cant glucoronidate it. Idiosyncratic response of aplastic anemia (fatal pancytopenia)

Question 109

Sulfonamides

Answer 109

Sulfisoxazole, Sulfamethoxazole

MOA: competitive inhibitors of dihydropteroate synthase, used for incorporation of PABA into dihydropteroic acid, a precursor for folate acid

trimethoprim exerts synergism

Absorbed rapidly from the GI tract 70-100%

Sulfisoxazole: tasteless and preferred for oral use in children. Fewer than .1% had toxic reactions

Sulfamethoxazole: oral for systemic and urinary tract infections (this is the one that is always used in combination with trimethoprim)

Resistance is by altering target enzymes and active extrusion

Toxicity: Older sulfanamides lead to crystaluria (bladder damage). Newer ones don’t crystallize. All of them cause anorexia, nausea, vomitting in 2%. Some can cause hemolytic anemia

Question 110

Azithromycin

Answer 110

Macrolide antibiotic

Bacteriostatic by inhibiting protein synthesis. Binds 50S ribosome subunit so no translocation

Resistance: efflux pumps, methylase enzymes, esterases (enterobacteriaaceae), alter 50S subunit

Oral and is rapidly absorbed and distributes widely throughout the body , except to the brain and CSF. aluminum and magnesium hydroxide antacids decrease peak serum concentrations. Dont take with food

Gastroenteritis from Campylobacter is treated with Erythromycin and H. pylori is treated with clarithromycin with omeprazole. Not sure

Question 111

Telithromycin

Answer 111

Similar spectrum of activity as Azithromycin. Can withstand macrolide resistance mechanisms (overcomes methylation of target) so better against S. aureus and S. pneumoniae

Oral absorption is 60%. 60-70% protein bound and concentrates in macrophages and white blood cells. 9.8 hours half life, can be given once daily

Doesn’t induce methylase

Question 112

Clindamycin

Answer 112

Macrolide antibiotic: binds 50S

Resistance: ribosome methylation, but not a substrate for macrolide efflux pumps (big benefit)

Fully absorbed

Kills all gut flora, except for C. difficile

High incidence of diarrhea (20%) and pseudomembranous colitis should limit its use to treat infections. Colitis: watery diarrhea, fever, elevated WBC. Skin rashes are common

Question 113

Fluoroquinolones

Answer 113

Don’t give to children, they get some form of arthritic pain

Ciprofloxacin, Levofloxacin

These agents are first line treatment for typhoid fever, patients with severe diarrhea.

Used IV if patient is vomitting

GI distress common in 17% of patients

Ciprofloxacin:

DNA gyrase inhibitor

GI distress in 17%

Causes joint swelling in patients under 17

Levofloxacin:

Increased risk of tendon tearing heralded by joint swelling

Question 114

Trimethoprim-sulfamethoxazole

Answer 114

acts on two steps of synthesis of tetrahydrofolic acid. Sulfonamide inhibits the incorporation of para aminobenzoic acid (PABA) into folic acid via dihydropteroate synthase. Trimethoprim prevents the reduction of dihydrofolate to tetrahydrofolate via dihydrofolate reductase

Trimethoprim is highly selective for DHFR of lower organisms, and humans get their folate from food sources. 100,000X dosage is needed to inhibit human enzyme

Resistance: plasmid encodes a different dihydrofolate reductase

Uses: Gram-negative infections, Urinary tract infections, GI infections for Shigellosis, Salmonella typhi, enteropathogenic E. coli

Adverse: maybe can induce folate deficiency, megaloblastosis, leukopenia, thrombocytopenia

Question 115

Diarrhea

Answer 115

Campylobactor, Shigella: Ciprofloxacin

C. difficile: Methronidazole

V. cholera: Tetracycline

Traveler’s diarrhea: Ciprofloxacin

Giardia lamblia: Metronidazole

Entamoeba histolyica: Metronidazole

Question 116

Cephalosporins

Answer 116

Inhibits bacterial cell wall synthesis similar to penicillin

3rd generations are less active than 1st gen against gram positive. They are more active against Enterobacteriaceae

Resistance: alterations of PBP or inability to reach site of action

2nd gen can treat E. coli. 3rd gen for Enterobacteriaceae

Adverse: hypersensitivity, cross-reactivity with penicillins, nephrotoxic, diarrhea

*High yield: Oral absorption:

1st gen: Cephalexin, cefadroxil,

2nd gen: cefaclor (most widely used second generation), loracarbef.

3rd: Cefpodoxime proxetil

Question 117

Antibiotic treatment of acute bacterial diarrhea

Answer 117

Salmonella:

Nontyphoid: ciprofloxacin or levofloxacin for 5-7 days

Typhoid: ciprofloxacin or ceftriaxone. For children: azithromycin

Shigella:

Ciprofloxacin or Levofloxacin or TMX-sulfa

Campylobacter jejuni:

Azithromycin or ciprofloxacin

E. coli:

Ciprofloxacin or levofloxacin. No treatment for enterohemorrhagic E. coli

Vibrio parahemolyticus:

no treatment

Vibrio cholera:

ciprofloxacin or doxycycline

Yersinia entercolitica:

doxycycline plus gentamicin

C. difficile:

metronidazole or for severe colitis, Vancomycin (risk of superinfection so limit usage)

H. pylori (not diarrhea)

Omeprazole, amoxicillin, metronidazole, clarithromycin

*avoid agents that slow peristalsis, as these can prolong fever and bacteremia

Question 118

Bismuth

Answer 118

– Create protective layer, may stimulate PG, mucus,
bicarbonate secretion
– Bismuth has direct antimicrobial effects and binds
enterotoxins

Clinical uses
– Dyspepsia, acute diarrhea, prevention of traveler’s
diarrhea
– Bismuth-based quadruple therapy against H pylor

Adverse:
– Coloring (black stool, darkening of the tongue)
– Short-term use only, avoided in renal insufficiency
– Prolonged usage may lead to bismuth toxicity resulting in
encephalopathy (ataxia, headaches, confusion, seizures)
– High dosage of bismuth salicylate (salicylate toxicity)