GI Flashcards
Bevacizumab
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
Erlotinib
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.
Cetuximab
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.
Panitumumab
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)
Irinotecan
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
5-Fluorouracil
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
Capecitabine
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
Streptozotocin
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).
Mitomycin
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
Doxorubicin
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
Epirubicin
Anthracycline indicated for treatment of breast cancer and gastric carcinoma
Same side effect profile as doxorubicin
Paclitaxel and Docetaxel
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)
Vinorelbine
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
Cisplatin
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)
Oxaliplatin
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
Gemcitabine
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
GI tract acidity/ treatment of peptic ulcers
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)
Antacids
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
Proton Pump Inhibitors
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.
H2-receptor antagonists
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.
Sucralfate
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
Misoprostol
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
Latanoprost
Topically active PGF2alpha derivative used for treatment of open angle glaucoma
Prostacyclin
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
Alprostadil
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
Aspirin
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)
Celecoxib
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
Meloxicam
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
Diclofenac
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
Diflunisal
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
Etodolac
Nonselective COX inhibitor
Can be given 3-4 times a day (not many specifics on this one)
Flurbiprofen
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
Ibuprofen
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
Indomethacin
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
Ketoprofen
Nonselective COX and lipoxygenase inhibitor
Probenicid prolongs its half life
Not superior to other NSAIDs in clinical efficacy
Ketorlac
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
Nabumetone
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
Naproxen
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
Oxaprozin
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
Piroxicam
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
Sulindac
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
Tolmetic
Nonselective COX inhibitor
Short half-life; not often used
ineffective at treating gout, and may cause thrombocytopenic purpura
Choice of NSAIDs
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
Acetominophen
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
Aminosalicylates
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)
Glucocorticoids Used In Inflammatory Bowel Disease
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
Purine Analogs (Azathioprine and 6-Mercaptopurine)
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)
Methotrexate
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
Anti-TNFalpha Therapy
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.
Eicosanoid effects on GI
PGE2 and PGF2alpha cause longitudinal smooth muscle contraction, circular smooth muscle contraction is caused by PGF2apha and PGE1 and is relaxed by PGE2. Administraction of PGE2 or PGF2alpha results in colicky cramps
LTB4 is synthesized by human colonic epithelial cells and is substantially increased in patients with inflammatory bowel disease
Interferons for Hepatitis
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,
Ribavirin
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
Adefovir
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)
Entecavir
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.
Lamivudine
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
Telbivudine
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
Tenofovir
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
Treatment of Chronic Hepatitis B
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:
- multiple antiviral agents: emtricitabine, entecavir, clevudine, telbivudine, tenofovir
- interferon alpha reserved for patients w/ persistent HBeAg and elevated transmaminase
Treatment of Hepatitis C
Hep C seldom clears on its own. It can lead to cirrhosis, hepatic failure, HPC
Treatment with pegylated interferon alpha and oral ribavirin
Benzodiazepines
Diazepam, Chlordiazepoxide, lorazepam
Used in acute ethanol withdrawal
binds GABAA receptor
Disulfuram
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
Naltrexone
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
Acamprosate
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.
Odansetron, Topiramate
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
Ethanol
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
Methanol
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:
- support of respiration
- 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
Ethylene Glycol
Polyhydric alcohol in antifreeze and solvents
Sweet taste
metabolized to toxic aldehydes and oxalate
Stages:
- excitation followed by CNS depression
- metabolic acidosis from lactate
- renal insufficiency due to oxalate in renal tubules
Fomepizole in standard of treatment
GI system autonomics
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
Anticholinergic Drugs
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
Metoclopramide and Domperidone
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.
Bulk-Forming Laxatives
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
Stool Surfactant Agents (softeners)
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
Osmotic Laxatives
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.
Stimulant Laxatives
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
Lubiprostone
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
Opioid Receptor Antagonist
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
Antidiarrheal agents
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
Pancreatic Enzyme Supplements
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
Ursodiol
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)
Antiemetic Agents
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
Serotonin 5-HT3 Antagonists
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
Aprepitant and Fosaprepitant
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
Phenothiazines and Butyrophenones (antiemetics)
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
Metoclopradmide and Trimethobenzamide
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.
H1 antihistamines/ anticholinergics for antiemesis
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
Dronabinol
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
Prokinetic Drugs
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
Metronidazole
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
Nitazoxanide
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
Paromomycin
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
Pyrimethamine-sulfadiazine
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
Iodoquinol
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
Benzimidazoles
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
Diethylcarbamazine
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?
Ivermectin
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
Praziquantel
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
Metrifonate
An organophosphate used initially as an insecticide, now as an anthelmintic
Works on cholinesterases of Schistosoma mansoni and S. haematobium
Oxamniquine
Used as second line to treat Schistosoma mansoni infections (second to praziquantel)
Not really used in US
Niclosamide
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
Piperazine
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
Pyrantel Pamoate
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
Penicillins
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
Vancomycin
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
Teicoplanin
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
Bacitracin
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
Tetracycline
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
Tigecycline
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
Chloramphenicol
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)
Sulfonamides
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
Azithromycin
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
Telithromycin
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
Clindamycin
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
Fluoroquinolones
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
Trimethoprim-sulfamethoxazole
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
Diarrhea
Campylobactor, Shigella: Ciprofloxacin
C. difficile: Methronidazole
V. cholera: Tetracycline
Traveler’s diarrhea: Ciprofloxacin
Giardia lamblia: Metronidazole
Entamoeba histolyica: Metronidazole
Cephalosporins
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
Antibiotic treatment of acute bacterial diarrhea
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
Bismuth
– 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)
