Gastrointestinal Drugs

® Acid-peptic disease: of upper GI tract caused by acid and pepsinàGERD, erosions/ulcers of mucosal lining of GI tracts
o Pathological players: Gastric acid, ¯mucosal resistance to acid, H.pylori, drugs (NSAIDS, warfarin, corticosteroids), stress (>65yrs), lifestyle, gastrinoma
® Zollinger-Ellison: hypersecretion of gastric acid and pepsin often d/t gastrinoma; associated with severe acid-peptic ulceration and diarrhea
® Carcinoid: neoplasm of GI tract or bronchi; may secrete serotonin and a variety of peptides
® Factors that ­ gastric acid secretion: histamine, ACh and gastrin (final pathwayàactivation of H+/K+ ATPase)
® To document infection with H.pylori: endoscopic biopsy of ulcer margin, serologic tests or urea breath tests (eradication results in rapid healing & ¯ recurrence)
® GERD: Abnormal relaxation of the LES; associated with ­BMI, ZE syndrome and drugs
o Non-pharm txt: small meals, weight loss, avoid bedtime acid rich drinks, elevate head of bead, lifestyle modifications
o Drugs: antacids, PPI +/- H2 blockers
Drug Name Class Description MOA Uses PK AE/Contraindications
Mg(OH)2àdiarrhea
Oral
Neutralize gastric Al(OH)2à constipation &
Weak bases that react with ¯absorption of tetracyclines w/ milk
Mg(OH)2 acid GERD hypophosphatemia
HCl to form salt & (Ca2+), antacids (Ca2+ or Mg3+) or iron
Al(OH)2 Antacids Gastritis CaCO3à hypercalcemia,
H2Oà­gastric pH via chelators
CaCO3 Provides quick PUD nephrolithiasis and
inactivation of pepsin ­absorption of weak bases (quinidine)
relief constipationà fecal
¯absorption of weak acids (Warfarin)
compaction
Capable of Cimetidineà
Reversibly blocks Gsà GERD Oral
1st reducing 60-90% gynecomastia, ­prolactin
¯cAMPà inhibition of Promote healing of IV- for acute stress ulcers
Cimetidine of HCl secretion levels, ¯libido, confusion in
H+/K+ ATPase
Acid-Peptic Diseases

duodenal/gastric ulcers Cimetidineàcrosses BBB & placenta;

Ranitidine following a single elderly
H2 Blockers Pre-op prophylaxis of inhibits CYP450
Famotidine dose Cimetidine + Ranitidineà
Ulcer recurrence common aspiration pneumonia
Nizatidine 2 nd No effect on ­creatinine levels
after monotherapy is Prophylaxis and TXT of acute 2nd Gen do not inhibit CYP450 and are
gastric emptying
stress ulcers longer acting than cimetidine
Nausea, Headache,
stopped
time Dizziness
Inhibit nearly GERD
100% of HCl Duodenal/gastric ulcers IV or oral Nausea and diarrhea (rare)
Omeprazole secretion with a Covalent bond formation H. pylori with ABx Omeprazole inhibits metabolism of Small ­resp/GI infections
Esomeprazole single dose with cysteine residue of MEN-1 neoplasia warfarin, Clopidogrel, phenytoin, Long term use: ¯serum
Proton Pump
Lansoprazole H+/K+ ATPase inside ZE Syndrome diazepam and cyclosporine Mg2+ and hip fractures
Inhibitors
Rabeprazole Activated after parietal cell canaliculus NSAID induced ulcers Prolonged use will ¯bioavailability of Pancreatitis,
Pantoprazole transport into àirreversible inactivation (support platelet aggregation B12, digoxin, and ketoconazole (Acid hepatotoxicity and
parietal cell & clot integrityàused in needed for absorption) interstitial nephritis
(prodrug) hemorrhagic ulcers)
H. pylori
Bind to motilin receptors &
Bacteriostatic Atypical Pneumonia Oral and IV
GI upset
Binds to 23S rRNA of the Community-acquired Inhibits CYP450à ­concentration of
Clarithromycin Macrolide 50S subunitàprevents pneumonia theophylline, oral anticoagulants
­QT intervalà arrhythmia
translocation and inhibits Pertussis Methylation of 23S rRNA prevents
Antimicrobials protein synthesis Corynebacterium drug bindingàresistance
hepatitis, rash, eosinophilia
used in Chlamydia
H.pylori Bacteriostatic
Binds to PBPàprevent Oral and IV
H. pylori Rash
crosslinking of
Amoxicillin b-lactams Gram (+) bacteria HSN reactions
peptidoglycan in cell b-lactamase cleaves b-lactams ringà
Some gram (-) bacteria Pseudomembranous colitis
wallàactivate autolytic resistance
enzymes

Fernanda Ponce pg. 1

 Bactericidal agent
Severe flushing,
Produces toxic H. pylori
tachycardia, hypotension
Metronidazole Anti-protozoal metaboliteàdamage DNA Anaerobes (C. difficile, Oral and IV
with alcohol (Disulfiram-
& inhibit electron Bacteroides)
like rxn), metallic taste, HA
transport
GI upset
H. pylori discoloration of teeth and
Chlamydia Oral and IV inhibition of bone growth
Binds to 30S subunità Rickettsia in children
Broad Spectrum
Tetracycline prevent attachment of M. pneumoniae Reduce uptake/enhance efflux out of superinfection
antibiotic
aminoacyl-tRNA Borrelia Burgdorferi bacterial cells by plasmid-encoded photosensitivity
Low dose TXT of acne transport pumps à resistance
Contraindicated in
pregnancy
Undergoes polymerization
and selective binding to Contraindicated with H2
Sulfated
Sucralfate necrotic tissueàbarrier to PUD blockers, PPIs, antacids
Mucosal disaccharide
acid (requires acidic pH)
Protective Stimulates PG synthesis
Agents
Selectively binds to ulcer BMT regimen: admin w/ metronidazole
Bismuth H. pylori
Pepto-Bismol and forms protective and tetracyclineà heals ulcers @ rate
Subsalicylate Augment Heals ulcers
coating against acid/pepsin of 90%
mucosal
PGE1 Activates EP receptors Prevention of NSAID induced
surface Diarrhea
(Gi)à ¯acid secretion, gastric ulcers Oral
defenses Uterine cramping
Misoprostol Infrequent use d/t ­mucin and bicarb
Abortifacient
AE and minimal production Less effective than PPIs or H2 Duration: minutes
benefits Causes uterine contraction

blockers in acute cases
Exacerbation of IBD

® Prokinetic drugs are used to relive GI symptoms of abdominal discomfort, bloating, heart burn, nausea, vomiting associated with GERD, gastroparesis, or GI movement disorders
Drug Name Class Description MOA Uses PK AE/Contraindications
Mediated by muscarinic activity Diabetic/post-op gastroparesis
Anti-dopaminergicà limit high
Prokinetic Drugs

5HT3 and D2 via 5HT4 agonist activityà

doses and long-term
blocker ­gastric emptying and Relief of SXS of GERD
Metoclopramide Antiemetic agent useàsedation, diarrhea,
intestinal motility
galactorrhea Parkinsonian
5HT4 agonist High dosesà5HT3 antagonist Nausea/vomit associated with
effects
activity chemotherapy
Gastroparesis
Arrhythmias
Cisapride 5HT4 agonist Stimulates ACh GERD
Contraindicated in pts w/ ­QT
Constipation
Colonic pseudo-obstruction in
Neostigmine AChE-I
Muscarinic hospitalized pts
agonists Resistance to Post-op bowel and bladder atony Long duration of
Bethanechol
cholinesterases (gastroparesis) action
Gastric emptying before upper GI
IV Tolerance may develop d/t
Erythromycin Macrolide motilin receptors agonist endoscopic procedures
Short term use extended use w/ gastroparesis
Gastroparesis

Fernanda Ponce pg. 2

 Gastrointestinal Drugs Continued
® Emesis (vomiting/throwing up): involuntary, forceful expulsion of contents of stomach through the mouth or sometimes from the nose
Drug Name Description MOA Uses PK AE/Contraindications
Oral (prophylaxis)
Autacoid that blocks chemoreceptor trigger zone and Chemotherapy and post-op
Ondansetron 5HT3 inhibitor and IV ­QT intervalàarrhythmias
enteric nervous system of 5HT3 receptors vomiting
Duration: 3-6hrs
Motion sickness
Diphenhydramine Hay fever Oral and Sedation
H1, a and M Competitively block central and peripheral H1 receptors
Cyclizine Angioedema parenteral Autonomic block
antagonist + a-receptors and M-receptors
Meclizine Sleep aid (oral) Duration: 6-8hrs CNS excitation (Rare)
Dystonia (parenteral)
Anti-emetic Agents

DOC for emesis associated Transdermal

Scopolamine Antimuscarinic
with motion sickness patch
Substance P antagonist
Aprepitant early and delayed emesis in Oral Dizziness, fatigue, diarrhea
NK1 blocker NK1(neurokinin 1) blocker in the CNS
cancer chemotherapy CYP interactions
Fosaprepitant IV
Inflammatory conditions Adrenal suppression
Organ transplantation Duration of Growth inhibition
Activation of glucocorticoid receptor alters gene
Glucocorticoid Hematologic cancers activity is longer Muscle wasting
Dexamethasone transcription
agonist/ than t½ d/t Osteoporosis
Methylprednisolone
Corticosteroids Choice of chemotherapy altering gene Salt retention
Combined with ondansetronàgreater effect (CINV)
induced nausea/vomiting transcription Glucose intolerance
(CINV) Behavioral changes
Extrapyramidal SXS
Phenothiazine
D2 and muscarinic antagonist Hypotension
(Prochlorperazine)
Sedation
Motion sickness
D2 blocker
Promethazine Anti-dopaminergic and anti-cholinergic Antipsychotic effects
Sedative
Antidopaminergic, antiemetic, antipsychotic and
Droperidol
neuroleptic analgesic agent
Dronabinol Cannabinoids CB1 receptor antagonist (central acting) CINV
Lorazepam
Beneficial effects d/t their sedative, anxiolytic, and
Alprazolam Benzodiazepines Anticipatory vomiting Potency is low
amnesic properties
Diazepam
Loperamide Toxic megacolon in children/ pts w/
Opioid derivatives that ¯gut motility with negligible
(Imodium) severe colitis
Antidiarrheals

CNS effects
Opioid Agonist Formulated with High dosesàCNS effects
Diphenoxylate Act via Gi mu-opioid receptorsà inhibit ACh release and
atropineà Toxic megacolon in children/ pts w/
(Lomotil) ¯peristalsis
¯abuse severe colitis
GI disturbances
Carcinoid syndrome: flushing, SC injection
Gallstones
diarrhea, R-sided murmurs
Bradycardia
Somatostatin VIPomaàcopious diarrhea Long acting
Octreotide Somatostatin receptor agonist Cardiac conduction anomalies
Analog Acute control of bleeding from formulaà
¯ both endocrine and exocrine
esophageal varices intramuscular
pancreatic activity → Nausea,
Acromegaly injection
cramps, steatorrhea
Bismuth Bismuth
Binds with toxins from E.colià¯inflammation Antacid and antidiarrheal
Subsalicylate Compound

Fernanda Ponce pg. 3

 Drug Name Class Description MOA Uses PK AE/Contraindications
Laxative
Senna Cramping
Stimulant
Bisacodyl Senna is used with docusate Chronic useàperceived need
for opioid induced constipation
Insoluble indigestible ­water retentionàstools
Methylcellulose Non-absorbable
Bulk forming derivatives of fruits become bulky Laxative Do not use with opioid induced
Psyllium Requires high
agents and veggies; Distention of bowelà constipation
Bran fluid intake
hydrophilic colloids peristaltic stimulation of gut
Mg(OH)2 Draw water into the lumen of Simple constipation Mg may be absorbedàtoxicity &
MgO GITà­motility Bowel prep for endoscopy renal impairment
Laxatives

Converted into lactic, formic

and acetic acid by intestinal
Lactulose Semi-synthetic bacteriaà ­osmotic effect Laxative
Osmotic agents
disaccharide sugar Hepatic encephalopathy
Draws out NH3from bodyà
preventing hyperammonia
Polyethylene Glycol Draw water into the lumen of Colonic lavage for endoscopic/
(PEG) GITà­motility radiologic procedures
Induces Laxative Rectal
Glycerin Irritation of anal mucosa
hyperosmotic effect Can be used as enema suppository
Stool Softeners Emulsify and soften stoolà
Docusate (Colace) Senna is used with docusate
lubrication (makes easier to
Mineral Oil for opioid induced constipation
pass)
Chloride Channel Prostanoic acid ­Cl secretion into GIà ­fluid Constipation associated IBS
Lubiprostone
Activators derivative content (IBS-C)
Alvimopan Opioid Block Gi mu-opioid receptorsà
DO NOT enter CNS Opioid induced constipation
Methylnaltrexone Antagonists ­ACh and peristalsis
® Inflammatory Bowel Disease: irritation and ulceration of the colon and rectum (Ulcerative Colitis) or the colon + more proximal parts of the GIT (Crohn’s Disease)

Drug Name Class Description MOA Uses PK AE/Contraindications

Nausea, vomiting, diarrhea
Inhibits eicosanoid
Converted to sulfapyridine HSN
inflammatory mediators
(antibacterial) and 5- Reversible oligospermia
Drugs used in IBD

Sulfasalazine
aminosalicyclic acid (5-ASA) BM suppression (d/t sulfapyridine)
Effects: proximal/distal
(anti-inflammatory) Mild-mod Crohn’s or UC Contraindicated in pts with sulfa
colon and rectum
Aminosalicylates allergy
Inhibits eicosanoid Various formulations designed
Mesalamine Little or no
inflammatory mediators to deliver drug to distal ileum
(5-ASA) toxicity
(IL1 and TNFa) and colon
Releases Mesalamine in the
Balsalazide Prodrug UC
large intestine @ site of UC
Adrenal suppression
Duration of
Growth inhibition
Hydrocortisone UC and Crohn’s activity is
Budesonideàcontrolled Activation of glucocorticoid Muscle wasting
Prednisone longer than
Glucocorticoids release in distal ileum and receptor alters gene Osteoporosis
Prednisolone Organ transplantation t½ d/t
colon transcription Salt retention
Budesonide Hematologic cancers altering gene
Glucose intolerance
transcription
Behavioral changes

Fernanda Ponce pg. 4

 Nausea
Cytotoxic to rapidly
Anticancer Mucosal ulcers
Methotrexate dividing immune Renal
Inhibit dihydrofolate reductase Rheumatic disorders Hematotoxicity
(MTX) cellsàinhibits purine elimination
UC and Crohn’s Hepatotoxicity
Immunosuppressants synthesis (S phase)
Teratogenic
6-mercaptopurine Nausea and vomiting
Azathioprine: prodrug of AML
(6-MP) Promotes apoptosis Myelosuppression
6-MP UC and Crohn’s
Azathioprine Hepatotoxicity
UC and Crohn’s remission/
acute flare-ups
Infliximab
Humanized mouse Ab Combo with MTX: RA, IV
targets TNFa (principle Infusion rxns and infections
Anti-TNFa Drugs Ankylosing spondylitis,
mediator in Crohn’s) Reactivation of latent TB
psoriatic arthritis
Adalimumab Human IgG Ab UC and Crohn’s remission
Progressive Multifocal
Natalizumab Anti-integrins Restricted use Blocks leukocyte integrins UC and Crohn’s
leukoencephalopathy (PML)
® Irritable Bowel Syndrome: characterized by diarrhea or constipation or alternating diarrhea and constipation (chronic SXS with no structural abnormalities)
o Frequent abdominal pain associated with: altered stool frequency, pain getting better with shitting, altered stool appearance
o Treatment based on symptoms
Drug Name Class Description MOA Uses PK AE/Contraindications
Hyoscyamine Delirium, hallucinations, seizures,
Drugs used in IBS

Dicyclomine Non-selective action on coma, tachycardia, HTN,

Anticholinergic IBS Diarrhea
Glycopyrrolate gut hyperthermia, mydriasis, ¯bowel
Methscopalamine sounds, urinary retention
Serious constipation (Rare)
Reduced smooth mm. activity Long acting
Alosetron 5HT3 Antagonists Severe IBS Diarrhea Ischemic colitis
in the gut High potency
Infarction
Opioid derivative that Act via Gi mu-opioid
Loperamide Opioid Agonists ¯gut motility with receptorsà inhibit ACh IBS Diarrhea
negligible CNS effects release and ¯peristalsis
Chloride Channel ­Cl secretion into GIà ­fluid
Lubiprostone Prostanoic acid derivative IBS constipation
Activators content
Gallstones in pts
Bile acid therapy for
Ursodiol Bile acid derivative Inhibit cholesterol gallstones refusing/not eligible for Oral
gallstones
surgery
Other

Pancreatic insufficiency in
Improves digestion of dietary pts with:
Replacement enzyme
fat, protein, and carbs Chronic pancreatitis
Pancrelipase Pancreatic enzyme from animal pancreatic
Pancreatectomy
extract
­absorption of Vit. ADEK Steatorrhea
Cystic Fibrosis
Gastric/pancreatic lipase
Orlistat Lipase inhibitor ¯absorption of Vit. ADEK Weight loss
inhibitor

Fernanda Ponce pg. 5



Fernanda Ponce pg. 6


® COX 2 Inhibitors: Celecoxib, Meloxicam
o Fewer GI side effects, but more CVS risks
o Meloxicam preferentially inhibits COX 2 over COX 1, but not as selective as celecoxib
o Rofecoxib & valdecoxib withdrawn from US d/t thrombotic events
Anti-inflammatory Actions
COX inhibitionà ¯PG synthesisàno PG
mediated inflammation
-Occurs with high doses of salicylates
Analgesic Actions
PGE2 sensitizes nerve endings to
bradykinin, histamine, etc.
NSAIDSà¯PGE2àrepression of pain
-Occurs with low doses of salicylates
Antipyretic Actions
Cytokines released from WBC during
infection/HSN/malignancy/inflammationà
­PGE2à­set point of the anterior
hypothalamic thermoregulatory center
NSAIDSà¯PGE2àno fever
-Occurs with low doses of salicylates
Drug interactions
ACE-I: ¯antihypertensive effect of
ACE-I + potential renal failure
Diuretics: loop, thiazide and K sparing
depend on PGà¯diuretic effect
Triple Whammy: NSAIDS constrict
afferent arteriole & ¯GFR; ACE-I/ARBs
dilate efferent arteriole & ¯GFR;
diuretics ¯plasma volume and ¯GFR;
Combo of NSAIDS + ACE-I +
Diureticàacute renal failure (monitor
for creatinine and K+)
Corticosteroids: ­frequency/severity
of GI ulceration
Warfarin: ­risk of bleeding
Fernanda Ponce pg. 7
NSAIDS
® Nonselective COX inhibitors: Aspirin, Diclofenac, Ibuprofen, Indomethacin (DOC for closure of the
ductus arteriosus in premies), Ketorolac, Naproxen, Piroxicam
o Aspirin: irreversibly acetylates COX (unique), all other salicylates are reversible; rapidly
deacetylated by esterases in the body forming salicylateàcan produce pharmacologic effects as
well
Mechanism of Action:
® Inhibition of COXàinhibition of the production of prostaglandins and thromboxanes
® COX 1: constitutive enzyme expressed in most tissues (including platelets) involved in cell-cell signaling
and in tissue homeostasis
o Dominant isoform in gastric epithelial cells
o Major source of cytoprotective PG formationàinhibition causes gastric damage
® COX 2: inducible isoform that is an immediate early-response gene product upregulated by stress,
growth factors, tumor promoters, and cytokines
o Major source of prostaglandins in inflammation and canceràinhibition=anti-inflammatory
o Constitutive in the kidney and brain
o Endothelial COX 2àprimary source of vascular prostacyclin
® Ability to relieve HA d/t inhibition of PG mediated vasodilation of cerebral vasculature
Contraindications Gout Adverse Effects
Aspirin and other salicylates are GI: d/t inhibition of PGI2 & PGE2 via inhibition of COX 1àgastric damage
contraindicated in children and -DOCàIndomethacin
-local irritation from contactàulceration
young adults (<20) with fever d/t -Do not use aspirin, salicylates and
-TXT: misoprostol, PPIs, AND H2 blockers
viral illnessàReye’s Syndrome tolemtin
-lowest risk: Celecoxib; high risk: Piroxicam
(hepatitis + cerebral edema) -Aspirin @ low dosesàinhibits
CVS: Imbalance b/w TXA2 and PGI2à vasoconstriction, platelet aggregation,
DOCàacetaminophen for secretion and thus urate excretion
antipyresis in children/teens
and @high dosesà­risk of renal
thrombosisàMI, stroke, death
calculi by inhibiting reabsorption
Renal: PGE2/PGI2 needed in pts w/ CHF, CKD,HTN, ¯renal perfusion to maintain
Aspirin in pregnancy (Category C
GFR; inhibitionà¯PGà¯GFR, Na/H20 retention, edema, ­BP, hyperkalemia &
risk in 1st & 2nd trimester; Category
Colon Cancer renal failure
D in 3rd)
-prolonged excessive useàanalgesic nephropathy (chronic interstitial nephritis)
Salicylates in pts with chronic liver Aspirin decreases risk by
50%àUsed in pts with FAP Aspirin HSN: d/t an ­in biosynthesis of leukotrienes
disease
Fun fact: aspirin also inhibits PGD2 -usually seen in pts w/ asthma, nasal polyps, or chronic urticariaàrhinitis,
Aspirin in pts w/ hepatic damage,
mediated flushing associated with angioedema, bronchial asthma, hypotension, shock etc.
hypoprothrombinemia, Vit K def.
or hemophilia d/t hemorrhage risk niacin used to ¯serum cholesterol, Celecoxib HSN: sulfonamide that usually causes rashes
¯LDL and ­HDL Hepatic: high doses of salicylates cause reversible hepatic injury
Therapeutic Uses Actions of Aspirin
Lungs: salicylates uncouple oxidative phosphorylationà­CO2 and ­alveolar ventilation
-Superior to opioids in the mgmt. of pain associated with inflam. -High doses directly affect medullaàhyperventilation and resp alkalosis;
-Pain from hollow viscera NOT relieved (Exception= menstrual Salicylism (mild intoxication)àdizzy, tinnitus, difficulty hearing, dim vision, mental
pain) confusion, sweat, thirst etc.
-TXT of musculoskeletal disorders @ high dosesà RA and -Toxic dosesàmixed resp alkalosis and metabolic acidosisàcentral resp. paralysis
osteoarthritis (symptomatic relief only, DOES NOT stop Platelets:
progression) Low doses irreversible inhibits TXA2 w/o affecting PGI2 production in endothelial cells à
-Approved for TXT: RA, osteoarthritis, acute gouty arthritis, ¯platelet aggregation & ­bleeding timeàcardioprotective;
ankylosing spondylitis, and dysmenorrhea Lack of TXA2 lasts for the lifetime of the platelet (7-10 days) b/c no nuclei=no synthesis of new
-Low doses are used prophylactically to: ¯ risk of recurring TIAs, COX
stroke, death; death in pts having acute MI; recurrent nonfatal
MI/death in pts w/ prior MI or unstable angina; MI and sudden Aspirinà salicylate + acetic acid
death in pts with chronic stable angina At low doses, salicylate conjugated to glycine & glucoronate by liverà1st order kinetics
Dose >1gàconjugation enzymes become saturatedàzero order kinetics
Acetaminophen: NOT an NSAID
® Analgesic and antipyretic drug lacking anti-inflammatory or anti-platelet effects
® Weak COX 1/COX 2 inhibitor in peripheral tissues
® Used to treat mild-moderate pain when an anti-inflammatory effect is not
necessaryàHA, myalgia, postpartum pain
® DOC for pain relief in osteoarthritis d/t safety and effectiveness
® DOC for short-term TXT of fever/minor pain in pregnancy
® DOC for TXT of fever/flu-like sxs in children
® Low GI, bleeding and renal risks
® Preferable to aspirin in pts with hemophilia, history of PUD or pts in which
bronchospasm is precipitated by aspirin
® Small amount is metabolized in liver by CYP2E1 to NAPQIàconjugated to glutathione
and excreted in urine
o ODàdepleted glutathione storesà ­NAPQIàhepatotoxicity
o AntidoteàN-acetylcysteine (donates a sulfhydryl group usually done by
glutathione)
® Narrow therapeutic rangeà pts w/ pre-existing liver disease or alcoholics have
increased risk of acetaminophen hepatotoxicity
® OD= most common cause of acute liver failure

Triple Whammy

Fernanda Ponce pg. 8


MOA
-Produce analgesia primarily by activating receptors in the brain and
spinal cord
-Close voltage gated Ca2+ channels on presynaptic nervesà↓NT
release (glutamate, ACh, NE, serotonin and substance P)
-Open K+ channels on postsynaptic nerves→ inhibit of postsynaptic
neurons
Spinal Analgesia: µ d and k receptors on spinal cord pain
transmission neurons & presynaptically on 1° afferents
-opioids inhibit release of excitatory NT (substance P and glutamate)
and the dorsal horn pain transmission neuron
-provide regional analgesia while minimizing unwanted resp
depression, N&V, and sedation assoc. w/ supraspinal actions
Supraspinal Analgesia: opioids inhibit inhibitory
NTs(GABA)àactivate pain-inhibitory descending neurons to inhibit
pain transmission neurons in the spinal cord
Peripheral Analgesia: µ receptors on peripheral terminals of sensory
neuronsàanalgesia @ the knees for example
-Opioids act concurrently at both spinal and supraspinal
sitesàincrease overall analgesic efficacy
- Opioid agonist (morphine) can act on µ receptors and evoke a
release of endogenous opioids that act at d and k receptors
- Glutamateàmain excitatory NT released from nociceptive nerve
terminals
Receptors: µ, δ, κ→ Gi
-Majority act at the µ receptor and produce analgesia, euphoria,
respiratory depression, and physiologic dependence
-δ & κ are found primarily at the spinal level→ analgesia
-Mixed agonist-antagonist compounds w/ agonist selectivity for the
κ-receptor (Pentazocine, Butorphanol, and Nalbuphine)à“ceiling
effectӈlimits the amount of analgesia attainable with these drugs
-psychotomimetic effects (psychosis, delirium,
hallucinations, etc.)ànot reversible with naloxone
-precipitate withdrawal in opioid tolerant ptsàfurther
limit clinical use
Fernanda Ponce pg. 9
Opioid Analgesics
Peripheral Effects
Hypotension→ due to peripheral vasodilation, inhibition of
baroreceptor reflex and increase in histamine release
Constipation→ universal (concomitant laxative use)
Biliary colic→ contraction of biliary smooth muscle
↓renal function→ ↓renal blood flow
Prolong labor by unknown mechanism on the uterus
Pruritus→ due to central effects and histamine release
Stimulate ADH, PRL and somatotropin; inhibit LH
CNS Effects
Analgesia→ reduce sensory and emotional components of
pain Euphoria→ floating sensation with ↓anxiety and
distress
Sedation and drowsiness
Respiratory depression→ ↓central response to CO2
Cough suppression→ ↓central cough center reflex
Miosis→ excites PS→ pinpoint pupils are pathognomonic
following toxic dose (mediated by Morphine and most µ and
k agonists)
Truncal rigidity d/t action @ supraspinal level
Nausea & vomiting → activate brainstem trigger zone
Clinical Uses
Analgesia→ moderate to severe pain
Acute pulmonary edema→ Morphine will ↓anxiety, preload
and afterload; if resp depression is an issueàFurosemide
Cough→ dextromethorphan, codeine, levopropoxyphene
and noscapine
Diarrhea→ Loperamide and Diphenoxylate
Anesthesia→ premedication and intraoperatively
Shivering → meperidine (activates α2 receptors)
Tolerance/Dependence/Addiction
-Frequent use→ loss in effectiveness→ tolerance
-Dependence→ physiologic withdrawal or abstinence
syndrome
-Addiction→ euphoria, indifference to stimuli and sedation
lead to compulsive use
-Physical dependence is common when used therapeutically,
but addiction is not
Adverse Effects
Normeperidine @ high doseà seizures
Nausea and vomiting
Sedation
Itching
Constipation
Urinary retention
Hypotension
Respiratory depression
Metabolism and Excretion
Converted to polar metabolites (mostly glucuronides)
-Morphine is conjugated to M3G (neuroexcitatory) or M6G(4-6x
more potent)à do not cross BBBàno CNS effects
-Effects of Morphine or hydromorphone should be considered in pts
with renal impairment
-Heroine (diacetylmorphine)àrapidly hydrolyzed to
monoacetylmorphineà morphine
-Remifentanil (ester)àrapidly hydrolyzed
-Meperidine, normeperidine metabolites may accumulate in pts w/
decreased renal fxn & pts on multiple high doses
-Fentanyl is metabolized by CYP3A4 (no active metabolites)
-Codeine, oxycodone, and hydrocodone metabolized by CYP2D6à
production of metabolites with greater potency
(Codeineàmorphine)
-Polar metabolites + glucuronides excreted in urine mainly
-Glucuronide conjugates can also be found in bile
Contraindications
-Using a pure agonist(morphine) + weak partial agonist
(Pentazocine)→diminish analgesia or induce a state of withdrawal
-Head injuries(­ICP)→ CO2 retention causes cerebral vasodilation
-Pregnancy→ fetal dependence
-Impaired pulmonary function→ acute resp. failure
-Impaired hepatic function→ ↓metabolism of morphine
-Impaired renal function→ longer t½
-Endocrine disease→ adrenal insufficiency(Addison’s) or
hypothyroidism(myxedema) can have prolonged or exaggerated
response to opioids
-Concurrent use of Opioids and MAO-Is
Drug Interactions
-Sedatives/hypnotics→ increase CNS depression (respiratory)
-Antipsychotics→ increase sedation, variable effects on resp.
depression and accentuate CV effects of anti-M & α-blockers
-MAO-I’s → life-threatening rxn especially with meperidine and
tramadolàexcitement, muscle rigidity, hyperthermia,
unconsciousness
 Properties of Specific Opioids
Drug Name Class Description Metabolism Other
High affinity for µ receptor Conjugated to M3G (neuroexcitatory) Metabolites are polar and do not readily cross the BBB
Morphine
Standard for analgesia or M6G (4-6x more potent) Metabolite effects may be increased in renal impairment
Hydromorphone
Treat severe pain
Oxymorphone
Rapid hydrolysis to 6-
Heroin 6-monacetylmorphine (6-MAM) and heroine are more Pharmacological actions are due to 6-MAM and
MAM→morphine
(Diacetylmorphine) liposoluble than morphine and cross BBB morphine
Excreted in urine as free or conjugated
-µ receptor agonist; negative inotrope
Normeperidine t½=15-20 hours so it accumulates when
-Not recommended d/t high metabolite toxicity via Accumulation of normeperidine
given large doses @ short intervals
normeperidine→ tremor, twitching, pupil dilation, (excreted by both kidney and liver)
Meperidine t½= 3 hours
Meperidine Strong hyperactive reflexes & convulsions can occur in pts with decreased renal
Agonists -Blocks reuptake of serotoninà Serotonin syndrome→ or hepatic functionàseizures,
Significant antimuscarinic effectsàcontraindicated in pts
delirium, hyperthermia, HA, rigidity, coma, dysregulation of dysphoria, myoclonus
w/ tachycardia
BP, death [DO NOT combine with MAO-I’s]
µ receptor agonist; anesthetic adjuvant
Metabolized by CYP3A4 in the liver Transdermal patches provide sustained release
Fentanyl Rapid onset and shot duration (15-30min)
No active metabolites TXT of chronic pain & breakthrough pain in cancer pts
100x more potent than morphine
Equal potency to morphine but with less euphoria/sedation
No active metabolites Used to manage opioid withdrawal, heroin addiction,
and longer half-life
Methadone Abstinence syndrome (withdrawal) is and chronic pain
µ agonist, NMDA antagonist and serotonin/NE reuptake
Levorphanol prolonged but less severe than in
inhibitor
heroine Can cause QT prolongation, torsades and death
Levorphanol is even longer acting than methadone
Codeine Less efficacious than morphine Codeine analgesic effect is due to
Oxycodone Usually combined with aspirin, acetaminophen etc. Metabolites have greater potency
Mild to metabolism by CYP2D6 to morphine
Hydrocodone Codeine has low affinity for opioid receptors
Moderate
Increased risk of seizures
Agonists Weak µ agonist and NE/serotonin reuptake inhibitor
Tramadol May cause serotonin syndrome[DO NOT combine with
Useful for neuropathic pain
MAO-I’s, reuptake inhibitors or TCAs]
Pentazocine µ partial Developed to reduce addiction potential of opioids
agonist + κ
Butorphanol Potent analgesics in opioid naïve patients,
agonist Buprenorphineàmgmt. of opioid addiction (initially use alone, followed by maintenance therapy w/
but precipitate withdrawal in patients w/
κ agonist + µ Buprenorphine and Naloxone to minimize abuse potential)
Nalbuphine Mixed Agonist- physical dependency
antagonist
Antagonists
Used in mild to moderate pain, but are not routine due to ceiling effect
µ partial 1st three may cause psychotomimetic
Buprenorphine agonist + µ effects, but not buprenorphine
Do NOT give to pts taking pure agonist drugsàreduction of analgesia or precipitation of
antagonist
withdrawal
Naloxone Opioid TXT of acute opioid OD
Naltrexone Antagonist Maintenance drug for addicts in TXT programs Longer duration of action ¯craving for alcohol in chronic alcoholics
Most effective cough suppressors Receptors are different than those associated with
Codeine Lower dose than that required for
Antitussives Dextrometorphanàfree of addictive properties & produces opioid action
Dextrometorphan analgesic effects
less constipation than CodeineàOTC medication Caution in pts taking MAO-Is
Prescription opioid (Schedule V)
TXT diarrhea
Diphenoxylate Act on µ or d High doseàCNS effects
Commercial preps contain Atropine to discourage OD
Antimotility receptors Prolonged useàdependence
Agents No analgesic Nonprescription opioid
Loperamide effect Does NOT cross BBB TXT diarrhea
No potential for addiction

Fernanda Ponce pg. 10



Fernanda Ponce pg. 11

 Immunosuppressive Agents
® Used to dampen immune response in organ transplantation and auto-immune disease
® Glucocorticoids are used in palliative care to alleviate sxs of pain, nausea, fatigue, anorexia, malaise and improve overall quality of life
® Cyclosporine ushered the era of organ transplantationà­rates of early engraftment, extending graft survival for kidneys & making cardiac/liver transplants possible
Drug Class MOA/Description Uses Adverse Effects Other
-Steroid hormones that bind to cytosolic Prevent/TXT transplant rejection
Prednisone -Short term use: HTN, hyperglycemia,
receptoràtranslocated to nucleus and binds to TXT autoimmune disorders
immunosuppression, psychotic rxns,
Methylprednisolone GREsà­ or ¯ gene expression Prevent/TXT transplant rejection
cognitive impairment
Prednisolone Glucocorticoids -¯inflam. mediators (TNF a , IL1,IL4) TXT autoimmune disorders -Long term: osteoporosis, weight gain,
-¯eicosanoids via activation of annexin I, MAPK
edema, cataract, poor wound healing, Longer half life
Dexamethasone phosphatase 1 or inhibition of NF-kb (¯COX2) Mgmt. of cancer-related pain ulcers, adrenal suppression and infections ¯ mineralocorticoid effects
¯
- cellular and humoral response
Organ transplantation Nephrotoxicity (occurs in majority) Metabolized by CYP3A4à many
Peptide abx binds to cyclophilinà complex inhibits
Uveitis Tremor, HTN, hyperglycemia, drug interactions
Cyclosporine Calcineurin Calcineurinà¯NF-ATà ¯T-cell activationà
RA hyperlipidemia, osteoporosis, hirsutism, (Grapefruit juice ↑ absorption by
Inhibitors ¯cytokines (IL2, IL3, IFNg etc.)
Psoriasis gum hyperplasia inhibiting p-glycoprotein)
(Immunophilin Prevent rejection of kidney, liver
Macrolide abx binds to FK-binding protein (FKBP)à Absorption= bile dependent
ligands) or heart transplant Nephrotoxicity, Neurotoxicity, HTN,
Tacrolimus complex inhibits Calcineurinà¯NF-ATà ¯T-cell 100x more potent than
Topicalàatopic dermatitis, hyperglycemia, hyperkalemia, GI upset
activationà ¯cytokines cyclosporine
psoriasis
Prevents re-stenosis of BV by
Proliferation Binds to FK-binding protein (FKBP)à Inhibits Myelosuppression, hepatotoxicity,
¯cell proliferation in pts w/ Nephrotoxic when combined
Sirolimus Signal mTOR(serine-threonine kinase)à block action of diarrhea, hypertriglyceridemia,
severe CAD [drug eluting stent] with cyclosporine
Inhibitors IL2à ¯T-cell proliferationà¯cytokines pneumonitis, HA
Renal Transplants
Immunomodulatory drug that inhibits TNFa and
Inhibitors of Erythema nodosum leprosum Peripheral neuropathy, constipation, rash, Teratogenicàphocomelia (no
Thalidomide angiogenesis
Angiogenesis 1st line for Multiple myeloma fatigue, hypothyroidism, ­risk of DVT limbs)
Enhances cell mediated immunity
Purine antimetabolite & prodrugàconverted to 6- Prevent organ transplant Allopurinol ­concentration by
BM suppression, GI upset, some ­ in
Azathioprine mercaptopurineà inhibit de novo purine rejection inhibiting xanthine oxidase
infection/malignancy
synthesisà¯B/T cell fxn, ¯Ig’s, ¯1L2 Severe RA needed to inactivate drug
RA, psoriasis, psoriatic arthritis, -Renal excretionàtoxicity in pts
Inhibit AICAR transformylaseàcompetitively inhibit Nausea, mucosal ulcers (most common)
ankylosing spondylitis, w/ ¯creatinine clearance
AMP deaminaseà­AMPà ­adenosine àact on
polymyositis, dermatomyositis, -Give leucovorin 24hrs after
Methotrexate A2b receptors & inhibit NF-kBà suppressed inflam. Leukopenia, anemia, stomatitis, alopecia,
Wegener’s, giant cell arteritis, weekly dose or daily folic acid to
fxn of Nf, Mf, dendritic cells and lymphocytes hepatotoxicity (­enzymes),
Cytotoxic SLE, vasculitis, graft vs host ¯toxicity in RA
-some effect on dihydrofolate reductase HSN pneumonitis
Agents disease -Contraindicated in pregnancy
Prodrug→ converted to mycophenolic acidà
Prophylaxis of transplant Nausea, vomiting, diarrhea, abdominal
Mycophenolate inhibits IMP dehydrogenase hence blocking de novo
rejection pain, HA, HTN, reversible
Mofetil GTP synthesis
Off label in SLE myelosuppression
Suppresses B and T cell activation
Diarrhea, reversible alopecia, rash,
Prodrug of teriflunomideàinhibits dihydroorotate Monitor CBC and liver fxn
Leflunomide RA myelosuppression, ­aminotransferase
DHà ¯UMPà ¯pyrimidine synthesis Contraindicated in pregnancy
activity
Alkylating Destroys proliferating lymphoid cells and alkylates Hemorrhagic Cystitis (treat with Mesna), Acrolein (drug
Cyclophosphamide SLE/ autoimmune diseases
Agents DNA in some resting cells BM suppression, infertility metabolite)àbladder carcinoma
Complete ophthalmologic exam
¯T-cell response to mitogens, ¯chemotaxis, Mild RA, SLE
Pts w/ G6PD deficiencyàhemolysis is recommended before/during
Hydroxychloroquine ¯DNA/RNA synthesis, stabilize lysosomal enzymes, Often used in combo w/
Retinal damage (Rare) TXT
trap free radicles methotrexate or sulfasalazine
-effectiveness seen in 3-6mon
Other
Nausea, vomiting, HA, rash, neutropenia
RA (d/t sulfapyridine)
Made of sulfapyridine + 5-aminosaicylic (5-ASA) Rare: thrombocytopenia + drug induced
Sulfasalazine UC (d/t 5-ASA) Metabolized by bacteria in colon
connected by a diazo bond lupus
Crohn’s, ankylosing spondylitis
Pts w/ G6PD deficiencyàhemolysis

Fernanda Ponce pg. 12

 Immunosuppressive Antibodies
Drug Class MOA/Description Uses Adverse Effects Other
Antilymphocyte Prior to stem cell transplant to prevent
Produced in horses and sheep via immunization
Globulin (ALG) graft vs. host disease
against human thymus cells
Antithymocyte Combo w/ other Immunosuppressants for
Polyclonal Abs bind to & destroy T-cells via complement
Globulin (ATG) solid organ transplants
Antibodies
Human IgG Ab against Rho(D) antigen Rh(-) women produce Rh Abs after birth of
Rho(D) Immune
Given at time of exposure to Rh(+) infant so that no Hemolytic disease of the newborn Rh(+) infant; In later pregnancies, Rh Abs may
Globin
maternal Abs to Rh are formed attack Rh(+) infantàerythroblastosis fetalis
® Blocking TNFa from binding to TNFR1/TNFR2à ¯inflam. cytokines and ¯adhesion molecules involved in leukocyte activation/ migration
® ­risk of infection/malignancy (lymphoma) or reactivation of TB, Hep B, and invasive systemic fungi is common with anti-TNFa Abs
o screen pts. for latent TB before and during TXT
Infliximab Chimeric anti-TNF Ab RA, psoriatic arthritis, ankylosing
Adalimumab Anti-TNF Fully human IgG1 anti-TNF Ab spondylitis, Crohn’s, UC
Bacterial sepsis CBC should be monitored regularly
Monoclonal Not a true Mab; contains the ligand-binding portion
RA, ankylosing spondylitis, plaque Cytopenias Contraindicated in pts with an active infection
Etanercept Antibodies of a human TNFa receptor fused to the Fc portion
psoriasis, and psoriatic arthritis
of human IgG1
Anti-IgE recombinant humanized Abà prevents
Pts >12 y.o w/ refractory asthma
Omalizumab release of inflam. mediators from basophils and
Chronic urticaria
mast cells after allergen exposure
Monoclonal Chimeric human-mouse IgG binds to IL2 receptor Used in comboàprevent renal transplant
Basiliximab
Antibodies on activated lymphocytes rejection
Combo w/ methotrexateàRA
Chimeric murine-human Ab that binds to CD20à
Rituximab Non-Hodgkins lymphoma (NHL)
depletion of circulating B-cells
Chronic lymphocytic leukemia (CLL)
IL-1 Receptor
Anakinra Recombinant human IL1 receptor antagonist Mod-severe RA
Antagonist
Mod-severe RA
Abatacept Fusion Protein Interferes with T-cell activation Mod-severe polyarticular juvenile
idiopathic arthritis
Immunostimulants
Drug Class MOA/Description Uses Adverse Effects Other
Recombinant IL2àpromotes production of Adjunct in renal cell carcinoma and
Aldesleukin
cytotoxic T-cells and activates NK cells malignant melanoma
Hairy cell leukemia, CML, malignant
IFN-a
melanoma, Kaposi’s Sarcoma, Hep B/C
Interferons
IFN-b Relapsing MS
IFN-g Chronic Granulomatous Disease
HSN, shock, chills,
Bacillus Calmette- Live attenuated culture of M. bovisàinduce Active against tumors fever, malaise,
Guerin (BCG) granulomatous rxn @ site of injection TXT & prophylaxis of bladder carcinoma immune complex
disease

Fernanda Ponce pg. 13


Types of Pain
Nociceptive: pain in response to a noxious stimulus
-somatic or visceral→ normal physiologic painàprevents further
damage d/t body’s autonomic withdrawal reflex
Inflammatory: when tissue damage is present
-still a normal response
Neuropathic: damage or dysfunction of the nervous system,
rather than stimulation of pain receptors [pathological]
-described as burning, tingling, shooting, electric like etc.
Functional: abnormal processing or function of the CNS in
response to a normal stimulus i.e. an exaggerated response
-seen in fibromyalgia and IBS
Non-opioid Analgesics
Used for mild to moderate pain
Non-opioid analgesics include acetaminophen and NSAIDS
Do not cause physical dependence or tolerance; they do have a
ceiling effect [but are often prescribed at doses in excess]
Acetaminophen: First line for lower back pain & osteoarthritis
-AE: hepatoxicity (risk ­ w/ Hep. and chronic alcoholism)
NSAIDS: pain of inflammation, especially RA and gout
Analgesic Dosing
Routine: in the initial stages of severe pain, doses are given at
fixed time intervals; dose can be gradually ­ until patient is
comfortable; next dose should be given before previous effect
has worn off
Rescue: short acting opioid (Fentanyl) given on “as needed” basis
for breakthrough pain (acute on chronic pain) in conjugation w/
fixed long-acting drugà usually seen in pts w/ cancer pain
à Fentanyl formulations: lozenge, sublingual tablet, buccal tablet
& buccal soluble film
Not Routine:
Meperidineà it has a short t½ & its metabolite, normeperidine
has no analgesics effect + t½ =15-20h→ significant AE when it
accumulates→ tremulousness, dysphoria, myoclonus & seizures
Mixed agonist/antagonist & pure agonist combination→
competition for receptor→ withdrawal reaction
(don’t forget psychotomimetic effects seen w/ mixed)
Routes of Administration
Oral/transdermal preferred for long-term use (modified
releaseàless frequent dosing + important for overnight relief)
IVàmost rapid onset and easiest titration, but short duration
PCA (patient-controlled anesthesia) pump allows patient to self-
administer a preset dose of parenteral analgesics
- Gold standard for management of acute post-op pain
- Morphine, hydromorphone, fentanyl & methadone given PCA
IM injectionsànot recommended d/t pain @ injection site + wide
fluctuations in drug absorption
Intraspinal opioids (epidural, intrathecal)àpost-op use
Fernanda Ponce pg. 14
Pain Management
Clinical Presentation Treatment of Pain
Mild (1-3) → non-opioid ± adjuvant (Acetaminophen/ Ibuprofen)
Acute: occurs as a result of injury as surgery, usually self-limited and
Moderate (4-6) → medium potency opioid ± non-opioid ± adjuvant
subsides after the injury heals
(Acetaminophen + codeine/oxycodone/Tramadol)
-typically nociceptive, but can be neuropathic pain
Severe (7-10) → high potency opioid ± non-opioid ± adjuvant
-associated with anxiety and HSN of SNS (­HR, ­BP, ­RR, miosis)
(morphine/hydromorphone)
Chronic: persists for months or years
-any of the types of pain can be chronic
Adjuvants are added as needed to
-associated with vegetative states (fatigue, ¯libido, ¯appetite) and
manage AE or augment analgesia
depressed mood
Chronic Malignant: associated with progressive disease that are usually
Combination of non-opioid and
life-threatening such as cancer, AIDS, dementia etc.
opioid is very efficacious
Chronic Non-malignant: associated with a non-life-threatening disease,
but lasts > 6 months past healing period
-pain associated w/ back pain, osteoarthritis, CHD, RA, etc.
Opioid Analgesics Analgesic Ceiling Effect
Moderate- severe pain [4-10] The dose beyond which there is no additional analgesic effect→ ­dose
Mild-Moderate Pain [1-6]
Morphine may ­ the likelihood of side effects (also NSAIDS)
Codeine
Hydromorphone -NSAIDS/acetaminophenàceiling effect
Hydrocodone
Oxymorphone -Combo of opioid +NSAIDàceiling effect=dose-limiting factor
Oxycodone
Levorphanol -Mixed agonist/antagonists (Pentazocine, Butorphanol, Nalbuphine
Meperidine [strong agonist]
Fentanyl and Buprenorphine) have ceiling effect→ poor choices for pts. w/ severe
Tramadol
Sufentanil pain (Combo w/ pure opioid agonist may precipitate acute pain/opioid
Methadone withdrawal sxs)
Management of Adverse Effects
Urticaria/Pruritus→ d/t histamine release via opioid induced mast cell
Nausea/Vomiting→ tolerance usually develops in a few days so
destabilization
symptoms may disappear; if not it can be treated with Hydroxyzine,
-managed with hydroxyzine or diphenhydramine (1st gen H1)
Metoclopramide, or Prochlorperazine
Constipation→ almost universal AE [very little tolerance]
Sedation→ tolerance developsà SXS will subside in a few days
-Stimulant laxative (Senna, Bisacodyl) should be prescribed when opioid
-can be managed with methylphenidate, amphetamine, or Modafinil
is started
Respiratory Depression→ NOT a life threatening AE because pain is a
-Combo of stimulant/softener (docusate, mineral oil, glycerin)àuseful
powerful stimulant to breathe and tolerance to respiratory depression
-Osmotic agent (MgOH2, lactulose) added if constipation persists
develops quickly
-Bulk-forming agents (psyllium) require substantial fluid intake→ not
-when respiration is compromisedà naloxone
recommended for pts with advanced disease or poor mobility
Analgesic Adjunctive Agents (Coanalgesics)
Anticonvulsants→ treatment of neuropathic pain
Useful in pain management, but not classified as analgesics
Gabapentin: postherpetic neuralgia
Antidepressants:
Pregabalin: postherpetic neuralgia, diabetic neuropathy & fibromyalgia
-TCA’s can relieve many types of neuropathic pain including diabetic
-MOA: block voltage gated Ca2+ channelsà¯glutamate, NE, Substance P
neuropathy, post-herpetic neuralgia, polyneuropathy & fibromyalgia
-AE: dizziness, somnolence & peripheral edema
-MOA: NE and serotonin reuptake inhibitors→ ↑descending inhibition of
Carbamazepine: DOC for trigeminal neuralgia
ascending pain pathways
-MOA: block voltage gated Na channels
-AE→ constipation, dry mouth, blurred vision, ↓cognition, tachycardia
-AE: drowsiness, dizzy, nausea, vomit, leukopenia, aplastic anemia(rare)
and urinary hesitation (anticholinergic activity); Orthostatic hypotension,
Glucocorticoids→ used in advanced illness (acute nerve compression,
falls, weight gain & sedation
­ICP, bone/visceral pain, anorexia, nausea, depressed mood)
-2° amines (Desipramine, Nortriptyline) have less AE than 3° amines
DOC = dexamethasone (pure glucocorticoid activity→ less AE), but
(Amitriptyline, Imipramine)
prednisone and methylprednisolone can also be used
-Use with caution in pts with glaucoma, BPH, CVD, ↑LFT’s
nd rd -improve appetite, nausea, malaise, and overall quality of life
-Contraindicated in pts with 2 /3 heart block, arrhythmia, long QT,
Hydroxyzine: ­analgesia in post-op/CA pain while ¯nausea & vomiting
severe liver disease or recent MI
Clonidine: for sympathetically maintained pain (oral or transdermal)
-SNRI’s→ Venlafaxine, duloxetine (Like TCAs but have antihistamine & a-
Lidocaine patch/ Capsaicin patch: postherpetic neuralgia
blocking effects + NO anti-M effects); better tolerated than TCAs
Caffeine: ­analgesic effects of acetaminophen & NSAIDS
-AE: nausea, sexual dysfxn and somnolence
 Drugs for Osteoarthritis
® Osteoarthritis: degeneration of cartilage in joints (usually the knees, hips & hands)à pain and disability
® The choice of drug depends on the severity and presence/absence of local inflammatory changes
Drug Description Uses Adverse Effects
st Fewer adverse effects than NSAIDS, but less
Acetaminophen No clinically significant anti-inflammatory activity 1 line for mod-severe osteoarthritic pain w/o signs of inflammation
effective
May be used in addition to or in place of
NSAIDS Mod-severe osteoarthritic pain w/ signs of inflammation Many AE
acetaminophen
NSAID available as a topical gel/solutionàuseful in
Diclofenac Local txt of osteoarthritis
pts w/ symptomatic disease limited to few sites
Duloxetine Selective serotonin & NE reuptake inhibitor Chronic musculoskeletal pain
Tramadol Mod-severe chronic pain in adults
Hydrocodone
Morphine Opioids Last resort for intractable osteoarthritis pain
Oxycodone
Adjunct in pts w/ inadequate benefit from NSAIDS, or those who can’t Severe skin burns and nerve damage
Capsaicin Topical gel
take NSAIDS for whatever reason Dried residueàcough, sneeze, eye irritation
Betamethasone Osteoarthritic pain in one or few affected joints (even those not
Intraarticular Corticosteroids
Triamcinolone obviously inflamed)

Fernanda Ponce pg. 15

 Rheumatoid Arthritis
Combination Therapy
® RA: autoimmune disease driven primarily by activated T-cells releasing inflammatory cytokines
® Pts w/ mod-severe RA, combo if non-biologic and biologic DMARDàmay be better for initial TXT
o Activation of B-cells and humoral response evidentàmost Abs created are IgG of unknown
® Combination of different biological DMARDSà­risk of infectionànot recommended
specificity elicited by polyclonal activation rather than response to an antigen
MTX + cyclosporine
® Drugs used: DMARDS, NSAIDS, and glucocorticoids MTX + Hydroxychloroquine
MTX + Leflunomide
o DMARDS can take 6wks-6mon to show clinical effects; are the only ones w/ potential to reduce MTX + sulfasalazine
MTX + gold
or prevent joint damage(delay and possibly stop progression), but have no analgesic effect MTX + Hydroxychloroquine + sulfasalazine
MTX + TNF Inhibitor
Drug Class Description MOA PK AE/Contraindications
Inhibits AICAR transformylase → final step in de novo Nausea, ulcers
DOC→ first DMARD prescribed for mild, moderate or Requires much lower
purine synthesis forming IMP Hepatotoxicity [dose related]
severe RA dose than what is
Methotrexate (MTX) Pseudolymphomatous rxn
-Decreases purine synthesis needed in CA
Also leads to the accumulation of adenosine which is a
-↓toxicity with leucovorin or folic acid chemotherapy
potent anti-inflammatory mediator → ↓NF-κB Contraindicated in pregnancy
Prodrug converted to an active metabolite
Inhibits dihydroorotate dehydrogenase → ↓UMP Can cause severe
Cells are arrested in G1 Frequent diarrhea, Alopecia,
hepatotoxicity when
Decreases pyrimidine synthesis rash Myelosuppression
Inhibits autoimmune T & B cell proliferation which combined with MTX
Leflunomide ↑aminotransferase activity
have ­need for DNA precursors (other cell are able to
Used for mild, moderate of severe RA in pts who
maintain basal pyrimidine requirements through salvage Monitor CBC and
don’t respond to MTX alone or may be benefit from Contraindicated in pregnancy
pathways) LFT’s
combo therapy
Effectiveness may
-Often used with MTX and sulfasalazine Ophthalmology exam before treatment and annually Hemolysis in pts with ↓G6PD
Hydroxychloroquine take 3-6month to be
-least toxicity of any DMARD, but also least effective thereafter for high risk pts Retinal damage is rare
Non-biologic apparent
DMARDS Effectiveness may Rash Hepatitis, leukopenia
Safe in pregnancy Diazo bond metabolized by bacteria in the colon to
Sulfasalazine take 2-3month to be Lupus like syndrome
Used for mildest cases of RA sulfapyridine (active DMARD) and 5-ASA
apparent Hemolysis in ↓G6PD
Many drug Nephrotoxicity
Inhibits Ag triggered signal transduction in T-cells Forms a complex with cyclophilin→ prevents Calcineurin interactions and Hirsutism & gum hyperplasia
Cyclosporine
Only used in severe cases d/t toxicity from dephosphorylating NFAT→ ↓IL2 nephrotoxicity→ Tremor, HTN, hyperglycemia,
limited use hyperlipidemia, osteoporosis,
Reduce dose in pts
Purine antimetabolite BM suppression GI
Converted to 6-MP→ inhibition of de novo purine taking allopurinol due
Azathioprine Only used in cases of refractory RA or w/ systemic disturbance
synthesis→ suppression of T & B cells to inhibition of
features (rheumatoid vasculitis) Infection and malignancy risk
xanthine oxidase
BM suppression, infertility
Active against RA
Generally limited to the most severe cases of RA w/ Alkylating agents→ crosslinks DNA→ prevents cell Hemorrhagic cystitis,
Cyclophosphamide only when given
systemic features (Vasculitis) replication Infection and malignancy risk,
orally
Fanconi’s anemia
Adalimumab ANTI-TNFaà mod-severe RA (1st line biologic Binds to soluble TNFα preventing its interaction with Act more quickly than
Infliximab DMARD) receptors→ downregulation of T-cell and macrophage non-biological
Etanercept Use in combo w/ MTXàsynergistic effects function DMARDS
Rituximab Given w/ MTX or another non-biologic DMARD
Given to pts not responding to DMARDs or anti-TNF
Abatacept
Biologic agents
Anakinra DMARDS Mod-severe RA Modestly effective IL1 receptor antagonist
Osteoporosis, weight gain,
Prompt and dramatic effect, but use is controversial Inhibit PLA2 and COX2
AE associated with edema, ulcers, HTN,
Glucocorticoids Used for short term symptomatic relief until Intra-articular injectionàrelieve acutely inflamed
long term use hyperglycemia, poor healing,
beneficial effects of DMARDs becomes apparent rheumatoid joint w/ min. AE
cataracts, adrenal suppression
NSAIDS Immediate analgesic and anti-inflammatory effect Used as bridge drugs for relief of symptoms

Fernanda Ponce pg. 16

 Gout
® Metabolic disease characterized by ­uric acid in the blood (hyperuricemia primarily d/t renal under ® End product of purine metabolism in the liveràuric acid
excretion)àdeposition of urate crystalsàinitiation of inflammatory processàacute gout attacks ® 60-70% eliminated by renal clearance; remainder excreted in feces
® Always preceded by hyperuricemia, but not necessarily vice-versa ® Crystals bind to TLRs on monocytesàphagocytosis + assembly of NALP3
® Podagra: urate crystal deposition in the 1st metatarsophalangeal joint (most common) inflammasomeàrelease of IL1bàBind to endothelial cellsàrelease of IL8 to recruit
® Acute Gout: Goalàcontrol pain Nfàrelease of IL1b again (positive feedback)
® Chronic Gout: Goalàachieve normal serum urate ® Drugs can increase plasma levels of uric acid
Drug Class MOA Description Adverse Effects Contraindications Other
Remember COX2
Bleeding Aspirin→ competes with uric
NSAIDS DOC= Indomethacin inhibitors ­CV
Na+ and H2O retention acid for secretion at the PTà
(Indomethacin) Other NSAIDS are also 1st line risk so use is
Renal insufficiency hyperuricemia
limited
Acute Gout

-Binds tubulin→ ↓polymerization→ no

Abdom. pain, nausea, vomiting, No longer used
microtubules→ ↓mobility of Pregnancy
diarrhea due to
Suppress leukocyte recruitment and granulocytes
Colchicine Chronic→ myopathy, troublesome
activation -Disrupts mitotic spindle blocking cell Use with caution in pts with
neutropenia, aplastic anemia, diarrhea side
division hepatic, renal or CV disease
and alopecia effect
-Inhibits synthesis/release of LT’s
-TXT of acute polyarticular gout Anti-
Widespread AEàmostly used
-Depot preps injected into a single inflammatory and
Glucocorticoids if contraindications exist or if Renal insufficiency
affected joint when refractory to immunosuppressi
no response
NSAIDs or colchicine ve effects
1st line for uric acid lowering therapy
Purine analog→ -If cutaneous rash develops,
-Formation of uric acid stones
competitively inhibits discontinue use
Agents that disappears w/ therapyàprevents HypersensitivityàSkin rashà
Allopurinol xanthine oxidase -Reduces doses of Initially may
¯uric acid nephropathy may progress to Steven-
facilitating dissolution
-Not recommended for asymptomatic
Mercaptopurine and ­attacks of gouty
synthesis Johnson syndrome [toxic
Chronic Gout

of tophi azathioprine→ also arthritis due to

hyperuricemia epidermal necrolysis]
metabolized by xanthine mobilization of
Structurally unrelated Not recommended for asymptomatic
Febuxostat oxidase tissue stores of
to Allopurinol hyperuricemia
uric acid→
Inhibits URAT1 (like Losartan and Renal stones (maintain large Gouty pts w/ nephrolithiasis
coadminister with
Fenofibrate)àno reabsorption in urine volume + urine pH>6 w/ or overproduction of uric
Increases rate of uric an NSAID or
Uricosuric kidneyà¯plasma urate Sodium bicarbonate or acid
Probenecid acid excretionàrenal colchicine
Agent -inhibits secretion of most potassium citrate) Renal insufficiency
stones
anionsà¯dose of other drugs excreted GI irritationàcaution in PUD Low dose
this way HSN rxn Aspirinàantagonize
Agent that Recombinant Uricase
For pts refractory to TXT w/ xanthine
Pegloticase ­uric acid (non-fxnal in humans
oxidase inhibitors
metabolism normally)

Fernanda Ponce pg. 17

 Migraine Treatment and Prophylaxis
® Hallmarkàdisabling headache generally associated w/ nausea and/or light/sound sensitivity
Drug Class MOA Description Adverse Effects Contraindications

Weak COX1/2 inhibitor in peripheral

Mild-Mod

Acetaminophen
Attacks

tissues 1st choice for mild to moderate

migraines not associated w/ Look on page 7 and 8
vomiting or severe nausea
NSAIDS COX1/2 inhibitor

Pts w/ coronary,
DOC for moderate-severe
Tingling, flushing, drowsiness, feeling cerebrovascular or other
Mod-Severe Attacks

Selective 5HT-1D & 5HT-1B receptors migraines

of heaviness/ tightness/ pressure in arterial disease & HTN
Sumatriptan Triptans chest
Subcutaneousàfast acting and most Sumatriptan and
Rareàangina, MI, arrhythmias, stroke, Cautionàpts w/ risk factors
effective naproxenàbetter pain relief than
death for vascular disease (Esp.
either used alone
diabetes)
Nausea/vomitingàpretxt w/ antiemetic
Dihydroergotamineàweaker (Metoclopramide)
Ergotamine Ergot Agonist at a-receptors, 5HT-1D & 5HT-1B Pts w/ arterial disease or
vasoconstrictor than ergotamine & Vascular occlusion & gangreneà
Dihydroergotamine Alkaloids receptors, and D2 receptors uncontrolled HTN
causes ¯adverse effects associated w/ OD & accelerated by liver
disease or fever
Propranolol
Prevention of Migraines

Timolol
80% of pts achieve complete or partial Continuous prophylaxis of
b-blockers
(1st line Agents)

Metoprolol
response migraine HA
Nadolol
Atenolol
TXTs manic episodes in bipolar GI side effects
Inhibits voltage gated Na+ channels and
Valproate disorder, epileptic seizures and Thrombocytopenia Teratogenic
T-type Ca2+ channels
prophylaxis of migraine HA Rareàhepatotoxicity
Antiepileptic
Somnolence, cognitive slowing,
Inhibits voltage gated Na+ channels TXTs epileptic seizures and
Topiramate nervousness, confusion, acute myopia, Teratogenic
GABAA agonist & glutamate antagonist prophylaxis of migraine HA
glaucoma, hyperthermia, renal stones
Amitriptyline
Used in combo w/ propranolol to
Nortriptyline TCAs Inhibit NE and serotonin reuptake Sedation, dry mouth, weight gain
­efficacy and ¯AE
Imipramine
Prevention of Migraines

Nausea, constipation, insomnia, HA,

Venlafaxine SNRIs Inhibit NE and serotonin reuptake Prophylaxis of migraine HA
(2nd/3rd line Agents)

sexual dysfunction
Calcium
Prevention of migraine, but
Verapamil channel CCB w/ most efficacy
evidence of effectiveness is weak
blockers
Blocks presynaptic voltage gated Ca2+
Gabapentin Antiepileptic Prophylaxis of migraine HA Sleepiness, dizziness, fatigue
channelsà¯glutamate release
Lisinopril ACE-I
¯migraine frequency by 30%
Candesartan ARB
Prophylaxis of chronic migraine in
Botulinum Toxin Toxin Pericranial injections
adults (15 or more HA/mon)
Naproxen
NSAIDS Short term prevention of migraine
Ibuprofen

Fernanda Ponce pg. 18

 Principle of Anti-Microbial Therapy
• Antimicrobialàinhibits growth/kills a microorganism
• Antibacterialà inhibits growth/kills a bacteria
• Antibioticàmicrobial product/derivative that kills/inhibits growth of a
microbial microorganism (includes synthetic drugs)
• Bacteriostaticàreversible growth inhibition; once Abx is removed, bacteria
begin to replicate again (do not use in immunocompromised)
• Bacteriocidalà irreversible growth inhibition; once Abx is removed, no
bacteria replicate again
o Should have an MBC equal to/slightly about the MIC
• Selective Toxicityà ability to injure/kill invading organism w/o harming
hostà minimizes adverse effects
• Broad Spectrumà effective against several groups (tetracycline &
chloramphenicol)
• Narrow Spectrumàeffective against few groups (isoniazid)
o Should be DOC when possible to minimize MDR
• Extended Spectrumà effective against gram (+) & some gram (-) (ampicillin
& amoxicillin)
• Postantibiotic Effectà when killing action of an agent continues once drug
plasma levels are below measurable levels
o lag time for bacteria to synthesize new proteins
o persistence of agent at target site
o enhance susceptibility host defense mechanismsàphagocytosis
Minimal Inhibitory Concentration (MIC)
• lowest conc. of Abx that prevents visible growth
• clinically obtainable Abx con. should be greater that the MIC
• measures by broth/tube dilution or disk sensitivity testing
• dose below MIC enables drug resistance
Minimal Bactericidal Concentration (MBC)
• performed in conjunction w/ MIC tube dilution
• lowest conc. of Abx that results in no growth
Antimicrobial Combination Therapy
• use of multiple drugs to treat an infection
• chosen for: emergencies, when infections are known/thought to be cause by
many organisms, achieve synergistic effect, prevent drug resistance, and
treat immunosuppressed
• Disadvantageà agents that only act on multiplying bacteria combined with a
bacteriostatic agentàless effective (b-lactam less effective when combined
with tetracyclines b/c they require cell to be actively proliferating)
Fernanda Ponce pg. 19
Selecting the Right Agent
1. Organism Identity
• Gram (+) vs gram (-)à quicker & cheaper than a culture, but less specific
• Gram (+) have thick peptidoglycan layer does not block diffusionàAbx that
damage cytoplasmic membrane can pass through
2. Empiric Therapy
• Given when immediate therapy is required (i.e. meningitis)
• Choose based on site of infection & patient history
• May require broad spectrum Abx initially
3. Site of infection
• Does the drug cross the BBB, etc.?
• Lipid solubility: Fluoroquinolones & metronidazole=lipid soluble
• MW: large drug is less likely to penetrate BBB
• Protein binding of drug: if bound, less free drug for BBB penetration
• PCN cannot reach therapeutic conc. in eye or prostate
4. Patient factors
• Immune system: imp for immunocompromisedàtxt aggressive
• Renal/hepatic dysfxn: metabolism/clearance is ¯à ­free drug conc.
• Poor perfusion: alters the kinetics of a drug
• Age: elderly have ¯kidney/liver fxn; kids may have AE to some drugs, etc.
• Pregnancy and lactation: teratogenic effects of some drugs
• Compliance to dosing schedule can affect resistance
5. Safety of the Agent
• Safest are those more selective towards bacteria
• Patient factors may also play role
6. Cost of Therapy
• May have similar efficacy buy huge price difference (clarithromycin)
7. Route of Administration
• Mild/non-life threatening treated with oral/topical drugs
• Serious infections or drugs that have poor GI absorption require parenteral
administration
Antimicrobial Resistance: occurs when the maximal level of an Abx tolerated by
the host does not halt bacterial growth
• 1°: gram (-) resistant to vancomycin
• Acquired: MRSA
• Mechanismsà spontaneous DNA mutations, DNA transfer of resistance, or
altered expression of proteins in drug-resistant organisms
Complications of Antimicrobial Therapy:
• HSN rxns ranging from urticaria to anaphylaxis
• Direct toxicity w/ direct action on host’s cellular processes
o Aminoglycosidesàirreversible ototoxicity via interference of
membrane fxn in hair cells
• Superinfections: when a new a secondary infection occurs during txt of a
primary infection

Antimicrobial Chemoprophylaxis
• Not recommended in all situations to reduce development of drug
resistance
• Should always be directed towards a specific pathogen (narrow
spectrum)
• No drug resistance should develop
• Use should be of limited duration
• Conventional therapeutic doses should be employedàdose should be
above their MIC or MBC so that all bacteria will be affected and risk of
developing resistance in remaining bacteria is minimized
• Only used in situations of documented drug efficacy

Synergism
• Sequential blockade→ trimethoprim + sulfamethoxazole
• Block drug inactivating enzymes→ clavulanic acid + amoxicillin
• Enhanced drug uptake→ aminoglycosides have increased permeability
after β-lactam treatment

Fernanda Ponce pg. 20

 Antimicrobials- Inhibitors of Cell Wall Synthesis (b-lactam Abx)
• Do not affect mammalian cells since they do not have a cell wall→ selective to bacteria • b-lactam Abx include: penicillins, cephalosporins, carbapenems and monobactams→ target PBP’s
• Require the microbe to be actively proliferating i.e. cell wall synthesis must be occurring • Some bacteria possess β-lactamase→ hydrolyze the β-lactam ring making Abx ineffective
• Penicillin binding proteins [PBP’s] are bacterial enzymes involved in peptidoglycan synthesis • Can be co-administered with β-lactamase inhibitors to protect the Abx from inactivation
MOA Description Fun Facts AE
Can undergo desensitization esp. for txt of syphilis in
-Bactericidalàbind to PBPs inhibiting the final -t½ = about 30-60 min Hypersensitivity (most common)
allergic pts
stage in peptidoglycan synthesisàno crosslink (exceptions are procaine & benzathine) -Major Ag determinant→ penicilloic acid
Time dependent killingà ­conc. only adds risk for AE;
-Different b-lactams bind to different PBPsà -Widely effective with little toxicity -Anything from a rash to anaphylaxis
length of time spent over MIC is the most important
different efficacies b/w drugs -Overuse→ ↑levels of resistance d/t PBP -Cross allergic rxns b/w β-lactam Abx can occur
Spectrum based on ability to reach the PBPsàsize,
-Mechanism of killing is indirect consequence of mutation [i.e. may also be allergic to cephalosporins]
charge, and hydrophobicity
inhibition of cell wall synthesisà activation of -All include a β-lactam ring Interstitial nephritis→ esp. methicillin
-gram (+): cell wall easily accessed
autolysinàbacterial enzymes which mediate cell PCN + aminoglycoside (gram +ve & -ve) → oliguria, fever, rash + EOS in urine
-gram (-): porins permit entry
lysis -Synergistic effect→ PCN facilitates GI disturbance
Mechanism of Resistance
-Oral absorption is impaired by food movement of aminoglycosides through -Pseudomembranous colitis [esp. ampicillin] or
-¯ penetration to target site: need porins to cross Gram
-Distribution: do not achieve sufficient levels in the cell wall other 2° infections (i.e. vaginal candidiasis)
(-) cell wall; lack of porinsà resistance (i.e.
prostate or eye; CSF penetration is poor but -Forms an inactive complex if placed in -diarrhea esp. w/ ampicillin & amoxicillin
Pseudomonas)
works in meningitis the same IV solution Maculopapular rash→ when ampicillin or
-Alteration of target site: alterations in PBPs influence
-Nafcillin, ampicillin & piperacillinà high levels in → DOC for Empiric treatment of infective amoxicillin is given for a viral infection, not a
binding affinity; mechanism responsible for penicillin
bile endocarditis… PCN G + gentamicin hypersensitivity reaction
resistance to pneumococci, methicillin resistance to
-Primarily excreted in kidney except for (nowadays a lot of MD’s use Vancomycin Neurotoxicity in epileptics/pts w/ renal disease
staph and vancomycin resistance to enterococci
Nafcillinàbile (useful in pts w/ renal insufficiency) instead of PCN d/t resistant strains) Nafcillin→ neutropenia
-Inactivation by bacterial enzyme: β-lactamase
-Oxacillin/Dicloxacillinàrenal and biliary -MRSA/ORSAàaltered PBP binding w/ Oxacillin→ hepatitis
production by most staph and many gram (-); production
excretion ¯affinity for β-lactam Abx Ticarcillinàinhibits platelet fxn & ­BTàbleeding
encoded w/I chromosome or acquired on a plasmid
Drug Spectrum of Activity Uses PK/PD Other
Gram (+) cocci
(Except Staphà β-lactamase, penicillin resistant -Benzathine & procaineà low but
Penicillins

Benzathine & procaineà

Penicillin G pneumococci, enterococci and MRSA) DOC for syphilis (benzathine) persistant conc. of Abx
repository PCNs, local
“Natural PCN” Gram (+) rods -Procaine peaks w/I hrs and lasts 4-
anesthetic effects
Penicillin G benzathine Gram (-) cocci Strep (rheumatic fever prophylaxis) 5days
Penicillin G procaine (Except N. gonorrheaà β-lactamase) Pneumococci -Benzathine peaks @ 24hrs and
Positive Coombs Test
Most anaerobes (except Bacteroides) lasts 26 days
Treponema Pallidum
Similar to PCN G Mild-mod oropharyngeal infections Oral
Penicillin V Positive Coombs Test
Less active against gram (-) DOC for Strep throat Acid stable
Methicillin β-lactamase producing Staph (except MRSA)
GI absorp. Of Nafcillin is erratic Methicillin is never used
Nafcillin Narrow spectrum of activityà ¯intrinsic activity DOC for Staph endocarditis w/o prosthetic valve (w/
clinicallyàcauses acute
Oxacillin than PCN G prosthetic valveà S. Viridans infection)
Dicloxacillin- Acid stable interstitial nephritis
Dicloxacillin Ineffective againstà enterococci, Listeria, Neisseria
HELPSS kill enterococci:
URT’s (H. influenzae & S. pneumo); UTI (E. coli)
Extended Spectrum Amoxicillin better absorbed in
P. mirabilis, Salmonella, Shigella Amoxicillinàused for
Gram (+) bacteria intestine (Oral)à ­blood and urine
Amoxicillin children and pregnancy d/t
Gram (-) bacillià can penetrate porins levels; absorp. not affected by food
Ampicillin -Amoxicillinàendocarditis prophylaxis during dental extended spectrum and
Susceptible to β-lactamasesàadmin w/ β-
or resp. tract procedures safety
Lactamase-I Acid stable
-Ampicillin used in combo w/ aminoglycosides to txt
Listeria and enterococci
DOC for pseudomonas; mod-severe infections where
gram (-) are suspectedà skin, gynecologic and intra-
Takes Care of Pseudomonas
abdominal infections
Carbenicillin Gram (+) bacteria Ticarcillinàinhibits platelet
Piperacillinà superior against Pseudomonas & some
Ticarcillin Gram (+) bacteria @ high doses fxn & ­bleeding timeà
Klebsiella
Piperacillin More resistant to β-lactamases, but still admin w/ β- bleeding diathesis
- admin w/ β-Lactamase-I d/t some susceptibility
Lactamase-I
Carbenicillin indanyl sodiumàoral therapy for
resistant UTIs (not effective outside UGT)

Fernanda Ponce pg. 21

 Antimicrobials- Inhibitors of Cell Wall Synthesis (b-lactam Abx) Continued
Drug Spectrum of Activity Uses PK/PD Other
β-Lactamase
Inhibitors
aka: penicillinase or cephalosporinase
Clavulanic Acid
Sulbactam Contain a β-lactam ring, but do not have significant antibacterial activity
Tazobactam Available only in fixed combinations with specific PCN’s
Bind and inhibit most (but not all) β-lactamases & protect hydrolysable PCNs from inactivation
MOA Description Fun Facts AE
Hypersensitivity- from urticaria-anaphylaxis
Moving from 1st to 3rd Generation:
Same MOA as PCN Incomplete cross reactivity with penicillins
Β-lactam Abx ↓’ing gram (+) activity
Bactericidalàbind to PBPs inhibiting the final stage in PCN-allergic pts are sometimes treated
Affected by same resistance mechanisms as PCNs ↑’ing gram (–) activity
peptidoglycan synthesisàno crosslink successfully w/ cephalosporins
-Mechanism of killing is indirect consequence of Pain at IM injection site + phlebitis
Most administered parenterally 4th generation effective against gram
inhibition of cell wall synthesisà activation of May ­nephrotoxicity of aminoglycosides
-Exceptions: cephalexin, cefaclor and cefiximeà (+) cocci & gram (-) bacilli→ broad
autolysinàbacterial enzymes which mediate cell lysis Superinfections→ C. diff (pseudomembranous
oral spectrum
colitis)
5th generation: similar to 3rd but are
Inactive against: LAME Cefamandole, Cefoperazone, cefotetan→
Only 3rd Gen reach adequate levels in the CSF unique in that they are active against
Listeria/ Legionella Contain N-methylthiotetrazole (NMTT)à inhibit
MRSA
Acinetobacter / Atypical [Chlamydia, Mycoplasma] Vit Kà ­PT & ­bleedingà
Mainly eliminated by kidney Time dependent killingà ­conc. only
MRSA hypoprothrombinemia (due to vitamin K
-Exceptions: Ceftriaxone and Cefoperazone→ bile adds risk for AE; length of time spent
Enterococci deficiency) + Disulfiram-like rxn→ avoid
over MIC is the most important
concomitant alcohol use
Drug Spectrum of Activity Uses PK/PD Other
Rarely a DOC for any infection (PCN preferred)
1st Generation: Gram (+) cocci Cefazolin:
Cefazolinà DOC for surgical prophylaxis against gram (+) infection b/c
Cefazolin PEcK: Proteus, E. coli, Klebsiella parenteral PCN G substitutes

Cephalosporins

it has long t½ (staph & strep on skin can infect the incision site)
Cephalexin Resistant to Staph Penicillinase Cephalexin: oral
Cephalexin: UTIs & staph/step infections (cellulitis, abscess)
2nd Generation: Cefamandole + Cefaclor: Sinusitis, otitis, and lower respiratory tract
Cefaclor infections d/t H. influenza or M. Catarrhalis→ when PCN is not able to
More active against gram (–) bacilli
Cefoxitin be used (i.e. mild allergic reaction to amoxicillin)
Weaker gram (+) activity
Cefotetan Cefotetan + Cefoxitin→ prophylaxis and therapy for abdominal & pelvic
Cefamandole cavity infections d/t gram (-) bacilli + Bacteroides
Cefotaxime + Ceftriaxone→ pneumococci w/ intermed. susceptibility to
PCN
Cefoperazone + Ceftazidime→ P. aeruginosa Can cross BBB- do not give
Gram (-) resistant to other b-lactam drugs
3rd Generation: Ceftriaxone: to pregnantàdisplace
Enterobacteriaceae (E. coli & Proteus)
Ceftriaxone Ceftriaxone → DOC for: parenteral & bilirubin from binding
Neisseria
Cefoperazone -N. gonorrhea (assume all gonorrhea is PCN resistant) highly protein siteàkernicterus
H. influenza
Cefotaxime -Meningitis (ampicillin resistant H. influenza) in children bound
Ceftazidime -Meningitis prophylaxis in exposed pts (including pregnant) (along Single injection of
Inactive against enterococci, Listeria, MRSA,
Cefixime with ciprofloxacin and rifampin) Cefixime: oral ceftriaxone as effective as
and Acinetobacter
-Lyme disease with CNS & joint infections otherwise use doxycycline 10 days of amoxicillin
-Reserved for txt of serious infections resistant to other drugs w/
exception of gonorrhea and acute otitis media
Effective against gram (+) of 1st gen and gram
More resistant to (b-
4th Generation: (-) of 3rd gen→ broad spectrum Empiric treatment of serious infections
Parenteral (IV) lactamases produced by
Cefepime Enterobacter, Haemophilus, Neisseria, some Never a DOC for mild infection
gram (-)
PCN resistant pneumococci
Binds to PBP2a found in MRSA
5th Generation: Skin and soft tissue infections d/t MRSA (esp. w/ gram (-) coinfection)
Like Ceftriaxone except its active against MRSA Parenteral
Ceftaroline Community acquired pneumonia when 1st line doesn’t work
Inactive against Pseudomonas, Acinetobacter,
& Bacillus
Fernanda Ponce pg. 22
 Antimicrobials- Inhibitors of Cell Wall Synthesis (b-lactam Abx) Continued
Drug Indication MOA PK/PD AE Other
DOC for Enterobacter infection and extended GI: nausea, vomit, Synthetic β-lactam Abx
Carbapenems

spectrum β-lactamase producing gram (-) diarrhea

Resist hydrolysis by most β-
Useful for infections caused by resistant organisms Imipenem forms a
lactamases
(not effective against MRSA) CNS toxicity @ high nephrotoxic
Imipenem
Parenteral levels→ seizures (more metabolite→ combine
Meropenem Resistance by producing
Very broad spectrumà gram (+) cocci, gram (-) rods, likely w/ Imipenem) with Cilastatin to
carbapenemases becoming a huge
aerobes, and anaerobes prevent metabolism,
problem→ restrict use
-effective against Pseudomonasàcombo w/ Partial cross reactivity reduce toxicity, and
aminoglycosides to txt with PCN increase availability
Only for aerobic gram (–) rods (Including Resists hydrolysis by most β- Little cross reactivity→
IV or IM
Monobactams

pseudomonas) lactamases can be used in pts with

DO NOT have activity against gram (+) bacteria or PCN allergy
Inhalation (CF pts w/
anaerobes Binds PBPs → inhibits cell wall Relatively nontoxic… Have monocyclic b-
Aztreonam pseudomonas)
synthesis ↑aminotransferase, skin lactam ring
UsesàUTIs, LRT infections, septicemia, skin/structure rash, thrombophlebitis, &
Penetrates CSF when
infections, intraabdominal infections & gynecological Eliminated in urine via renal tubular pain at injection site
inflamed
infections secretion (monitor renal fxn) Inhalationàcough
Binds D-Ala-D-Ala terminus of
Fever, chills, phlebitis NOT
nascent peptidoglycan Oral→ Abx assoc.
Bactericidal against gram +ve only Red man/Red neck Nephrotoxic
pentapeptide→ inhibit pseudomembranous
Effective against multi drug resistant organisms syndrome→ infusion Ototoxic
transglycosylaseàprevent colitis OR Staph
(MRSA, PCN resistant S. Pneumo, enterococci) related flushing on face Thrombophlebitis
elongation & cross- enterocolitis otherwise
and upper torso d/t
Synergistic with aminoglycoside to treat enterococcal
linkingà↓polymerization and there is poor oral
histamine Resistance due to:
Vancomycin enhanced susceptibility to lysis absorption
endocarditis (DOC) Modification of the
Ototoxicity & nephrotoxic binding site (lactate
-Penetrates CSF when inflamed Usually given as slow
Serious gram (+) infections by β-lactam resistant when drug accumulates replaces Ala) →
(meningitis) IV infusion (60-90m) to
organisms or if pts are allergic to first line drugs (i.e. β- (i.e. renal failure)→ also Plasmid mediated
-90-100% excretion by the kidneys avoid red man
lactams) seen with changes in drug
(drug accumulation in pts w/ renal syndrome
aminoglycosides permeability
insufficiency)
Bactericidal against resistant gram (+) including
vancomycin resistant strains & S. aureus Constipation
Novel mechanism
Not effective against gram (–) Binds cell membrane via calcium Nausea, HA, Insomnia
makes it useful against
dependent insertion of its lipid tail→ IV
MDR bacteria
Usesà Complicated skin infections d/t aerobic gram depolarization→ K+ effluxàcell Myopathy→ monitor
Daptomycin
(+), S. aureus bacteremia (including R sided infective death Can accumulate in creatine phosphokinase
Resistance can develop
endocarditis d/t MRSA/MSSA), severe infections d/t renal insufficiency (discontinue use of statins
in 48 hours over course
VRE & MRSA Limited use d/t resistance as they have the same
of single TXT
Should not be used to TXT pneumonia b/c pulm effect)
surfactant antagonizes drug
Peptide Abxàinterferes w/
Gram (+) only Unique
dephosphorylation cycle of the lipid Nephrotoxic→ cannot be
Bacitracin Mainly topical for TXT of mixed bacterial infection of Topical Abx cream mechanismàNo cross
carrier that transfer peptidoglycan given systemically
the skin, wounds, or on mucus membranes reactivity
subunits to growing cell wall

Gram (+) and gram (–) Inhibits cytoplasmic enol-pyruvate

Fosfomycin transferase in early stage of cell wall Oral
Uncomplicated lower UTI’s, but is not first line synthesis

Fernanda Ponce pg. 23

 Antimicrobials- Inhibitors of Protein Synthesis
® Bind to and interfere with ribosomes (Bacterial ribosomeà 70S)
® Considered broad-spectrum Abx w/ most acting as bacteriostatic agents
® 70S ribosome is similar to mammalian mitochondrial ribosomesàstructural similarity
® Overuseà resistanceà becoming a huge problem
responsible for some AE observed
Class Drug Indication MOA PK/PD AE Other
DOC for: Concentrated intracellularly Teratogenic
Variable oral absorption
Chlamydia, Mycoplasma, Lyme disease without CNS via passive diffusion & via They all cross the
occurring in upper SI & impaired Aerobic/Anaerobic
or joint involvement, Rickettsia (RMSF, typhus), energy dependent placenta/ excreted in
by food (except Doxycycline and Gram(+) & gram(-)
Cholera, & Anthrax prophylaxis transport breast milk (Category D)
Minocycline)
- ¯by multivalent cationsà don’t Widespread resistance is
Tetracyclines

Most common use is treatment of severe acne and Reversible binding to 30S GI effects→ N/V/D
take with milk or antacids plasmid mediated→ 3
rosacea subunit→ prevents binding Superinfection
mechanisms:
of aminoacyl-tRNA to
Doxycycline Doxycycline: lipid soluble→ -↓influx or ↑efflux
Resp. tract, sinuses, middle ear, urinary tract & acceptor siteà prevent Discoloration and
Minocycline Parenteral admin. for STI’s & -New proteins interfere
intestine infections addition of amino acids to hyperplasia of teeth &
Tetracycline prostatitis w/ binding to ribosome
Empiric therapy for community acquired PNA growing peptide stunting of growth→
-Enzymatic inactivation
not suitable for children
Minocycline: high conc. in
Syphilis in pts allergic to PCN Bacteriostatic under 8
tears/saliva→¯ meningococcal Expired tetracyclines can
Useful against intracellular
carrier state cause Fanconi’s syndrome→
Combination TXT: microbes Hepatotoxicity
defective reabsorption at
Duodenal ulcer d/t H. Pylori (quadruple therapy) Nephrotoxicity
Mainly excreted in urine except the PCT
Malaria prophylaxis & TXT Concentrates in liver, kidney, Photosensitivity
doxycycline→ feces
TXT of Plague, tularemia, brucellosis spleen, skin Dizziness/vertigo
Similar to tetracyclinesà IV only Little resistanceà
AE similar to
Glycylcycline

Broad spectrum against MDR Gram (+) (MRSA, binds 30S subunit, but 5x Bile/fecal eliminationàno
tetracyclines
overcome efflux pumps
VISA, VRE), some gram (-) and anaerobes more tightly dosage adjustment for pts w/ and/or ribosomal
Tigecycline renal insufficiency needed protection
Contraindicated in
Usesà complicated skin, soft tissue & Black Box Warning:
pregnancy and children
intraabdominal infections, community acquired PNA Increased risk of mortality→ Excellent tissue and intracellular Proteus & Pseudomonasà
under 8
use as last resort penetration intrinsically resistant
Serious toxicity→ short
Bactericidal against aerobic gram (-) Post-Abx effect + concentration regimen (<5d)
Relatively stable against
MRSA in vitro (but not adequate as monotherapy) dependent killing (­conc. to
resistanceà
Synergistic effect w/ cell wall inhibitors Passive diffusion and active ­killing) → once daily dosing Nephrotoxicà
Resistance mechanism:
Aminoglycosides

Gentamicin transport via O2 dependent neomycin, tobramycin,

-Plasmid encoded enzymes
Neomycin Used in combination TXT: serious infections like process across membranes Parenteral only except gentamicin
modify or inactivate drug
Amikacin septicemia, nosocomial RTIs (Pseudomonas), -inhibited by divalent neomycinà topical/oral
-↓accumulation
Tobramycin complicated UTIs & intraabdominal infections, cations, ­osmolality, ­pH, & Ototoxic (auditory or
-Altered or deleted
Streptomycin osteomyelitis anaerobic environment Well distributedàHigh levels in vestibular)à neomycin,
receptor on 30s subunit
Usually discontinued after identification of organism renal cortex & inner ear amikacin; ­risk w/ loop
due to mutation
“Mean DOC for infective endocarditis: Gentamicin + Irreversible binding to 30S diuretics & pregnancy
GNATS Vancomycin or PCN subunit prior to ribosome Poor penetration of CSF, biliary
Lactulose acidifies the gut
cannot kill Streptomycin→ DOC for plague (Yersinia) formation→ misreads tree and bronchial secretions Neuromuscular
nd lumen, trapping NH4+
anaerobes” Oral neomycin→ 2 line for hepatic mRNA and inhibits blockade
-also causes prebiotic effect
encephalopathy→ reduce formation of NH3 by gut translocation 99% excreted in urine (contraindicated in
(suppress urease producing
bacteria; Alternativesà Lactulose (DOC), oral unchangedà ¯dose in pts w/ Myasthenia Gravis)
bugs) & osmotic diarrhea
Vancomycin, metronidazole or rifaximin renal insufficiency
Allergic skin rxns

Fernanda Ponce pg. 24

 Antimicrobials- Inhibitors of Protein Synthesis Continued
Class Drug Indication MOA PK/PD AE Other
Mainly for gram (+) & some gram (-) Inhibition of CYP450 except
Resistance Mechanism (plasmid
Legionella, Mycoplasma, Mycobacteria, BacterioSTATIC (-cidal at Erythromycin→ 1st azithromycinà statins
encoded):
Rickettsia & Chlamydia high concentration) generation contraindicated d/t ­myopathy
-↓permeability or active efflux
All have broader spectrum of activity except -Others have GI effects (d/t motilin)
Macrolides

-Produce esterase that hydrolyzes

erythromycinà not active against S. aureus Reversible binding of improved oral Cholestatic hepatitis w/ azithromycin
drug
Erythromycin No cross reactivity with PCN→ Good choice for 50S subunit→ inhibition of absorption (stable at & erythromycin
-Modify binding site by methylation
Clarithromycin pts with a PCN allergy transpeptidation, gastric pH) and ­QTà Torsades de Pointe
or chromosomal mutation
Azithromycin translocation & chain ↑bioavailability Anaphylaxis, Stevens-Johnson
Telithromycin Usesà URT and soft-tissue infections (H. elongation Syndrome & pseudomembranous
-Partial cross resistance w/
influenzae, S. Pneumo, Staph, enterococci) -similar binding site as Azithromycin & colitisà rare
clindamycin & streptogramins
Empiric TXT of community acquired PNA clindamycin & Telithromycin have Telithromycin→ hepatotoxicity, MG
-Complete cross resistance b/w
(combined with β-lactam for inpatients) chloramphenicolàcross greater tissue exacerbations & visual
erythromycin, azithromycin, &
DOC for Mycoplasma Pneumoniae resistance penetration disturbancesà don’t use for
clarithromycin
Erythromycin→ DOC for B. pertussis sinusitis/bronchitis (minor illnesses)
Synergistic effect when given as comboà Infusion relatedà venous irritation,
Streptogramins

Bind to separate sites on 50S

bactericidal against gram (+) cocci & MDR arthralgia, myalgia Resistance is uncommonà not used
IV only
Quinupristin bacteria (Strep, PRSP, MRSA, E. faecium) much and given as combo
Penetrate Mf & PMNs
Dalfopristin GI effects
Inhibit CYP3A4
Usesà restricted to infections caused by drug- E. faecalis is intrinsically resistant
Long post-Abx effect
resistant Staph or VRE CNS effectsà HA, pain
Broad spectrum bacterioSTATIC agent against Enters cell via active Oral/IV/topical Resistance mechanisms:
GI distress
aerobic/anaerobic gram (+) and gram (-) including transportà reversibly binds Wide distributionà -chloramphenicol acetyltransferase
BM depressionà reversible dose
Rickettsia, N. meningitides, H. influenzae, to 50S subunità inhibits enters CSF& CNS inactivates drug
related or irreversible aplastic
Chloramphenicol Salmonella, & Bacteroides, VREs peptidyltransferase -altered permeability
anemia
Toxicity limits use to life-threatening infections Can antagonize bactericidal Inhibits hepatic Can inhibit protein synthesis in
Gray baby syndrome (cyanosis) d/t
w/ no alternatives drugs like Penicillins & oxidases (CYP3A4 & mitochondrial ribosomesà BM
drug accumulation
Outside USà topical TXT of eye/ear infections aminoglycosides CYP2C9) toxicity
Mainly BacterioSTATIC against
Resistance mechanisms:
anaerobic/aerobic gram (+) & Bacteroides Pseudomembranous colitis d/t
-receptor site mutation
Usesà abscess, abdominal infections; skin & Reversible binding of Oral or IV superinfection w/ C. difficile (most
-receptor modification
soft tissue infections d/t Strep, Staph & some 50S subunit→ inhibition of likely)àpotentially fatal
-enzymatic inactivation
Clindamycin MRSA; prophylaxis of endocarditis in PCN transpeptidation, Good penetration
allergic pts translocation & chain including abscesses GI irritation- diarrhea & vomiting
Cross resistance w/ macrolides
Combo TXTà alternative for PCP w/ elongation and bones Skin rashes
Most gram (-) aerobes &
Primaquine; alternative for toxoplasmosis w/ Neutropenia and impaired liver fxn
enterococcià intrinsically resistant
pyrimethamine
BacterioSTATIC (-cidal against Strep & C. Resistance mechanisms:
Well tolerated for short adminà GI,
perfringens) against gram (+) (Staph, Strep, 100% bioavailability -¯binding to target site d/t mutation
Binds to 23S rRNA of 50S nausea, diarrhea, HA, rash
enterococci, Cornybacterium, Listeria, TB) w/ oral & IV No cross-resistance d/t unique site
Linezolid subunità inhibits formation Long termà reversible
Weak reversible MAO
of 70S initiation complex myelosuppression, optic/peripheral
Usesà MDR infections (VRE, nosocomial enters CSF inhibitoràcan interact w/
neuropathy & lactic acidosis
PNA…) adrenergic/serotonergic drugs
Narrow spectrum macrocyclic Abx: Gram (+)
GI complaints
aerobes & anaerobes only, especially Clostridia Binds and inhibits sigma Oral→ negligible Also helps prevent recurrence of C.
Fidaxomicin subunit of RNA polymerase systemic absorp. w/ diff, so it may actually be more cost
Safety/effectiveness not established
Usesà C. Diff colitis in adults (metronidazole or ­fecal conc. effective
in patients under 18
oral Vancomycin first)
Most gram (+) cocci, including MRSA and most
Strep, but NOT enterococci Monoxycarbolic acid Abx Local & dermatologic effectsà
Mupirocin Intranasalà MRSA eradication in nose binds to isoleucyl transfer- Topical/nasalàMRSA burning, edema, tenderness, dry Long term useà resistance
Topicalà impetigo or 2°infected traumatic skin RNA synthetase skin, pruritus
lesions d/t S. aureus or S. pyogenes

Fernanda Ponce pg. 25

 Antimicrobials- Drugs that affect Nucleic Acid Synthesis
Class Drug Indication MOA PK/PD AE Other
GI distress, peripheral neuropathy, Resistance emerges
1st gen: 1st gen→ ­gram (-) activity
Broad spectrum Rash, Photosensitivity, CNS effects rapidly in 2nd
Nalidixic acid 4th gen→­gram (+) activity; broadest
Bactericidal generation (esp. C.
(Quinolone) w/ ­activity for atypical PNA agents Good oral bioavailability
Black Box Warning: CT problems jejuni, gonococci,
2nd gen: 2nd genàis synergistic with β-lactams
Only class that are direct esp. tendon rupture→ Gram (+) cocci,
3rd genà is good against S.
Fluoroquinolones

Ciprofloxacin Well distributed into all

inhibitors of bacterial DNA contraindicated in pregnant or Pseudomonas &
3rd gen: pneumoniae, some enterococci, MRSA tissues including
synthesis nursing mothers, <age 18 (d/t AE of Serratia)
Levofloxacin Clinical: bones/cartilage
Arthropathy + erosion of CT except
4th gen: 1st→ Uncomplicated UTI’s (only
Enter bacteria via porins→ if benefits outweigh risks)) D/t chromosomal
Moxifloxacin achieve therapeutic concentration in multivalent cations (Fe, Zn,
inhibit DNA replication via mutation:
Gemifloxacin the urine) Ca) interfere with
interference with QT prolongation→ 3rd & 4th gen -in DNA gyrase
2nd→ Traveler’s diarrhea (ETEC) absorption→ similar to
rd th topoisomerase II (DNA subunits (gonococci)
3 & 4 gen→ have P. aeruginosa in CF pts (even children); tetracyclinesàdon’t take
gyrase) & IV High risk of superinfection w/ C. diff, and topo IV
enhanced activity alternate to Meningitis prophylaxis with milk or antacids
C. Albicans, and Strep -expression of efflux
against S. 3rd→ Prostatitis (E. coli)– not PCN
Resp. quinolones (3rd & 4th pumps (S. aureus, S.
pneumoniae, H. STI’s, except syphilis Adjust dose in renal
gen) used as 2nd line for Theophylline, NSAIDS, and pneumo, M.
influenzae, M. Acute sinusitis, chronic bronchitis, TB dysfunction, except
outpatient or 1st line for corticosteroids enhance toxicity Tuberculosis)
Cararrhalis & other Commonly used to txt Community moxifloxacin
inpatients or in the
atypical intracellular acquired PNA (CAP)
presence of comorbidities 3rd & 4th gen→ ↑warfarin, caffeine Cross resistance is
pathogens 4th→ CAP (used as monotherapy)
& cyclosporine levels prevalent
GI distress Fever, rash
Structural analogs of Oral or topical
Bacteriostatic against gram (+) and photosensitivity, etc. Resistance d/t plasmid
PABAà first precursor in Can accumulate in renal
Sulfonamides

gram (-); poor against anaerobes

Resistance when used alone, so it is
Sulfamethoxazole
mostly used in triple combo therapy
Sulfadiazine
Sulfasalazine
Topicalà ocular, burn infections
Oral→ simple UTI
Sulfasalazine→ Inflammatory bowel
disease (UC or Crohn’s), enteritis
bacterial folate synthesis
Competitive inhibition of
dihydropteroate synthase
→ ↓bacterial folic acid
synthesis
PABA→ DHF→ THF→
purines→ DNA
failureàalter dose
Hypersensitivity (Partially cross- transfers & random
allergenic) mutations:
Crystalluria (nephrotoxicity) -altered drug affinity
Acetylated in liver→
Hematopoietic disturbance, esp. for enzyme
precipitates at neutral or
with ↓G6PDàhemolytic/aplastic -↓cell permeability
acidic pH→ kidney damage
anemia, thrombocytopenia, etc. -enhanced PABA
Kernicterus→ contraindicated in production
Warfarin, phenytoin, and
infants & newborn <2monsà -↓intracellular
MTX can increase plasma
competes with bilirubin to bind accumulation
levels
albumin

Similar to Sulfa drugs, but 10-50x more

Structurally similar to folic Anti-folate effects→ megaloblastic
potent Mostly excreted unchanged Resistance d/t
acid anemia, leukopenia (treat with
Bacteriostatic against gram (+) and via kidney -↓cell permeability
leucovorin aka folic acid)à
Trimethoprim gram (-) -­DHF reductase
Inhibits DHF reductase→ Contraindicated in pregnancy
Reaches high conc. in --↓binding d/t altered
↓purine, pyrimidine &
Usesà UTI’s, Bacterial prostatitis prostate/vaginal fluid DHF reductase
amino acid synthesis Rash, pruritus
(after Cipro), Bacterial Vaginitis

Bactericidal Combination of
DOC for prevention & TXT of PCP, trimethoprim and AE seen w/ sulfonamides AIDS pts have
Uncomplicated UTI’s, Nocardiosis sulfamethoxazole Usually oral, but can be IV Dermatologic (Steven-Johnson increased incidence of
Cotrimoxazole Alternate for Toxoplasmosis, syndrome) AEàfever rash,
(TMP-SMX) respiratory, ear and sinus infection (d/t Synergistic effects by Well distributed including GI issues leukopenia, and
H. influenza and M. Catarrhalis) inhibiting sequential steps CSF Hemolytic anemia diarrhea mostly
Backup drug for cholera, salmonella, in THF synthesis Contraindicated in pregnancy
Shigella, MRSA, Listeria

Fernanda Ponce pg. 26


Antimicrobials- Miscellaneous & Urinary Antiseptics
Class Drug Indication MOA PK/PD AE Other
Bactericidal against anaerobes
(Bacteroides & Clostridium) and
Oral, IV, Rectal, or GI, Stomatitis, Peripheral neuropathy
protozoa Antimicrobial, Amebicidal,
Topical (vaginal gel) with long term use
Antiprotozoal
DOC for C. diff infections,
Widely distributed HA, Dark urine, metallic taste
trichomoniasis, giardiasis, intestinal Forms cytotoxic products
including CSF/brain Leukopenia, dizziness & ataxia
amebiasis, and amebic hepatic under anaerobic
Metronidazole Opportunistic fungal infections
abscess conditions that interferes
Elimination via Disulfiram-like reactionàavoid
Anaerobic or mixed intraabdominal with nucleic acid synthesis
hepatic metabolism- alcohol
infections (reductive bioactivation of
à may accumulate
Vaginitis (trichomonas, bacterial its nitro group by
in hepatic Avoid in 1st trimester pregnancy→
vaginosis, Gardnerella vaginalis) ferredoxin)
insufficiency unknown safety
Brain abscess
Part of triple therapy for H. pylori
Anorexia, Nausea/vomiting
Gram (+) and gram (-) Bacteriostatic &
Neuropathy & Hemolytic anemia in Antibacterial activity in urine
Antiseptic

Bactericidal
Rapid elimination → pts w/ ↓G6PD but little/no systemic effect
Urinary

(Pseudomonas & many strains of

therapeutic levels
Nitrofurantoin proteus are resistant) Reduced by bacteria in
are only found in Contraindicated in pts with Slow emergence of resistance
urine→ reactive
urine significant renal insufficiency, and no cross resistance
Use is limited to prophylaxis & TXT of intermediates that
pregnancy (38-42wks) and infants (<1
lower UTI’s damage bacterial DNA
mon)

Fernanda Ponce pg. 27

 Clinical Use of Antimicrobials
Drugs for Gram (-) Bugs Drugs for Gram (+) Bugs Aerobic Only Bactericidal Drugs Renal Elimination Hepatic Elimination
Aztreonam, Aminoglycosides Aminoglycosides, b-lactams, Chloramphenicol
Fluoroquinolones, Aminoglycosides
Penicillin G/V, Anti-Staph Anaerobic Only Clindamycin
Anti-pseudomonas Penicillins Metronidazole, Vancomycin, Most cephalosporins
Penicillins, 1st generation Erythromycin
Aztreonam Metronidazole, Clindamycin Streptogramins Fluoroquinolones
Cephalosporins, Vancomycin, Clarithromycin
2nd generation Cephalosporins Penicillins
Daptomycin, Bacitracin, Aerobic and Anaerobic Bacteriostatic Drugs Nafcillin
3rd generation Cephalosporins Sulfonamides
Streptogramins, Penicillin G/V, Carbapenems, Metronidazole
Aminoglycosides Clindamycin, Macrolides, Tetracyclines [doxy = bile]
Aminoglycosides, Clindamycin, Cephalosporins,
Clindamycin Sulfonamides, Tetracyclines, TMP-SMX
Linezolid Tetracyclines, Glycylcyclines, Moxifloxacin (partly + biliary)
Trimethoprim Vancomycin
Chloramphenicol, Quinolones
Effects on Fetus and Neonate Nonsurgical Prophylaxis Surgical Prophylaxis C. Difficile Colitis
When procedure Most common cause:
Aminoglycosides→ damage to 8th cranial nerve of fetus
is associated with Clindamycin, Ampicillin,
Tetracyclines and Glycylcyclines→ tooth enamel dysplasia and
Prevention of CMV, HIV, > 50% infection in Amoxicillin, Cephalosporins,
inhibition of bone growth
influenza, meningococcemia untreated cases Fluoroquinolones
Sulfonamides→ kernicterus (displace bilirubin from albumin)
and TB infections (GI,
Chloramphenicol→ Gray baby syndrome (aplastic anemia)
Hysterectomy, C- Treatment:
Fluoroquinolones→ tendon rupture/damage
Animal or human bite wounds section, Joint Oral Metronidazole = DOC
Nitrofurantoin→ hemolytic anemia
Chronic bronchitis replacement, Oral Vancomycin
Trimethoprim→ folate deficiency
Open fracture Fidaxomicin(↓recurrence)
Metronidazoleà unknown safety
surgery) Fecal microbiota transplant
Treatment of MDR infections Bacterial Meningitis in Adults Community Acquired Pneumonia
Prophylaxis: Most often caused by S. pneumoniae
Anti-staph PCNs→ β-lactamase producing gram (+) Rifampin Atypical pathogens include: Mycoplasma, Legionella, Chlamydia
Carbapenems→ β-lactamase producing gram (+) & gram (-) Ciprofloxacin Empiric Therapy:
Aztreonam→ β-lactamase producing gram (-) Ceftriaxone For a previously healthy pt. w/o antimicrobial use in past 3m→
Vancomycin→ MRSA and enterococci
Macrolide or Doxycycline
Daptomycin→ MRSA, enterococci and VRE
Presence of comorbidities, recent use of antimicrobial or
Tigecycline→ MDR gram (+) and some gram (-)
immunosuppressed→ Resp. fluoroquinolone or β-lactam + macrolide
Streptogramins→ MRSA and VRE
Inpatient, non-ICU→ Resp. fluoroquinolone or β-lactam + macrolide
Linezolid→ MRSA and VRE
Inpatient, ICUà β-lactam + azithromycin or resp. fluoroquinolone
Rifampin→ MRSA
Inpatient allergic to PCNàResp. fluoroquinolone + Aztreonam
Infective Endocarditis (IE) Endocarditis Prophylaxis Syphilis and UTI’s in pregnancy
In order to get IE→ abnormal valve + bacteremia
Can be diagnosed with cultures, echo and clinical symptoms Most common during dental or respiratory procedures DOC for syphilis no matter what the stageà PCN G
Most often caused by Staph and Strep (esp. Viridans) -the only drug with documented efficacy during pregnancy
Standard: Oral amoxicillin
Empiric treatment should only be started after 3 separate cultures PCN allergy (Oral drugs): Clindamycin, cefazolin or macrolide Pregnant w/ PCN allergyà undergo desensitization
have been obtained and you are waiting for the results:
Native valve (S. Viridans or S. Bovis) →PCN G or ceftriaxone + IV or IM meds: Ampicillin May develop a Jarisch-Herxheimer reaction→ fever, chills,
gentamicin -PCN allergyà Clindamycin or cefazolin myalgia, tachycardia…
- MRSA or allergyà Vancomycin or ceftriaxone + gentamicin -It is not an allergic reaction and the drug should be continued
-If MIC is high (>0.5µg)à ampicillin or Vancomycin + gentamicin (Pretreatment with prednisolone may help)
Native valve (Staph)→ Nafcillin or oxacillin
-If they have a PCN allergyàcefazolin UTI TXT (E. coli) → Cotrimoxazole, Ciprofloxacin, Nitrofurantoin,
-If resistantàvancomycin
Prosthetic valve→ Vancomycin + gentamicin +/- rifampin
ItalicsàNOT MENTIONED IN OUR or Amoxicillin + clavulanic acid
Pregnant and have UTI → PCN or cephalosporins (however,
-If resistant to Vancomycin→ Linezolid or Daptomycin + gentamicin NOTES ceftriaxone can cause kernicterus) or nitrofurantoin
+/- rifampin

Fernanda Ponce pg. 28

 Pathogen DOC Alternate Pathogen DOC Alternate
Anaerobe b-lactam + b-lactamase rd PCN G, chloramphenicol,
N. meningitides 3 gen. cephalosporin
(aspiration) inhibitor; clindamycin fluoroquinolone
Actinomyces Penicillin Nocardia TMP-SMX
Cephalosporins, TMP-SMX,
Clindamycin, carbapenems,
b-Lactamase-I,
Bacteroides Metronidazole penicillins + b-Lactamase-I, Proteus Ampicillin
aminoglycosides,
chloramphenicol
fluoroquinolone
Anti-pseudomonal b-
Bordetella Pertussis Macrolide TMP-SMX Pseudomonas Levofloxacin, aminoglycosides

Antimicrobial Therapy by Pathogen

Lactam + ciprofloxacin
Chloramphenicol,
Campylobacter Azithromycin Erythromycin, ciprofloxacin Rickettsia Doxycycline
fluoroquinolones
Azithromycin, erythromycin, Ceftriaxone, Chloramphenicol, TMP-SMX,
Chancroid Salmonella
ceftriaxone, ciprofloxacin fluoroquinolone ampicillin
Aminoglycosides + anti-
C. trachomatis Macrolide, doxycycline Serratia Fluoroquinolone
pseudomonal b-Lactam
C. difficile Metronidazole Vancomycin, Fidaxomicin Shigella Ampicillin, TMP-SMX Fluoroquinolone, ceftriaxone
Treponema
Clostridium Penicillin +/- Clindamycin Cephalosporins, doxycycline Benzathine PCN G Doxycycline (PCN allergic pt.)
Pallidum
Aminoglycoside, TMP-SMX,
Enterobacter spp. Carbapenem, Cefepime Trichomoniasis Metronidazole
fluoroquinolone
Ampicillin +/- gentamicin, Linezolid, Daptomycin,
Enterococcus spp. Tularemia Streptomycin Gentamicin, chloramphenicol
vancomycin +/- gentamicin streptogramins
Cephalosporins, Penicillins +/- b-Lactamase-I,
E. coli Yersinia Streptomycin Doxycycline
fluoroquinolones TMP-SMX, aminoglycosides
Cephalosporin, clindamycin,
S. Pneumo
G. Vaginalis Metronidazole Clindamycin PCN G, amoxicillin fluoroquinolone, macrolide,
PCN-susceptible
TMP-SMX
H. Influenzae (otitis, 2nd/3rd gen. Cephalosporin, PCN-resistant 3rd gen cephalosporin, Vancomycin, linezolid,
Amoxicillin
sinusitis, etc.) amoxicillin-clavulanic acid (PRSP) fluoroquinolone streptogramins
S. Aureus/
H. Influenzae
Ampicillin-sulbactam, Epidermis Anti-staph PCN (Nafcillin, Cephalosporin, clindamycin,
(meningitis, Ceftriaxone, cefotaxime
Meropenem Methicillin- oxacillin, Dicloxacillin) fluoroquinolone, imipenem
epiglottitis)
susceptible
Daptomycin, doxycycline,
Methicillin-
Klebsiella Ceftriaxone, cefotaxime Fluoroquinolones Vancomycin, linezolid fluoroquinolone,
resistant
streptogramins
Legionella Fluoroquinolones, macrolide TMP-SMX, doxycycline Brucella Doxycycline + macrolide
Listeria Ampicillin +/- gentamicin TMP-SMX
Amoxicillin-clavulanic acid,
M. Catarrhalis 2nd/3rd gen. Cephalosporin, Azithromycin, Clarithromycin
TMP-SMX
M. pneumoniae Macrolide, tetracycline Resp. fluoroquinolone
N. Gonorrhoeae (+ Ceftriaxone + azithromycin,
Azithromycin, doxycycline
chlamydia) doxycycline

Fernanda Ponce pg. 29

 Antimycobacterial Drugs
® Mycobacteria (intracellular) are intrinsically resistant to most Abx (Resistance quickly develops)
® Initial phase of 3-4 combo drug regimen is 8 weeks followed by continuation of 18 week
® Therapy can take mon-yrs b/c of slow division and combinations of drugs are often required
® The goal of therapy is to kill the bacilli, prevent emergence of drug resistance, and
® MTB is a small aerobic non-motile bacillus that divides every 16-20h
eliminate persistent bacilli from host to prevent relapse→ multiple drugs for a long time
® Latent TB prophylaxis is for patients who have been recently exposed or immunocompromisedàcan
® Direct observed therapy (DOT) may be needed in non-compliant patients/resistant strains
be treated with a single drug as opposed to combo therapy
® 1st line combination therapyà pyrazinamide + isoniazid + rifampin + ethambutol
® All1st line drugs are safe in pregnancy, but 2nd line are all teratogenic
Class Drug Indication MOA PK/PD AE Other
Oral, IV, IM
Synthetic analog of pyridoxineà
Most potent anti-TB drug part of supplement B6 CYP450 inhibition Peripheral neuritis (corrected Resistance→ chromosomal
combo therapy by pyridoxine (B6) mutations resulting in:
Sole drug for latent infection à6-9 Prodrug activated by KatG Diffuses into all body supplementation) - deletion of KatG
mon (Use rifampin for INH intolerant (Mycobacterial catalase-peroxidase) fluids, cells and Hepatoxicity -mutated binding sites on
Isoniazid (INH)
pts) Target enzymes InhA/AcpM (enoyl caseous material Lupus like syndrome acyl carrier proteins
Bacteriostatic against stationary phase acyl carrier protein reductase) & KasA -overexpression of InhA
of TB (b-ketoacyl-ACP synthase) are Metabolized in liver via Safe in pregnancy but ­risk of
Bactericidal against rapidly dividing TB blocked→ ↓mycolic acid synthesis→ acetylation or genetics- Hepàgive B6 NO cross-resistance
↓cell wall synthesis careful w/ fast/slow-
acetylators
First Line Agents

Part of combo therapy Oral and parenteral

Bactericidal against intracellular & Well distributed
Light chain proteinuria
extracellular mycobacteria: MTB and Prototype including CSF Resistant strains emerge
GI distress
M. Kansasii; Gram (+) and gram (-) rapidly→
Rifamycins

Orange body fluids

Rifampin including MRSA Binds to the β subunit of bacterial DNA Undergo enterohepatic - point mutation in the rpoB
dependent RNA polymerase→ ↓RNA
Thrombocytopenia, rash,
UsesàTB, latent TB (4mon) in INH cycling & both parent geneà¯affinity the β subunit
nephritis, liver dysfunction
intolerant pts, leprosy, meningitis synthesisà block transcription drug + metabolites are -↓permeability
prophylaxis, MRSA/PRSP (with excreted in feces
Vancomycin) CYP450 inducer
Part of combo therapy Rifampin substitute to those that are Not enough data to
Rifabutin
DOC in HIV pts d/t less CYP450 effects intolerant recommend use in pregnancy
Dose dependent visual disturbance→ red/green
Part of combo therapy Inhibits arabinosyl transferase
colorblindnessàdon’t use in kids too young to receive emb gene mutations→ rapid
Ethambutol MTB and M. Kansasii encoded by emb gene (involved in cell
sight tests resistance if used alone
Usesà all forms of TB wall synthesis)
HA, confusion, hyperuricemia, neuritis
Well absorbed orally &
Non-gouty polyarthralgia,
well distributed
Part of combo therapy Enzymatically hydrolyzed to active Hyperuricemia→ acute gouty Resistant strains:
(including CSF)
Pyrazinamide Recommended use in pregnancy when pyrazinoic acidà lower pH of the arthritis, hepatotoxicity, -lack pyrazinamidase
Adjust dose in BOTH
benefits>risks (Category C) environment myalgia, porphyria, rash, - have increased efflux
renal/ hepatic
photosensitivity
insufficiency
TXT of life-threatening disease→ Aminoglycoside used for drug resistant Limited use due to increasing
Streptomycin
meningitis, miliary, or severe organ TB strains resistance
2nd Line

Teratogenic; severe GI,

When treating resistant
Ethionamide Congener of INH (no cross resistance) neurologic & endocrine
strains, fluoroquinolones are
effects; hepatotoxicity
often added to strengthen
Levofloxacin Used in combo when infection is resistant to first line drugs Teratogenic & pts <18 y.o
treatment (up to two years)
Amikacin Used for streptomycin resistant or MDR strains Teratogenic

Fernanda Ponce pg. 30

 Antimycobacterial Drugs Against M. Leprae and M. Lepromatis
® Leprosy (aka Hansen’s disease)- Primarily a granulomatous disease of peripheral nerved
® 3 drugs used in combination: Dapsone, Clofazimine and Rifampin
and mucosa of URT
Class Drug Indication MOA PK/PD AE
Well absorbed and distributed
High levels in skin Hemolysis (esp. in ↓G6PD)
Sulfa related Bacteriostatic agent to
Inhibits dihydropteroate synthetase → Erythema nodosum leprosum (TXT→ steroid)
Dapsone TXTà Leprosy
↓folic acid synthesis Acedapsone-repository CYP450 inhibitor
Pneumonia d/t P. jiroveci (PCP) in HIV+
formàinhibitory plasma GI, fever, hepatitis, methemoglobinemia
concentrations for several months
Phenazine dye that binds DNA inhibiting Red-brown skin discoloration (harmless)
Bactericidal against M. leprae
Clofazimine replication May generate ROS GI irritation, Eosinophilic enteritis
Some activity against MAC
Anti-inflammatory action Does NOT produce erythema nodosum
+ Dapsone for pauci-bacillary skin lesion (1-5 lesions) for 6mon
Rifampin
+ Dapsone and Clofazimine for multi-bacillary skin lesions (>5 lesions) for 12mon
Drugs Active against Atypical Mycobacteria
® Present in environment but communicable from person to person ® Susceptible to different TB drugs; combination therapy required d/t resistance
Species Features Treatment
M. Kansasii Resembles TB INH + rifampin + ethambutol
M. marinum Granulomatous cutaneous disease 2 drug combo: Rifampin, ethambutol, clarithromycin, minocycline, doxycycline and sulfonamides
M. avium complex (MAC) Pulmonary disease Clarithromycin + ethambutol +/- rifampin
M. chelonae Abscess, sinus tract ulcer; Bone, joint or tendon infection Clarithromycin (monotherapy is usually successful)
M. fortuitum Abscess, sinus tract ulcer; Bone, joint or tendon infection Amikacin, Cefoxitin, levofloxacin, sulfonamides, imipenem

Fernanda Ponce pg. 31

 Antivirals
Drug Class Description MOA Indication PK/PD AE Other
Prophylaxis (started w/i Oral prodrug Nausea, vomit,
Influenza A & B
48hrs of onset) hydrolyzed in the liver/ diarrhea, abdom. AE alleviated when
Oseltamivir
Modest effect on SXS Analog/inhibitor of sialic acid gut pain, insomnia, taken w/ food
Oseltamivir: kids
Neuraminidase when given 24hrs after substrate (viral Renal excretion vertigo
>1yr and adults
Inhibitors exposure neuraminidase)à inhibit Inhaled/intranasal
Respiratory Infections

viral release and spread Absorbed excreted in Airway irritation Avoid in severe
Zanamivir Zanamivirà kids
Resistant strains to urine; Unabsorbed in HA, GI sxs asthma, COPD
>7yrs and adults
influenza A reported feces
Influenza A only
Uncoating Inhibitors used Oral
(current strains are GI effects
as prophylaxis and + Amantadine: crosses Monitor
Block viral M2 protein (H resistant) Amantadine: CNS
treatment BBB; Renal excretion & Amantadine in
channels) needed for fusion Highly resistant d/t effects (seizure,
Amantadine Ion Channel may accumulate psych pts, epilepsy,
with the cell membrane a.a. substitution in insomnia, etc.)
Rimantadine Blockers 50% of pts are naturally Rimantadine: renal impairment &
(required for viral uncoating M2 protein seen
resistant Extensive hepatic cerebral
and nucleocapsid release) w/i 2-4 day→ no Pregnant/nursing
Cross resistance b/w drugs metabolism before atherosclerosis
longer 1st line Category C
occur elimination in urine
treatment
Oral, IV, aerosol
Active against both RNA & Competitively inhibits GTP Dose dependent Negative pregnancy
RSV (in kids) Persists in RBCs (16-40
DNA viruses formation & prevents viral transient anemia test is required
Synthetic HCV (combo w/ days)
mRNA cappingàInhibits (binds to RBCs) before TXT and
Ribavirin Guanosine IFNa)
use 2 forms of RNA-dependent RNA- ­bilirubin monthly during for
Analog Lassa fever Pregnancy (Category
contraception to avoid polymerase→ ↓viral protein Nausea, anorexia, female pts or female
X) and pts w/ Hx of
pregnancy synthesis fatigue, HA, insomnia partners of male pts
psych disorders

HBV (pts >1y.o)
HCV (combo w/ Parenteral Toxic accumulation
Inhibits RNA and DNA
Ribavirin) Metab by liver & Fever/chills (flu-like) of theophylline may
Innate immune response synthesis by activating host
Condyloma kidney Fatigue occur
IFNa Interferon Does not target viral gene cell ribonuclease that
Acuminata Mental depressionà May potentiate
products directly degrades viral mRNA to
Hairy Cell PEGylated to improve txt w/ SSRIs Zidovudine induce
↓infection
Leukemia PK myelosuppression
Hepatic Infections

Kaposi’s Sarcoma
Triphosphate from: Inhibits
Must be phosphorylated to HBV-RT & HIV-RT Well tolerated- HA, GI
HBV Limited use d/t
Lamivudine active (triphosphate) form Monophosphate form: Chain complaints, dizziness
HIV resistance
by cellular kinases termination via incorporation Lactic acidosis
into DNA by HBV polymerase
Nucleotide/ Lamivudine: cytosine Competes with natural
Nucleoside analog substrates→ Inhibits HBV
Analog Entecavir: guanosine DNA polymeraseà ¯priming May exacerbate
Lamivudine Avoid drugs with
analog of HBV DNA pol, severe hepatitis
Entecavir resistant strains of renal toxicity
¯transcription of (-) strand after
HBV and HIV Lactic acidosis
Actions are suppressive from mRNA, ¯synthesis of discontinuation
rather than curative (+) HBV DNAà inhibit HBV
RT
Reversible binding to non-
Fatigue, anemia Telaprevir
Boceprevir Protease Used in adults who failed structural protein 3 (NS3) HCV (with IFN & Oral
Nausea, HA, associated w/ mild-
Telaprevir Inhibitors TXT with IFN or ribavirin serine protease & ribavirin) Metabolized by liver
Dysgeusia severe rashes

↓replication

Fernanda Ponce pg. 32


Drug Class Description
Prototype
Synthetic Guanosine analog
Acyclovir Commonly used for genital
herpes infections &
prophylactically in the
immunocompromised
Valacyclovir Prodrug of acyclovir
Analog of acyclovir with
Ganciclovir
­activity against CMV
Herpes Infections
Antivirals Continued
MOA Indication PK/PD AE Other
CMV is resistant →
3 phosphorylation
altered/deficient
steps by thymidine Topical→ local
thymidine kinase
HSV1 & 2 kinase for activation irritation
Competes with dGTP→
VZV Oral→ HA, N/V/D
causes chain termination Cross resistance to other
EBV (HSV4) Accumulates in renal IV → acute renal
and inhibits viral DNA “cyclovirs” via:
failure failureà minimize
polymerase -altered/¯thymidine
IV-DOC for HSV encephalitis with slow infusion
kinase
Greater oral and prior hydration
-altered DNA pol w/
bioavailability
¯affinity for drug
Must be phosphorylated iV Resistance:
DOC for CMV retinitis and Myelosuppression
by viral (UL97 kinase) Excreted in urine -↓phosphorylation
CMV prophylaxis in Dose Dependent
and other cell kinases (UL97)
immunocompromised Neutropenia

DNA chain termination Oralàrapid hydrolysis -mutations in

Valganciclovir Purine/ Prodrug of ganciclovir Contraindicated in
DNA polymerase in intestine and liver phosphotransferase or
Pyrimidine Herpes simplex keratitis pregnancy [Cat. C]
inhibitor viral DNA pol (UL54)
Analogs
Not phosphorylated by viral HSV IV, intravitreal, topical Nephrotoxicity- may
DNA chain terminator
kinases Ganciclovir resistant HSV Must co-admin. w/ be reduced by Resistance d/t mutations
Cidofovir DNA polymerase
Requires activation by host probenecid (blocks hydration & in viral DNA polymerase
inhibitor
cell kinases TXTs CMV retinitis in HIV+ tubular secretion) probenecid
Monophosphorylated by
Acyclic guanine
viral thymidine kinase
Active formà triphosphate HSV1 & 2 Low occurrence of clinical
Penciclovir DNA chain termination Topical Mild erythema
form VZV resistance
DNA polymerase
TXT of cold sores
inhibitor

HSV1 & 2
Ophthalmic ointment Irritation of eye
Thymidine analog that Triphosphate form Vaccina virus
(too toxic for systemic Palpebral eyelid
Trifluridine inhibits thymidylate incorporated into DNA DOC: HSV keratoconjunctivitis
use) edema
synthetase causing fragmentation in immunocompromised and
t½ = 12 min Light intolerance
recurrent epithelial keratitis
Electrolyte
CMV retinitis in
Analog of disturbance (Ca,
immunocompromised
Does NOT require pyrophosphate → Mg, K, PO4)
Acyclovir resistant HSV & Resistance d/t point
Foscarnet phosphorylation to be selectively inhibits IV only Anemia, CNS
CMV Retinitis mutations in polymerase
active!!! binding site on viral DNA effects, genital
Ganciclovir resistant CMV &
polymerase ulcers
VZV
Nephrotoxic

Fernanda Ponce pg. 33

 Antiretroviral Drugs
® HIV is a retrovirus that infects CD4+ T-cells ® Diagnosis: Ab or Ag testing (usually w/i few weeks of infection), ELISA, western blot, new
® Transmission: contact w/ body fluids (blood, semen, vaginal secretions, breast milk etc.), rapid tests (<30min) on blood/saliva
transplacental or perinatal ® Therapy is usually initiated when CD4+ <500 or in the following conditions: pregnancy, Hx of
® RNA dependent DNA polymerase = Reverse transcriptase AIDS defining illness, HIV associated nephropathy or HIV/Hep B co-infection
MOA Resistance PK/PD Adverse Effects
Analogs of native ribosides that lack a Emerges rapidly if used alone Dose needs to be adjusted in Inhibition of mitochondrial DNA polymerase→ peripheral
3’OH→ terminates DNA elongation Most common is a mutation at viral codon renal insufficiency neuropathy, myopathy, lipoatrophy and lactic acidosis
(i.e. competitive inhibition of RT) 184 (Didanosine and Stavudine are the worst; don’t give initially)
Nucleoside/tide Reverse Transcriptase Inhibitors (NRTIs)

Cross resistance more likely in drugs w/ Usually not metabolized by Pancreatitis

Must be phosphorylated by cellular similar structures (i.e. b/w same analogs) CYP Myelosuppression→ especially Zidovudine
enzymes & incorporated into DNA by RT When resistance to lamivudine develops, pts Cardiomyopathy
usually have sensitivity to zidovudine and Tenofovir→ ↑didanosine Liver toxicity is rare but fatal
Most have activity against HIV1 and HIV2 tenofovir restored levels Dyslipidemia & insulin resistanceà esp. Zidovudine & Stavudine
Drug Description PK/PD AE/ Contraindications
Bone marrow suppression (neutropenia, anemia), GI intolerance, HA, insomnia, hepatitis,
Oral diabetes
Zidovudine Penetrates well across BBB Concurrent use w/ Gancicloviràadditive neutropeniaà don’t do it
Thymidine Analog
(ZDV, AZT) Dose adjustment in pts w/ Toxicity potentiated by: probenecid, acetaminophen, lorazepam, indomethacin,
cirrhosis cimetidine
Stavudine & ribavirin may ¯blood levels d/t activation by same pathway
Thymidine analog
Peripheral neuropathy and fatal lactic acidosis
Stavudine
Oral Hyperlipidemia, neuromuscular weakness, ­aminotransferase levels, diabetes, pancreatitis
(d4T) Strong inhibitor of mitochondrial b and g DNA
Avoid concurrent use with neuropathic drugs
polymeraseàmay lead to toxicity

Adenosine analog Acid labile→ best when taken Pancreatitisàesp. in alcoholics and pts with hypertriglyceridemia
Didanosine in fasting state or with an CNS effects, insulin resistance, retinal changes, optic neuritis, diarrhea, hepatic dysfunction
(DDL) Strong inhibitor of mitochondrial DNA antacid & peripheral neuropathy
polymerase Penetrates BBB/CSF Avoid concurrent use with Tenofovir
Take with food to ↑
Adenosine analog
bioavailability GI adverse effects (N/V/D, flatulence), renal toxicity, ¯bone density & osteomalasia
Tenofovir
Long t1/2→ once daily dosing Significant drug interactions→ ­didanosine (associate w/ ¯CD4+) and ¯atazanavir
(TDF) Preferred NRTI in current regimens
Monitor creatinine in renal concentration (boost w/ ritonavir) as well as ­conc. of some PIs
Fixed combos: emtricitabine +/- efavirenz
insufficiency
Cytosine analog
Few adverse effects → may cause HA or dry mouth
Lamivudine
(3TC) NO effect on mitochondrial DNA synthesis or
High levels of resistance with a single AA substitution
BM precursors
Cytosine analog
Emtricitabine
Once a day dosing Hyperpigmentation of palms and solesàmore frequent in dark skinned individuals
(FTC) structural relative of lamivudine
Preferred NRTI in current regimens
Guanosine analog
Hypersensitivity reaction→ sensitized individuals should never be rechallenged
Abacavir
GI distress, HA, dizziness
(ABC) Several mutations required for resistance→
Avoid alcohol
slow to develop

Fernanda Ponce pg. 34

 Antiretroviral Drugs Continued
MOA Advantages Disadvantages Adverse Effects
Lack of effect on host forming blood -Cross resistance with NNRTI’s
Non-Nucleoside/tide Reverse Transcriptase

Highly selective, noncompetitive inhibitors -Skin rash w/I 4 weeks of initial therapy
elements -Many drug interactions
of HIV-1 reverse transcriptase -GI effect, fat accumulation after long term use
- More susceptible to high-level drug
All NNRTI’s bind at same allosteric site -Steven Johnson syndrome: fatal skin rash
Lack of cross resistance with NRTI’s d/t resistance d/t single a.a change in
Inhibition of RNA- & DNA-dependent DNA polymerase -All are metabolized by CYP3A4 but can act as
distinct binding sites NNRTI binding pocket
DO NOT require phosphorylation by cellular enzymes either inhibitors or inducers or both
-High incidence of HSN reactions
Inhibitors (NNRTIs)

Drug Description PK/PD AE/ Contraindications

Induces CYP3A4 and CYP2B6- Severe (fatal) hepatotoxicity→ don’t use in women w/ CD4> 250 or men w/ CD4> 400
­metabolism of PIs (no dose Rash→ titrate at ½ dose for 14 days to ¯ risk of serious epidermal reactions
Nevirapine Metabolized by CYP3A4 and CYP2B6 then
adjustment needed), BC, Steven Johnson syndrome
(NVP) excreted in the urine
ketoconazole, methadone, Mutations and resistance can develop rapidly because the target site is specific and non-
quinidine, theophylline & warfarin essential for the enzyme
Oral with a long half-life→ once a day
Not 1ST line agent→ results in ­CNS effects: vivid dreams, ¯conc., depression (possible association w/ suicide)
dosing
Efavirenz increased CD4 count & ↓viral load Rash, Steven Johnson syndrome
(EFV) ­TAG, ­HDL, ­cholesterol (monitor lipid levels before and during therapy)
Extensively metabolized to inactive
Potent CYP3A4 and CYP2B6 inducer Pregnancy cat D→ neural tube defects; avoid in 1st trimester (can use after if best choice)
products
Oral Rash
Rilpivirine Extensively metabolized to inactive Insomnia, depression
products ­liver enzymes
MOA PK/PD Adverse Effects Indications/Resistance
-Poor oral bioavailabilityà affected by
Reversible competitive inhibitors of HIV aspartyl Inhibitor and substrate for CYP→
protease→ normally responsible for cleavage of
high fat meals (combine w/ PK enhancer -Paresthesia, nausea, vomiting, diarrhea
-Rhabdomyolysis with statins,
to improve bioavailabilityà allows for a -Hyperglycemia, insulin resistance,
polyprotein (gag and pol) into RT, protease and -Excessive sedation with midazolam
¯dose and ¯frequency) hyperlipidemia
integrase -Resp. depression with fentanyl
Prevents maturation of virus→ production of non-
-Substrate for CYP3A4 (except Nelfinavir) -Disturbance in CHO and lipid metabolism
Protease Inhibitors (PIs)

infectious virions Rifampin & St. John’s Wort→

& P-glycoproteinàmost require PK Redistribution of fat→ buffalo hump and
contraindicated
enhancer cushingoid appearance (lipodystrophy)
Do not require intracellular activation
-Bound to plasma proteins
High levels of resistance can occur after
Atazanavir has less AE than other PI’s
Active against both HIV1 and HIV2 stepwise accumulation of mutations
“Navir tease a protease”
Drug Description PK/PD AE/ Contraindications
Well absorbed w/ food ­PR interval, benign hyperbilirubinemia, rash, nephrolithiasis
Atanavir Given with Ritonavir (RTV)
Highly protein bound Admin. Must be > 12hrs apart from H2 blockers and antacids (may ¯absorption)
(ATV) Structurally unrelated to other PIs
Metabolized by and inhibits CYP3A4 Contraindicated w/ proton pump inhibitors
Darunavir Inhibits HIV protease resistant to other We absorbed w/ food
Rashà avoid in pts w/ sulfur allergy
(DRV) PIs Metabolized by and inhibits CYP3A4
Least protein bound
Indinavir Reduce dosage w/ hepatic insufficiency
Given with Ritonavir (RTV) ¯Absorption w/ meals
(IDV) Rash, blurred vision, nephrolithiasis & hyperbilirubinemia (pt. must stay hydrated)
inhibits CYP3A4
Avoid enzyme inducers (St. John’s Wort) & oral solutions w/ EtOH (disulfiram,
Lopinavir One of the preferred PIs Poor intrinsic bioavailability
metronidazole)
(LPVr) Given with Ritonavir (RTV) inhibits CYP3A4
Generally, well toleratedà diarrhea, nausea, flatulence, asthenia, pancreatitis, HA
Metabolized by CYP3A4 & CYP2C19 CYP inhibitor
Nelfinavir
Cannot be boosted by Ritonavir (RTV) Major metabolite (CYP2C19)àantiviral Diarrheaà control w/ Loperamide
(NFV)
activity equal to parent compound Nausea and flatulence

Fernanda Ponce pg. 35

 Antiretroviral Drugs Continued
Drug Description PK/PD AE/ Contraindications
Approved for use in TXT-experienced adults w/ evidence of HIV
Inhibitor

Injection site reactionsàpain, erythema, induration…

Fusion

replication (no activity against HIV2)

Enfuvirtide Parenteral admin only Hypersensitivity, eosinophilia, possible ­incidence of
Structurally similar to gp41à mediates membrane fusion
(T-20) bacterial pneumonia
Binds to gp41 on viral envelope preventing the virion from fusing
No interactions with other antiretroviral
with the cell membrane
Inhibitor

Metabolized by CYP3A4→ reduce dose Well tolerated but there is a risk of hepatotoxicity
Entry

Selective & specific binding to CCR5àblocks entry of CCR-5 tropic

Maraviroc when combined with PI’s
virus into the cell
Substrate for CYP3A4 & P-glycoprotein Pts must be screened for CCR-5 tropism before starting

Description MOA AE
Integrase Strand Inhibitors

Generally, well toleratedà rash, nausea, HA, diarrhea,

Used in combo w/ other antiretroviral
Most popular antiretroviral class currently d/t good side effect
profile and favorable effects on lipid metabolism
(INSTIs)
Bind integrase (needed for replication of HIV1 and
insomnia
HIV2)àspecific inhibition of final step in integration of viral
Rare: ­creatine phosphokinase, myopathy,
DNA into host cell DNA (insertion)
rhabdomyolysis and hypersensitivity

Drug PK/PD Drug Interactions AE

Primarily eliminated by glucoronidation via UGT1A1 Well tolerated (nausea, HA, diarrhea)
Dolutegravir Can occur d/t CYP3A integrations
+ some contribution from CYP3A4 Some reports of organ dysfxnàdiscontinue drug if so
Metabolized by CYP3A4
Elvitegravir Can occur d/t CYP3A integrations Well tolerated (nausea, HA, diarrhea)
May require PK enhancer (Cobicistat)
¯levels w/ Rifampin, Tipranavir Well tolerated (nausea, HA, diarrhea)
Raltegravir Primarily eliminated by glucoronidation via UGT1A1
­levels w/ PPIs Can cause ­creatine phosphokinase

Drug Description MOA
Enhancer

Ritonavir Protease Inhibitor used in fixed dose combo w/ other PIs except Nelfinavir
Potent inhibitors of CYP3A4
PK

(RTV) Never used alone

s

Ritonavir: ­plasma conc. of antiretrovirals (ARVs) allowing for ¯dosing

Used commonly in combo with the INSTI Elvitegravir
Cobicistat Cobicistat: no ARV activity of its own
Also used with Darunavir and Atazanavir
Current Recommendations
Combination Therapy/HAART d/t resistance Regimes:
Infant Born to HIV+ mother:
INSTI + 2 NRTI’s (used for most pts)
àZidovudine for 6 weeks given immediately after birth
Goalsà suppress viral load replication, restore/preserve à Raltegravir + tenofovir + emtricitabine
immune function, ¯HIV-related morbidity/mortality & improve à Dolutegravir + tenofovir + emtricitabine
Pregnant:
quality of life
Ritonavir + Lopinavir+ zidovudine or lamivudine
PI (+PK enhancer) + 2 NRTI’s
HIV infected patients should be vaccinated against (1° → Ritonavir boosted Darunavir + tenofovir + emtricitabine
Needle stick post exposure prophylaxis: start w/i 72hrs
prophylaxes): Hep A, Hep B, Influenza & S. pneumo
2 NRTI’s or if more severe exposure 2 NRTI’s + PI or NNRTI
Avoid 2 agents of same nucleotide analog
àRaltegravir + Tenofovir + emtricitabine
Live vaccines (MMR, Varicella and Herpes Zoster) are Avoid overlapping toxicity & genotypic/phenotypic
Given for 28 days or until pt. shows HIV- status
contraindicated when CD4< 200 characteristics of the virus

Fernanda Ponce pg. 36



Fernanda Ponce pg. 37

 Antiparasitic Drugs
Treatment of Amebiasis:
® Amebiasis (amebic dysentery)àintestinal tract infection caused by Entamoeba histolytic
Asymptomatic Intestinal Infection: Diloxanide Furoate(DOC); Altà Iodoquinol, Paromomycin
® Can be acute or chronic; symptomatic or latent
Mild-mod intestinal infection: Metronidazole + Diloxanide Furoate(DOC); Altà tetracycline,
® SXS range from mild diarrhea to fulminating dysentery
Tinidazole, or erythromycin + Diloxanide Furoate
® Life cycle completed by trophozoites returning to cyst form in the rectum and being
Severe Intestinal infection: Metronidazole or Tinidazole + Diloxanide Furoate(DOC); Altà
expelled in feces
tetracycline or emetine/Dehydroemetine + Diloxanide Furoate
® Goals of therapy: eliminate invading trophozoites & eradicate intestinal carriage of Hepatic Abscess & extraintestinal: Metronidazole or Tinidazole + Diloxanide Furoate(DOC);
organism Altà emetine/Dehydroemetine + chloroquine + Diloxanide Furoate
Drug Class MOA Clinical Use PK AE
-Oral
GI distress
DOC for invasive amebiasis in combination with a -Well distributed (body
Disulfiram like
luminal agent (Diloxanide Furoate) (alternative fluids & CSF)
Non-enzymatic reduction with reactionàavoid alcohol
treatment includes tetracycline, Tinidazole, or -Metabolized by CYP450 via
reduced ferredoxinàcytotoxic Metallic taste
Metronidazole erythromycin + Diloxanide Furoate) hepatic oxidation &
“Mixed” compounds that bind proteins and Dark urine
glucoronidation
Luminal and DNAà cell death Oral moniliasis
G. Lamblia, T. vaginalis, H. pylori, C. diff Anaerobic
Systemic Agents Leukopenia, dizziness,
cocci & gram (-) bacilli Safety in pregnancy not
ataxia
Antiamebics

established
2nd Gen nitroimidazole Same as metronidazole
Amebiasis, Amebic liver abscess, Giardiasis and
Tinidazole Similar to metronidazole, but but shorter duration of
Trichomoniasis
better tolerated & ¯TXT course effects
DOC for ASYMPTOMATIC amebiasis
Diloxanide Converted in gut to Diloxanide
combination with metronidazole for moderate to GI distress
Furoate freebase active form
severe infections

Active against luminal trophozoite and cyst forms of
Luminal Agents Rash, diarrhea
E. Histolytica
Iodoquinol Oral Peripheral neuropathy→
Alternate to Diloxanide Furoate for mild-severe
Act in bowel optic neuritis
infections
lumen Only effective against luminal forms of E. Histolytica
Aminoglycoside AbxàAmebicidal and tapeworm Diarrhea & GI distress
Paromomycin Binds 30s subunità ¯protein + tetracyclines for mild intestinal disease HA, dizziness, rashes &
synthesis and ¯intestinal flora Alternative for cryptosporidiosis in AIDS pts ant to arthralgia
Diloxanide Furoate for mild-severe infections
Eliminates trophozoites in liver Combined with metronidazole and Diloxanide
Chloroquine
abscess Furoate
Inhibits protein synthesis by
Systemic Agents IM or SC Pain at injection site,
blocking Backup drugs for severe intestinal or hepatic
Emetine Concentrates in the liver for Nausea, Dizziness, Rash
ribosomal movement along mRNA amebiasis
Dehydroemetine about 1mon Cardiotoxicity,
Combine with a luminal agent
Slow metab & elimination Neuromuscular weakness
Active in intestinal wall and liver

Fernanda Ponce pg. 38


® Nematodes: elongated roundworms that possess a complete digestive system & cause infections
of intestines as well as blood and tissue infections
® Trematodes: leaf-shaped flat worms characterized by the tissues they infect: liver, intestines, and
blood flukes
® Cestodes: Flat, segmented body which attaches to host intestine; lack mouth and digestive
system throughout life cycle
Drug MOA
Albendazole Benzimidazoles
Inhibits microtubule synthesis and
glucose uptake→ decreased ATP
productionà immobilization & death
of the worm
Mebendazole
Benzimidazoles
Thiabendazole
Antihelminthics
Inhibits microtubule aggregation
GABA agonist→ Cl- influx
Ivermectin hyperpolarizes parasitic muscle or
nerve cell→ paralysis/death of parasite
Piperazine GABA agonist
Depolarizing neuromuscular blocker→
persistent activation of nicotinic
Pyrantel Pamoate
receptors & inhibition of AchEà↓Ach
and paralysis
Immobilizes microfilariae rendering
Diethylcarbamazine
them susceptible to host defenses
Tetracycline Abx→ indirectly kills
Doxycycline Wolbachia (intracellular symbiont of
filarial parasites)
Increases permeability of cell
membranes to Ca2+→ contracture and
Praziquantel
paralysis or worm musculature →
detachment of suckers from vessels
Inhibits helminth electron transport
Bithionol
chain
Inhibits parasites mitochondrial
Niclosamide phosphorylation of ADP and possibly
anaerobic metabolism as well
Fernanda Ponce pg. 39
Antiparasitic Drugs Continued
® For most cases, broad spectrum agents cure/control worm infection
® Cysticercosis, echinococcosis, filariasis, & trichinosisàsystemic infections that respond partially
to anthelminthic drugs
® Can act either locally (to expel worms from GI tract) or systemically (to eradicate adult helminths
or developmental forms)
Clinical Use PK AE
-Oral-absorption enhanced by high fat -HA & nausea for short txt (1-3 days)
meals -Hepatotoxicity, agranulocytosis or
Cestodal infestationsà DOC for
-Extensive 1st pass metab.à forms active pancytopenia with Hydatid txt (3 mon)
cysticercosis (Taenia Solium larvae), hydatid
metabolite -Dying parasites→ inflammatory response in
disease (Echinococcus granulosis)
Contraindicated in pregnancy and the CNS (hyperthermia, convulsions, mental
children <2 changes, HA)
DOC for the following:
-Oral-almost insoluble in aqueous
Whipworm (Trichuris trichiura) Abdominal pain, diarrhea, HA Dizziness
solution→ ­fat meal ­absorption
Pinworm (Enterobius vermicularis) Contraindicated in pregnancy
-1st pass→ inactivation
Hookworms (N. americanus, A. duodenale) Use caution in cirrhosis & children <2
-parasites expelled in feces
Roundworm (Ascariasis lumbricoides)
Oral- almost insoluble in H2O→ ­fat meal Most toxic of the group
Threadworm (Strongyloides stercoralis)
­absorption CNS→ dizziness/seizure
Cutaneous larva migrans (CLM)
Contraindicated in pregnancy and Erythema multiforme
Early trichinosis
liver/kidney disease Steven-Johnson
DOC for the following:
Oral Mazzotti-like reaction w/ onchocerciasis→
Onchocerciasis/river blindness (Onchocerca
Does not cross BBB fever, dizziness, somnolence, hypotension
volvulus)
Avoid other GABAergic’s (benzos and
Cutaneous larva migrans (CLM)
barbs) Contraindicated in pregnancy & meningitis
Strongyloides
Alternative treatment for pinworm and
Expulsion of worm via peristalsis Contraindicated in pts w/ seizure disorders
roundworm
Poor oral absorption→ exerts effect in
Roundworm, pinworm & hookworm Nausea, vomiting, diarrhea
the GIT
-Oral- rapid absorption with meals Due to host response following death of
DOC for lymphatic filariasis, loiasis and
-Coadminister with antihistamines or parasite→ fever, myalgia, rash, leukocytosis,
tropical eosinophilia
steroids to reduce AE arthralgia, HA, malaise
Wuchereria bancrofti
onchocerciasis
DOC for Schistosomiasis Drowsiness, dizziness, malaise, anorexia
Oral
Trematode: C. Sinensis, P. Westermani CYP450 interactions
Extensive 1st pass metabolism by CYPs
Cestode: D. latum, T. Solium & saginata Contraindicated in pregnancy, nursing
Inactive metabolites excreted in urine/bile
T. SoliumàAlbendazole is DOC mothers and ocular cysticercosis
DOC for sheep liver fluke (Fasciola hepatica)
Alternative treatment for pulmonary
paragonimiasis
Pretreat with a laxative to purge all dead
2nd line for most cestode infection Use is uncommon d/t efficacy of Praziquantel
segments and ova (which can cause
Not lethal to cestodes ova, just the scolex & No longer available in US
cysticercosis)
segments Safety not established in pregnancy or kids <2
Avoid EtOH for 1 day
 Antiparasitic Drugs Continued- DOCs used in Treatment
Nematode Infections Trematode Infections Cestode Infections
Ascariasis Echinococcosis
Albendazole, Pyrantel Pamoate or Fasciola hepatica
Ascaris lumbricoides Bithionol Echinococcus granulosus Albendazole
Mebendazole (Liver fluke)
(roundworm) (dog tapeworm)
Enterobiasis Schistosomiasis Taeniasis
Enterobius vermicularis Mebendazole or Pyrantel Pamoate S. mansoni, S. japonicum, Praziquantel Taenia Solium Praziquantel or Niclosamide
(pinworm) S. Haematobium (pork tapeworm)
Trichuriasis Taeniasis
Clonorchis Sinensis
Trichuris trichiura Mebendazole or Albendazole Praziquantel Taenia Saginata Praziquantel or Niclosamide
(oriental liver fluke)
(whipworm) (beef tapeworm)
Hookworm Disease
Pyrantel Pamoate or Mebendazole Paragonimus Westermani Cysticercosis
A. duodenale Praziquantel Albendazole or Praziquantel
or Albendazole (lung fluke) Taenia Solium larvae
N. americanus
Onchocerciasis (River Diphyllobothriasis
Blindness) Ivermectin Diphyllobothrium latum Praziquantel or Niclosamide
Onchocerca volvulus (fish tapeworm)
Cutaneous Larva Migrans
(creeping eruption,
Albendazole or Ivermectin
dog/cat hookworm)
Ancylostoma spp.
Visceral Larva Migrans
(Toxocariasis) Albendazole Other Protozoal Infections
Toxocara spp.
Trichinosis Albendazole or Mebendazole DOC for Giardia Lamblia &
Trichinella spiralis add corticosteroids if severe Trichomonas Vaginalis
Metronidazole
Lymphatic filariasis
Trypanosomiasis
Wucheria bancrofti Diethylcarbamazine Metronidazole or suramin
(African Sleeping Sickness)
Brigia malayi
Loiasis
Hemolytic stage of Trypanosomiasis
Loa Loa Diethylcarbamazine Pentamidine
& P. Jiroveci infections
(African eye worm)
Strongyloidiasis
Toxoplasmosis Pyrimethamine + Clindamycin
Strongyloides stercoralis Ivermectin
(toxoplasmic encephalitis) or Sulfadiazine or folinic acid
(threadworm)
Sodium Stibogluconate/
Leishmaniasis (all stages)
amphotericin B
DOC for & P. Jiroveci infections TMP-SMX (Cotrimoxazole)

Fernanda Ponce pg. 40

 Antimalarial Drugs
Parasite Life Cycle:
Malarial paroxysmàfever, anemia, jaundice & hepatosplenomegaly (occur»every 2-3 days)
® Anopheles mosquito inoculates plasmodium sporozoitesàinitiate human infection
® Sporozoites invade liver cellsàtissue schizonts that mature in the liver (exoerythrocytic P. falciparumà most severe form d/t microvascular effects (likely to be fatal if untreated)
stage) -cerebral malaria: irritabilityàseizuresàcoma
® Merozoites released from liveràinvade erythrocytes -SXS: RDS, diarrhea, severe thrombocytopenia, spontaneous abortions & hypoglycemia
® Gametocytes develop in RBC before being taken up by mosquitoàcompleting cycle
P. falciparum & P. Malariae: only one cycle of liver cell invasion (ceases in <4wks)àonly Evaluation & Diagnosis:
erythrocytic parasite must be eliminated -consider in any pt. w/ known travel history
P. vivax & P. Ovale: have dormant hepatic stage (hypnozoites)à both erythrocytic & hepatic -DON’T initiate TXT until dx is confirmed w/ thin/thick blood smear
-prophylaxis: insect repellent, insecticides, bed nets
parasites must be eliminated
Treatment based on: Infecting species, clinical status of pt., drug susceptibility to infection
Incubation Period:
P. vivax & P. falciparumà different resistance patterns in different geographical areas
P. vivaxà2-17 days
Uncomplicated malariaà txt w/ oral antimalarials
P. Ovaleà 16-18 days
Complicated malaria (pt. w/ sxs other than malarial paroxysm)àtxt aggressively w/ parenteral
P. falciparumà 9-14 days
antimalarials
P. Malariaeà 18-40 days (can be years)
Drug Indication MOA PK/PD Resistance AE
Concentrates within
parasite food vacuoles,
DOC for treatment and prophylaxis of vivax and
raising the internal pH → P. falciparum has mutations in the Pruritus (esp. Africans)
ovale (non-falciparum & uncomplicated Oral
inhibition of growth putative transporter (PfCRT) Nausea, vomiting, abd. Pain, HA,
falciparum malaria) t½ = 3-5 days
anorexia, malaise, blurry vision,
Chloroquine Preferred chemoprophylaxis in areas w/o
Interferes with Contraindicated in pts with: urticaria
resistant falciparum Safe in pregnancy &
biocrystallization of Hb to young children Psoriasis or porphyria Hemolysis in ↓G6PD
Highly effective against blood schizonts but not
hemozoin (non-toxic Retinal or visual field issues ECG changes in toxic doses
against liver parasites
polymer) → lysis of parasite
and RBC
Quinine→ oral
Uncommon, but increasing Cinchonism→ tinnitus, HA, nausea,
Quinidine→ parenteral
Derived for cinchona tree especially in SE Asia dizziness, flushing and visual
1st line for severe falciparum disease disturbance Hypersensitivity
Do not combine with
(alternative in chloroquine resistant areas) ↓O2 uptake and CHO Discontinue if hemolysis, HSN or Hematologic disturbance
mefloquine
Quinine May need to combine with doxycycline metabolism cinchonism develops Hypoglycemia (↑insulin release)
Quinidine Uterine contractions
Can ↑warfarin &
Highly effective against blood schizonts Intercalates DNA → Safe to use in pregnancy b/c Severe hypotension: rapid IV
↑digoxin
but not against liver parasites ↓replication and benefits outweigh the risks QT prolongation
↓transcription Avoid in pts with visual or auditory Blackwater feverà hemolysis and
Reduce dose in renal
disturbance or cardiac abnormality hemoglobinuria
insufficiency
Effective against mild to moderate chloroquine
Destruction of asexual Uncommon
resistant strains of falciparum & vivax Oral only
blood forms of malarial Associated with resistance to Higher dose: leukocytosis,
t½ = 20 days→ weekly
pathogens through quinine, but not chloroquine thrombocytopenia,
Chemoprophylaxis for falciparum & vivax→ dosing
unknown mechanisms ­aminotransferase, arrhythmias,
Mefloquine only one for pregnant prophylaxis against
Contraindicated in pts with bradycardia
chloroquine resistant strains Do not give with:
Chemically related to epilepsy, psych problems,
Quinine/Quinidine
quinine (don’t combine arrhythmia or sensitivity to related Neuropsychiatric toxicity
Combo w/ artesunateàuncomplicated malaria Halofantrine
them) drugs
in SE Asia

Fernanda Ponce pg. 41

 Antimalarial Drugs Continued
Drug Indication MOA PK/PD Resistance AE
Resistant strains require repeated GI upset and HA
DOC for eradication of dormant liver form of Oral
Metabolites may act as therapy with higher doses Leukopenia, agranulocytosis,
vivax and ovaleàonly agent that is active Metabolites are less
oxidants disrupting leukocytosis, arrhythmia
Primaquine against the dormant liver forms active, but have more
mitochondria and binding to Contraindicated in pregnancy and
potential to induce
DNA G6PD deficiency (test prior to Hemolysis or methemoglobinemia
Chemoprophylaxis for all strains hemolysis
beginning treatment) in ↓G6PD
Used in the treatment and prophylaxis of
Malarone
uncomplicated falciparum
= Disrupts mitochondrial
Active against tissue and erythrocytic schizonts Oral Contraindicated in pregnancy GI upset, HA, rash
Atovaquone + election transport chain
Chemoprophylaxis 1-2days before travel &
Proguanil
stopped 1 week after exposure
Pyrimethamine Combo for chemoprophylaxis GI issues, rashes, itching
Inhibitors of Folate Synthesis
Proguanil Intermittent preventive therapy in high risk
Generally used in
patients Proguanil- mouth ulcers, alopecia
combinations
Mild/moderate chloroquine resistant falciparum
Common for P. Falciparum
(Pyrimethamine-Sulfadoxine) Pyrimethamine-Sulfadoxine:
Pyrimethamine + Proguanil→ Oral
erythema multiforme, Steven
Sulfadoxine inhibit DHF reductase Safe to use in pregnancy
Pyrimethamine + Proguanil→ slow action Johnson syndrome, toxic necrolysis
against erythrocytic forms
Sulfonamides inhibit
Proguanil→ some hepatic forms Sulfadoxine: hematologic, GI, CND.
dihydropteroate synthase
Sulfonamides→ erythrocytic schizont Dermatologic and renal toxicity
Active against erythrocytic schizonts of all
species (NOT active against liver stage)
GI upset, Vaginal candidiasis
Contraindicated in pregnancy and
Photosensitivity
Combo w/ quinine→ completes therapy for children <8
Doxycycline Discoloration & hypoplasia of teeth,
severe falciparum after giving quinine,
stunting of growth
quinidine or artesunate Clindamycin can be an alternative
Fatal hepatotoxicity in pregnancy
Chemoprophylaxis against most forms if taken
daily
Very short t½; Not
Derived from the qinghaosu plant good for prophylaxis
Binds iron, breaking down Should not be used as a single High doses: Neurotoxicity & QT
Coartem= artemether + lumefantrine peroxide bridges→ Artesunate: oral, IV, agent to protect against resistance prolongation
Artemisinin generation of free radical IM, rectal
Treatment of severe falciparum (given IV) that damage proteins within Artemether: oral, IM, If given aloneàadmin for 5-7 days Can be used more in 2nd & 3rd
No effect on hepatic stages the parasite rectal to avoid recurrent parasitemia trimesters; 1st trimester can be used
Dihydroartemisinin: for txt of severe malaria
oral only
Halofantrine Effective against erythrocytic stage of all spp. irregular absorption Use is limited; Teratogenic cardiac toxicity
Fixed dose combo w/
Lumefantrine Effective against erythrocytic stage of all spp. Well tolerated Minor ­QT (insignificant clinically)
artemether

Fernanda Ponce pg. 42

 Treatment Guidelines for Malaria
Plasmodium Spp. Resistance Recommended Drugs
P. falciparum No known resistance Chloroquine or Hydroxychloroquine
1. Malarone*
Chloroquine-resistant 2. Coartem*
P. falciparum
or unknown 3. Quinine + Doxycycline
4. Mefloquine
Uncomplicated
P. Malariae No known resistance Chloroquine or Hydroxychloroquine
Malaria
P. vivax or P. Little resistance 1. Chloroquine + Primaquine
Ovale reported 2. Hydroxychloroquine + Primaquine
1. Quinine + Doxycycline + Primaquine
P. vivax Chloroquine-resistant 2. Malarone + Primaquine
3. Mefloquine + Primaquine
All Species Chloroquine-sensitive Chloroquine or Hydroxychloroquine
Uncomplicated 1. Mefloquine
P. falciparum Chloroquine-resistant
Malaria in 2. Quinine + Clindamycin
Pregnancy P. vivax Chloroquine-resistant Mefloquine
*Pregnant pt. w/ P. vivax or P. ovaleà chloroquine prophylaxis for duration of pregnancy
1. Quinidine + Doxycycline or
Clindamycin (all IV) à can progress to
Severe Malaria All Species No known resistance oral Quinine + Doxycycline
2. Artesunate followed by Malarone,
Clindamycin or Mefloquine
1st Trimester: Quinidine or Artesunate
Severe Malaria in
All Species No known resistance 2nd/3rd Trimester: 1. Artesunate
Pregnancy
2. Artemether
Malarial All Species Chloroquine-sensitive Chloroquine
Chemoprophylaxis All Species Chloroquine-resistant Mefloquine, Doxycycline, or Primaquine
Malarial All Species Chloroquine-sensitive Chloroquine
Chemoprophylaxis
All Species Chloroquine-resistant Mefloquine
in Pregnancy
* Malarone= Atovaquone-Proguanil; Coartem= Artemether + Lumefantrine

Fernanda Ponce pg. 43


® Superficial mycoses: affect skin, mucous membranes, hair, & nailsà dermatophytoses & superficial
candidiasis
® Subcutaneous mycoses: affect the dermis, subcutaneous tissues & adjacent bone
® Systemic mycoses: affect internal organs (most difficult to txt & often life-threatening)
o Commonà Candidiasis, Cryptococcosis, Aspergillosis
® Fungiàeukaryotic w/ ergosterol cell membrane (instead of cholesterol)àtargeted in development of
antifungals
Drug MOA
Ketoconazole
Inhibits 14-α-sterol demethylase
(CYP450 enzyme) → blocks
conversion of lanosterol to
Fluconazole
ergosterol→ disruption of
membrane function and increased
permeability
Higher specificity for fungal CYP than
human CYP enzymes, but imidazoles
are less specific than triazoles
Itraconazole
Systemic Relatively non-toxic fungistatic
Drugs for agents
Subcutaneous
and Systemic
Voriconazole
Mycoses
Posaconazole
Polyene macrolide produced by
Streptomyces nodosus
Binds to ergosterol→ forms pores in
cell membrane→ leakage/death
Can also binds to cholesterol and
forms poresàrenal toxicity (avoid
Amphotericin using Na loading-admin saline w/
B drug)
Broadest spectrum→ active against
yeasts (endemic mycoses) and
pathogenic moldsà Candida,
Cryptococcus, Histoplasma,
Blastomyces, Coccidioides, Mucor &
Aspergillus
Fernanda Ponce pg. 44
Antifungal Drugs
Clinical Use
Strong inhibitor of CYP3A4 →
potentiates toxicity of warfarin
and cyclosporine
Narrow spectrum + AE→ only used
for chronic mucocutaneous
candidiasis & dermatophytes
DOC→ esophageal,
oropharyngeal, vaginal or urinary
candidiasis, candidemia &
Coccoidiomycosis
DOC for maintenance therapy
(after initial txt with amphotericin
B) AND prophylaxis of
cryptococcal meningitis
DOC for dimorphic fungi→
Blastomycosis, Sporothrix and
Histoplasma
Dermatophytoses, onychomycosis
Aspergillus (replaced by
Voriconazole)
DOC for invasive aspergillosis
Candidemia, Scedosporium spp. &
Fusarium spp., invasive Candida
Similar spectrum to itraconazole
Active against Zygomycetes
(Mucor), Aspergillus/Candida
prophylaxis
-All life threatening fungal
infections
-DOC for Mucormycosis,
cryptococcal meningitis,
Blastomycosis, Coccidiomycosis,
extracutaneous Sporotrichosis,
and others
-Given to pts w/ neutropenia &
fever who don’t respond to broad
spectrum Abx
-Used as initial therapy to ¯fungal
burden, then continue on an azole
-DOC for deep fungal infections
during pregnancy
® Increased risk of fungal infection in immunocompromisedà pt. undergoing chemo,
organ transplant pt. or HIV+ pt.
® Alter cell membrane permeabilityà Polyenes, Azoles, Allylamines
® Block nucleic acid synthesisà Flucytosine
® Disrupt microtubule functionà Griseofulvin
® Disrupt fungal cell wallà Echinocandins
PK/PD AE Other
Best absorbed at a Inhibits human CYP→
low pH or PPI’s/H2 ↓testosterone → gynecomastia,
Imidazole
blockers can ¯libido & ¯potency/menstrual
interfere irregularities
Seldom use d/t AE
Poor penetration into High dose: inhibit adrenal steroid
CSF synthesis→ ↓plasma cortisol
High oral Triazole
Moderate CYP3A4 inhibition, but
bioavailability & CSF Ineffective against
strong inhibitor of CYP2C9→
penetration aspergillus or other
↑plasma phenytoin, zidovudine &
filamentous fungi
warfarin
Renal excretion -Alternative to
(other azoles are Amphotericin B for non-
Widest therapeutic indexà
hepatic) severe cryptococcal
permits more aggressive dosing
meningitis
Inhibition of CYP3A4→ fatal
Metab by CYP3A4 Triazole
arrhythmias when given with
Pulse/intermittent
cisapride or quinidine
Poor bioavailability dosing ¯AE & cost b/c
and penetration into drug accumulates in nails
Absorption reduced by antacids,
CSF for months
H2 blockers and PPI’s
Transient visual disturbance Triazole
Numerous drug interactions due to metabolism by and Similar spectrum to
inhibition of CYP2C19, 2C9, and 3A4→ limited use itraconazole
Inhibits CYP3A4 Triazole
Better absorbed w/ Broadest spectrum w/
high fat meals Amphotericin B
Infusion related→ fever, chills, Lipid formulations have
Highly insoluble
muscle spasms, HA, hypotension, ¯incidence & severity of
(formulated as a
vomitingà pretreat w/ nephrotoxicity
deoxycholae colloidal
antihistamine, glucocorticoids, -Liposomal Amphotericin
suspension) and
antipyretics or meperidine to help B (L-AMB)
poorly absorbed
-Amphotericin B lipid
from GIT→ IV admin
Renal toxicityà azotemia, ¯GFR, complex (ABLC)
(slow to avoid AE)
tubular acidosis (­Mg, ­K wasting) - Amphotericin B colloid
dispersion (ABCD)
Low penetration into
Anemia d/t ↓EPO, abnormal liver
CSF→ intrathecal
fxn tests (monitor) Crosses placenta
admin for meningeal
Metabolites in urine over
disease (rare)
Intrathecal admin→ seizures, etc. long period of time
 Antifungal Drugs Continued
Drug MOA Clinical Use PK/PD AE Other
formation of 5-FU
Enters cell via cytosine permease→ converted Pyrimidine antimetabolite Oral Combination with
from gut floraà BM
to 5-FU and then to 5-FdUMP→ inhibits Narrow spectrum fungistatic used in Distributed in most amphotericin B is
toxicityà anemia,
thymidylate synthetase→ blockage of synergistic combinations to avoid body tissue including synergistic
leukopenia,
Systemic Flucytosine dTMPà ¯DNA synthesis development of resistance CNS
thrombocytopenia,
Drugs for Eliminated in urine Not converted into active
derangement of
Subcutaneous 5-FUTP also formed→ incorporated into RNA Combo w/ amphotericin B for ¯dose in renal metabolites in mammalian
liver enzymes &
and Systemic to inhibit protein synthesis Candida &/or cryptococcal infections impairment cells
toxic enterocolitis
Mycoses
Active against candida (esophageal & GI issues, flushing
Echinocandin that Inhibits synthesis of β (1-3)-
candidemia) and aspergillus, but NOT Avoid co-admin w/ Large cyclic peptides linked
Caspofungin D-glucans in the fungal cell wall→ disruption Only IV
C. neoformans cyclosporineà to a long chain fatty acid
of cell wall and death
Febrile, neutropenic pts w/ fungus ­liver enzymes
Fungistatic Absorption improved Induces CYP450:
Replaced by newer drugs
Enters via energy-dependent processà Only used to txt dermatophytosis→ when given with fatty ­metabolism of
Griseofulvin like Itraconazole &
Disrupts mitotic spindle→ inhibition of skin, hair and nails (2-6wk duration) foods many drugs like
Terbinafine
Systemic mitosis Accumulates in keratin Warfarin
Drugs for Fungicidal GI upset, rash, HA,
Allylamine
Superficial Inhibits squalene epoxidaseà prevents taste disturbance Can also be used as a topical
Oral
Mycoses Terbinafine synthesis of lanosterol (ergosterol Does not affect cream for the treatment of
Most effective against Accumulates in keratin
precursor) & causes accumulation of toxic P450→ no drug tinea cruris and corporis
onychomycosis
levels of squalene interactions
Azoles Oral Ketoconazole, fluconazole and Itraconazole txt dermatophytoses (ringworm), candidiasis, tinea versicolor, piedra, tinea nigra, fungal keratitis
Polyene macrolide

Only used for candidiasis in Too toxic for IV admin Other topical drugs for
Structurally similar to amphotericin B with Little significant
Nystatin cutaneous, vaginal or oral Not absorbed from the superficial mycoses:
the same MOA: Binds to ergosterol→ forms toxicity
administration GIT, skin or vagina Imidazoles Terbinafine
Topical Drugs pores in cell membrane→ leakage/death
for Amphotericin (Look on page 44 for
Polyene Cutaneous candidiasis Topical
Superficial B everything else)
Mycoses Clotrimazole commonly used topically & available (Look on page 44 for
Azoles Negligible absorption Rare
Miconazole OTC to txt vulvovaginal candidiasis everything else)
Allylamine (Look above for everything
Terbinafine Txt of tinea cruris, corporis, & pedis Topical cream
Inhibits squalene epoxidase else)
Treatment of Fungal Infections
Infection Primary Therapy
Esophageal Candidiasis IV or Oral Fluconazole
Urinary Candidiasis IV or Oral Fluconazole
Oropharyngeal Candidiasis Mild: Topical Clotrimazole or Nystatin; Moderate-severe: Oral Fluconazole, AIDS pt.: Oral Fluconazole
Vulvovaginal Candidiasis Topical Azoles or Oral Fluconazole
Recurrent Vulvovaginal Candidiasis Oral Fluconazole
Candidemia IV Fluconazole or an IV Echinocandin (Caspofungin)
Cutaneous Candidiasis Topical Amphotericin B or Topical Azole or Topical Nystatin
Cryptococcosis Topical Amphotericin B + Oral Flucytosineà followed by Oral Fluconazole
Invasive Aspergillosis IV Voriconazoleà followed by oral Voriconazole
Mucormycosis Amphotericin B
Fusariosis Amphotericin B
Onychomycosis Oral Terbinafine or Oral Itraconazole or Oral Fluconazole

Fernanda Ponce pg. 45

 Pneumocystis Jirovecii Pneumonia
® P. jirovecii causes pneumocystis pneumonia (PCP)
® Fungus that responds to antiprotozoals and DOES NOT respond to
antifungals
® PCPàmost common cause of pneumonia in immunosuppressed
® Most common opportunistic infection in HIV+ pts
® SXSàfever, dyspnea and cough
Therapy
® DOC for txt of PCP & prevention OF P. jirovecii in
immunocompromisedàco-trimoxazole (TMP-SMX)
® AEà skin rash, neutropenia, hepatitis & fever
® Alternatives:
o Clindamycin + Primaquine
o Dapsone + Trimethoprim
o Atovaquone
o Pentamidine
® Pts w/ moderate-severe disease should also be given prednisone

Fernanda Ponce pg. 46

 Intro to Anticancer Drugs
Principles of Cancer Chemotherapy:
-Chemo is used to stop CA cells from multiplying, invading, metastasizing &
ultimately killing the patient
-Primary Chemotherapy: chemo administered as the 1° txt in pts who present
w/ advanced CA for which no alternative txt exists; main txt approach in pts w/
advanced metastatic CA
-Neoadjuvant Chemotherapy: use of chemo in pts w/ localized CA for which
alternative therapies are less effective; administered prior to surgery to reduce
the size of 1° tumor so that surgical resection can be made easier
-Adjuvant Chemotherapy: administered after local txt modalities (i.e.
surgery/radiation) has been performed; destroys microscopic cells that may be
present after local txt & ¯incidence of both local & systemic recurrenceà
improve overall survival
® IFNa in pts w/ primary malignant melanoma
® Antihormonal agents in postmenopausal pts w/ ER+ breast CA
-Site-directed Chemotherapy: Direct instillation into sanctuary sites (intrathecal -Myelosuppressionà use Filgrastim to txt neutropenia
or peritoneal) or regional perfusion of the tumor (intra-arterial)
Tumor Susceptibility to Chemotherapy:
-Growth fractionà% of actively dividing cells at any given point in time
-malignant neoplasms w/ ­growth fraction (leukemia & lymphoma) are more
sensitive to chemo
-¯growth fraction tumors (solid tumor- carcinomas of the colon, lung CA) are
less responsive to chemo
Treatment Protocols:
-Combination chemotherapy= standard approach (exceptionsà
Choriocarcinoma and Burkitt’s) b/c:
® Achieve maximal killing of tumor cells: use drugs w/ known efficacy and
different MOA so each drug kills a separate fraction
® Prevents development of drug resistance: use drugs that act at different
phases of the cell cycle & have different MOAs
® Combos may be Synergistic & effective against a broader range of cell
lines
® Keep toxicity profile acceptable, w/o causing lethal organ damage:
combine drugs w/ different toxic profilesà wide range of side effects, but -Cell cycle-nonspecific: effective against replicating or resting cells in G0 phase
¯risk of lethal damage
Fernanda Ponce pg. 47
Log Kill Hypothesis: A constant fraction of tumor cells are killed during chemo
(i.e. killing follows 1st order kinetics) à need repeated doses to eradicate CA
Challenges to Chemotherapy:
-Toxicity to normal cells- most chemo agents act on cell proliferation; rapidly
dividing normal cells (BM & mucous membrane cells) are targeted
-Resistance of tumor cells: usually develops d/t mutations in target (ex. DHF
reductase mutation- MTX resistance)
Treatment Induced Tumors:
-Most antineoplastics are mutagens (carcinogenic)à neoplasms may arise 10+
yrs after original CA was cured (especially with alkylating agents)
Common Adverse Effects (Toxicity):
-Nausea and vomitingà txt w/ 5HT3 blockers and NK1 inhibitors
-Stomatitis & Alopecia
® Strong: Cytarabine, Alkylating agents, Doxorubicin, Daunorubicin,
Vinblastine
® Moderate: Carboplatin, Methotrexate, 5-FU
® Mild: Bleomycin, Vincristine, Asparaginase
-Doxorubicinàcardiotoxic (txt w/ Dexrazoxane)
-Cyclophosphamide & Ifosphamideà hemorrhagic cystitis (txt w/ Mesna)
-Bleomycinà pulmonary fibrosis
-Cisplatinàrenal toxicity (txt w/ cytoprotective agent, Amifostine)
-Leucovorin rescues BM from Methotrexate
Resistance to Cytotoxic Drugs:
-Primary: no response to the drug on 1st exposure
-Acquired: single drug (d/t ­gene expression) or multidrug (MDR) (emergence
to several different drugs after exposure to a single agent)
® P-glycoprotein (MDR1)à most imp. efflux pump responsible for MDR
Classifications of Anticancer Drugs:
-Cell cycle specific: effective only against replicating cells (most effective in
hematologic malignancies & tumors that have a large growth fraction)
(most effective against low growth fraction solid tumors & high growth fraction
tumors)


Fernanda Ponce pg. 48

 Anticancer Drugs- Antimetabolites (exert effect on S phase)
Class Drug MOA Indication AE PK Resistance Other
Choriocarcinoma, Myelosuppression, mucositis, -¯ drug transport via In cases of overdose or
-IV, intrathecal, or oral
Osteosarcoma, Breast, head & alopecia, stomatitis, N/V/D reduced folate carrier or high dose protocols,
Folate Analogs

-Renal excretionà fix

Intracellular conversion to MTX neck, bladder CAs, 1° CNS Hepatic fibrosis & cirrhosisà folate receptor protein administer antidote I.e.
dose in pts w/ renal
polyglutamates via FPGS lymphoma, Non-Hodgkin’s ­liver enzymes, Pulm fibrosis, -¯MTX polyglutamates leucovorin (THF
Methotrexate dysfxn
(folypolyglutamate synthase)àInhibits lymphoma Neurotoxicity w/ IT -­DHF reductase levels derivative) àprovides
(MTX) -Be careful when admin
DHF reductaseà block synthesis of THFà admin.àmeningismus + anti- -altered DHF reductase cells with reduced folate
w/ aspirin, NSAIDs, PCNs
¯DNA & ¯RNA synthesis Non neoplastic: ectopic inflam. response in CSF w/ ¯affinity for MTX to rescue cells from
& Cephalosporinsà
pregnancy, abortion, RA, Renal damage (crystals deposit -¯accumulation of drug toxicity & ¯AE (will not
inhibit renal excretion
psoriasis, IBD, & vasculitis in tubules; prevent w/ hydration) via activation of MDR1 reverse neurotoxicity)
-Oral & well distributed
except in CSF Also Metabolized by
BM suppression, Hepatotoxicity,
Converted to 6-MP ribose phosphate (thio- -Metabolized by -¯HGPRTà inability to xanthine oxidase- when
N/V/D
6- iosinic acid/TIMP) by salvage pathway Thiopurine transform 6-MP to TIMP given in combo w/
Acute lymphoblastic leukemia Dysfxnal RNA and DNA d/t
Mercaptopurine enzyme, HGPRT→ inhibits de novo purine methyltransferase -­dephosphorylation allopurinol, dose must
Purine Analogs

(ALL) incorporation of guanylate

(6-MP) synthesis and blocks formation of AMP & (TPMT)à pts w/ -­metabolism of drug to be reduced accordingly
analogs (Triphosphate form
GMP from IMP deficiency must be given thiouric acid to avoid toxic levels of
incorporated into DNA & RNA)
¯dose drug
-renal excretion
-Metabolized by
Converted to thioguanosine
Thiopurine No drug interaction with
monophosphate (TGMP) by HGPRTà Nonlymphocytic leukemias
BM suppression methyltransferase allopurinol d/t
6-Thioguanine inhibits PRPP to ¯purine synthesis, inhibits
Hepatotoxicity (TPMT)à pts w/ inactivation by
(6-TG) guanylate kinase so GMP¹GDP, & can be Synergistic w/ Cytarabine for
Nausea, vomiting, diarrhea deficiency must be given deamination & NOT
converted to TGTP & dTGTPà txt of AML
¯dose oxidation
incorporated into RNA & DNA
Breast, GI, pancreas,
Fluoropyrimidines esophagus, liver, anus, head & Hand/Foot syndrome→
neck CA’s
erythematous desquamation of IV, topical for skin CA
Addition of leucovorin:
5-Fluorouracil Converted to 5-FdUMPàforms ternary 1st Line-Colorectal CA (w/ palms & soles ­cytotoxic effects of 5-
Penetrates into CSF
complex w/ thymidylate synthase & N5, N10 leucovorin) Myelosuppression, mucositis, FU→ ­RNA interference
methylTHFà incorporation into DNA + Topical: keratosis & superficial alopecia, diarrhea &
Thymineless death (­N5, N10 methylTHFà basal cell carcinoma neurotoxicity
­5-FU activity)à -3 enzymatic conversion
↓DNA synthesis Metastatic colorectal CA (1st Severe toxicity seen when pt. stepsà2 steps in liver
Also converted to 5-FUTPà incorporated line) & metastatic breast CA has deficiency of DPD and last step converted
Capecitabine Oral prodrug of 5-FU
(Tumors express ­levels of (dihydropyrimidine DH) by thymine
Pyrimidine Analogs

in RNAà interfere w/ RNA processing &

fxn thymine phosphorylase) enzymeà catabolizes drug phosphorylase in tumor
cell
-IV b/c deactivated by
Deoxycytidine Analog
S-phase specific; Competitively inhibits deamination in the
Biotransformation to
DNA pol-a(↓DNA synthesis), DNA pol-b Myelosuppression, mucositis, intestinal mucosa
Limited to hematologic active form→ Ara-CTP
Cytarabine (↓DNA repair) & is incorporated in nausea, vomiting -Does not enter CSF
malignanciesà AML and non- (Cytarabine
(ara-C) RNA/DNAà interference of chain @ high dosesà neurotoxicity: -Metabolized via
Hodgkin’s lymphoma triphosphate)
elongation & defective ligation of new Ataxia oxidative
Not active against solid
DNA fragments deaminationàara-U
tumors
-excreted by kidney
Broad spectrum activity
Converted to Gemcitabine against: Myelosuppression IV infusion
diphosphateàInhibit ribonucleotide -Solid tumors: NSCLC, (neutropenia), flu-like syndrome,
Gemcitabine reductaseà↓DNA synthesis sarcomas, Ovarian, Pancreatic nausea & vomiting Deaminated to
Deoxycytidine Analog
(dFdC) -Incorporation of triphosphate form into & Bladder CA, soft tissue Renal microangiopathy difluorodeoxyuridine
DNAà inhibits DNA polymeraseà chain sarcoma syndromesà HUS, TTP (not cytotoxic)à
termination -Hematologic: non- Hodgkin’s Elevated liver enzymes [AST/ALT] excreted in urine
lymphoma

Fernanda Ponce pg. 49



Fernanda Ponce pg. 50

 Anticancer Drugs- Microtubule Inhibitors (exert effect on M phase)
Class Drug MOA
Bind to b-tubulinà ¯ability of b-tubulin
Vinblastine to polymerize w/ a-tubulinà disrupts
assembly of microtubules (help w/
Vinca
movement, phagocytosis & axonal
Alkaloids
transport & mitotic spindle formation)à
Vincristine cells arrested in metaphaseà death by
apoptosis
Paclitaxel Bind to b-tubulin (at different site than
Vinca alkaloids)à promote microtubule
polymerization & inhibit
Taxanes
depolymerizationà enhance & stabilize
microtubule proliferationà cells
arrested in mitosisà death by apoptosis
Docetaxel
Indication
Hodgkin’s & non-Hodgkins
lymphomas, breast CA & germ
cell CA
Hematological: ALL, Hodgkin’s &
non-Hodgkins lymphomas
Pediatric: rhabdomyosarcoma,
neuroblastoma, Wilms’ tumor
Solid tumors: ovarian, advanced
breast, NSCLC, SCLC, head &
neck, esophageal, prostate &
bladder CAs + Kaposi’s Sarcoma
Abraxane àmetastatic breast CA
2nd line: advanced breast CA,
NSCLC
Activity against head & neck,
SCLC, gastric, bladder & advanced (neuropathy less frequent than
platinum refractory ovarian CA
AE Other
BM suppression (dose limiting)
Alopecia, N/V
Potent vesicant (blister agent)àtake
Metabolized by CYP450 &
care w/ admin.
excreted in feces
Neurotoxicity (d/t inhibition of
Fix dose in liver dysfxn
microtubules) w/ peripheral neuropathy
Paralytic ileus, optic atrophy, mild
myelosuppression, alopecia, SIADH
HSN (pretxt w/ dexamethasone,
diphenhydramine & H2 blocker)à
Abraxane (albumin bound form) does
not cause HSN and ¯myelosuppression
Metabolized by CYP450 &
Myelosuppression, hypotension,
excreted in feces via
arrhythmias, neuropathy, N/V
hepatobiliary route
Myelosuppression (dose-limiting),
Fix dose in liver dysfxn
neutropenia, Fluid retention (pretxt w/
dexamethasone), neurotoxicity
Paclitaxel), mucositis, alopecia, HSN

Anticancer Drugs- Epipodophyllotoxins

Class Drug MOA Indication AE Other

Etoposide Topoisomerase II inhibitorà DNA damage Testicular CA and SCLC Myelosuppression Do not penetrate BBB
through strand breakage Nausea and vomiting Excreted in urine
Teniposide Blocks cells in late S and early G2 phase Refractory childhood ALL Alopecia BothàIV; Etoposideàoral

Fernanda Ponce pg. 51

 Anticancer Drugs- Camptothecins (exert effect on S-G2 phase)
Class Drug MOA Indication AE Other
Topoisomerase I
2nd line: advanced ovarian CA following Nausea and vomiting
Topotecan inhibitorà Renal excretion (Adjust dose in renal dysfxn)
initial txt w/ platinum based chemo, SCLC Myelosuppression
inhibition of
cutting and re-
Myelosuppression Prodrug converted in liver to active form, SN-38 (1000x
ligating ssDNAà Metastatic colorectal CA (combo w/ 5-FU
Irinotecan Diarrhea (early form, w/- 24hrs, d/t more potent than parent compound)
DNA damage & Leucovorin)
cholinergic activityàtxt w/ atropine) Eliminated in bile and feces (adjust dose in liver dysfxn)

Anticancer Drugs- Antitumor Antibiotics

Class Drug MOA
Contains DNA-binding region and
iron-binding domain at opposites
Cell cycle endsà ROS generated from
specific agent Bleomycin reduced ironàss and ds breaks
acting at G2 in DNA d/t oxidation of DNA-
bleomycin-Fe (II) complex à
inhibits DNA synthesis
-Binds to cell membranesà alter
fluidity & ion transport
Anthracyclines -Inhibits topoisomerase II
Doxorubicin
-­affinity for binding to DNA via
Cell cycle intercalationàblock DNA/RNA
nonspecific synthesis & ­DNA strand breaks
-Forms ROS generated from
reduced iron
Daunorubicin
Indication AE Other
Most serious: Toxicity in tissues with low Inactivated by
hydrolase activityà Pneumonitis and bleomycin
Hodgkin’s and Non-Hodgkin’s Lymphoma Pulmonary Fibrosis (pulm toxicity=dose hydrolase
Germ cell tumor, head & neck CA, Squamous cell CA limiting)
of skin, Cervix & vulva CA Renal excretion
Skin hyperpigmentation, mucositis, (Adjust dose in
Minimal BM suppression (like vincristine) renal dysfxn)
Major activity against breast, endometrium, ovary,
testicle, thyroid, GI, bladder, liver and lung CAs; soft
Cardiotoxicityà dose-dependent, dilated
tissue sarcomas IV
cardiomyopathy assoc. w/ HF d/t ROS;
Childhood CA: neuroblastoma, Ewing’s sarcoma,
Dexrazoxane (iron chelator) → ¯ROS
osteosarcoma, rhabdomyosarcoma Eliminated in feces
damage
Hematological CA: ALL, multiple myeloma, via biliary
Myelosuppression (dose-limiting),
Hodgkins & non-Hodgkin’s lymphomas excretionà reduce
Nausea, vomiting, alopecia, mucositis,
-Commonly used in combo w/ cyclophosphamide, dose in pts w/ liver
Erythema at sites of prior
cisplatin & 5-FU dysfxn
radiationà“radiation recall rxn”
AML
Limited efficacy against solid tumors

Fernanda Ponce pg. 52

 Anticancer Drugs- Alkylating Agents
Class Drug MOA
Cell cycle non-specific BUT occur
1° in rapidly growing tissues (BM,
GI tract and reproductive
Cyclophosphamide system)à late G1 and S phase
Alkylation w/i the nucleus at the
N7 position of guanine on a ss or
ds DNA via cross linking (most
Nitrogen
major alkylating agents are
Mustards
Ifosfamide bifxnal w/ two reactive groups) -BM suppression, N/V, alopecia,
→ abnormal base pairing with
thymine or depurination by
excision of guanine→ strand
Mechlorethamine breakage
Mutagenic Carcinogenicà ­risk
Melphalan
of 2° malignancies (esp. AML)
Carmustine (IV)
Potent vesicantsà damage
Nitrosoureas tissues @ site of admin +
Lomustine (Oral)
produce systemic toxicity (care
Alkyl Sulfonates Busulfan must be taken to avoid
extravasation during admin.)
Nausea & vomità common
Methylhydrazines Procarbazine
(pretxt w/ 5HT3 antagonist)
Resistance via ­activity of DNA
repair enzymes, ­activity of
Dacarbazine
Triazines glutathione/associated proteins
(DTIC)
& ¯transport of drug into cell
Fernanda Ponce pg. 53
Indication
Broad range (widely used) →
Breast/ovarian CA & soft tissue hydration (­fluid intake and thus urine
sarcomas
Non-Hodgkin’s lymphoma &
CLL
Neuroblastoma, Wilms’ tumor
& rhabdomyosarcoma
Hodgkins Lymphomaà
replaced by more stable
alkylating agents
Multiple myeloma
Breast/ovarian CA
Brain tumors (can cross BBB)
Lymphomas
CML
Hodgkin’s & non-Hodgkin’s
lymphoma
Brain tumors
Hodgkin’s Lymphoma, Soft
tissue sarcoma, Malignant
melanoma, neuroblastoma
AE
Hemorrhagic cystitisà prevent by
output to minimize accumulation) &
parenteral admin. of Mesna (sulfhydryl
compound reacts w/ Acrolein)
-BM suppressionàpancytopenia,
Nausea, vomiting, alopecia, sterility
­risk of platelet suppression,
neurotoxicity and urinary tract toxicity
nephrotoxicity, Hemorrhagic cystitis cyclophosphamide
(*hydration + pretxt w/ Mesna)
Severe nausea & vomiting
Severe BM depression
Alopecia, immunosuppression
BM suppression, N/V/D, oral ulcerations,
hepatotoxicity, pulmonary fibrosis
Myelosuppression, Renal failure,
Pulmonary fibrosis
Myelosuppression, pulm. fibrosis, N/V
CNS acute toxicity, leukopenia,
thrombocytopenia, potent
immunosuppressive, Disulfiram-like
reaction
­carcinogenic potentialà­risk of AML
Myelosuppression (mild-moderate)
Nausea and Vomiting
Other
-Activated by hepatic CYP450
enzymes(Metabolized by
CYP2B6 mostly)
-Toxic metabolite→ Acrolein
(irritates the bladder mucosa)
-Given orally or IV
Prodrug activated in liver by
CYP3A4
More potent version of
IV
Very unstableà must make
solution just prior to admin.
Given IV onlyà strong vesicant
Highly lipid-solubleà readily
able to cross BBB
No cross resistance w/ other
alkylating agents
One metaboliteàweak MAO
inhibitorà AE when given w/
other MAO-Is & tyramine
containing foods
IV
Potent vesicant

Drug MOA
Cell cycle non-specific
Cisplatin
Binds DNA at the N7 position
of guanineà forms
intrastrand & interstrand
cross-linksàinhibition of DNA
synthesis and fxn
Carboplatin
Anticancer Drugs- Platinum Analogs
Indication
Broad range against solid
tumorsà esp. testicular,
ovarian & bladder CA
Curative therapy for
testicular CAs (in combo
w/ Vinblastine &
bleomycin)
Ovarian, breast, bladder
head & neck CAs
NSCLC & SCLC
AE PK Other
Nausea & vomiting, Myelosuppression (mild-
moderate), Neurotoxicity→ peripheral neuropathy IV Cisplatin + Amifostine
& ototoxicity, Nephrotoxicityà dose limiting (cytoprotective agent) →
Cleared by
(pretxt w/ hydration and diuresis), Electrolyte indicated to ¯nephrotoxicity
kidneys and
disturbancesà¯Mg2+, ¯Ca2+, ¯K+, ¯PO43-, associated w/ repeat admin;
excreted in
Anaphylactic-like rxns
urineà fix dose in
pts w/ renal
¯Nausea, neurotoxicity, ototoxicity and Cisplatin analog
dysfxn
nephrotoxicity than Cisplatin ¯toxic & emetogenic, but has
Myelosuppressionà dose-limiting ­myelosuppression

Anticancer Drugs- Miscellaneous

Drug MOA
Hydrolyzes asparagine to
aspartic acid and ammonia→
Asparaginase
¯glutamine à ¯L-asparagineà
inhibition of protein synthesis
Urea analog→ inhibits
Hydroxyurea ribonucleotide reductase→
↓DNA synthesis
Stimulates NK cells through
IFN-a increased expression of HLA
molecules on tumor cells
Indication
Childhood ALL
Malignant melanoma, CML, ovarian CA, 1°
squamous cell CA of head & neck (excluding lip)
Increases HbF in sickle cell pts
Hairy cell leukemia, Kaposi’s sarcoma, Renal cell
CA, antiviral activity against HPV (Condyloma
acuminata), HBV & HCV
AE
Hypersensitivity, ↓clotting factors, G1 specific
liver abnormalities, pancreatitis,
seizure & coma
Myelosuppression, N/V/D, skin rash,
hyperpigmentation, macrocytosis
Flu like sxs
Other
Isolated from bacteria
Neoplastic cells lack asparagine
synthaseàrequire exogenous L-asparagine,
but normal cells are able to synthesize it
S phase specific

Fernanda Ponce pg. 54

 Anticancer Drugs- Hormonal Agents
Class Drug MOA Indication AE Other
Induces lymphocyte apoptosis -Lymphocyte derived neoplasms: ALL, Immunosuppression→ Mood
Often used in palliative
lymphoma, multiple myeloma swings, poor wound healing
Glucocorticoids Prednisone care to improve feelings of
Increases number of platelets and -Autoimmune hemolytic anemia and Osteoporosis
well-being
RBCs thrombocytopenia d/t CLL Hyperglycemia
Antagonist on breast CA Hot flushes, thrombosis, fluid Bind to estrogen
Selective Estrogen Tamoxifen Prevention & txt of ER+ breast CA
Agonist in non-breast tissues retention, N/V receptors & act as an
Receptor
Estrogen Inhibitors

Prevention of postmenopausal Tamoxifen: ↑risk for agonist or antagonist

Modulators Antagonist in endometrium & breast
Raloxifene osteoporosis & prophylaxis of breast CA endometrial CA d/t depending on the target
(SERMS) Agonist in boneà inhibit resorption
in postmenopausal women w/ ­risk endometrial hyperplasia tissue
Selective Estrogen Pure estrogen receptor antagonist
Binds and inhibits
Receptor
Fulvestrant Tamoxifen-resistant breast CA estrogen receptor
Downregulators ­ER degradation & ¯number of ER
dimerization
(SERDS) molecules in cells
Anastrozole Inhibit aromataseà block conversion Non-steroidal reversible
Adjuvant chemo in ER+ breast CA Hot flush and headache
Aromatase Letrozole of androstenedione to estrone competitive inhibitor
Inhibitors (primary estrogen in postmenopausal Adjuvant chemo in ER+ breast CA that is Steroidal irreversible
Exemestane Mood change, acne, hair growth
women) or estriol in adipose tissue resistant to Tamoxifen inhibitor
Androgen Non-steroidal competitive androgen Mild gynecomastia (frequent)
Flutamide Prostate CA
Androgen Inhibitors

Receptor Blockers inhibitor Reversible hepatotoxicity

GnRH analogs
Pulsatile adminà ­FSH & LH release
Continuous dose produces biphasic
response: Initial flare-up of androgen
Initial phase can be
Gonadotropin dependent CA, ↓bone mass,
Gosrelin -initial (flare) phase: ­FSH & LH counteracted w/
Releasing Prostate CA hot flashes, impotence,
Leuprolide releaseà ­testosterone concurrent admin of
Hormone Analogs gynecomastia, testicular
-delayed phase: continuous presence Flutamide for 2-4 wks
atrophy
of GnRHàdown-regulation of GnRH
receptorsà¯LH, FSH, & testosterone
à suppress steroidogenesis

Fernanda Ponce pg. 55

 Anticancer Drugs- Signal Transduction Inhibitors
® Signal transduction (Cell signaling)àprocess initiated by cell-surface receptors that transmit molecular signals from a cell’s exterior to its interior
® Protein kinases (tyrosine kinases, serine/threonine kinases, or kinases w/ activity towards all 3 residues)àcritical to signal transduction pathways that regulate cell growth and adaptation
to extracellular environment
Class Drug MOA Indication AE
Gefitinib Inhibits EGFR tyrosine kinase signal transduction→ growth NSCLC
Erlotinib inhibition and apoptosis NSCLC & carcinoma of the pancreas
Inhibitors of
EGFR (ErbB1) Colorectal CAà efficacy restricted to tumors expressing wild-type KRAS
Cetuximab Monoclonal Ab against EGFR tyrosine kinase
& HER2/neu Head and neck CA
(ErbB2) Lapatinib EGFR and ErbB2 inhibitor NSCLC & carcinoma of the pancreas
Trastuzumab Humanized monoclonal Ab against HER2/neu
Breast CA w/ HER2 overexpression Cardiotoxicity
(Herceptin) (ErbB2)àmediates ADCC
Inhibitors of Bcr-Abl+→ CML, AML
Inhibits Bcr-Abl & c-kit tyrosine kinase activity→ inhibition of
BCR-ABL & C- Imatinib c-kit+àgastrointestinal stromal tumor (GIST)
proliferation and induces apoptosis
KIT Idiopathic hypereosinophilic syndrome
Inhibitors of
RAS/MAP Inhibits RAF serine/threonine kinase, VEGF-R2, VEGF-R3 &
Sorafenib Renal cell CA
Kinase PDGFR-b
Pathways
Proteasome Inhibits proteasome activityà growth inhibition and Multiple myeloma
Bortezomib
Inhibitors apoptosis Mantle cell lymphoma
Angiogenesis Renal Cell CA
Sunitinib Inhibits angiogenesis, VEGF-R1, VEGF-R2 & PDGFR
Inhibitors GIST

Gefitinib Lapatinib Trastuzumab

Imatinib

Fernanda Ponce pg. 56