PHM Exam 4

Drugs in inflammation, infection, and cancer

What is inflammation?

• Normal, protective response to tissue injury caused by trauma, noxious chemicals, or microbiologic agents

• Body’s effort to inactivate/destroy invaders or irritants and set the stage for repair

• Inflammatory process subsides after

Prostaglandins in inflammation

• All tissues produce prost. in minute quantities

• Act locally and are rapidly metabolized at site of action

  • do not circulate in blood in significant concentrations

  • thromboxanes and leukotrienes related to prosta. → synthesized from same precursors

• Prostaglandins → modulating pain, inflammation, allergic rxns, fever

  • responsible for

  • acid secretion, mucus production in GI

  • Uterine contractions

  • Renal BF

Synthesis of Prostaglandins

• Arachidonic acid is precursor

• Free arachidonic acid released by phospholipase A2

  • phopho. A2 synthesizes arachidonic acid from phospholipids

  • then processed by 2 major pathways into eicosanoids (prostaglandins + related compounds)

    • cyclooxygenase

    • lipooxygenase

Synthesis of prostaglandins: cyclooxygenase pathway

• Cyclooxygenase

  • prosta + related compounds

  • Two isoforms of enzymes exist

  • COX-1 → regulates normal cellular processes (GI protection, vascular homeo, platelet aggregation, repro/kidney func)

    • responsible for production of prostanoids (prosta/thromboxanes)

  • COX-2 → brain, kidneys, bone

  • increases in expression during inflammation and chronic disease

  • Expression of COX-2 → increase during chronic inflammation

    • Inflammatory mediators (TNF-a and IL-1) → COX-2 expression

    • inhibited by glucocorticoids

• Differences in binding shape between COX-1 and COX-2 allows for development of selective COX-2 inhibitors

Synthesis of prostaglandins (lipooxygenase pathway)

• Lipooxygenase pathway

  • form leukotrienes

  • Anti-leukotriene drugs (zileuton, zafirlukast, montelukast) → trt asthma

• Actions of prostaglandins

  • bind to GPCRs

  • local signal that fine tune response of specific cells

  • actions depend on tissue and enzymes at site

• Ex:

  • TXA2 → recruitment of platelets for aggregation and local vasocontriction

  • Prostacyclin (PGI2) → inhibits platelet aggregation and vasodilation

  • net effect depends on the balance of these two prostaglandins

Prostaglandins: therapeutic uses

• Control many physio functions (acid secretion/mucus, uterine, kidney)

  • useful for many disorders

• Alprostadil

  • neonates with congenital heart conditions → keep ductus open for surgical time

  • ED

• Lubiprostone

  • Any kind of constipation

  • Mechanism: stims Cl- in intestinal epi → increase fluid secretion → laxative effect

• Misoprostol

  • protect stomach lining → chronic NSAIDs

  • prostaglandin receptors on parietal cells → reduce GI secretion

  • also stims mucus and bicarbonate

  • NSAIDs diclofenac + misoprostol

  • increase uterine contraction

    • off label → labor induction/abortive

• Prostaglandin E2 analogs

  • Dinoprostone (synthetic) → cervical ripening / induction and abortifacient

  • relaxes cervix → induces contraction

• Prostaglandin F2a analog

  • latanoprost → open angle glaucoma

  • prostglandin receptors → increase uveoscleral outflow → reduce intraocular pressure

  • Bimatoprost → eyelash prominence, length, darkness increase, for eyelash hypotrichosis

    • adverse: iris color change, number or pigment change in eyelashes, etc.

• Prostacyclin (PGI2) analogs

  • esoprostenol (natural) and synthetics (iloprost + treprotinil) → vasodilators → pulmonary arterial hypertension

  • increase CO and O2 delivery → reduce pulmonary arterial resistance

  • short t1/2

    • iloprost → freq. dosing

  • Adverse: dizziness, headache, flushing, bronchospasm, cough

NSAIDs

• Group of chemically dissimilar agents that differ in antipyretic, analgesic, and anti-inflammatory activities

  • Salicylic acid derivatives (aspirin, salsalate)

  • Propionic acid derivatives (diclofenac, etodolac, indomethacin, ketorolac)

  • Enolic acid derivative (meloxicam)

  • Fenamates

  • selective COX-2 inhibitor (celecoxib)

• NSAIDs decrease prostaglandin synthesis → inhibiting COX enzymes

• Differences in efficacy and safety explained by COX selectivities

  • inhibit COX-2 → anti-inflammatory/analgesic

  • inhibit COX-1 → CVS events and adverse events

Aspirin and other NSAIDs mechanism/action

• Irreversible inhibitor of COX (unlike other NSAIDs)

• anti-inflammatory effects at high doses only

  • low doses → prevent CVS (stroke, myocardial infarction)

• Mechanism

  • inactivates cyclooxygenase

    • others are reversible

• Anti-inflammatory action

  • decreases prostaglandins and inflammation

• Analgesic

  • NSAIDs reduce pain by inhibiting COX-2 and reducing PGE2 synthesis

    • PGE2 sensitizes nerve endings

  • NSAIDs have equivalent analgesic efficacy, mild-moderate musculoskeletal pain

    • ketorolac → more severe pain

• Antipyretic effect

  • reduce PGE2 synthesis/release → reset thermostat to normal

  • no effect on normal temp

Aspirin and other NSAIDs therapeutic uses

• Anti-inflammatory and analgesic uses

  • trt of osteoarthiritis, gout, RA, and common conditinos (headache, arthralgia, myalgia, dysmenorrhea)

  • Combining NSAIDs with opioids → malignancy pain

    • Addition of NSAIDs → lower opioid dose

  • Lower doses of salicylates are analgesic, higher are anti-inflammatory

• Antipyretic use

  • aspirin, ibuprofen, naproxen → fever

  • aspirin avoided in patients <19 yrs + viral infections → prevent reye syndrome

• Cardiovascular applications

  • irreversibly inhibits TXA2 synthesis → reduces vasoconstriction and platelet aggregation

  • low dose aspirin used prophylactically to reduce recurrent CVS

  • chronic use of aspirin allows for continued inhibition as new platelets generated

• External applications

  • Salicylic acid is keratolytic → acne, corns, calluses, warts

  • Methyl salicylate → counterirritant → arthritis creams and sports rubs

  • Diclofenac → topical for OA

  • Ocular ketorolac → conjunctivitis + inflammation + pain in ocular surgery

Aspirin NSAIDs kinetics and adverses

• Rapidly deacetylated by estrases → salicylate

• unionized salicylates → absorbed passively in small intestine

• Cross BBB, placenta, and absorbed through intact skin

• salicylates hepatically metabolized and cleared renally at low doses

  • low dose → decrease uric acid

• high doses of aspirin → zero order kinetics

• Other NSAIDs

  • well absorbed orally, plasma protein bound, metabolized hepatically, renal excretion

• Adverse

  • GI

    • dyspepsia, bleeding

    • PGE2 and PGF2a produced by COX-1 → protective mucus

    • inhibit COX-1 → reduces beneficial levels → increased gastric acid secretion, reduced mucus → GI bleeding and ulcers

  • Take NSAIDs with food or fluids

  • High risk GI patients → proton pump inhibitors / misoprostol

  • Increased bleeding risk

    • inhibits COX-1 TXA2 → reduced platelets → no first step in thrombus formation → prolonged bleeding time

    • withhold aspirin 1wk prior to surgery

    • Non-aspirin NSAIDs not used for anti-platelet effects, can still prolong bleeding

    • patients taking aspirin for CVS avoid NSAID concomitant

  • Renal effects

    • reduce PGE2 and PGI2 → for renal BF

    • cause Na/H2O retention → edema

    • heart failure/CKD most at risk

    • antihypertensive meds reduced efficacy

    • renal injury

  • Cardiac effects

    • COX-1 → protective effect (reduce TXA2)

    • Selective COX-2 reduced PGI2 (increase risk for cardiovascular events)

    • CVS disease → avoid NSAIDs besides aspirin, naproxen least harmful is CVS and NSAID necessary

  • Other

    • can cause more leukotriene production → asthma exacerbations

      • NSAIDs + asthma caution

    • CNS: tinnitus, headache

    • 15% taking aspirin have hypersensitivity rxn

      • urticaria, bronchoconstriction, angioedema

• Drug ints

  • Salicylates are 80-90% plasma protein bound

    • displaced from protein binding sites → free salicylate

    • or displace other highly bound protein drugs → increase their free conc.

• Toxicities

  • salicylism

    • hyperventilation, mental confusion, tinnitus

  • severe salicylism

    • restlessness, delirium, hallucinations, convulsions, coma, etc.

  • children prone

• Pregnancy

  • NSAIDs only if benefits outweigh risks

  • acetaminophen preferred

  • third trimester → avoid NSAIDs → risk of premature closure of ductus arteriosus

Celecoxib

• Selective COX-2 reversible inhibitor

• Uses

  • rheumatoid arthritis (RA), osteoarthritis, acute pain

• Kinetics

  • dose adjustment for hepatic impairment, avoid in extensive renal/hepatic impairment

• Adverse

  • dyspepsia, abdominal pain

  • less GI bleeding than other NSAIDs and dyspepsia than others (lost when combined with aspirin)

  • CVS

  • anaphylactoid rxns to NSAIDs

  • fluconazole → increase serum lvls

Acetaminophen

• inhibits prostaglandins in CNS → antipyretic and analgesia

• less effect on COX in peripheral tissues → weak NSAID activity

• no effect on platelets

• not an NSAID

• uses

  • pain and fever

    • choice in children

  • gastric risks/complaints

• kinetics

  • portion → NAPQI → liver damage

  • normal doses of acetaminophen → NAPQI reacts with glutathione in liver → nontoxic substance

• Adverse

  • depletes glutathione at large doses → NAPQI → hepatic necrosis

    • high risk patients → hepatic impairments

    • N-acetylcysteine antidote

    • avoid in patients with hepatic impairment

Disease modifying antirheumatic drugs (DMARDs)

• Inappropriate activation of immune system → inflammation/immune mediated diseases like RA

  • In RA, WBCs view synovium as outsider → initiate inflammatory attack

  • WBC → more T-lymphocytes → more monocytes/macrophages → more pro-inflammatory cytokines (TNF-a and IL-1)

  • B lymphocytes → rheumatoid factor and other antibodies → maintain inflammation → further joint damage, pain

• Pharmacotherapy for RA → anti-inflammatories and immunosuppressive agents

• Goals

  • reduce pain/inflammation

  • halt/slow disease progression

• Traditional DMARDs (methotrexate, hydroxychloroquine, leflunomide, sulfasalazine) in RA

  • slow course of disease, induce remission, prevent further joint destruction

• Start ASAP to prevent progression

  • monotherapy with DMARDs initiated

  • additional DMARD added later

• NSAIDs/glucocorticoids also used

Methotrexate

• Folic acid antagonist → inhibits cytokine and purine biosynthesis → immunosuppressive/anti-inflammatory effects

• Mainstay trt for RA (alone or combo)

  • 3-6wk response time

  • much lower dose than needed for cancer chemo

Hydroxycholorquine

• Early, mild RA or combined with methotrexate

• Unknown mechanism, 6wk-6mo effect time

• Adverse

  • less adverse effects on liver/immune system

  • ocular toxicity (retinal damage and corneal deposits), CNS disturbances, etc

Leflunomide

• Causes cell arrest of autoimmune lymphocytes

• Mechanism: inhibits dihydroorotate dehydrogenase → inhibits pyrimidine synthesis

• Uses

  • trt of RA alone or in combo

Sulfasalazine and Glucocorticoids

• Sulfasalazine

  • similar to leflunomide for RA, mechanism unclear

  • 1-3mo onset, GI adversities

• Glucocorticoids

  • potent anti-inflammatory, provide symptomatic relief and used until DMARDs are effective

  • long term use → many adversities, used at lowest dose and shortest duration possible

Biologic Therapies in RA (biologic DMARDs)

• IL-1 and TNF-a are pro-inflammatory cytokines involved in RA

  • WBC increase → increased T-lymphocytes → monocytes and macrophages → TNF-a and IL-1 increase

• Biologic DMARDs

  • TNF-a inhibitors (etanercept)

  • IL-6 receptor antagonists

  • Costimulation blocker → abatacept

  • Anti-CD20 antibody → rituximab

• Biologic DMARDs decrease signs and symptoms of RA, decrease progression, improve physical function

  • onset is 2wks

• Biologic used when traditional dont work, recommend adding a TNF-a inhibitor or another biologic when methotrexate is nonresponsive

• Significant immunosuppressivem and immunomodulatory effects

  • Increase risk of infection

    • do not combine TNF-a inhibitors and non TNF biologic DMARDs → severe infection

Adalimumab

• Recombinant monoclonal antibody

• Binds to TNF-a and blocks interaction with cell surface TNF-a receptors

Certolizumab

• Humanized antibody → neutralizes actions of TNF-a

• SQ biweekly

• Same adverses

Etanercept

• Fusion protein → binds to TNF-a → blocks interaction with cell surface receptors

• Combo of etanercept and methotrexate → more effective than either alone

• SQ weekly

Golimumab

• Binds to TNF-a → neutralizes biological activity

• SQ 1mo with methotrexate

• may increase liver enzymes

Infliximab

• Binds to TNF-a and inhibits binding

• Not indicated for monotherapy

  • development of anti-inflixmab antibodies → reduces efficacy

  • combo MTX

Tocilizumab and Sarilumab

• Recombinant monoclonal antibodies → bind to IL-6 and inhibit activity

Biologic DMARDs: Abatacept and Rituximab

• T lymph need 2 interactions to become active

  • antigen presenting cell (macrophage/B)

  • CD80/CD86 protein on antigen presenting cell must interact with CD28 on T cell

• In RA, B lymph perpetuate inflammatory responses through

  • Activating t lympho

  • producing antibodies and rheumatoid factor

  • producing pro-inflammatory cytokines

• Abatacept

  • recombinant fusion protein + costimulator modulator

  • competes with CD28 for binding to CD80/86 → reduces T cell activation

  • IV every 4 wks

• Rituximab

  • Chimeric murine/human antibody against CD20 antigen found on B lymphocytes

  • IV every 16-24wks → B cell depletion

Tofacitinib, Baricitinic, Upadacitinib

• Janus kinases → enzymes that modulate immune cell activity in response to binding of inflammatory mediators

• These drugs inhibit janus kinases

• Used to trt RA with tolerance to methotrexate/TNF-a inhibitors

• Many drug ints!!

Drugs used for trt of gout

• Metabolic disorder → high levels of uric acid in blood

  • hyperuricemia → imbalance between production/and excretion of uric acid

  • causes urate crystals in tissues (joints and kidneys)

  • crystals → inflammatory response → infilitration of granulocytes

• Signs/symptoms

  • pain, swelling, tenderness, and redness in affected joints

• Goal

  • lower uric acid level below saturation point

  • interfere with uric acid synthesis

  • increasing uric acid excretion

Trt of acute gout vs chronic gout

• Acute gout

• Several conditions cause acute gout (diet rich in purines, kidney disease, alcohol consumption)

• Effective agents

  • NSAIDs

  • Corticosteroids

  • Colchicine

• Intra-articular administration of corticosteroids when one or two joints affected

• Systemic for extreme cases

• Prophylactic urate lowering therapy recommended if

  • 2+ gout attacks a yr

  • CKD, kidney stones, tophi

• Chronic gout

  • reduce freq of attacks and complications

• trt includes

  • inhibit uric acid synthesis

    • xanthine oxidase inhibitors → reduce uric acid synthesis

    • 1st line

  • Increase uric acid excretion

    • 2nd line

  • Rapid changes in serum urate concentrations by starting urate lowering therapy can precipitate acute gout

    • low dose cholchicine

    • NSAIDs

    • corticosteroids

Colchicine

• Acute gout attacks, neither uriosuric or analgesic, relieves pain

• Mechanism

  • binds and depolymerizes tubulin → reduces neutrophil migration into the inflamed joint

  • binds to miotic spindles and blocks cell division

• Uses

  • anti-inflammatory activity for gout, 12 hrs

  • prophylactically to prevent acute gout attacks in patients

Allopurinol

• Xanthine oxidase inhibitor and purine analog → decreases uric acid synthesis

• Uses

  • gout and hyperuricemia secondary to other conditions

    • well tolerated and preferred over others in this class

  • Acute gout attacks may happen more freq in first months of therapy

  • Colchicine, NSAIDs, corticosteroids, given concurrently to control acute attacks

Febuxostat

• Xanthine oxidase inhibitor similar to allopurinol

• less renal elimination, less adjustment for GFR

• greater risk of heart disease

ProbeneCid

• uricosuric drug

• blocks PCT reabsorption of uric acid

• avoid if creatinine clearance is low

Pegloticase

• Recombinant form of enzyme urate oxidase or uricase

• converts uric acid → allantoin → nontoxic renal excrete

• For patients who fail with xanthine trt

• IV every 2wks

• Anaphylaxis adversities

Intro to antibacterial chemo

• Takes advantage of biological difference between humans and bacterial cells

• Exhibit selective toxicity to bacteria

• Selective toxicity is relative

• Factor that need to be considered when selecting proper agent

  • Identify infecting microorganism

  • susceptibility of invader

  • site of infection

  • patient factors

  • safety of agent

  • cost of therapy

Selection of antimicrobial agent: identification

• Sample examination prior to treatment

• Gram staining

  • rapid assessment

  • identifies morphological features of organism in sterile body fluids

• Bacterial culture

  • for conclusive diagnosis and susceptibility

  • done before trt

• Other techniques

  • microbial antigens

  • DNA/RNA detection

  • Host immune response detection

Selection of antimicrobial agent: Empiric therapy

• Needed for critically ill patients

  • ideally, start after infecting organism is identified and susceptibility is determined

• Timing

  • acutely ill patients req immediate trt

  • should start after specimen collection for lab analysis but before results

• Selecting a drug

  • depends on infection site and medical history

  • broad-spectrum therapy may be indicated when infective agent is unknown or poly-microbial infection

Selection of antimicrobial agent: Susceptibility of invaders

• Susceptibility guides choice of antimicrobial therapy

  • some have predictable susceptibility (streptococcus pyogenes, neisseria, meningitids)

  • most gram-negative bacteria → unpredictable and req testing

• Bacteriostatic vs bactericidal

  • bacteriostatic → arrest proliferation, immune system the eliminates

    • stop prematurely → second round infection

  • Bactericidal → kill the bacteria

    • choice for immunocomprised patients and seriously ill

• Minimum inhibitory conc (MIC)

  • lowest conc that prevents visible bacterial growth

  • measure of susceptibility

• Minimum bactericidal conc (MBC)

  • lowest conc that causes 99.9% decline in colony count

Selection of antimicrobial agent: effect of the site of therapy (the BBB)

• Antibiotic should reach site of infection in effective conc

• Natural barriers to drug delivery formed via capillary structure of tissues

• Brain capillaries specifically

• The following factors control entry of antibacterial agents in CSF

  • drug lipid solubility

    • lipid soluble (chloramphenicol and metronidazole) penetrate CNS

    • B-lactam antibiotics (penicillin) → limited penetration

    • Meningitis → BBB disrupted → can enter then

  • Molecular weight

    • low weight drugs → cross BBB

  • Protein binding

    • extensive binding → no crossing

Selection of antimicrobial agent: Patient factors

• Overall CAUTIONS:

  • renal: vanomycin, aminoglycosides

  • hepatic: erythromycin/doxycycline

  • young pts: tetracyclines/fluroquinolones

  • pregnancy: teratogenics

who care

• Immune system

  • Alcoholism, diabetes, HIV, malnutrition, autoimmune disease, pregnancy, can affect immunocompetence

  • Immunocompromised may req more intensive antibiotic therapy

• Renal Function

  • evaluated by serum creatinine lvls

  • poor kidney function → accumulation of certain antibiotics

  • monitoring serum lvls may be needed (vanomycin, aminoglycosides)

• Hepatic function

  • erythromycin/doxycycline → caution

• Poor perfusion

  • decreased circulation to areas reduces amount of antibiotic that reaches that area → difficult to trt infections

• Age

  • Elimination processes suboptimal in infants and elderly

    • higher risk of accumulation toxcitity

  • tetracyclines and fluroquinolones → risky for young pts → bone development

• Pregnancy + Lactation

  • many cross placenta barrier or enter breast milk

  • teratogenics → unsafe for fetus/infant

• Risk of multi-drug resistance organisms

  • common risk factors like prior anti-microbial therapy, hospitilization, immunosuppressive diseases)

  • broad spectrum coverage needed

Selection of antimicrobial agent: Safety and cost

• Safety

  • penicillin are least toxic and target a unique process in bacteria

  • other antibiotics less specific → cause toxicity

• Cost of therapy

  • many drugs have similar effects, varying costs

  • ex: trt of methicillin resistant staphylococcus aureus (MRSA)

    • vancomycin, clindamycin, daptomycin, or linezolid

    • cost is important

Route of administration

• Oral route is preferred

  • outpatient and economical

  • different degrees of bioavailability

• Parenteral route

  • used for antibiotics poorly absorbed by GIT

    • vancomycin, aminoglycosides

    • hence why they come out in the peepee and not the poopoo

Determinants of rational dosing

• Based on dynamics and kinetics

• 3 important things to consider

  • Conc-dependent killing

    • bacteria killed increases w/ conc.

    • aminoglycosides

  • Time dependent killing (conc. independent)

    • b-lactams, glycopeptides, macrolides, clindamycin, linezolid

    • efficacy calculated by time conc. is above MIC

  • Post antibiotic effect (PAE)

    • Growth suppression even when conc. is below the MIC

    • once daily dosing

Chemotherapeutic spectra

• Narrow spectrum antibiotics

  • act only on a single or limited group of organisms

  • isoniazid → only for mycobacterium tuberculosis

• Extended spectrum antibiotics

  • gram + and quite a few gram -

  • ampicillin

• Broad spectrum

  • effective against a wide variety of organisms

  • tetracyclines, fluoroquinolones, carbapenems

  • precipitate super infection (C diff)

Combinations of antimicrobial drugs

• Single agent is preferable and should

  • minimize toxicity

  • reduce emergence of resistance

  • reduce superinfection

• Some situations req combo of antibiotics

• Advantages of combos

  • Synergism

    • more effective than either alone

    • B-lactams + aminoglycosides

  • Infection of unknown origin

  • Presence of organisms of variable sensitivity

• Disadvantage

  • selection pressure and resistance development

  • drug interactions

  • more toxicities

  • wasted potential

Drug Resistance

• When max tolerated dose does not stop proliferation

• Some are inherently resistant

  • most gram - → resistant to vancomycin

• Bacteria develop resistance by

  • spontaneous mutation or acquired resistance

  • pressure selection

• Mechanisms of resistance

  • Genetic alterations happen when

  • DNA undergoes spontaneous mutation

  • DNA moves on from one organism to another

• Altered expression of proteins

  • modification target sites: alteration of antibiotic target site → resistance to one or more related antibiotics

    • Resistance to B-lactam → altering 1+ penicillin binding proteins → decreased binding of target antibiotic

  • Decreased accumulation: decreased uptake or increased efflux → drug cannot reach action site in sufficient conc

    • Gram - → reduce penetration of B-lactams by changing structure of porins

    • Efflux pumps reduce intracellular drugs

  • Enzymatic inactivation

    • B-lactamases → inactivate ring of penicillins

    • Acteyltranferases → chloramphenicol or aminoglycosides by transferring acetyl

    • esterases → hydrolyze lactone ring of macrolides

Prophylactic use of antibiotics

• Certain situations req prophylactic use of antibiotics

• Indiscriminate use → resistance and superinfection

  • should be restricted to situations where benefits > risks

  • duration should be

    • reduced to a minimum

    • monitored to prevent resistance

Complications of antibiotic therapy

• Hypersensitivity

  • occurs freq

    • penicillins → hives to anaphylaxis

    • Stevens-johnson syndrome patients or toxic epidermal necrolysis → rxn to antibiotic should never be rechallenged

• Direct toxicity

  • cause toxicity by directly affecting hosts cellular processes

  • Aminoglycosides → ototoxicity

• Superinfections

  • Drug therapy can change normal microbial flora → opportunistic organisms to grow

    • req secondary trt

Cell Wall Inhibitors

• interfere with synthesis of cell wall

  • composed of peptidoglycan polymer linked via cross-links

• req actively proliferating for max efficacy

• Most important members of this group

  • B-lactam antibiotics

  • Vancomycin

  • Daptomycin

Penicillins

• Cell wall inhibitors

• Penicillins

  • Widely effective with min toxicity but resistance reduced efficacy

  • Mechanism of action

    • interfere with last step of cell wall synthesis → expose unstable membrane

    • Cell lysis → osmotic pressure or by activating autolysins

    • time dependence

    • effective against rapidly growing organisms+peptidoglycan cell wall

    • Penicillin binding proteins (PBPs)

      • inactivate PBPs on bacterial membrane

      • PBPs involved in cell wall synthesis

      • cause morphological changes or lysis

      • alterations in PBPs confers → resistance to penicillins

    • Inhibition of trans-peptidase

      • PBPs catalyze cross linkages of peptidoglycan chains

      • reduces formations essential for wall integrity

    • Production of autolysins

      • bacteria produce degradative enzymes → remodeling of wall

      • penicillin block cell wall formation before autolysin action

      • cause cell wall inhibition and destruction of existing wall of autolysins

  • Antibacterial spectrum

    • depends on ability of drug to penetrate and interact with PBPs

    • Factors affect spectrum include size, polarity, and hydrophobicity

    • Gram + → easily permeated by B-lactam

    • Gram - → outer liposaccharide membrane → barrier to water-soluble B-lactam

      • permeate through porins

Penicillin antibacterial spectrum

• Natural: amoxicillin and ampicillin (extended spec)

  • susceptible to inactivation

  • used for gas gangrene and syphilis

• Antistaphylococcal: methicillin, oxacillin, dicloxacillin

  • resistant to B-lactamases

  • MSSA and MRSA

    • no gram - infections

• Uses

  • URI

  • prophylactic dentistry

• Antipseudomonal: Pipercillin and Ticarcillin

  • P. aeruginosa

  • + B-lactamase inhibitors to extend spectra

Penicillins (resistance)

• resistance

  • natural resistance occurs with absence of peptioglycan wall (mycoplasma pneumonia)

  • Acquired via plasma mediated genetic alterations (B-lactamases)

• B-lactamase activity

  • enzymes hydrolyze b-lactam rings → loss of drug activity

  • major cause of resistance

  • gram + → secrete B-lactamase extracellularly

  • Gram - → inactivate B-lactam in periplasmic space

• Decreased drug permeability

  • drugs fail to reach target PBPs

  • efflux pumps reduce drug conc intracellularly (Klebsiella pneumoniae)

• Altered PBPs

  • modified PBPs reduced affinity for B-lactam antibiotics

Penicillin kinetics/adversities

• Absorption

  • incompletely absorbed and sensitive to acid

  • alters intestinal flora

  • food decreases absorption

• Distribution

  • well distributed, not to CNS unless inflamed

• Elimination

  • tubular secretion/GF

• Adverse

  • Hypersensitivity

    • 5% of pop

    • rashes → angioedema and anaphylaxis

    • cross allergic rxns

  • Diarrhea

    • disruption of normal bacterial flora

    • worsens with incomplete absorption

    • pseudomembranous colitis (C diff)

  • Nephritis

    • common with methicillin

  • Neurotoxicity

    • penicillins block GABA and cause seizures

  • Hematologic toxicity

    • decreased coagulation and cytopenia

Cephalosporins

• more resistant to B-lactamase + CNS

• Antibacterial spectrum

  • 1st gen

  • MSSA + ecoli, pneumoniae, proteus mirabilis

  • 2nd gen

  • 3 additional gram - → H influenzae, enterobacter aerogenes, neisseria

  • cefotetan + cefoxitin → anaerobes

  • 3rd gen

  • enhanced gram - bacteria

  • ceftriaxone and cefotaxime → meningitis

  • ceftazidime → P. aeruginosa

  • 4th gen

    • cefepime

  • advance gen

    • ceftaroline → MRSA, skin infections, and pneumonia

Carbapenems

• Synthetic B-lactam antibiotics

• Imipenem (anything -enem)

  • cilastatin for protection

• Antibacterial spec

  • resists hydrolysis by B-lactamase

  • active against B-lactamse + and - organisms, P. aeruginosa

• Kinetics

  • Imipenem → IV + CSF

Monobactams

• Aztreonam

• resistant to B-lactamases

• Antibacterial

  • gram + pathogens, P. aeruginosa

B lactamase inhibitors

• Contain B-lactam ring but do not have antibacterial activity

• protect antibiotics from inactivation

Vancomycin

• Mechanism

  • binds to peptidoglycan precursors → disrupt polymerization → bactericidal

• Uses

  • MRSA, MRSE, and enterococcal infections

  • IV for prosthetic heart valves and patients undergoing implantation

  • Resistant strain emergences → restrict use of vancomycin to serious infections

Daptomycin

• conc dependent (unlike penicillin)

• alt for trt of MRSA, resistant gram +, vancomycin resistant bacteria

• uses

  • trt of skin and skin structure infection

  • never used in pneumonia

Telavancin

• glycopeptides

• Mechanism

  • inhibits bacterial wall synthesis like vancomycin

  • disrupts cell membrane

• Uses

  • alternative to vanco/dapto for skin infections, resistant gram +

  • hospital acquired/ventilator bacterial pneumonia

Fosfomycin

• Mechanism

  • blocks cell wall synthesis by inhibiting enzyme

• Uses

  • UTIs caused by E coli or E. faecalis

  • one time dose for UTIs

Polymyxins

• Detergent disrupts cell membrane → leakage

• 2 forms of polymyxins used

  • Polymyxin B → parenteral, opthalmic, otic, topical

  • Colistin → IV/inhaled

• salvage therapy for those with multi-drug resistance

Intro to antibacterial pt 2

• Several antibiotics exert effects by targeting bacterial ribosomes → inhibit protein synthesis

• Different from mammalian ribosomes

  • bacterial → 30S/50S subunits

  • mammalian → 40S/60S

• Targeting bacterial ribosomes → reduce adverse rxns

• Mitochondrial ribosomes resemble bacterial ribosomes

  • high conc of chloramphenicol or tetracyclines → toxicity

Tetracyclines

• Mechanism

  • reversibly bind to 30S subunit of ribosome

    • prevents binding of tRNA → inhibits protein synthesis

• Antibacterial spec

  • broad spectrum bacteriostatic

• Uses

  • acne + chlamydia

• Resistance

  • efflux pumps (most common)

  • enzymatic inactivation

  • produce proteins that prevent binding to ribosome

• Distribution

  • calcifying tissues

  • Minocycline/doxycycline → CNS

  • Minocycline → saliva/tears

Glycylcyclines (Tigecycline)

• Mechanism

  • bacteriostatic, reversibly binds to 30S subunit

• Antibacterial spec

  • broad spec

    • MRSA, multi-drug resistant streptococci, VRE, Acinetobacter baumannii

  • Tigecycline → inactive against morganella, proteus, providencia, pseudomonas

• Resistance

  • overexpression of efflux pumps

• Kinetics

  • IV, large Vd, hepatic dose adjustment

• Adverse

  • acute pancreatitis

  • discoloration of teeth

Aminoglycosides

• serious infection due to aerobic gram -

• Mechanism

  • through porin channels → 30S

  • conc dependent bactericidal drug

  • Have post-antibiotic effect (PAE)

• Antibacterial spec

  • Broad spec → multidrug resistant strains

Macrolides and Ketolides

• Erythromycin

  • 1st clinical application

  • drug of first choice, alternative to penicillin allergists

• Clarithromycin/azithromycin

  • improved erythromycin

• Telithromycin

  • first “ketolide” agent

  • keto → macro resistant gram +

• Mechanism

  • irreversibly bind to 50S subunit → inhibit protein synthesis

  • Bacteriostatic, bactericidal at higher doses

• Antibacterial Spec

  • respiratory infections

  • preferred for urethritis

Clindamycin

• Mechanism

  • irreversibly binds to 50S (macrolide)

• Antibacterial spec

  • gram + organisms → MRSA, streptococcusm anaerobic bacteria

• Resistance

  • C diff always resistant to clinda

• Adverse

  • clinda → C diff

Fidaxomicin

• Mechanism

  • sigma subunit of RNA polymerase → disrupt transcription → cell death

• Antibacterial spec

  • very narrow spectrum of activity

  • C Diff

Oxazolidinones (linezolid/tedizolid)

• Mechanism

  • bind to 23S of 50S subunit

  • Uses: Alternative to daptomycin for VRE

Lefamulin

• 1st antibiotic → community-acquired pneumonia (CAP)

• Mechanism

  • 50S subunit

• Antibacterial spec

  • bacteriostatic → S aureus/strep pyogenes

  • Bactericidal → S. pneumoniae, mycoplasma pneumoniae, H. influenzae

Chloramphenicol

• Mechanism

  • binds reversibly to 50S

• Uses: life-threatening infections with no alternatives

Quinupristin/Dalfopristin

• Mechanism

  • bind to separate sites on 50S, long PAE

  • Dalfo → disrupts peptide chain elongation

  • Quin → terminates elongation prematurely

• Uses: severe VRE infection with absence of other options

Fluoroquinolones

• Great efficacy, broad spec, safe

• closely tied to C diff infection

• Mechanism

  • binds to DNA gyrase (gram -) and topoisomerase IV (gram +) → block DNA ligation → cell death

• Adverse

  • boxed warnings → tendinitis, tendon rupture

  • QT prolongation

• Examples of clinically useful fluoroquinolones

• Ciprofloxacin

  • traveler’s diarrhea, typhoid, anthrax

  • 2nd → intra-abdominal, lung, skin, urine infections

• Levofloxacin

  • 1st line → CAP

• Gemifloxacin

  • broad spec → CAP

• Delafloxacin

  • broad spec → MRSA/enterococcus

  • acute bacterial skin and skin strucute infection, CAP

Folate Antagonists

• Nucleic acid synthesis reqs folic acid, cell proliferation halts without folic acid

• Two classes of antibiotics that block folic acid

  • Sulfonamides: inhibit de novo synthesis of folate

  • Trimethoprim: blocks conversion of dihydrofolic → tetrahydrofolic acid

  • both interfere with DNA synthesis

  • combining the two → synergistic

Sulfonamides

• Effective and low cost

• Mechanism

  • inhibit folic acid synthesis by competing for dihydropteroate synthetase

• Antibacterial spec

  • broad spec

  • UT and nocardia infections

  • Sulfadiazine + pyrimethamine → toxoplasmosis

  • Sulfadoxine + pyrimethamine → malaria

Trimethoprim

• Mechanism

  • inhibits folic acid activation

• Antibacterial spec

  • resembles sulfamethoxazole

    • greater potency

  • UTIs or prostatitis

Cotrimoxazole

• Combo of trimethoprim and sulfamethoxazole

• Mechanism

  • inhibits 2 sequential steps in folic acid activation

• Uses

  • UTI, prostatitis, respiratory, soft tissue infections

urinary tract antimicrobials

• UTIs most common bac infection

• prevalent in women/elderly

• Causative pathogens

  • E. coli (80%)

  • Staphylococcus Saprophyticus

• Trt options

  • cotrimoxazole and fluroquinolones

  • methenamine, nitrofurantoin, fosfomycin

    • concentrate in urine

Methenamine

• Mechanism

  • acidic media → ammonia and formaldehyde

  • denatures bacterial proteins and nucleic acids → death

    • do not develop resistance to formaldehyde

• Antibacterial spec

  • chronic suppressive therapy to reduce UTI freq

Nitrofurantoin

• Mechanism

  • inhibits DNA, RNA, protein synthesis

  • inhibits enzymes and damages DNA

  • resistance less likely

• Antimicrobial spec

  • gram - and + in UT

  • E coli, klebsiella, enterococcus, staphylococcus

• Kinetics

  • 40% excreted in urine unchanged

• Adverse

  • pulmonary fibrosis, neuropathy, autoimmune hepatitis

Fosfomycin

• Mechanism

  • cell wall inhibitor

  • blocks cell wall synthesis by inhibiting enzyme that catalyzes peptidoglycan synthesis

• Uses

  • UTIs with E coli or enterococcus faecalis

• Kinetics

  • excreted in active form, high conc in urine over days → one time dose

• Adverse

  • vaginitis

Principles of cancer chemotherapy

• Should cause apoptosis or lethal cytotoxicity in cancer cells

• Target DNA or essential processes in cells

• Ideally would specifically target cancer cells

• Goal of trt

  • Eradicate neoplastic cells

    • cell burden reduced by surgery/radiation followed by chemo

  • Control disease progression

  • Extend survival

  • Improve QOL

    • in late stages, goal becomes palliation

• Indications for trt

  • when neoplasms are disseminated/surgery is not available

  • supplemental trt to attack micrometastases after surgery

    • adjuvant chemo

  • neoadjuvant chemo → prescribed prior to surgery to control size

  • maintenance chem → prolong remission

Tumor susceptibility and growth cycle

• Cancer cells in their replicated cycle influence susceptibility to chemo

  • rapidly dividing cells → more sensitive to therapy

  • non-dividing cells (in G0) survive

• Cell cycle specificity

  • every cell goes through cell cycle to grow

  • drug target replicating cells → cell cycle specific

  • Cell cycle nonspecific → more effective but more toxic

• Tumor growth rate

  • starts high and then slows

  • tumor burden reduced by surgery, radiation, cell cycle nonspecific drugs

Treatment regimens and scheduling

• Dosing calc based on body surface to tailor therapy

• Log Kill Phenomenon

  • cell death follows first order kinetics

  • Ex: leukemia diagnosed when there are 10⁹ leukemic cells

    • if 99.9999% killed then 10⁴ are left

    • asymptomatic and remission

    • remaining cancer cells are not eliminated so further trt req

• Pharmacological sanctuary

  • find sanctuary in tissues like CNS where transport is constrained

  • may req radiation of craniospinal axis or intrathecal drug admin

  • drugs may not penetrate certain areas

• Trt protocols

• combo of drugs

  • drugs with diff mechanisms/toxicities prescribed together at full dose

    • potentiated response

  • drugs with similar toxicities combined at smaller doses

• Advantage of drug combo

  • max killing within tolerated toxicity

  • affects a broader range of cell lines

  • reduce/prevent resistance

• Identified by acronyms

  • ex: non-hodgkin lymphoma → R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin)

  • scheduled intermittently to reduce infection chances / allow immune system to recover

Problems associated with chemo

• Resistance

  • some cancers naturally resistant (melanoma)

  • other acquire via mutation

  • trt should be intense, short, and intermittent

• Multidrug resistance

  • P-glycoprotein → pumping drugs out of cells

  • Cross resistance → cells resistant to one drug also resistant to another

• trt induced tumorigenesis

  • antineoplastic agents are mutagens → cause DNA damage

  • secondary tumors that develop from cancer therapy do not respond to therapy strategies

• Toxicity

  • affect rapidly proliferating normal cells (GI/bone marrow)

• Common adverse effects

  • NTI

  • V, stomatitis, bone marrow suppression, alopecia

  • Myelosuppression

  • Bladder toxicity, cardiotoxicity, pulmonary fibrosis

  • tumor lysis syndrome

Antimetabolites

• Compete with normal metabolites for vital metabolic processes

  • Interfere with availability of normal nucleotide precursors

    • inhibiting nucleotide synthesis

    • interfering with DNA/RNA synthesis

  • maximally effective in S phase

Methotrexate (MTX)

• Antimetabolite

• Mechanism

  • folic acid antagonist → inhibits hihydrofolate reductase (DHFR) → inhibits pyrimidine synthesis

• Use

  • used in combo for ALL, burkitt lymphoma, breast cancer, bladder cancer, neck cancer

    • MTX derivative pemetrexed → NSCLC

    • Derivative pralatrexate → T-cell lymphoma

  • DMARD for RA, psoriasis, crohns

• Resistance

  • lack DHFR, thymidylate synthase, glutamylating enzymes

  • overamplification of DHFR

  • reducing MTX influx

• Adverse

  • Manage toxicity → leucovorin

6-mercaptopurine (6-MP)

• Used for remission of ALL

• Mechanism

  • 6-MP → TIMP by HGPRT

    • TIMP → inhibits purine/AMP

    • TIMP → nonfunctional DNA/RNA

• Resistance

  • reduced HGPRT → reduced intracellular 6-MP activation

  • increased dephosphorylation

  • increased metabolism

5-flurouracil (5-FU)

• Depletes cells of thymidine, reducing DNA synthesis

• use → slowly growing solid tumors

• Mechanism

  • converted intraceullarly to 5-FdUMP → inhibits thymidylate synthase by competing with dUMP

    • reduces DNA synthesis

    • nonfunctional RNA synthesis

• Resistance

  • reduced 5-FdUMP formation → increased thymidylate synthase lvls

Fludarabine

• used for AML, hairy cell leukemia, lymphoma

• block DNA/RNA synthesis

Cladribine

• AML, hairy cell leukemia, lymphoma

• Blocks DNA elongation, can penetrate CNS

Capecitabine

• Inhibits thymidylate synthase

• Colorectal/metastatic breast cancer

Cytarabine

• AML

• poor oral and CNS

Azacytidine

• AML

• inhibit RNA

Gemcitabine

• Pancreatic cancer and NSCLC

Anti-tumor antibiotics

• disrupt function by

  • dna intercalation

  • topoisomerase inhibition

  • free radical generation

• cell cycle nonspecific (except bleomycin)

  • doxorubicin, anything -rubicin

Anthracyclines

• Doxorubicin (red devil)

• various application

• Mechanism

  • dna intercalation and fragmentation

  • block dna/rna synthesis

  • inhibit dna repair → inhibit topoisomerase II

  • stimulate free radicals

• Kinetics

  • inactivated by GIT, IV only, vein/urine discoloration

  • poor CNS, low Vd

  • extensive hepatic metabolism

• Adverse

  • irreversible cardiotoxictiy

Bleomycin

• (G2) specific → testicular and lymphoma

• Mechanism

  • bind to DNA and iron → free radicals that attack DNA

• Resistance

  • increased bleomycin hydrolase or amidase

  • Increased efflux

  • upregulation of DNA repair mechanisms

Alkylating Agents

• Covalently bind to nucleophilic groups on various cell components → destruction of macromolecules

• cell cycle nonspecific

• mutagenic and cause secondary malignancies

  • cyclophosphamide

  • carmustine/iomustine

  • dacarbazine

  • temozolomide

  • procarbazine

  • mechlorethamine

  • melphalan

  • chlorambucil

  • busulfan

Cyclophosphamide

• Alkylating Agents

• Related to mustard agents

• single or combo utility

• Mechanism

  • activated by hydroxylation → phosphoramide mustard + acrolein → alkylate + disable DNA

• Resistance

  • increased DNA repair, decreased drug permeability, cross resistance

• Adverse

  • bladder toxicity