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Drug/Application Clinical Mechanism Drug Interactions/ CommentsUses Side Effects

Antibiotics Drugs used to treat infectious agents

Dosing: Antibiotics with low PAE – optimize the duration of time the serum is > MIC; Those with high PAE – peak conc. is important

Used in three ways: Empirical therapy1. Determine if infected2. Identify site of infection3. Ascertain possible pathogens4. Predict susceptibility5. Obtain specimens for testing Definitive therapy Prophylactic therapyPossible routes of administration: IM, SC, IV, topical

Pharmacokinetics: successful therapy depends on the drug’s ability of killing the pathogen without causing harm

Distribution: Difficult sites to access: brain, eye, prostate – contain permeability barriers

Elimination: Most eliminated by kidney unless otherwise noted

Post-antibiotic effect (PAE): suppression of bacterial growth after removal of antibiotic. PAE usually seen in gram (+) bugs, sporadically in (-) bugs.

Antibiotics that inhibit cell wall synthesis (β-lactams and glycopeptides) have minimal or no PAE against gram (-) bugs

Aminoglycosides- PAE-concentration-dependent killing

-lactams- no PAE-time above MIC determines efficacy

Direct effects: the result of direct interaction b/w the drug and/or one its metabolites and a specific tissue or organ in the body.

Hypersensitivity – Type I HS rxn, Coomb’s (+) hemolytic anemia, serum sickness, and Stevens-Johnson syndrome

Changes in microbial flora - all antibiotics may lead to pseudomembranous colitis

Drug interactions – esp. with Warfarin – enhances anti-coagulation

Host factors – genetics, age Pregnancy

Minimum inhibitory conc. (MIC) – the smallest conc. of the drug that inhibits the growth

Minimum bactericidal conc. (MBC) – the conc. of the drug that will kill the bacterium

Bactericidal: achievable blood concentration is > MBC

Bacteriostatic: achievable concentration > MIC, but below MBC

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INHIBITORS OF CELL WALL SYNTHESIS

-lactams

Bactericidal

Non-competitive inhibitors of transpeptidases (penicillin-binding proteins-PBPs)Resistance mechanisms: Inactivation of antibiotics

by β-lactamase – most common mechanism, those produced by S. aureus, hemophilus, and E. colo are relatively narrow in substrate specificity and woll hydrolyze penicillins but NOT cephalasporins

Modification of target PBP’s – mech for MRSA and penicillin resistance in pneumococci

Impaired penetration of drug to target PBP’s – presence of impermeable membram (gram neg)

Presence of an efflux pump

Possess a four member nitrogen-containing beta lactam ring

Inhibit bacterial growth by interfering with a specific step in bacterial cell wall synthesis.

Β-lactam antibiotics are structural analogs of the natural D-Ala-D-Ala substrate and are covalently bound by PBP’s at the active site.

Binding leads to inactivation of the transpeptidase reaction – inhibiting peptidoglycan synthesis.

High therapeutic index Type I – mediated by IgE –

urticaria, rhinitis, angioedema, conjuctivits, or systemic anaphylaxis

Type II – rare, interaction of IgG or IgM with antigen complement activiation, eg. Hemolytic anemia

Type III – most common – serum sickness, arthralgia, rash, fever, lymphadenopathy, or vasculitis

Type IV – CMI: cutaneous eruptions or thrombocytopenia

Cell wall is composed of a complex cross-linked polymer, peptidoglycan, consisting of polysaccharides and polypeptides

PBP in bacteria catalyze the transpeptidase reaction that removes the terminal alanine to form cross link with a nearby peptide

Penicillin Beta-lactam ring fused to a 5-member, sulfur containing thiazolidine

Modification of side chain differing properties

Inhibitor of cell wall synthesis

Penicillin allergy occurs in 0.5% of patients

* Standard penicillins Targets gram (+) Probenecid-inhibits tubular secretion of penicillin- used therapeutically

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*Penicillin G(benzylpenicillin - IV)(crystaliine penicillin G – IM)(Benzathine penicillin G – long lasting – 1 mo)

Route – IV, IM Syphilis – treated with

Benzathine penicillin G Rheumatic fever – treated

with Benzathine penicillin G

Neurosyphilis and meningitis due to S. Pneumoniae and Neisseria meningitides.

Meningococcal infection Streptococci (S. pnemo)

Pharmacokinetics – penetrates CNS in high doses

Elimination: Primarily renal (10% by glomerular filtration and 90% tubular secretion)

HS reaction: rash, serum sickness, and rare anaphylaxis

Hematologic – Coombs (+) hemolytic anemia, rare

Neuromuscular irritability/seizures – associated with high dose penicillin therapy in patients with renal failure

Probenecid - inhibits tubular secretion, can be used to increase blood concentration and prolong the half-life

Resistance – in S. pneumoniae and meningococci in some parts of the world

*Penicillin V (phenoxymethylpenicillin)

Route - Oral More stable in the presence of acid than Penicillin G

*Antistaphylococcal penicillins(Methicillin – allegic intestinal nephritis)(Nafcillin – IV, preferred to above, metabolized by liver)(Oxacillin)

Penicillin resistant staphylococci (S. aureus)

Treat methicillin-sensitive staphylococcal infections (not active against MRSA)

Stable to staphylococcal beta-lactamase

Hematologic – esinophilia Neutropenia may occur with

long course (>21d) of nafcillin

Hepatic dysfunction with high dose oxacillin

*Dicloxacillin Minor staphylococcal infections

Antistaphylococcal penicillin Structural analog of oxacillin

Well absorbed after oral administration

*Aminopenicillins Enhanced activity against gram (-) bacilli

Some streptococci Enterococci and L.

monocytogenes – has more activity against than Pen G

E. coli, proteus mirabilis, H. in fluenza, samonella, and shgella

Broad spectrum

Addition of an amino group to the penicillin side chain

Inhibitor of cell wall synthesis Not -lactamase resistant Distribution – Similar to other beta-

lactams, can reach CSF in presence of inflamed meninges

Elimination – primarily kidney, biliary excretion also occurs

Macropapular rash in patients with mononucleosis, Chronic Lymphocytic Leukemia, or on allopurinol

Spectrum: Gram (+) Gram (-) bacilli Formulated with beta-

lactamase inhibitors to increase the spectrum of activity

*Amoxicillin Route – oral Aminopenicillin *Ampicillin Route – IV

Meningitis Aminopenicillin Large dose – enters CSF

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*Antipseudomonal penicillins Same spectrum as aminopenicillins plus additional activity against gram (-) bacilli including Pseudomonas aeruginosa (used in combo with aminoglycoside)

IV

Exteded spectrum aminopenicillins Not stable against beta-lactamase Inhibitor of cell wall synthesis

Subclasses Carboxypenicillins:

ticarcillin Ureidopenicillins:

piperacillin

-lactamase inhibitors Available only in fixed-dose combination with beta-lactamase sensitive penicillins

Inhibit beta-lactamases produce by staphylococci, gonococci, H. influenza, B. fragilis, and some enterobacteriaceae

Used in the treatment of intra-abdominal infections, bite wound infection and infected cutaneous ulcers

Beta-lactamase inhibitor Contain beta-lactam ring Covalently bind bacterial -

lactamase w/o intrinsic antibiotic activity

Non-competitive inhibition

Other combinations:Ticarcillin/clavulanatePiperacillin/tazobactam

*Clavulanate (Augmentin) Used in combination with AMOXICILLIN

See above for uses

Beta-lactam antibiotic with a beta-lactamase inhibitor

*Sulbactam (Unasyn) Used in combination with AMPICILLIN

See above for uses

Beta-lactam antibiotic with a beta-lactamase inhibitor

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Cephalosporins Activity against gram (-) bacteria increases from 1st gen. to 3rd gen.

Antistaphylococcal activity decreases from 1st gen. To 3rd gen.

No loss of antistreptococcal activity

Activity against enterobacteriaceae superior to that of aminopencillins

Resistant to most -lactamases

Beta-lactam ring fused to a six-member sulfur-containing dihydrothiazine ring

Individual cephalosporins are created by side-chain substitutions


Approximately 10% cross-allergenicity between cephalosporin and penicillin

Avoided in patients who show IgE-mediated penicillin allergy

Classified into different generations based on their spectrum

First Generation Cephalosporin Activity against Streptococci Staphylococci E. coli P. mirabilis Klebsiella pneumoniae Useful against skin and

soft tissue infections due to streptococcus pyogens or S. aureus

Prophylaxis against infection following surgical procedures

Used as alternatives to penicillins in penicillin=allergic individuals

*Cefazolin IV only Skin/soft tissue infections

1st generation

*Cephalexin (Keflex) Oral 1st generation

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*Second Generation Cephalosporin

Genrally used against mixed aerobic/anaerobic infections

Against B. fragilis (ONLY 2nd gen)

Activity against H. influenzae (β-lactamase producers or not)

Community-acquired respiratory tract infections due to S. pneumoniae or H. influenzae

Against enterobacteriaceae

Children infections: streptococci, S. aureus, and H. influenzae

Not used for meningitis

Cefuroxime Cefprozil

*Third Generation Cephalosporin - look for the “t” for third

Increased activity against aerobic gram (-) bacilli

Esp. against Enterobacteriaceae and H. influenza

Reduced activity against S. aureus

Treat nosocomial pneumonia: gram - bacilli

IV

Stable to beta-lactamases that are produced by H. influenza and N. gonorrhoeae, and many of those produced by enterobacteriaceae

NOT effective against type I chromosome mediated inducible cephalosporinase produced by Enterobacter sp., citrobacter freundii, serratia marcescens, and P. aeruginosa

Oral form is available but has reduced activity, only used for enterobacteriaceae

*Cefotaxime Activity against meningeal pathogens (S. pneumoniae, N. meningitidis, and H. influenzae)

3rd generation Enters CNS

*Ceftriaxome Activity against meningeal pathogens (S. pneumoniae, N. meningitidis, and H. influenzae)

3rd generation Enters CNS

*Ceftazidime Active against P. aeruginosa

3rd generation

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*Fourth Generation Cephalosporin

Excellent activity against enterobacteriaceae and P. aeruginosa

Good activity against S. aureus

Cefepime – IV NO activity against:MRSAEnterococciListeriaB. fragilis

Carbapenems Broadest spectrum of all antibiotic

Beta-lactam ring fused with a 5-member carbon containing penem ring


Meropenum – similar activity as imipenem but does not produce toxic metabolite and is slightly more active against aerobic gram (-) bacilli and less active against gram (+) cocci

*Imipenem

‘Rambocillin- blows everything away, including your kidney’

Very broad spectrum IV onlyUsed against Streptococci Enterobacteriaceae P. aeruginosa Hemophilus species Anaerobic bacteria, inc. B.

fragilis

Has better penetration and access (through pore channels) to the periplasmic space in gram (-) bacteria

Resistant to -lactamases Pharmacokinetics: low oral

bioavailability, well distributed to most tissue, and excreted by the kidneys

Seizures Elimination: broken down by

the kidney by human beta-lactamase (dehydropeptidase-1) to a nephrotoxic metabolite

ALWAYS co-administered with Cilastatin, a dehydropeptidase-1 inhibitor

NOT active against enterococcus faecium, legionella, mycoplasma, or chlamydia sp.

Monobactams Monocyclic beta-lactam – single ring structure attached to a sulfonic acid group

*Aztreonam

‘A bullet through an AZ tree is a negative thing’

Targets aerobic gram (-) bacilli inc. P. aeruginosa

No activity against gram (+) bacteria or anaerobes

IV only

Only binds transpeptidases of gram (-)

Essentially nonallergic

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Glycopeptides *Vancomycin - Bactericidal‘Vanquishes gram (+)’

Targets gram (+) bacteria -esp. those resistant to -lactams

MRSA β-lactam resistant strains

of coagulase (-) staphylococci, enterococci, and pneumococci

Serious infections with S. aureua, enterococci in pts. intolerant of β-lactam antibiotics

Given orally for C. dificile Used as an IV Endocarditis prophylaxis

for selected GU or GI procedures in β-lactam intolerant pts.

Inhibits cell wall synthesis Covalently binds terminal two D-

alanine residue at the free carboxyl end of pentapeptide

Sterically hinders the elongation of peptidoglycan backbone

Unable to penetrate the cell membrane of gram (-) bacteria

Low oral availability Excreted unchanged by the kidneys,

half-life = 6 hrs Diffuses across serous membranes

into pleural, pericardial, synovial, and ascitic fluid

Enters CNS only at high doses Unaffected by beta-lactamase

production or PBR alteration

No cross-reactivity between beta-lactams and vancomycin

Patients with anuria, half-life = 7 days

Nephrotoxicity Ototoxicity ‘Redneck’ or ‘red-man’

syndrome- histamine release w/ rapid infusion-slow infusion better

15% of enterococci resistant to vancomycin

Vancomycin-resistant enterococci (VRE) is often resistant to all other antibiotics incurable

VanA – Genes are carried on Transposable elements thant encode enzymes responsible for resistance

D-Ala-D-Ala terminal is converted to D-Ala-D-lactate on resistant enterococci

S. aureus strains gaining enterococcal transposon

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INHIBITOR OF PROTEIN SYNTHESIS

Ribosomes are the site of protein synthesis in both prokaryotic and eukaryotic

The differences in ribosomes between bacteria and humans provide a useful target for antibiotics

Selective toxicity for bacteria

Ribosomes: Bacteria – total 70SSmall: 30S = 16S + 21 proteinsLarge: 50S = 23S 5S rRNA’s + 21 proteins Humans – total 80SSmall: 40SLarge: 60S

*Aminoglycosides

‘A mean guy hits his opponent in the ear and kidney. He drops, paralyzed.’

Bactericidal for aerobic gram (-) bacteria, staphylococci (in combo), and mycobacteria (in combo)

Used only in serious infections due to enterobacteriaceae and P. aeruginosa and in a hospital setting

IV only Once daily dosing/ single

large dose – conc. dependent killing therefore the peak conc./MIC ration is the best predictor of bacterial killing

Significant post antibiotic effect (PAE)

Synergistic w/ penicillins

Irreversible inhibitors of protein synthesis

Crosses outer membrane through porin channels (passive diffusion)

Then actively transported across the cell membrane by an oxygen dependent mechanism

Binds IRREVERSIBLY to the 30S ribosomal subunit

Blocks initiation of protein synthesis Blocks further translation and elicits

premature termination Incorporation of incorrect amino

acid Absorbed poorly for GI Highly polar compounds – don’t

enter cell readily Low intracellular conc. except in

proximal renal tubule Do NOT enter CSF Excreted by kidneys – glomerular

filtration Half-life = 2-3 hr Consist of two or more amino sugars

linked by glycosidic linkage to a hexose nucleus

Nephrotoxicity – concentrates in renal tubules - Reversible- Increased when combined with another nephrotoxic drug

Ototoxicity (auditory and vestibular) - permanent

Risk of toxicities are dose and duration dependent

Control with MONITORING Neuromuscular paralysis Half-life in renal impairment

= 24 – 48 hr

Resistance: Bacteria produce

transferases enzymes that inactivate the aminoglycoside

Mutation of porin or of the 30S subunit

Aminoglycoside-modifying enzymes (AMEs) differ among aminoglycosides – so bacteria may be resistant to one but not to another

Anerobic bacteria are innately resistant to aminoglycosides - lack the oxygen dependent transport

Other aminoglycoside: - Amikacin – contains structural change that prevents its inactivation by many bacterial enzymes- Neomycin

*Streptomycin Activity against mycobacterium tuberculosis

Aminoglycoside

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*Gentamicin Hospital use Anti-Tb drug Used in combo with

penicillin, ampicillin or vancomycin to treat enterococci and Listeria monocytogenes

IV Opthalmic prep available

Most active aminoglycoside for synergy in combo therapy

*Tobramycin Most active against P. aeruginosa

IV Opthalmic prep.available

Aminoglycoside

*Macrolides Treat respiratory tract infections

Alternate to penicillin to treat streptococcal pharyngitis

Atypical strains of TB Mild community acquired

pneumonia Treat hospitalized

community acquired pneumonia (with IV 3rd gen. cephalosporin), Active against:

- Pneumococci- M. Pneumoniae- C. pneumoniae- Legionella species Drug of choice to treat

pertussis and Legionella

Inhibits prokaryotic protein synthesis

Do not affect the donor acceptor transfer reaction

Prevent translocation of peptidyl tRNA from the acceptor site to the donor site, thus halting protein synthesis

Macrocyclic lactone ring to which deoxy sugars attach

SEE BELOW Resistance: Reduced permeability or

reduced active efflux of drug

Production of esterases that hydrolyze macrolides

Ribosomal binding site mutation

NOT active against enterobacteriaceae or P.aeruginosa

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*Erythromycin

‘Someone with diarrhea and whooping cough laying a wreath on a Legionnaire’s cross (gram +)

Group A streptococci Staphylococci Bordetella pertussis Corynebacterium Diphtheriae Campylobacter jejuni Mycoplasma

pneumoniae Legionella species Chlamydia species

Macrolide Contains two sugars moieties

attached to 14-atom lactone ring Administered with enteric coating

due to destruction by stomach acid Partly metabolized by the liver by

N-demethylation Mainly excreted unchanged in the

bile Only 5% excreted in the urine Do not penetrate the CSF

High incidence of GI upset- binds to motilin receptors

Poorly tolerated - dyspepsia, nausea, and vomiting

Elevates serum theophylline Prolong QT interval when

combined with non-sedating antihistamines- caution b/c of Torsades de Pointe risk

Interferes with the metabolism of other drugs

Available as erythromycin base and various salts and esters

Weak activity against H. influenza

*Clarithromycin Increase spectrum of activity

See above plus against H. influenza

Active against Mycobacterium avium complex (pathogen in pts. with AIDS)

Very active against H. pylori

Macrolide Semi-synthetic derivatives of

erythromycin – addition of a methyl group

Increased absorption Increased half-life Metabolized in the liver to 14-

hydroxyclarithromycin (also has antibacterial activity)

Eliminated via hepatic metabolism and urinary excretion of intact drug

Less GI effects than erythromycin

Prolongs QT interval – see above

Primarily hepatic metabolism

Spectrum: extended beyond erythromycin

*Azithromycin Increase spectrum of activity

See above plus against H. influenza

Active against Mycobacterium avium complex (pathogen in pts. with AIDS)

Treat urethritis and cervicitis caused by C. trachomatis

Once daily therapy

Macrolide Semi-synthetic derivatives of

erythromycin – adds methylated nitrogen to the lactone ring

Increased absorption Increased half-life – slow

elimination Produces lower serum conc. Has a large volume of distribution,

tissue conc exceeds serum conc by 10 to 100-fold

Penetrates most tissue Does NOT penetrate CSF Better absorption Eliminated in urine and feces

Less GI effects than erythromycin

Fewer drug interactions

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C. Lincosamides Inhibits prokaryotic protein synthesis

*Clindamycin Oral or IV administration Active against: Streptococci Staphylococci (not

MRSA) Anaerobic bacteria, inc. B.

fragilis Several protoza Used as an alternative to

beta-lactams

Binds to the 50S ribosome at the same site as macrolides



Metabolized by liver

Higher risk of pseudomembranous colitis by C. difficile

Resistance due to mutation of the ribosomal binding site

Causes cross-resistance to macrolides

NO activity against enterococci or aerobic gram (-) bacilli

*Tetracyclines

‘T-A-G 30S’


Chlamydiae Mycoplasmas Spirochetes Rickettsial infections Legionella Brucella

Binds 30S rRNA, directly blocking the binding of the AA-charged tRNA to the acceptor site of the ribosome-mRNA complex

Excreted by kidneys and in the bile Do not penetrate CSF

Strong affinity for developing bone and teeth - Yellow-brown discoloration

GI adverse effects – nausea, vomiting, and diarrhea

Photsensitization Vestibular reactions (with

minocycline) CONTRAINDICATION:

pregnancy, children < 8 yrs Chelated by divalent or

trivalent cations - ↓ absorption with Ca, Mg, Al-containing antacid, dairy products, Ca supplements or sucralfate

Resistance- due to changes in the transport mechanism decrease accumulation of tetracycline in the bacteria

Widespread use resistance among pneumococci, group A streptococci, and staphylococci

*Tetracycline Administered qid Binds 30S rRNA, directly blocking the binding of the AA-charged tRNA to the acceptor site of the ribosome-mRNA complex

Short acting

See above

*Doxycyline Once – twice a day administration

Binds 30S rRNA, directly blocking the binding of the AA-charged tRNA to the acceptor site of the ribosome-mRNA complex

Long half-life

See above

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*Chloramphenicol

‘Like pouring chlorine bleach on organisms/baby/bones’


NOT used as 1st line therapy in US

Alternative tx. for bacterial meningitis

Used for meningitis (S. pneumoniae, N. meningitidis, and H. influenzae)

Treat brain abscess Broad spectrum

Binds to the 50S subunit at the peptidyltransferase site to prevent transpeptidation

Enters CSF and brain parenchyma Conjugated in liver to its inactive

form glucuronide (neonates are less able to conjugate)

Serious toxicity virtually obsolete in US

Gray baby syndrome - ↑ serum chloramphenicol: abdominal distension, vomiting, cyanosis, and circulatory collapse.

Myelosuppression – dose dependent (reversible)

Irreversible aplastic anemia (rare but fatal)

Huge use in 3rd world Not effective against

enterobacteriaceae

*F. Streptogramins IV Twice daily dosing Gram (+) bacteria Against Staphylococci

(inc. MRSA), streptococci, and enterococcus facecium (inc. resistant forms)

B form binds to the 50S ribosome at the same site as macrolides



Streptogramins A and B act synergistically

Rapidly cleared by nonrenal mechanisms

Large PAE

Types: Quinpristin/dalfopristin

(Synercid) – IV

*Oxazolidinones- Linezolid Gram (+) pathogens Inc. MRSA, penicillin-

resistant pneumococci, macrolide-resistant streptococci, and vancomycin-resistant enterococci

Saved for the treatment of resistant bugs

Inhibitor of bacterial ribosomal protein synthesis

Binds to the 50S subunit near its interface with the 30S subunit preventing the formation of the 70S subunit

100% oral bioavailability Distribution volume of >0.8L/kg Good tissue penetration Clearance is nonrenal and

nonhepatic Metabolized by nonenzymatic

oxidation

To be approved Resistance is infrequent

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INHIBITORS OF DNA SYNTHESIS

*Fluoroquinolones

Bactericidal

Oral – use in outpatient Broad-spectrum Against aerobic gram (-)

bacilli Enterobacteriaceae Hemophilus species Moraxella catarrhalis Respiratory

fluoroquinolones (newer) – improved activity against S. pneumoniae, inc. penicillin resistant strains

The addition of fluorine atom to the quinolone nucleus enhances activity against gram (-) bacteria

Inhibits both: DNA gyrase in gram (-) by binding

to DNA-enzyme complexes – interfering with DNA replication

Topoisomerase IV- gram (+) High oral bioavailability Divalent cations interfere w/

absorption Large volume of distribution –

penetrate prostate, lung, bile, and ascitic fluid

Penetrates CSF – but little clinical use for meningitis

Elimination by kidneys

Generally well-tolerated Common: nausea, vomiting,

and diarrhea Occasional: HA, dizziness,

insomnia, skin rash Photosensitivity Abnormal liver function test Hallucinations/Delirium Seizures, increase risk with

NSAIDS Prolonged QT Damage growing catilage -

Arthropathy/tendonitis CONTRAINDICTION:

pregnancy, younger then 18 Inhibits eukaryotic

topoisomerase II at high conc.

Others: Levofloxacin, moxifloxacin, and gatifloxacin

Overuse has eroded utility Resistance due to 1)

mutations in DNA gyrase and Topoisomerase IV 2) decrease permeability

DNA-gyrase – responsible for introducing neg. supercoils into the DNA

Topoisomerase IV – separates interlinked daughter DNA molecules following replication

*Ciprofloxacin

‘Flock of sinners gyrating’

Oral Broad spectrum Pseudomonas aeruginosa Anthrax

See above Increase serum theophylline levels

No prolonged QT

Weak activity against S. pneumoniae

*Metronidazole

Bactericidal

‘An underground metro-no air’

Anaerobic bacteria, esp. against B. fragilis

Choice for C. difficile associated diarrhea/colitis

Certain protozoa: giardiasis, ambiasis, and trichomoniasis

Acne rosacea

Nitroimidazole Enters bacterial cell by passive

diffusion Reduced by nitroreductase

Produce short-lived intermediate compounds or free radicals that interact with DNA and possibly other macromolecules leading to the disruption of DNA and inhibition of nucleic acid synthesis

Large volume of distribution Enter CSF and brain Metabolized by liver, metabolite has

antibacterial activity Excreted primarily in urine

Nausea and vomiting Disulfiram-like reaction with

ethanol (avoid EtOH up to 48 hrs after administration)

Psychosis w/ disulfiram

Aerobic bacteria – inherently resistant, lack nitroreductase

Acquired resistance can develop decreased uptake or decreased nitroreductase production

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Drug/Application Clinical Mechanism Drug Interactions/ CommentsUses Side Effect

INHIBITORS OF RNA SYNTHESIS

*Rifamycins Inhibit bacterial RNA synthesis by inhibiting DNA-dependent RNA polymerase

Metabolized by liver

Impart an orange color to all body fluids, esp. urine

Resistence: Mutation in the DNA-dependent RNA polymerase

*Rifampin Anti-tuberculous therapy

Activity against staphylococci, N. meningiditis, H. influenza, and Legionella pneumophila

Eliminate nasal carriage state of N. meningiditis and S. aureus

Used orally, IV form is also available

See above Enters CSF Potent inducer of hepatic

microsomal enzymes

Hepatotoxicity Flu-like syndrome/ Drug

fever Drug Interactions: increases

the metabolism of many drugs, e.g. glucosteroids, oral contraceptives, quinidine, phenytoin, barbiturates, theophylline, clarithromycin, ketoconazole, intraconazole, cyclosporine, warfarin

*Antifolates Antagonize folate syntetic pathway by 1) inhibition of dihydropteroate synthetase (DHPS) 2) or dihydrofolate reductase (DHFR)

Sulfonamides (sulfa drugs)

Bacteriostatic

Rarely used due to high rates of bacterial resistance and superiority of other drugs

Antifolates Inhibits dihydropteroate synthase

(DHPS)- blocking bacterial dihydrofolate synthesis from PABA

Excreted unchanged by kidney

Most allergenic of all antibiotics-macropapular rash

Greater risk in HIV pts.Life Threatening Stevens-Johnson syndrome:

flu-like syndrome involving rash, cardiac, renal, GI, and pulmonary complications

Toxic epidermal necrolysis

Resistance: organisms that use pre-formed folic acid, altered DHPS, increased PABA production, decreased permeability

Trimethoprim

Bacteriostatic

Active against Enteriobacteriaceae

Rarely used alone

Antifolate Inhibit dihydrofolate reductase Excreted unchanged by kidney

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*Sulfamethoxazole-Trimethoprim(TMP/SMZ)

Bacteriocidal

Oral and IV form UTI Prevention and treatment

of Pneumocystis carinii Enterobacteriaceae H. influenzae Many strains of

streptococci and staphylococci

Sulfonamide and Trimethoprim Combination targets both steps in

folate synthesis Results in antibacterial activity that

is 20 –100 x greater than sulfonamide alone

Excreted unchanged by kidney Penetrates CNS – but not used

See sulfonamides Not active against P. aeruginosa or anaerobic bacteria

Other *Nitrofurantoin Oral

UTI Active against most

Enteriobacteriaceae and enterococci

Mechanism of action unknown High oral bioavailability Low blood conc. – not adequate to

treat infection High urinary and renal conc. Activity reduced in an alkaline pH

No cross-resistance Long-term use peripheral

neuropathy and pulmonary fibrosis

Hemolytic anemia in pts. with G6PD deficiency

Not active against P. aeriginosa

Not effective to treat a UTI caused by proteus species due to alkaline pH

Anti-TB drugs Use in combination Duration of therapy- Isoniazid + rifampin = 9 mo course- Addition of pyrazinamide for 1st two mo, permits shortening of total duration to six months If drug resistant organism,

use 4 drugs (ethambutol or streptomycin)

If sputum (+) after 3 mo, use DOT, and conduct susceptibility studies

Empiric therapy: isoniazid, rifampin, pyrazinamide, streptomycin, and ethambutol

Isoniazid and rifampin are the most active

Susceptibility testing is performed, then:

Pyrazinamide (1st 2 mos.), rifampin, isoniazid (6 mos) if susceptible

Difficulties with treating Tuberculosis: Mycobacteria are slow

growing organisms Very resistant to antibiotics Have a lipid rich

mycobacterial cell wall, very impermeable

Organism mostly resides intrcellularly, poor penetration

Develop drug resistance

16


*Isioniazid (INH)

Bactericidal

-M. Tuberculosis Less active against

atypical mycobacteria As a single agent used for

latent infections (prophylaxis)

Prevention of TB in close contacts of active cases of pulmonary TB

Inhibits mycolic acid synthesis, which are a componet of the cell wall

Acts on actively growing TB Penetrates all tissues, including CSF Penetrate phagocytic cells, so active

against extracellular and intracellular organisms

Prodrug - activated by mycobacterial catalase-peroxidase (katG)

Metabolized by liver N-acetyltransferase

Genetics determines if rapid/slow acetylators adjust dose

INH-induced Hepatitis Peripheral neuropathy at high

doses or in slow acetylators and in pts with predisposing conditions (associated with pyridoxine deficiency) – treated with pyridoxine

Resistance develops with mutations in the katG enzyme and in pther proteins

Single drug therapy 10 – 20% prevalence of isoniazid resistance in clinical isolates

*Rifampin

Bactericidal

Single drug therapy Access poorly accessible

organisms, such as intracellular organisms and those sequestered in abscesses and lung cavities

See antibacterials

Inhibits RNA synthesis Inhibit bacterial RNA synthesis by

inhibiting DNA-dependent RNA polymerase

Readily penetrates most tissues and into phagocytic cells

Metabolized in liver, turn body fluids red-orange

Hepatotoxicity Flu-like syndrome Induces microsomal

Cytochrome p450- increases metabolism of many drugs-protease inhibitors, etc.

No cross-resistance to other antimicrobial drugs, but cross-reactivity to other rifamycin

Resistance: altered RNA Pol

*Pyrazinamide (PZA) First-line drug used in conjunction with INH and rifampin in short course (6 mo) regimens

Kills intracellular M. tuberculosis

Mechanism of action is unknown Activated by mycobacterial

pyrazinamidase Taken up by macrophages and

exerts its activity against intracellular organisms residing here

Hyperuricemia that may precipitate acute gout (common)

Hepatotoxicity

Resistance due to mutations that impair conversion of PZA to its active form

No cross-resistance with INH or other antimycobacterial drugs

*Ethambutol

Bacteriostatic

Enhances uptake of rifampin into bacteria

Inhibits mycobacterial arabinosyl transferase, which is involved in the polymerization reaction of arabinoglycan

Essential component of mycobacterial cell wall

Alters cell wall permeability Well absorbed, eliminated in feces

and urine in unchanged form

Dose-related: Retrobulbar (optic) neuritis which causes loss of acuity and red-green color blindness

Monitoring at high doses

Resistance develops quickly, so always administered in combination

17


*Streptomycin Active against extracellular TB

Aminoglycoside antibiotic (see under AB section)

Binds IRREVERSIBLY to the 30S ribosomal subunit

Blocks initiation of protein synthesis Blocks further translation and elicits

premature termination Incorporation of incorrect amino

acid Penetrates cell poorly

Ototoxic Nephrotoxic

Antivirals Inhibit steps in viral replication: 1. absorption to and penetration into susceptible host cell 2. uncoating of viral nucleic adic 3. synthesis of early regulatory proteins 4. synthesis of RNA or DNA 5. Synthesis of late, structural proteins 6. Assembly of viral particles 7. release from cell

serf Non-HIV viral infections Influenza Herpes virus (HSV, VZV,

CMV) Hep C, RSV DNA viruses: ASH B

(adenovirus, small pox, herpes, Hep. B)

* Oseltamavir/Zanamavir Anti-influenza Neuraminidase inhibitor for both influenza A & B-prevents binding

Prophylaxis Lessen duration of illness

by 1 day*Amantidine/Rimantidine Anti-influenza

No activity against Influenza B.

Prophylactic and lessen severity of symptoms

Must be started within 48 hrs. of onset

Inhibit un-coating of viral RNA of influenza A by binding M2 protein.

GI intolerance CNS complaint –

nervousness, difficulty in conc., lightheadedness

Reduced dose in pts > 65 and in pts with renal insufficiency

18


*Acyclovir Antiherpes agent Oral, IV and topical

formulation Primary and recurrent

genital herpes ORAL: Shortens duration

of symptoms, time of viral shedding, and time of resolution of lesions

IV: tx for herpes simplex encephalitis and neonatal HSV infection

Higher doses for VZV – shortens duration and lesions

Acyclic guanosine derivative that lacks a 3’-OH on the side chain

Converted to monophosphate derivative by virus-specified thymidine kinase – therefore only active in infected cells

Then cellular enzyme convert it to the di and tri- compounds

Inhibits viral DNA syn. by 2 mechanisms: 1) Competitive inhibition of deaxyGTP for the viral DNA polymerase 2) Chain termination following incorporation into the viral DNA

Elimination: Glomerular filteration and tubular secretion

Enters CNS

Generally well-tolerated Nausea, diarrhea, and HA IV infusion associated with

renal insufficiency or neurologic toxicity (may include tremors and delirium)

Resistance - via mutation of viral thymidine kinase or DNA Pol.

Valcyclovir – L-valyl form of acyclovir – achieves plasma levels 3 –5 times higher

*Ganciclovir Anti-herpes IV and oral Potent activity against

cytomegalovirus (CMV) IV use: CMV retinitis,

colitis, and esophagitis in AIDS pts.

IV use: Reduces incidence of symptomatic CMV disease of administered before organ transplantation

IV use: CMV pneumonitis in immunocompromised pts. in combo w/ CMV Ig

Acyclic guanosine analog Phosphorylated (activated) by CMV

protein kinase phosphotransferase or HSV thymidine kinase

Competitively inhibits viral DNA polymerase

Incorporated into DNA- chain terminator

Enters CNS Clearance related to creatine

clearance

Myelosuppression, particularly neutropenia

19


Anti-HIV (p.44) Multi-drug regimens essential b/c resistance develops

*Nucleoside Reverse Transcriptase Inhibitors (NRTI)

Active against HIV-2 and HIV-1

Important component of multi-drug regimens

Substrate for reverse transcriptase, which converts viral RNA into proviral DNA before its incorporation into the host cell chromosome

Pro-drug –phosphorylated by cell enzymes

Incorporation into DNA -terminates chain elongation

Lactic acidosis Severe hepatomegaly with

steatosis

*AZT (Zidovudine) / Didanosine (ddI), Zalcitabine (ddC), Abacavir, 3TC

Nucleoside ReverseTranscriptase Inhibitors (NRTI)

See above Chain terminators; viral RT is

‘sloppier’ than host enzymes, more susceptible

See Above

*Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI)

Specific activity against HIV-1

Bind directly to a site on the viral reverse transcriptase (not same as NRTI)

Blockade of RNA- and DNA-dependent DNA polymerase activities

Metabolized in liver by CYP450 enzymes

Multiple drug interactions, including protease inhibitors

Rapid resistance develops – need to use as a multi-regimen

No cross resistance b/w NNRTIs and NRTIs or protease inhibitors

*Protease Inhibitors Combination therapy is necessary to combat resistance

Bind reversibly to the active site of HIV protease, preventing cleavage of gag-pol polyproteins into mature products

Prevent a new wave of infection High affinity for HIV proteases Poor systemic bioavailability Undergo oxidative metabolism by

CYP3A4 – occurs in liver

Nausea, vomiting, diarrhea, and paresthesias

Glucose intolerance Diabetes Hypercholesterolemia Hypertriglyceridemia Prolonged administration –

Cushingoid syndrome: fat redistribution, esp. central fat accumulation, buffalo hump, breast enlargement, and subcutaneous lipomas

Drug interactions occur with other protease inhibitors, NNRTIs and non-HIV drug

Protease is essential for the production of mature infectious virions during HIV replication

Drugs: Saquinavir/Indinavir/Nelfinavir/Ritonavir/Amprenavir/Lopinavir

20


*Antifungals Systemic drugs (oral or IV) for systemic infection

Oral drugs for mucocutaneous infections

Topical drugs for mucocutaneous infection

MODE OF ACTION (4 classes):- Polyene macrolides that lead to an alteration of membrane funtion- DNA and RNA synthesis inhibitors- Azole derivatives that inhibit sterol 14-α-demethylase, a key enzyme in ergosterol biosynthesis- 1,3-β-glucan synthase inhibitors

*Amphotericin B

Fungicidal

“Ampho-terrible”

IV (colloid suspension w/bile salt, and deoxycholate)

First line therapy for life-threatening mycotic infection

Broad spectrum, inc. Candida albicans and Cryptococcus neoformans

Organisms causing endemic mycoses

Pathogenic molds Used for systemic

infections Intrathecal therapy for

fungal meningitis Lipid drug formulation

(Liposomal Amphotericin B) – created to decrease toxicity ($$$)

Binds ergosterol (cell membrane sterol specific for fungi) and alters the permeability of the cell by forming pores

Leads to cell death Poorly absorbed from GI Large tissue distribution 2-3% reach CNS Mostly metabolized, excreted slowly

in urine Half-life = 15 days No adjustment required in

hepatic/renal failure

Binds to human membrane sterols toxicity

Immediate infusion reaction: fever, chills, vomiting, HA, muscle spasms (prevented w/ slowing infusion rate of decreasing dose OR by pre-medication with antipyretics or meperidine)

Renal toxicity, presents with renal tubular acidosis, severe K and Mg wasting

Resistance occurs when ergosterol binding is imparied

Initial therapy for serious fungal infection, then replaced w/ azole drug

Facilitates entry of flucytosine

Flucytosine Active only against yeasts Converted to 5-fluoruracil Myelosuppression Resistance: Mutant permease prevents entry into cell

Griseofulvin

‘A grease covering the skin, blocking further infection’

Concentrates in keratinized epithelium, blocking fungal microtubules and preventing growth. Prevents infection of new cells.

- Nystatin (topical/ ‘swish and swallow for thrush’

21


*Azoles Broad spectrun Candida species Cryptococcus neoformans Endemic mycoses Aspergillus infections

Reduction of ergosterol synthesis by inhibiting 14--demethylase (cytochrome P450 dependent enzyme system), inhibiting growth

Increased affinity for fungal cP450

Relatively non-toxic GI: nausea and vomiting Abnormal liver enzymes Clinical hepatitis (rare) CP450 metabolism

Other: Itraconazole

*Ketoconazole Limited use due to toxicity See above Less selective for fungal P450

Inhibition of human cP450 interferes with biosynthesis of adrenal and gonadal steroid hormones

Endocrine effects: Gynecomastia, infertility, and menstrual irregularities

Alter the metabolism of other drugs

Other drugs can influence its blood levels (H2 blockers and rifamycins)

*Fluconazole Oral Treatment and secondary

prophylaxis of cryptococcal and coccidiodal meningitis

See above Enters CNS Good bioavailability

Less drug interactions Least effect on human

cytochrome P450 system

Poor activity against aspergillus

Polyenes Alters fungal cell membrane permeability

Binds ergosterol, disrupting membrane structure; causes leakage and cell death

22


Anesthetics Depth of anesthesia: ↑ BP indicates patient is feeling pain (too little anesthesia), ↓ BP indicates excessive anesthesia (respiratory depression).

General anesthetic: produces unconsciousness

Objectives of general anesthesia: (1) Unconsciousness (2) Analgesia (3) SKM relaxation (4) ↓ reflexes (gag, etc.)

Inhaled anesthetics Quickly gets in, quickly gets out via lungs.

Important actions at sites in the brain and the spinal cord.

Act at the synapse. Interact with the hydrophobic regions of the membrane protein.

Inhibition of AA GABAA and glycine receptors by interacting with specific sites in the transmembrane domain 2 and 3 of the receptor protein.

The most hydrophobic anesthetics are the most potent.

Blood-gas partition coefficient: if low, less affinity for blood, gets into brain more easily (lower MAC). Also leads to faster emergence from anesthesia.

Oil-gas partition coefficient: if high, more affinity for CNS, less likely to remain in blood (lower MAC). Little effect on emergence.

Organ effects:CNS: - Depressed - ICP with intracranial massesRespiration: - ventilationCV: - Depressed - Dose-related, (-) inotrophic effects - Peripheral vasodilation - Decreased blood pressure - Nodal arrhythmia - PVC’sUterus: - Inhibit contractionHepatic/Metabolic: - Blood flow is diminished- Decreased renal fxn.

Nausea and vomiting Nausea and vomiting temperature

Anesthetic activity depends on partial pressure.

Volume % = partial pressure/ atmospheric pressure

Minimum alveolar concentration (MAC): conc. of anesthetic in alveolar gas that prevents the response to pain in 50% of patients.

Nitrous oxide Non-volatile (anesthetic) MAC = 105 Blood-gas coefficient = 0.4 Oil gas coefficient = 1.4

23


Halothane/ Enflurane/Isoflurane/Desflurane/Sevoflurane

Volatile Halothane- Bradycardia Other volatile – mild

tachycardia Desflurane and isoflurane-

excite CNS when inhaled amount is sharply increased HTN and tachycardia

Malignant hyperthermia: Produces SER dumping of Ca++, ↑ metabolism/ contraction leads to excessive heat generation, ↑ CO2 leads to acidosis. Fever, tachycardia, tachypnea, dysrhythmia, muscle rigidity, mottled skin, cyanosis, CV instability

Treatment: dantrolene (muscle relaxant).

All volatile gases have much lower MAC’s than NO, this means less drug is needed for induction

IV anesthetics Induction or maintenance of anesthesia

Enhance inhibitory neurotransmission or inhibit excitatory neurotransmission

IV: depends on renal/hepatic clearance. Specific antagonists may be available.

Dose-dependent respiratory depression

Cause apnea for 30 – 90 sec after induction of anesthesia

Barbiturates Most commonly used: thiopental and methohexital

GABAA receptor agonist Cardiovascular depression by ↓ myocardial contractile and ↓ systemic vascular resistance

May precipitate episodes of acute intermittent porphyria

*Sodium pentothal Thiopental Most commonly used IV

induction of anesthesia Administered by infusion

for cerebral protection

Highly alkaline – tissue damage if injected extravenously

‘Truth serum’ Used for cerebral

protection

Methohexital Oxybarbiturate Administered rectally for

induction in children

24


Benzodiazepines Most common: Midazolam Anxiolytic Sedation

GABAA receptor agonists Cardiovascular depression by ↓ myocardial contractile and ↓ systemic vascular resistance

Diazepam and Larazepam also used

*Midazolam Administered intramuscularly

Administered orally as a sedative premedication in pediatric patients

Water soluble – less local irritation At physiological pH, it rearranges to

a more active lipid soluble form

*Etomidate Used for intravenous induction in pts. With CV compromise

Carboxylated imidazole derivative Pain on injection GABAA receptor agonist

Indirectly cause myoclonic movements during induction

Produces no CV depression in HEALTHY patients

CV depression in compromised pts - compensatory ↑ in sympathetic activity

Adrenal suppression

Used in cardiac-compromised patients

*Propofol‘Milk of amnesia’

Induction and maintenance of anesthesia or for sedation

Antiemetic Rapid emergence and a

feeling of well-being Ambulatory surgery

2,6- diisopropylpylphenol GABAA receptor agonist

Pain on injection – egg-lecithin emulsion

Cardiovascular depression by ↓ myocardial contractile and ↓ systemic vascular resistance

*Ketamine Intramuscular induction in children or in uncooperative patient.

Dissociative anesthetic used in veterinary medicine

Structurally related to PCP NMDA (glutamate) receptor

blocker Stimulates the sympathetic NS and,

therefore, stimulates the CV system Direct myocardial depressant

Increases cerebral metabolism and intracranial pressure

Changes in mentation Catatonia, hallucinations Bronchodilation CONTRAINDICTION:

- pts. at risk for cerebral ischemia- Intracranial hypertension- Careful: critically ill pts. with depleted catecholamine reserves, pts. with CAD

Cerebroprotective action by preventing excitatory AA-mediated neurotoxicity through its blockade of the NMDA receptor

Little respiratory depression

25


Neuromuscular blockers Muscle relaxants *Succinylcholine Tracheal intubation

When rapid onset is required

Depolarizing neuromuscular blocker, acts at NMJ

Initially causes fasciculation Desensitization of Ach receptor Broken down by plasma

cholinesterase Onset within 1 min. Clinical duration 2-3 min. Full recovery 10-12 min.

Bradycardia + asystole: rare Myalgias 24 to 48 hours after

administration IOP, ICP Hyperkalemia – in pts. with

UMN and LMN lesions, major crush injuries, burns or prolonged immobility

Phase II block- prolonged neuromuscular block

Cholinesterase SNPs or long-term succinylcholine infusion can lead to phase II block

Non-depolarizing Selected on 1. Onset and duration 2. Route of metabolism and/or elimination 3. Cardiovascular side effects.

Competitively inhibits Ach receptor

Partial to complete blockade occurs over the narrow range of 75% - 100% of receptor occupancy.

Metabolism and elimination is important in pts. with impaired organ clearance

CV effects: - Vagolytic effects ↑ HR- Autonomic block ↓ HR- Histamine release ↑ HR and hypotension- or NO CV effects

Antagonized by neostigmine.

Neostigmine side effects blocked by atropine

Blockade is monitored by electrical stimulation of nerve

Mivacurium Short acting Motor end plate acetycholine receptor antagonist

Duration of action 20 min. Metabolized by plasma

cholinesterase

Histamine release

Atracurium, cis-Atrcurium, Vecuronium, and rocuronium

Intermediate acting Rocuronium – most rapid

onset and succinylcholine is contraindicated

Motor end plate acetycholine receptor antagonist

Duration of action 30 – 45 min. Atracurium and cis-atracurium are

metabolized by a nonenzymatic mechanism (Hoffman elimination) and by ester hydrolysis

Vecuronium, cis-Atrcurium, rocuronium: NO cardiovascular effect

Atracurium: Histamine relaease

Atracurium and cis-atracurium are independent of hepatic or renal function

*d-tubocurarine (curare), pancuronium, doxacurium, and pipecuronium

Long-acting Motor end plate acetycholine receptor antagonist

Pipecuronium: NO cardiovascular effects

Pancuronium: Vagolytic effect

D-tubocurarine: Autonomic ganglionic blockade and Histamine release

26


Local anesthetics Produce a transient and reversible loss of sensation in a circumscribed area of the body

Topical anesthesia Blockade of peripheral

nerves Spinal or epidural

blockades Intravenous regional

anesthesia Systemic uses: Anti-

arrhythmic, pain syndromes

Interfere with nerve conduction, by blocking the influx of Na+ ions, thereby preventing the depolarization of the nerve

Binds to sodium channels at site exposed during activity

- More active neurons are more quickly blocked - Blocks both sensation and motor function - Conformational change 80% block required for anesthesia Does not alter resting membrane

potential or threshold potential

Systemic Toxicity Initial symptoms: CNS-

lightheadness, dizziness, seizures, tinnitus

Higher serum conc.: ↓ myocardial contractility and systemic vasodilatation hypotension (blocks sympathetic conduction)

High systemic conc.: Cardiac arrhythmia (inc. VF)

PHYSIOCHEMICAL CHARACTERISTICS:

The more lipid soluble, the more potent

The lower the pKa and the greater the lipid solubility greater rate of onset

The lower the pKa more anesthetic in unionized form

The uncharged form (base) diffuses more readily than charged form (acid)

Duration of action correlates with the degree of binding to generalized proteins in vitro

Esters Mostly hydrolyzed by plasma cholinesterase

Allergenic reactions can occur

- Skin rashes- Bronchspasms

*Procaine Route – infiltration, spinal Sodium channel blocker Slow onset Short duration

Chloroprocaine Route – epidural Peripheral nerve block

Sodium channel blocker Fast onset Short duration

Tratrcaine Route – topical, spinal Sodium channel blocker Slow onset Long duration

Amides Metabolized in the liver

Allergic reactions: RARE Stable in solution

*Lidocaine Route – topical, infiltration, spinal, epidural

Peripheral nerve block IV regional anesthsia

Sodium channel blocker Fast onset Moderate duration

27


Opioids Narcotic analgesic Opium-like drugs Cross tolerance occurs to all

members of opioid class

Opioid poisoning: coma, pinpoint pupils, respiratory depression

Physical dependence: desire to avoid withdrawal

Psychological dependence: preference for drugged state

*Morphine Pain management Given parenterally, but in

large doses it is effective orally

Hospice Mix – morphine + flavored syrup

Antitussive (rarely used) Antidirrheal (rarely used)

Major active ingredient in opium opioid receptor agonist Receptors located on nerve cells in

the brain, spinal cord, digestive system, etc

Low oral bioavailability Metabolism – inactivated by

glucuronide formation in the liver then excreted in urine

0.02% of dose crosses BBB Crosses placenta Ion trapping in stomach Duration of action: 4 –6 hours Effects:

- CNS: Inhibitory: Analgesia, Euphoria, Drowsiness, Respiratory depression, Depression of cough reflex, Decreased sympathetic outflow

Stimulatory: Stimulation of CTZ, Release of PRL and ADH, Miosis

- Cardiovascular: Bradycardia, Decrease BP, Postural hypotension, Release Histamine peripheral vasodilatation, Cerebral vasodilatation due to increased pCO2 Increased ICP

-Constipation, Inhibits gastric emptying, Inhibits flow of bile, Enhances absorption of fluid

OPIOID POISONING Triad: Respiratory Depression, coma, miosis

Nausea and vomiting Constipation Orthostatic hypotension Dependence develops after

long term therapy Opioid withdrwal syndrome

- 8-12 hr: lacrimination, rhinorrhea, yawning, sweating- 10-16 hr: Restless sleep- 16-24 hr: anorexia, dilated pupils, restlessness, tremor, gooseflesh- 48-72 hr: PEAK- anorexia, severe sneezing, irritability, insomnia, diarrhea, chills/sweats, abdominal cramps, orgasm, muscle pain, leg muscle spasms, waves of gooseflesh- 7-10 days: recovery form acute phase of withdrawal- Months: Narcotics huger

Alcohol extract of opium – Laudanum

Deodorized camphorated tincture of opium – Paregoric

Acute withdrawal state can be stopped with an opioid agonist

28


*Heroin Not medically used Diacetylmorphine Opioid receptor agonist 3 – 5 times more potent then

morphine Crosses BBB much more effectively

than morphine, where it is converted rapidly to morphine in brain.

High abuse potential

*Codeine Antitussive Antidiarrheal Pain management – not as

effective as morphine

Methylmorphine Opiod receptor agonist 1/6 – 1/10 as potent as morphine Demethylated in brain to form

morphine Orally active – resists hepatic

metabolism

Low abuse potential

*Meperidine (Demerol) Analgesics Phenylpiperidine derivative Opioid receptor agonist 10% as potent as morphine Short duration of action (2 –4 hr) Not antitussive or constipating

Respiratory depression Convulsions – toxic

metabolite (normeperidine) Does NOT suppress cough

reflex NON-constipating Abuse potential = morphine

Withdrawal – more rapid time course than for morphine and heroin

Methadone (Dolophine) Oral analgesic Antitussive Heroin addict rehab –

prevents withdrawal

Diphenylheptane derivative Opioid receptor agonist Orally bioavailable Does not induce euphoria

Antitussive Constipation

Rehabilitation- eliminates needle fixation, prevents withdrawal for 24+ hrs, given in doses large enough to induce tolerance to heroin, allows for stabilization, pts become addicted to methadone vs. heroin

29


Other Opioid Agonist d-Propoxyphene (Darvon) Analgesic Weak opioid agonist

Strength between aspirin and morphine

Moderate abuse potential

Fentanyl (Sublimaze) Anesthesia Epiduraly following

abdominal or pelvic surgery

Potent opioid receptor agonist 80x more potent than morphine Short duration of action

High abuse potential

*Dextromethorphan (Romilar) Antitussive (OTC) Specific opioid receptor agonist Not analgesic

Vey low abuse potential

Diphenoxylate and Loperamide Antidiarrheal Opiod receptor agonist Opioid Antagonist Reverse effects of opioid

agonist drugs

*Naloxone (Narcan) Reverse opioid agonist effects during an overdose

receptor competitive antagonist

Contains a bulky allyl group substitution at the nitrogen function of the piperidine ring

Poor oral bioavailability Short duration of action (1 – 4 hrs)

Non-toxic – but must be administered slowly to avoid triggering a opiod withdrawal syndrome

IV

Naltrexone (Trexan) Prevent opioid readdiction in detoxified patients

receptor competitive antagonist

High oral bioavailability

Opioid Agonist-Antagonist Analgesics Antagonist effects at opioid receptor

Agonist actions at opioid receptor

Less abuse potential than opioids

Pentazocine (Talwin) Analgesic Weak antagonist effects at opioid receptor

Agonist actions at opioid receptor

Respiratory depression at low dose BUT has ceiling effect i.e. not dose dependent

Low abuse potential High doses – dysphoria and

psychomimetic effects May precipitate withdrawal

symptoms in a person with opioid tolerance dependence

*Buprenorphine (Temgesic) Analgesic Treatment for opioid

dependent persons

Potent partial opioid agonist-antagonist

Schedule III drug

Does NOT replace methadone therapy

30


Anti-inflammatory Drugs NSAIDS Analgesic (esp. HA and

Somatic pain) Antipyretic Anti-inflammatory

(alleviate symptoms)

COX-1 and COX-2 inhibitors Anti-inflammatory/Antipyretic:

blocks synthesis of TNF- and IL-1, which normally act on anterior hypothalamus to synthesize PGE2. PGE2 raises the ‘set-point’ and causes edema.

Analgesic: Somatic pain results from inflammation that triggers pain-inducing PGs.

Due to the inhibition of COX-1

Blocking PGI2: GI intolerance/ulceration- PGs maintain blood flow and reduce acid secretion

Blocking PGI2 and PGE2: Renal insufficiency/ hypertension- PGs increase renal blood flow; can lead to fluid retention. Caution in those with hypertension or CHF using ACE inhibitors or diuretics.

Blocking PGF2: Inhibits uterine contraction-prolongs pregnancy, increases perinatal mortality and risk of postpartum hemorrhage (contraindicated in 3rd trimester)

Blocking TXA2: Decreases platelet aggregation

Aspirin induced asthma/allergy: due to shunting to LOX pathway

Reye’s syndrome- associated febrile illness/ viral infection, do not give salicylates to children

General Properties of NSAIDS:

Most are effective against fever, pain, and inflammation

Gastrointestinal upset is a frequent side effect

Most show cross sensitivity in aspirin sensitivity

Most are highly bound to plasma proteins

Symptoms of inflammation are affected more than the underlying cause.

31


*Aspirin Reduce fever Diminish pain (dull, aching

pain) Anti-inflammatory RA

Irreversibly acetylates COX-1 (which is constituently expressed)

Blocks COX-2 (responsible for inflammatory actions)

↓edema: Decreased pathological movement of fluid and cellular elements from the vasculature

Decreased migration of leukocytes into tissue by decreasing adhesion molecule expression, and, therefore, decreased release of lytic enzymes

Antipyretic: Leukocytes release IL-1, which causes the formation of PGE2 by the COX enzyme (blocked by aspirin )that acts on the thermoregulatory region of the anterior hypothalamus, raising the set point. Suppress the production of TNF and IL-1B

Analgesic: Inhibition of the synthesis of PG’s, mainly peripheral pain

Anti-inflammatory: Blocks expression of leukocyte adhesion molecules. Induces synthesis of lipoxins and adenosine release (both anti-inflammatory).

Metabolized in liver; 1st order at low conc., zero order kinetics at high conc.

See above Most effective anti-platelet NSAID because of irreversible acetylation

Ibuprofen COX-1 and COX-2 inhibitor Gastrointestinal toxicity Reversible renal failure in pts.

with intrinsic renal disease who are > 65, HTN, CHF, using diuretics and ACE inhibitors

Use with misoprostol (PG analog) – provide gastrointestinal protection

*Celecoxib (Celebrex) Arthritic conditions Selective COX-2 inhibitor No gastrointestinal side effects

Not used prophylatively against MI

Rofecoxib Selective COX-2 inhibitor Not used prophylatively against MI

*Acetaminophen (Tylenol) Analgesic Inhibits COX-3, located in brain Well tolerated Treat hepatotoxicity with 32

Antipyretic Less effective in reducing

inflammation Not effective in reducing

peripheral inflammation or producing endogenous antipyretics

tissue 3 Metabolic Pathways: Metabolized

by glucuronidation (60%), sulfation (35%), and oxidation mediated by cytochrome P450s (3%)

Oxidation products are toxic but are detoxified by glutathione (limited amount in liver)

Hepatic injury (centrilobular necrosis) with doses > 4g/day

Interactiion with ethanol:Acutely: EtOH induced cytochromes (no effect because cytochromes are occupied with EtOH met.)Chronic followed by abstinence: Now cytochromes metabolize acetaminophen →toxic metabolite

Exacerbated by glutathione depletion seen in alcoholics

acetylcysteine- helps replenish glutathione

Corticosteroids Glucocorticoid activity- increase glycogen deposition, anti-inflammatory

Mineralocorticoid activity- mimics aldosterone: sodium retention

USES: anti-inflammatory, Immunosuppresion

Oral Inhalation: Asthma IV or IM Topical

Endogenous cortisol- Hypothalamus secretes CRH, stimulates ACTH in anterior pituitary, regulated by negative feedback from cortisol.

Carbohydrate metabolism – Increase gluconeogenesis by converting AA to glucose and glycogen; induce hepatic enzymes that increase formation of glucose from pyruvate

Lipid metabolism – redistribution that causes buffalo hump and moon face

Muscle atrophy due to gluconeogensis

Glycogen deposition in liver Exacerbates peptic ulcers Painless perforation CNS toxicity: Insomnia,

changes in mood, irritability, psychopathy

Immunosuppressive Glaucoma, lens opacities Osteopenia/osteonecrosis Acute adrenal insufficiency

after abrupt withdrawal Diabetes mellitus

Considerations when selecting a steroid:

- Anti-inflammatory effects- Sodium retention- Deposition of liver glycogen Doesn’t stop RA disease

progression

Hydrocortisone (cortisol) Anti-inflammatory: 1. Promotes transcription of the gene encoding IκBα, which inhibits transcription of inflammatory cytokines (IL-6 and IL-8) by binding to the transcription factor NF-κB. 2. Produce peptides that stabilize membranes and reduce release of arachidonic acid.

Anti-inflammatory activity: 1 Mineralocorticoid activity: 1 Short duration of action

Prototype natural glucocorticoid

33


*Prednisone Asthma AI disorders Inhalation, oral

Anti-inflammatory activity: 5 Mineralocorticoid activity: 1 Intermediate duration of action

Prototype synthetic glucocorticoid

Dexamethasone Anti-inflammatory activity: 25

Mineralocorticoid activity: 0

Long duration of action

Anti-inflammatory activity: 25 Mineralocorticoid activity: 0 Long duration of action

Cushing’s Disease test: Pituitary (ACTH-

producing) tumor is cortisol resistant: cortisol, ACTH but ACTH inhibited by exogenous (high dose) dexamethasone

Adrenal (cortisol-producing) tumor: cortisol, significantly ACTH- will show no further ACTH drop

Ectopic ACTH-producing tumor: cortisol, ACTH, non-responsive to dexamethasone challenge

Betamethasone Anti-inflammatory activity: 25 Mineralocorticoid activity: 0 Long duration of action

Migraine-treatment Ergot based Chronic use of NSAIDs

can lead to headache syndrome

Vascular phase: triggered by changes in serotonergic brain stem function constriction then dilation of vessels (due to spreading cortical excitation-aura) activation of CN V nocieoceptive pathways with neurogenic inflammation

*Ergotamine and DHE Moderate to severe Migraine treatment

Complex 5-HT, DA, NE partial agonist/antagonist

Constriction of arteries and veins

Nausea Induce abortion Contraindication in

pregnancy, HTN, coronary, cerebral, and peripheral vascular disease

DHE is a more efficacious vasoconstrictor

34


*Sumatriptan (Imitrex) Moderate to severe Migraine treatment

Available in US: subcu, oral (IV elsewhere)

Selective agonist 5HT-R1 located in extracranial circ. to cause vasoconstriction.

Anaphylaxis Contraindication in

pregnancy, CAD, postmenopausal, men >40, diabetes, obesity, HTN, smokers, hyperlipidemia, family hx. of vascular disease

First does given under medical supervision

Prophylactic therapy More than 2-3 attacks/mo Last longer than 48 hrs Significant functional

impairment Inadequate relief for tx or

have unacceptable side effects

Attacks occur after a prolonged aura

Drugs used: Beta-blockers TCA Calcium channel blockers Anticonvulsants Combo of above MAO inhibitors – interactions with

many foods (COUNSEL!!!)

*Methysergide Prophylactic prevention of migraine

Given intermittently with monitoring for fibrotic complications

Ergot derrivative Complex 5-HT, DA, NE

agonist/antagonist

Retroperitoneal fibrosis with ureteral obstruction

Contraindiction in CAD, gastritis, HTN, connective tissu disease and pregnancy

35


Anti-Rheumatic Drugs Rheumatoid Arthritis: morning stiffness >1 hour

Swelling in hands and 3 other joints

Erosion on X-ray Rheumatoid

nodules/pannus: inflammatory exudate overlying synovium

Rheumatoid factor (IgM IgG)

Goals of therapy: 1. Relieve pain and

inflammation 2. Prevent joint destruction 3. Maintain function

*NSAIDS See anti-inflammatory RA

COX-1 and COX-2 inhibitor Help control inflammation and pain Improve mobility, flexibility, ROM Improve quality of life Relatively low-cost

Does not affect disease progression

GI toxicity common Renal complications CNS toxicity

*Corticosteroids (Low dose) See anti-inflammatory RA

- low dose (< 7.5 mg/d)- Intra-articular injections can be used for individual joint flares

Modify gene transcription of inflammatory and non-inflammatory mediators

Bridge gap between initiation of DMARD therapy and onset of action

Anti-inflammatory and immunosuppressive effects

Does not affect disease progression

Tapering and d/c of use is often unsuccessful

Low dose result in skin thinning, ecchymoses, and Cushinoid appearance

Osteopenia, osteoporosis, osteonecrosis

Endocrine: Adrenal insufficiency, hyperglycemia, DM and hypercholesterolemia

GI: PUD with NSAIDS Muscle: Myopathy

36


DMARDs (Disease-modifying anti-rheumatic drugs)

Anti-inflammatory Slow inflammatory disease

progression

Myelosuppression Choice of DMARD:Cost, convenience of administration, convenience of toxicity monitoring, compliance, comorbid disease, toxicity, severity and prognosis of patient

*Methotrexate The “Gold Standard” Psoriasis Rheumatoid arthritis Graft vs. host disease Wegener’s granulomatosis

Folic acid analog Antimetabolite Inhibits dihydrofolate reductase-

limiting ‘active THF’ production- also directly blocks DNA, RNA, and protein synthesis

Dosing: initial- 7.5 mg/wk,then increase, max dose 20mg/wk

Short half-life, renal tubular secreted non-metabolized in urine

Pulmonary pneumonitis and/or fibrosis

GI: nausea, anorexia, dirrhea, LFTs ↑

Skin: mucositiis Heme: ↓ blood counts, bone

marrow suppression Other: nodulosis,

opportunistic infections Renal tubular dysfunction Hepatic cirrhosis in RA

dosing Contraindication: EtOH

abuse, pregnancy, hepatitis, severe hepatic, renal, hematologic or interstitial lung disease

Monitoring: Initial – CBC, LFTs, alb, hepatitis B and C serology, consider CXR, PFT’sF/U – CBC, LFTs, alb q 6-8 wks, creatine periodically Gold standard DMARD S-phase specific, but

effects on protein and RNA synthesis may ‘self-limit’ this effect

Sulfasalazine Mild-moderate RA Broken down to 5-aminosalicylate (anti-inflammatory properties) and sulfapyridine (which has some immune modulatory affects)

Dosing: Maintenance dose – 1 gm BID, max. is 4 gm/day

Contraindication: Documented allergic rxn to sulfa drugs or aspirin, severe hepatic or hematologic disease.

GI: nausea, vomiting, anorexia, LFTs

Skin: rash, urticaria, Steven-Johnsons syndrome (rare)

Heme: neutropenia, anemia, thrombocytopenia

Monitoring: Initial – CBC, LFTs, G6PDF/U – CBC, LFTs, every 6 –8 wks.

Azathioprine Used for moderate to severe RA

Prodrug form of 6-mercaptopurine Inhibits nucleic acid synthesis-

purine analog

Not to be used in conjunction with allopurinol

Rarely used

37


Hydroxychloroquine Mild RA, alone or in combination with other drugs (esp. Methotrexate)

Dosing: Start 200 mg BID and keep under 5.0 mg/kg

Not shown to prevent erosion

Contraindication: Preexisting retinopathy

GI: nausea, vomiting, anorexia

CNS: irritability, nervousness Heme: anemia Eye: retinopathy, macular

atrophy

Monitoring:Initial – Ophtamological exam, G6PD (if suspected)F/U: Ophth exam q 6 – 12 mo.

Newer DMARDs *Leflunomide New generation DMARD

RA Taken orally

Inhibits dihydroorotate dehydrogenase, an intermediate in the pyrimidine synthetic pathway (decrease synthesis)

Reduces pain and inflammation Retartds structural damage evidence

by x-ray, e.g. erosions and joint space narrowing

Selectively targets autoimmune lymphocytes (T helper cells)

Early onset of action

Hepatotoxicity gastrointestinal

Fast acting (~ 4 weeks) Expensive Better than methotrexate

*Etanercept RA Given every 2 wks

Binds to TNF-α to prevent binding to receptor

Slow radiologic progression of joint damage (more than MTX?)

Multiple sclerosis Aplastic anemia Systemic infection/sepsis Worsening of CHF Reactivation of prior

granulomatous disease Long-term effects unknown

*Infliximab RA Given once a month

Chimeric IgG 1K monoclonal antibody

Binds specifically to human TNFα Neutralizes TNFα biologic activity

by binding both soluble and transmembrane forms, thus inhibiting binding of TNFα with its natural receptor

Shown to prevent erosion (w/ MTX)



38


*Anakinra RA Recombinant human IL-1ra produced in E. coli

Identical to human IL-1ra except with an additional 1 n-termainal methionine

Half-life = 6 hrs Reduce radiologic progression of

joint damage



Gout treatment Gout Characteristics: Acute attacks of crystal

induced arthritis Chronic deposits of

monosodium urate in and around joints and cartilage and in the renal parenchyma

Uric acid kidney stones Hyperuricemia

Hyperuricemia is secondary to increased uric acid production or decreased renal clearance.

Causes:Increased Production- Gout Lesch-Nyhan syndrome Lymphoproliferative disease Cytotoxic drugs Sickle cell anemiaDecreased Renal Clearance- Intrinsic renal disease Renal failure Gout Lead nephropathy Decreased excretion due to

competition Organic acids Increased lactate Increased ketone bodiesOther- HTN, CAD

*Colchicine Acute gout – no longer used

Prophylaxis – low oral dose

Interrupts the inflammation triggered by the phagocytosis of urate crystals by inhibiting the release of a chemotactic glycoprotein from PMN and synoviocytes

Spindle poison Metaphase arrest Microtubular poison

Oral: Nausea Vomiting Diarrhea Severe abdominal painIV: Increased morbidity and

mortality

39


NSAID: Acute Gout Prophylaxis

COX-1 and COX-2 inhibitors Decrease the inflammation

associated with gout

Newer drugs have fewer side effects

Do NOT use aspirin or other salicylates

Opioids and intra-articular glucocorticoids are useful in persons who cannot take NSAIDs

*Allopurinol Gout prophylaxis Overproducers

Competitive inhibitor of xanthine oxidase

Xanthine oxidase converts hypoxanthine to xanthine and converts xanthine to uric acid

Lowers production of uric acid, lowers serum uric acid, and decreases uric acid excretion

Also inhibits de nova production of purines

Immunologic Bone marrow depression Skin rash VasculitisDrug Interaction 6-mercaptopurine and

azathioprine – cancer drug that is metabolized by xanthine oxidase

Transiently increases serum uric acid levels as uric acid is mobilized- can lead to attack of acute gout

Oxypurinal Gout prophylaxis Overproducers

Metabolite of allopurinol Inhibitor of xanthine oxidase Also inhibits de nova production

of purines

Immunologic Bone marrow depression Skin rash VasculitisDrug Interaction 6-mercaptopurine and

azathioprine – cancer drug that is metabolized by xanthine oxidase

Transiently increases serum uric acid levels as uric acid is mobilized- can lead to attack of acute gout

*Sulfinpyrazone/ *probenecid Gout prophylaxis Under-excretors

Diminish renal tubular reabsorption of uric acid

Promotes uricosuria Lowers serum uric acid

Contraindication in hyperuricemia associated with uric acid nephropathy

Transiently increases serum uric acid levels as uric acid is mobilized-can lead to attack of acute gout

40


Ethanol *Ethanol Used socially

Treat methanol poisoning (IV)

Treat ethylene glycol intoxication

Mechanism of action: Bind to GABA type A receptors facilitating the entrance of Cl- into the cell thereby causing cellular depression

Metabolism: In the liver 1) Metabolized by alcohol dehydrogenase to acetaldehyde 2) Metabolized by aldehyde dehydrogenase to acetate 3) which is activated to acetyl CoA in peripheral tissues

Both reactions are redox reactions that increases the NADH/NAD+ ration, affecting other metabolic pathways that require NAD+: glycolysis, CAC, pyruvate dehydrogenase, fatty acid oxidation, and gluconeogenesis

Distribution: Tissues with a high water content and that are highly perfused receive the most amount of EtOH

Side Effects Glucose intolerace Alcoholic hypoglycemia Alcoholic ketoacidosis Lactic acidosis CNS: Behavioral syndrome,

cerebellar syndrome, Wernick-korsakoff syndrome, cerebellar atrophy, central pontine myelinosis, demylination of corpus callosum, mamillary body destruction

GI: local irritant, stimulate gastric acid production, gastric and duodenal ulcers, vomiting, acute and chronic pancreatitis, hepatic steatosis, hepatitis, cirrhosis

Withdrawal syndrome: psychologic and physical – treat physical with benzodiaepines

Interactions Acute – Metabolized by

CYP2E1, so increases sensitivity of drugs metabolized by this enzyme

Chronic – Induces CYP2E1 so the metabolism of drugs is increased in the absence of EtOH

Alcoholics - develop metabolic tolerance due to increased CYP2E1

Contraindications Pregnancy – FAS Breast feeding

Factors influencing the BAC: Conc. of EtoH Irritant properties Type of beverage Blood flow at site of

absorption Rate of ingestion Food

41


*Methanol Metabolized to formaldehyde and formic acid

Visual damage Acidosis

Treated with hemodialysis, ADH inhibitor, or IV ethanol

*Pyrazole Methanol intoxication Inhibits alcohol dehydrogenase Decreases the metabolism of EtOH

*Disulfiram Aversion therapy for alcoholism

Inhibits aldehyde dehydrogenase Leads to the build up of

acetaldehyde to the point of causing noxious effects

Nausea Sweating Vomiting Increased heart rate

*Ethylene glycol Ingredient in antifreeze ADH mediates its metabolism to glycolic and oxalic acids

Severe CNS depression Renal damage (due to build

up of oxalic acid) Meabolic acidosis (due to

build up of glycolic acid)

Treated with hemodialysis, ADH inhibitor, or IV ethanol

Drugs of Abuse Motives for Using Obtain perceived

therapeutic benefit (not abuse)

Improve performance Obtain a rewarding

subjective effect

Psychological dependence – results from craving for the drugged state in preference to the undrugged state

Physical dependence- the appearance of a withdrawal syndrome in the absence of the drug

Hallucinogens AKA: Psychedelics and psychotomimetic

Important neurotransmitters: NE, dopamine, serotonin (5-HT)

Induce altered states of consciousness

*Lysergic Acid Diethlamide (LSD)

AKA: Acid, boomers, yellow sunshine

Antagonist and agonist effects on 5-HT receptors- Synesthesia

5-HT2 on post-synaptic side, 5-HT1A on both pre and post synaptic neurons

Raphe nuclei – involved in sleep, exerts presynaptic actions at 5-HT1A receptor to decrease function of 5-HT neuron

Agonist effects on presynaptic 5-HT1A autoreceptors to decrease release of 5-HT

Produces altered perception without clouded consciousness

Perceptual sphere: visual hallucinations

Affective sphere: extreme emotional lability

Cognitive sphere: variation in logic

Revelation: special insight Chronic effects – flashbacks

which are transient, chronic abuse → depression/suicide

Treatment: “Talk-downs”, maintenece of a quiet environment, subdued lighting; Diazepam, haloperidol, risperdone PRN

42


Dimethyltryptophan Synthetic hallucinogen AKA: Business man trip

(BMT) Dose: 1mg

Same as above Short duration of action (30 min)

Lethal: 10 – 15 mg/kg

Bufotenin Rarely seen in US Same as above 10 times less potent than LSD

Pilocybin Magic mushrooms of Mexico

Same as above – acts on S-5HT1A receptor

10 times less potent than LSD

Psychomotor stimulants *Amphetamine Management of ADD or

hyperkinesis in children – has paradoxical calming effect

Release of newly synthesized monoamines: epinephrine, dopamine, and NE from brain neurons

Rewarding effects are mediated through the mesolimbic and mesocortical dopamine systems

Alertness Wakefulness Increased vigilance Increases physical and mental

energy Tolerance develops rapidly Large dose: induces euphora,

improved self-confidence, increased speech activity, and improved ability to concentrate

Amphetamine-induced paranoia

Secondary depression Physiological effects:

increased BP, increased temp, and appetite suppression

Toxicity: Seizures, cardiac arrhythmias, CVA, HTN and severe anxiety

Treatment of overdose: Induce emesis, gastric lavage, urine acidification, haloperiodol

Similar drugs: mescaline, dimethoxymethylamphetamine, and methylene dioxy amphetamine

43


*Methylated Amphetamine (MDMA)

AKA: Adam, ecstasy, XTC, clarity, lover’s speed

Previously used for psychotherapy

Street form: MDA

Acts at alpha receptors – stimulating both adrenergic and noradrenergic neurons

Increases 5-HT release and blocks uptakes

MDA- metabolite

Stimulant and psychedelic effects

Neronal toxicity in animal models – destroys dorsal neurons

Muscle tension Nausea Blurred vision Chills MDA – Serenity, joy, insight,

and self-awareness; toxicity: profuse sweating, skin reactions, and confusion

Treatment: talk down, and diazepam (rarely used)

*Cocaine Routes of administration: topical- nasal mucosa, IV, smoked

Local anesthetic Ingredient in Brompton’s

mixture for cancer pts

Causes a massive release of dopamine at the synaptic cleft

Prevents the re-uptake of dopamine, NE, and serotonin

Acts on pleasure centers of brain Rapid onset of action when inhaled

Intense euphoria Increased self-confidence Increased energy Chronic use: disruption of

sleeping and eating, psychological disturbance

Strong psychological dependence

Toxicity: HTN< tachycardia, diaphoresis, mydriasis, vasospasms MI and CVA

Brompton’s mixture: cocaine, methadone, and alcohol

Treatment: Acute anxiety with Diazepam, seizures with chlordiazepoxide, cocaine psychosis with haloperidol

*Phenyclidine (PCP) AKA Angel dust Often used as an adulterant

to marijuana or sold as LSD, mescaline, etc.

Chemically related to ketamine Psychotomimetic Open channel blocker: Non-

competitive antagonist at the NMDA glutamate receptor (blocks the excitatory NT)

Reabsorbed through the enterohepatic circulation

Persist for days to weeks

Euphoria Hallucinations (often

auditory) Can induce (+) and (-)

symptoms of schizophrenia R – rage E – erythemia D – dilated pupils D – delusions A – amnesia N – horizontal nystagmus E – excitation S – dry skin

Treatment: Stabilization of CV and respiratory system and protection for self-inflicted harm. HTN – diazoxide; Convulsions – Diazepam; mechanical respiratory assistance; activated characoal

Clinical presentation: HTN, convulsions

With alcohol – respiratory depression

44


Marijuana Prepared from the leaves and flowering tops

Anti-emetic in cancer Decrease IOP Appetite stimulation

Active ingredient: delta-tetrhydrocannabinol (THC)

Acts on cannabinoid receptor which is a G-protein coupled to cyclase

THC receptors are concentrated in the hippocampus (memory), substantia nigra (reticulata), and cerebellum (motor and balance)

No receptors in the medulla Fat soluble Slow excretion - half-life = 56 hrs,

can be detected up to 120 hrs after last use.

Improve mood and alter cognitive ability

Exaggerated perception of time

Sense of well-being or euphoria

Vivid visual imagery with novel sight and sound

Munchies Motivational syndrome with

chronic use Chronic use - ↓ imuune

system

Withdrawal syndrome: restlessness, agitation, insomnia, sleep ECG disturbance, nausea, cramping

Chemotherapeutic agents Cell cycle specific (CCS): - schedule-dependent cytotoxicity (repetitive/ prolonged administration better) -Majortiy are active in S phase

OR Cell cycle non-specific

More rapidly growing tumors (embryonal>lymphomas>sarcomas>squamous cell carcinomas>adenocarcinomas) are more susceptible to chemotherapeutic agents

Larger tumors have central ischemia- less blood-borne delivery of anti-cancer agents; less O2 to form radicals from radiation

Bone marrow: Leukopenia and lymphocytopenia, immunosuppression, thrombocytopenia

GI: Nausea and vomiting, oral and intestinal ulcerations, diarrhea

Hair: Alopecia Gonads: Ammenorrhea,

infertility, impaired spermatogenesis, sterility

Kidney: Depends on cancer Fetus: Teratogenesis Nadir- low point of

myelosuppression Majority produce: - Myelosuppression

- Alopecia (reversible)

Each individual treatment can reduce the tumor burden by 99%

Prevent alopecia by scalp cooling- vasoconstriction leads to less drug delivery

Antiemetic Prevent nausea and vomiting

*Ondansetron Antiemetic 5-HT-3 inhibitor Prochlorperazine Antiemetic Dopamine antagonist Lorazepam and Dexamethasone Antiemetic CNS-targeting agent

45


Alkylating Agents *Mechlorethamine Lymphomas, esp.

Hodgkin’s disease IV

Alkylation of DNA Nitrogen mustard

Phlebitis Nausea and vomiting Alopecia Myelosuppression (rapid

nadir, granulocytes and platelets)

*Cyclophosphamide (Cytoxan) Solid tumors (lung, breast) Hematologic cancers

(myeloma, acute leukemia, non-Hodgkin’s)

IV or PO Also used as a DMARD

Alkylating agent- cross-links guanines-CCNS

Metabolized to active form by cytochrome P450

Hepatically cleared, slowly excreted in urine

Bladder toxin: Acrolein, a toxic metabolite, accumulates and causes fibrosis, acute ulceration, ↑ risk for cancer

Myelosuppression – rapid Nadir, ↓ thrombocytopenia

Alopecia – transient Emetic potential – low - mod

To prevent acrolein toxicity:

Hydrate – high urine flow Frequent voiding Nucleophilic thiols to

conjugate acrolein Mesna forms monomer

that inactivates acrolein*Carmustine (Nitrosurea) CNS tumors

Multiple myeloma IV

Alkylating agent (carbonium ions)-CCNS

CNS penetration Metabolized to active form by

cytochrome P450 Toxic products: -DNA alkylating corbonium – crosslink DNA - Isocyanates- inactivate proteins (not anti-tumor) Excretion via hepatic inactivation

with urinary elimination

Hepatotoxicity Profound and delayed

myleosuppression – 6 wk. Nadir, 8 wk recovery

Phlebitis due to ethanol diluent

Platinum Analogs *Cisplatin Testicular cancer

Ovarian cancer Head and neck cancer Limited myelosuppression

Platinum analog-alkylating agent-CCNS

Binds DNA nucleophiles following the loss of Cl- side group to the low Cl- intracellular environment – intra-strand guanosine crosslinks most toxic

Heavy metal damage to renal tubular epithelium due to reduced creatinine clearance and BUN elevation

Severe emesis Peripheral neuropathy Rare HS: ototoxicity

Avoid renal damage by: High urine flow Diuretic use

*Carboplatin Ovarian cancer (Head and neck) Slowly activated

Platinum analog-alkylating agent-CCNS

Binds DNA nucleophiles following the loss of carboxyl side group

No neurotoxic effects Greater myelotoxicities –

thrombocytopenia Decreased vomiting

46


DNA Intercalating Agents DNA binding antibiotics –CCNS Derived from streptomoycetes Plana chromophore slides b/w

stacked nucleotides in DNA helix – distorts helix

Myelosuppression

Doxorubicin (Adriamycin) Broad spectrum Heamatologic cancers Solid tumors, esp. sarcomas

and breast cancer

Anthracycline Antibiotic Intercalation of DNA blocks both

DNA and RNA synthesis Quinone moiety promotes radical

formation Inhibition of DNA Topoisomerase

II – Accentuates strand breaking activity of topo II while inhibiting ligase activity, leading to cell lysis

Long half life (24 –36 hrs) Biliary secretion

Myelosuppression – short Nadir (8 – 10 d)

Moderate nausea and vomiting

Alopecia – prevent w/ scalp cooling

Congestive heart failure-heart has low antioxidant activity – prevent w/ continuous drug infusion

Colors urine red

Topoisomerase Inhibitors *Etoposide Small cell lung cancer

Refractory lymphomas Testicular cancer

Epipodophyllotoxin derivative DNA Topoisomerase II inhibitor CCS for G2 phase Results in the production of DNA ds

breaks

Myelosuppression: granulocytopenia, short nadir (8 – 10 d)

*Irinotecan Pro-drug Refractory solid tumors Non-small cell lung cancer

Topoisomerase I inhibitor CCS for late S/early G2 phase Stabilizes TOPI –I nicked DNA

‘cleavable complex’ causing strand breaks to persist

Hydrolyzed to active product Half-life: 11 hrs Glucuronidated in liver

Diarrhea Myelosuppression:

Neutropenia

Topiomerase I – alter the topology of DNA during transcription and replication

Schedule-dependent toxicity – frequent administration to increase toxicity

47


Antimetabolites Structurally similar to DNA and RNA

Needs metabolic activation Schedule dependent toxicity Dose-limiting myelosuppression

*6-Mercaptopurine Oral adminstration to organ allograft pts.

Oral admin: remission of ALL in children

Purine antimetabolite-CCS for S phase

Inhibits de novo purine biosynthesis

Blocking the amination of phosphoribosyl pyrophosphate by glutamine

DNA miscoding by direct insertion of metabolite of 6-MP into DNA/RNA

Inactivated by xanthine oxidase

Granulocytopenia Do not use w/ allopurinol

Azathioprine is prodrug form of mercaptopurine

*Cladribine (2-cda) Hairy cell leukemia – curative

Non-Hodgkins lymphomas CLL Infusion for 7 d

New purine antimetabolite- CCS for S phase

Inhibits adenosine deamininase - leads to lethal accumulation of deoxyribonucleosides in cells

Myelosuppression

*Cytarabine Remission induction and maintenance of acute myelogenous leukemia

Infuse for 5 – 10 d

Cytidine (pyrimidine) analog-CCS for S phase

Inserted in growing DNA chain DNA chain terminator Inactivation by deaminase (liver)

Myelotoxicity Conjunctivitis – acute Cerebellar dysfunction –

chronic

*Gemcitabine (Gemzar) Palliative care of pancreatic cancer – reduces pain, maintenance of wt, increased energy level

Cytidine (pyrimidine) analog-CCS for S phase

Inhibit deoxycytidin synthesis Insertion into chain – premature

DNA chain termination

Well-tolerated – low toxicity Does not increase survival

*5-Fluorouracil Colon cancer Solid tumors: breast, head

and neck IV – constant infusion

Uracil (pyrimidine) analog- partially CCS for S phase

Inhibits DNA synthesis by inhibiting thymidine biosynthesis – forms complex: FdUMP-reduced folate-thymidylate synthetase

RNA chain terminator by insertion Plasma half-life: 10-20 min

Myelosuppression – minor with continuous infusion, major w/ intermittent tx

Stomatitis Diarrhea

48


*Imatinib (Gleevec) Chronic myelogenous leukemia

Gastrointestinal stromal tumors

Dose and schedule dependent

Inhibits t(9;22) bcr-abl tyrosine kinase, stopping cell proliferation and inducing apoptosis

Metabolized by CYP3A4, eliminated in feces

Half life 18 hr (parent), 40 hr (metabolite)

Unusually well-tolerated Nausea Fluid retention Muscle cramp Chronic tx: suppression of

WBC and platelets

Resistance: Point mutation or c-abl overexpression

Bcr-abl tyrosine kinase – only in tumor cells

*Methotrexate Cancers: ALL, osteogenic sarcoma, breast, head and neck, cervical

Non-malignant: psoriasis, RA, GVHD, Wegener’s

Can be administered directly into CNS

CCS for S phase – self limited Folic acid antagonist Inhibit DHFR – blocks conversion

to THF (active form) Inhibition of thymidylate synthetase

– blocks DNA syn. Half-life: 2-4 hrs Renal tubular secretion

Lethal myelosuppression- reversed by Leucovorin – fully reduced folate – given 24 – 48 hrs. high dose MTX

Mocositis Dermatitis Renal tubular dysfuction Daily doses: cirrhosis

Resistance: DHFR gene amplification

*Leucovorin Treat MTX toxicity Fully reduced folate Given 24 – 48 hrs after high dose

MTX

Microtubular Inhibitors *Vincristine Hematologic cancers Vinca alkaloid

CCS- M-phase microtubule inhibitor, binds in S phase

Bind tubulin subunits, capping the microtubule and preventing elongation, disrupting chromosome segregation

Long half-life – 30 hrs Excreted in bile

Peripheral neuropathy –Parethesis, ↓ reflexes, paralytic ileus, jaw pain

SIADH – rare Management- delay or reduce

next dose NOT myelotoxic

Tubulin fxn: 1) Intracellular solute

transport 2) Cell movement 3) Nuclear scaffolding 4) Formation of mitotic

spindles

*Vinblastin Solid tumors Vinca alkaloid CCS- M-phase microtubule

inhibitor, binds in S phase Bind tubulin subunits, capping the

microtubule and preventing elongation, disrupting chromosome segregation

Long half-life – 30 hrs Excreted in bile

Myelotoxic: granulocyte and platelet suppression

Short Nadir: 8-10 d Infection and bleeding Tumor pain – rare Management – Antibiotics or

platelet transfusion

49


*Paclitaxel (Taxol) Solid tumors Advanced and refractory

ovarian cancer IV

CCS- M-phase microtubule inhibitor

Binds complete microtubules, causing clumping and disrupting mitosis

Short half-life 6-8 hrs Excreted in bile

HS rxn to Cremophor EL – bronchospsms, dyspnea, hypotension

Myelosuppression – short Nadir (10-14d)

Peripheral neuropathy

Cremophor EL (vehicle) – premedicate with dexamethasone, diphenhydramine, or ranitidine, cimetidine

Steroid Hormones *Tamoxifen Breast cancer

Suppressive but not-curative in estrogen-responsive tumors

May be efficacious in tumors that are estrogen receptor negative (rarely)

Anti-estrogen-CCNS Breast estrogen receptor

antagonist Bone, endometrium estrogen

receptor agonist

Acute disease flare Menopause symptoms inc.

hot flashes

Hormonally dependent breast cancers:

Post menopausal ↑ estrogen and

progesterone receptors Response to hormonal

manipulation Long disease-free period

after 1º tx*Megestrol Breast cancer Progestin agent

Decreases Estrogen receptors Enhances estrogen metabolism

Appetite and weight gain Fluid retention Vaginal bleeding

*Anastrozole Breast cancer Reversible selective aromatase inhibitor – blocks estrogen syn.

Lethargy Adrenal insufficiency Dermatitis

Give w/ dexamethasone and mineralocorticoids

*Leuprolide Prostate cancer Palliative care inc.

decreased bone pain Subcu pellet in abdomen

GnRH derivative Acutely: agonist - ↑ FSH and sex

hormones Chronically: antagonist - ↓ FSH and

sex hormones (castration levels)

Well-tolerated Hot flashes

Monoclonal Antibodies *Trastuzumab (Herceptin) HER2-/Neu (+) Breast

cancers Highly effective in combo

with cytotoxic drugs

Humanized murine Ab binds to erb-b2 receptor (HER-2/Neu), member of EGFR family.

Leads to antibody dependent cellular cytotoxicity

First infusion rxn – fever, chills, and rigors

Enhanced antracycline-induced cardiotoxicity

Erb-b2 receptor –over-expressed in 20-25% of breast cancers- poor prognosis

*Rituximab (Rituxan) B cell non-Hodgkin’s lymphoma

Humanized murine monoclonal Ab binds to CD20

Blocks cell signaling (proliferation) → apoptosis

First infusion rxn CD-20: on immature B cells

50


Parkinson’s Drugs *Levodopa (w/ Carbidopa) Decrease Parkinson signs

Initial improvement Chronic use: effectiveness

decreases due to progression of disease

Dopamine precursor - restores dopamine conc. in the basal ganglia

Low bioavailability due to decarboxylation and MAO in gut

Choreiform movements of face and limb – limits dose

On-off effect Nausea and anorexia –

treated w/ peripheral dopamine antagonist

Hypotension High doses: psychotic effects

– confusion, insomnia, and nightmares

Administered with peripheral dopa decarboxylase inhibitor (carbidopa)

*Pergolide Parkinson Used in combo w/ levdopa

Dopamine receptor agonist – mimics endogenous dopamine

Paranoia Hallucinations Confusion and Nightmares Dyskinesia Vomiting

Decreases levadopa side effects

*Seligiline Effective in early Parkinson Can be used in combo with

levodopa

Selectively inhibits MAO-B, in dopaminergic neurons

Increases Dopamine by preventing metabolism

Less wine-cheese effect Fatal hyperthermia in combo

w/ meperidine, fluoxetine, or cocaine

Does not retard neurodegenerative process

*Benztropine Useful in patients taking neuroleptics

Muscarinic receptor antagonist Dry mouth Heat stroke Impaired vision Urinary retention Constipation Drowsiness Confusion

*Amantidine Parkinson’s Benefit decreases with

long-term use

Antiviral drug Releases endogenous dopamine (?)

Minor

51


Anti-anxiety Drugs *Buspirone Anti-anxiety

Takes 1 wk to work Oral

Mechanism unknown Serotonin 1a receptor agonist (?) Half-life 2-4 hrs Metabolized in liver

Mild sedation No withdrawal syndrome

*Diazepam Anti-anxiety and insomnia Sedation in mania Spastic due to CP or

tetanus Anesthesia – milk of

amnesia EtOH detox Seizures – status

epilepticus

Long-acting benzodiazepine GABA-A receptor agonist – binds

to alpha-2 subunit plus others to increase Cl channel opening thereby hyperpolarizing the cell

Half-life 20-80 hrs Penetrates CNS Liver metabolism, renal excretion Active metabolite

Sedation Ataxia Dependence Death when combined with

EtOH Amnesia Withdrawal effect: seizures

and agitation Crosses placenta

Gradual withdrawal to avoid seizure

Alpha-2 subunit – binding here causes anti-anxiety effects

Other subunits are responsible for anesthetic effects

*Flumazenil Block sedating effects of benzos

Benzodiazepine receptor antagonist

Precipitate withdrawal symptoms

Anti-psychotics Schizophrenia Intractable hiccups Huntington’s chorea Ballism Tourette’s syndrome Acute psychotic depression

Act mainly on D2 receptors, with the atypicals also acting on serotonin receptors

Also have limited action at α-adrenergic, cholinergic, histamine

Higly lipophilic Metabolism by cP450

SEE NOTES Occupancy > 85% → extra-

pyramidal movements due to increased sensitization of unoccupied receptors to dopamine

Cross placenta Neuroleptic malignant

syndrome – needs immediate care

α-adrenergic – control excitement, postural hypotension

Cholinergic – atropine side effects

Histamine - sedation

*Haloperidol (+) Symptoms of schizophrenia

Typical anti-psychotic Blocks D2 receptors in the limbic

and mesocortical areas – need to block > 75%

High potency

Extra-pyramidal movements Sedation

*Chlorpromazine Schizophrenia Typical anti-psychotic Block D2 receptors Low potency

Photosensitivity Large autonomic effects Sedation Extrapyramidal movements

52


*Thioridazine Schizophrenia Typical anti-psychotic Block D2 receptors Low potency

Pigmentary degeneration of retina – browning of vision

Large autonomic effects Abnormal cardiogram –

prolong Q-T Sedation Mild Extrapyramidal

movements

*Clozapine (-) and (+) Symptoms of schizophrenia

Atypical anti-psychotic Block Serotonin receptors and D2

receptors Low potency – blocks 35% of D2

receptors

Agranulocytosis in 1% Large autonomic effect Sedation No extrapyramidal movement

*Dantrolene Neuroleptic malignant syndrome

Malignant hyperthermia Serotonin syndrome

Direct muscle relaxant All characterized by having a labile system

Anti-depressants Depression Panic or phobic disorders OCD Enuresis Anorexia and bulimia Treat for 1 – 6 mo

Depression: Dysregulation of NE and 5-HT leads to alterations in the NE and 5-HT receptors

Antidepressants re-regulate receptor sensitivity

Takes 2 wks for re-regulation

Non-compliance due to over-sedation, anticholinergic side effects, or sexual dysfunction

Drug selection is based on past response to drug, susceptibility to side effects, compatibility w/ other drugs pt. is taking

*Fluoxetine (Prozac) Depression SSRI Potent blockers of serotonin

reuptake Active metabolite w/ half-life of 128

hrs.

Nausea, HA, nervousness, and insomnia

Some sedation Anorganism, impotence, ↓

libido (30-40%) Fatal interaction w/ MAOI →

Serotonin Syndrome

Treat serotonin syndrome with Dantrolene, avoid by spacing out tx. switch (4wk. For Prozac)

53


*Tranylcypromine Depression MOAI Prevent the metabolism of

monoamime NT – increasing the conc. at nerve terminal

Wine-cheese effect Dry mouth, constipation,

difficult urination (no direct anticholinergic effects)

Sedation Weight gain Sexual dysfuction CV: orthostatic hypotension Monoclonic jerks in sleep Serotonin syndrome w/SSRI Enhances depressive effects

of EtOH

Wine-cheese effect: Tyramine, usually broken down by GI MAOI’s, is taken into nerve endings where it causes massive NE release → HTN crisis, tachycardia, HA< chest pain, dilated pupils, nausea and sweating

Treat w/ α-adrenergic blocker

*Setraline (Zoloft) Depression SSRI Potent blockers of serotonin

reuptake

Nausea, HA, nervousness, and insomnia

Some sedation Anorganism, impotence, ↓

libido (30-40%) Fatal interaction w/ MAOI →

Serotonin Syndrome

Treat serotonin syndrome with Dantrolene, avoid by spacing out tx. switch (2 wks)

*Imipramine Depression TCA – tertiary Blocks reuptake of

norepinephrine and serotonin

Anticholinergic – dry mouth, blurred vision, constipation, urinary retention and speech blocking

Postural hypotension Tachycardia, arrhythmia,

ECG abnormalities, A-V block

Sedation – take QHS Weight gain Tremor and akathisia Lowers seizure’s threshold Sexual dysfunction: resolves

Treat tremor w/ propranolol

Used for SUICIDE

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*Lithium Mood stabilizer Acute mania Manic episode of bi-polar

disorder Slow onset – intiate tx. w/

benzo or anti-psychotic Severe recurrent depression

Substitutes sodium in generating action potentials

Pumped out slowly → accumulates → partial ndepolarization

Enhancement of serotonin effects Inhibition of NE and dopamine

release Augmentation of Ach synthesis 2nd messenger systems → reduced

response to muscarinic and α-adrenergic stimulation

Renal clearance

Narrow therapeutic index (0.8-1.2 meq/L) – check serum conc. regularly

Tremor – alleviate w/ propranolol

Decreased thyroid function Polydipsia and polyuria Edema ECG abnormalities -

depressed T wave Excreted in breast milk Therapeutic overdose – treat

w/ hemodialysis, peritoneal dialysis

Physical work-up and renal function before prescribing

Anti-convulsants Steady plasma conc. must be reached before changing dose

Epilepsy is a chronic brain disorder 10-30% don’t respond to therapy General site of action: Sodium

channels, GABA

*Ethosuximide Uncomplicated absence seizures

Inhibiting low threshold voltage dependent (T-type) calcium channels in thalamocortical neurons

Drowsiness GI distress: nausea and

vomiting HA

*Topiramate Adjunctive or monotherapy for all types of seizures

3 mechanisms of action: Na channel blocker Enhancement of GABA at GABA-A

receptors AMPA receptor antagonist

Somnolence and fatigue Dizzyness Difficulty concentrating Speech disorders and ataxia

*Lamotrigine Adjunctive or monotherapy for all seizures

Inhibits release of excitatory amino acids

Some dizziness, ataxia, somnolence, and fatigue

Rash in 5% Increased elimination when

taken with carbamazepine, phenytoin, and pheno

Decreased elimination with valproic acid

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*Phenobarbital Suppress seizure activity, elevate seizure threshold, and limit spred from a focus

Generalized tonic/clonic Partial seizures Status epilepticus

Barbiturate Enhance GABA inhibition by

increasing Cl channel opening Bind to BZD binding → increase the

frequency of opening but not the time

Sedation and impaired cognitive function

Ataxia Withdrawal syndrome Osteomalacia Paradoxical hyperactivity in

some children Agitation and confusion in

elderly pts. May WORSEN absence

seizures

Used in children

*Phenytoin (Dilantin) Generalized tonic/clonic Partial seizures Status epilepticus Oral

Na channel blocker Maintains Na channel in inactive

state for a prolonged perion Follows Zero-ordered kinetics –

small changes in dose → large changes in plasma level

Metabolized in liver, half life is 24 hrs.

Dizzyness, ataxia, nystagmus, diplopia

Gingival hyperplasia Hirsutism Skin rash Mental confusion Altered vit. D and Ca

metabolism Tetratogenic

Minmal drowsiness and general depression

Use w/ caution in liver disease

Fosphenytin – used for Status epilepticus (IV)

*Carbamazepine Generalized tonic/clonic Partial seizures Status epilepticus Focal epilepsy in children

Na channel blocker Increase central NE transmission Adenosine partial agonist (?) Metabolism: 95% hepatic, half life

is 12 hrs Induces own metabolism by

increasing microsomal enzymes

Drowsiness Disequilibrium Blurred vision Ataxia

Need to increase dose over time

*Valprocic Acid Absence seizures Myoclonic seizures Partial seizures: complex

Inhibits metabolism of GABA Prolongs recovery of Na channels Some inhibition of low threshold

voltage dependent (T-type) calcium channels

Anorexia Nausea Vomiting Hand tremor at high doses Alopecia Weight gain Hepatoxic Neural tube defects Increase Phenobarbitol levels

in blood

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*Gabapentin Partial seizures Neuropathic pain Psychiatric conditions

Unknown Indirectly increases CNS GABA

levels, ↑release (?) Absorption shows saturability from

GI Renal elimination

No drug interactions Mild: somnolence, fatigue,

ataxia, and dizzyness

*Tiagabine Adjunctive therapy in adults and children (>12) for tx of partial seizures

Interfers with GABA reuptake 96% protein bound, half-life is 7-9

hrs

Impaired concentration Somnolence and fatigue Dizzyness and nervousness

Drugs effecting micrsomal enzymes will increase its metabolism

*Diazepam Absence seizures Myoclonic seizures Atonic seizures

Benzodiazepine Enhances GABA actions by

increasing the frequency of Cl channel opening → hyperpolarized

CNS depression Drowsiness Ataxia Dysarthria Respiratory depression and

bronchial hypersecretion

Side effects may lessen w/ long term use

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