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MBC


  • [lowest] that kills 99.9% of inoculum
  • Used for serious infections: endocarditis, meningitis, sepsis



MIC


  • [lowest] that prevents growth of culture
  • determined for most infections



Antibiotics that cross BBB


  • antibiotic must accumulate in CSF @ therapeutic levels
  • inflammation facilitates penetration of antibiotic
  • Penicillins: 3rd gen. Cephalosporins



Antibiotics that cross Prostatic Epithelium


  • Fluoroquinolones



Crossing the lipid barrier: lipid solubility & pKa


  • + lipophillic = + crossability
  • Uncharged= + crossability



Immune System
  • Patient factors



  • Immunosuppression in general = need for higher dose or longer tx.



Hepatic & Renal Dysfunction
  • Patient Factors



Accumulation of antibiotics --> toxicity unless dosage is modified

Kidney:
most drugs eliminated in urine, (elderly affected)

Liver
: erythromycin, tetracycline


Pregnancy & Lactation
  • Patient Factors



Placenta permeable to ALL antimicrobials, most have no effects
  • Tetracyclines: tooth dysplasia & inhibits bone growth
  • Aminoglycosides: ototoxic
  • Anthelmintics: embryotoxic/teratogenic



Poor Perfusion & Age
  • Patient Factors



  • ↓Q --> ↓ [antimicrobial]
Neonates: kidney/liver not developed     



Contraindicated in Neonates


  • Chloramphenicol: Gray baby syndrome
  • Sulfonamides: kernicterus



Contraindications in Young Kids


  • Tetracycline: inhib. bone growth
  • Fluoroquinolones: inhib. cartilage growth



Bacteriostatic Drugs


inhibit proliferation of bacteria & reduce the spread of infx. until immune system eradicates mo.



Bactericidal Agents


Kill bacteria: [] or time-dependent killing


Narrow Spectrum Antibiotic


Acts only on a single group of mo's
  • Pen G: Gm+
  • Isoniazid: Mycobacterium



Extended Spectrum Antibiotics


Effective against Gm+ & few Gm-
  • Amoxicillin



Broad Spectrum Antibiotics


Wide range of microbial species; may --> superinfection


Combination Therapy (Pros/Cons)


Pros
  1. Synergy: B-lactams/Aminoglycosides, Sulfanomides/Trimethoprim
  2. Serious, polymicrobial infx.
  3. Empiric therapy
  4. Used for mycobacterial & HIV infx.: decrease resistance
Cons
  1. antagonism: Ex. B-lactams only effective when mo's are proliferating, so using a static agent would antagonize the -cidal drug



Drug Resistance


Resistance= when bacterial growth is not inhibited by the [highest] that the patient can tolerate

  1. Innate resistance
  2. Resistant Strains: spontan. mutation, acquired & selection (alteration in protein expression in resistant mo)



Genetic Alterations
  • Drug resistance



  1. Spontaneous mutation: chromosomal bc of nt changes. Ex. Rifampin-resistant-M. tuberculosis
  2. DNA transfer of plasmids: plasmids passed between cells (result of overuse) Ex. pts. w/ Vanc-R-SA have obtained the R plasmid from Vanc-R-enterococcus



Altered Protein Expression
  • Drug Resistance



  1. Alteration in target proteins: Δ PBP in MRSA, modification of 50S ribosome in Azithro-R-Gm+ mos
  2. Reduced accumulation: mos produce LPS layer or use an efflux pump to ↓ [Ab], Tetracyclines
  3. Enzymatic inactivation: mos produce Ab-inactivating enzymes, Ex. B-lactamases



CTI (Chemotherapeutic Index)


CTI = Toxicitypt/toxicitypathogen
=LD50pt/LD(orED)50pathogen
HIGH CTI = selective toxicity
Ampho"terrible" B: CTI=2 (bad!)


Complications with Antimicrobial Therapy


  1. Hypersensitivity: Ex. Penicillins & Sulfonamides (sx. urticaria --> shock)
  2. Direct Toxicity: Elevated [serum] --> direct actions on cellular fx. Ex. Aminoglycosides-->directly damage Organ of Corti
  3. Superinfections: bc of broad spec, or combination therapy



Superinfections


Caused by use of broad spectrum Ab that destroys normal flora of upper resp. & GI/GU tracts
  • C.difficile --> pseudomembraneous collitis
  • Staph Aureus--> staph. enterocolitis
  • Candida--> intestinal candidiasis



Classification of Antimicrobials


  • Chemical Structure (11)
  • Mechanism of Action (5)
  • Activity against specific kids of mos (6)



Inhibition of Cell Wall Synthesis: Bactericidal
  • Mechanism of action



  • B-lactams (Penicillins, Cephalosporins, Monobactams, Carbapenems)
  • Bacitracin
  • Vancomycin: inhibits synthesis of phospholipids & peptidoglycan X-linking
  • Fosfomycin
  • Cycloserine: antimycobacterial



Inhibition of Metabolism
  • Mechanism of action



  • Sulfonamides: inhibit folic acid synthesis of mo



Inhibition of protein synthesis
  • Mechanism of Action



  • Tetracyclines: bind to 30S bacterial ribosome & block tRNA binding to mRNA ribosome complex
  • Aminoglycosides: irreversible inhib, diffuse through channels formed by proteins of Gm- bacteria-->30S:misreading of the DNA
  • Macrolides: bind 50S & block translocation of the ribosome
-mycin: think protein synthesis inhibitor, EXCEPT for 1. Vancomycin 2. Fosfomycin 3. Daptomycin



Inhibition of DNA/RNA fx. or synthesis
  • Mechanism of action






Inhibition of cell membrane function
  • Mechanism of action



  • Daptomycin (unique: depolarizes membrane potential)
  • Polymyxins: bind to & disrupt cell membranes




B-lactam Abs
  • Penicillins




Peptide Ab



Sulfonamides



Tetracyclines



Aminoglycosides



Lincosamides
  • Lincomycin
  • Clindamycin




Macrolides: 14-16 mem. lactone ring
  • Erythromycin
  • Clarithromycin




Ketolide: (macrolide + ketone @C3 +carbanamine)
  • Telithromycin




Fluoroquinolones



Oxazolidinone
  • Linezolid




Streptogramins


Common (& safe) for Peds. (& Preggos)


  1. Penicillins: Amoxicillin, Augmentin, Pen. V
  2. Cephalosporins: Cephalexin, Cefprozil, Cefurox
  3. Macrolides: Erythromycin, Azithromycin, Clarithromycin
  4. Co-trimoxazole (SMX-TMP)



Common Antibiotics (List)


  1. Amoxicillin
  2. Augmentin (Amox/Clavulanate)
  3. Azithromycin
  4. Cephalexin
  5. Levaquin
  6. SMX-TMP
  7. Valtrex
  8. Fluconazole: (crosses BBB & antifungal)
  9. Doxycycline
  10. Penicillin V (oral of Pen G)
  11. Ciprofloxacin
  12. Omnicef: 3rd gen, broadest oral cephalosporin
  13. Avelox
  14. Clindamycin
  15. Mupirocin



  • B-lactam Antibiotics



Cell wall synthesis (must be actively proliferating) inhibitors: inhibit transpeptid. & X-linking
4-mem B-lactam ring essential to activity
  • Penicillins
  • Cephalosporins
  • Carbapenems
  • Monobactam: Aztreonam (Azactam)



Penicillins (Classes)
  • B-lactam antibiotics



  1. Standard Penicillins: G (Pfizerpen) & V               Depot Penicillins: Benzathine pen G (Biciliin L-A), Benzathine pen G/Procaine pen G, Procaine pen G
  2. Antistaphylococcal Penicillins: Naficillin, Oxacillin, Dicloxacillin
  3. Extended Spectrum Penicillins: Amoxicillin, Amoxicillin/K+Clavulanate (Augmentin), Ampicillin, Ampicillin/sulbactamNa (Unasyn)
  4. Antipseudomonal Penicillins: Ticarcillin/K+Clavulanate (Timentin), Piperacillin, Piperacillin/tazobactamNa (Unasyn)
  5. Penicillin & Aminoglycides = synergy



B-lactamase inhibitors (can use with mos that produce B-lactamases)
  • B-lactam antibiotics



  1. Augmentin: amox/clavulanate
  2. Unasyn: amp/sulbactam
  3. Timentin: ticarcillin/clavulanate
  4. Zosyn: piperacillin/tazobactam



Cephalosporin Antibiotics
  • B-lactam antibiotics



Generations
  1. Cephalexin (Keflex, Panixine), Cefazolin, Cefadroxil
  2. Cefzil, Ceftin, Zinacef, Cefaclor, (Cefoxitin, Cefotan)
  3. Rocephin, Claforan, Fortaz (Tazicef), Cefizox, Omnicef, Suprax, Cedax, Vantin, Spectracef
  4. Cefepime (Maxipime)



Carbanapenems
  • B-lactam antibiotics



  1. Iminipenum (Primaxin IM/IV): broadest B-lactam on market, UTIs (Entero, Proteus) Resp. tract (Strept. pneum & Klebsiella) & Nosocomial (Serratia & Acinetobacter)
  2. Meropenem (Merrem IV): like Primaxin but >Gm- & <Gm+
  3. Doripenem (Doribax): same as Merrem but +Pseudomonas
  4. Ertapenem (Invanz): like Primaxin but INACTIVE against Pseudomonas & Acinetobacter



PharmacoKINETICS


what the body does to the drug


PharmacoDYNAMICS


what the drug does to the body


Size & MW
  • nature of drugs



MW: 100-1000
too small = no selectivity
too large = poor absorption

large & hydrophillic: need endocytosis



Drug-Receptor Bonds
  • nature of drugs



Covalent (irreversible), electrostatic (cation + anion), weak hydrogen, van der waals, hydrophobic bonds


Lipid Diffusion


governed by Fick's law, HH predicts charge under different conditions

Ionized: more water soluble (excreted in urine)
Non-ionized: more lipid soluble (absorbed!)

drugs may be ionized or non-ionized depending on the pH of the environment, & whether the drug is a weak acid or weak base


Weak Acids


acid in acid = absorption (more uncharged molecules)
acid in base = excretion (more charged molecules)

acid= non-ionized, can donate a proton
drug in acidic environment = lots of protons around


Base Acids


base in acid = excreted
base in base = absorbed

bases are not protonated & can accept a proton





Absorption/Excretion
Henderson-Hasselbach


lower the pH of the environment = greater the fraction of protonated drug

log (prot/unprot) = pKa - pH


Ex. of alkalinization of urine


Overdose on a weak acid (Aspirin), alkalinize the urine (with ammonium bicarb) so excretion will be accelerated


General Rule of absorption/excretion


weak acids: excreted faster in basic urine, reabsorbed faster in acidic urine

weak bases: excreted faster in acidic urine, reabsorbed faster in basic urine

To acidify: give ammonium chloride
To alkalinize: give sodium bicarb


Fick's Law and interpretation


Rate = (C1-C2) x (perm/thickness) x A

drugs are absorbed faster with large surface area (small intesting vs. stomach), and thinner membranes (lung vs. skin)

governs: lipid diffusuion, aqueous diffusion

Transport & Endocytosis: NOT governed


Bioavailability


extent to which a dose of drug reaches its site of action

PO & Rectal: go to liver first, so by the time the drug has been metabolized and distributed systemically, only a fraction is left



Oral (enteral) Route
Pros & Cons


+: safest, most convenient, economical

-: limited absorption, vomiting, destruction of drug, nutrition intrx, compliance, drug must pass through digestive epithelium & vascular endothelium



Oral Route: local & general tx.


Local tx: used as GI protectant of digestive tract, tx. intestinal infx, ideally drug will not be absorbed fully

General
tx: common route of administration: digestive absorption is followed by drug diffusion throughout the body



Digestive Absorption


Mouth-->rectum
Mouth: fast absorption, avoids hepatic transfer, ex. Nitroglycerin (angina), avoids 1st past metabolism

Stomach: A=1m2, pH=1-4, low flow rate (0.2L/min)
  • nuetral molecules & nonionzed acids = absorbed bc acidic pH
  • bases are secreted into the gastric fluid from the blood and are ionized by protonation in acidic gastric fluid
Intestine:  large area = good diffusion (1L/min), pH=6-8 majority of drugs absorbed here


First Pass Metabolism
  • Digestive absorption



drug: liver-->R. heart-->pulmonary transfer--> L heart --> body (systemic)

In intestines & liver: metabolites  are created (generally inactive)

explains low efficacy of drugs, especially in low doses


Form (presentation) of the drug
  • Factors modifying digestive absorption



Drops: immediately available, more rapid & higher [max.]
Tablets: must disentegrate & be emulsified
explains > poisionings w/ drops

Sustained release: can delay absorption for >8hrs.
+: reduced freq. of dosing, maintenance of effect, decreased SE
helpful in antidepressant therapy



Foods
  • factors modifying disgestive absorption



bioavailability when taken with meals:
  • reduced: Tetracyclines, isoniazid, penicillamine, captopril
  • unchanged: amoxicillin
  • increased: propranolol (+ due to - in 1st pass metabolism)



Digestive transit
  • factors modifying digestive absorption



Modifications:
  1. Pathologic: vomiting, diarrhea...
  2. Drug-induced: acceleration or slowing of transit
can modify the kinetics of absorption & bioavailability


Direct chemical actions between drugs
  • factors modifying digestive absorption



  • Cholestyramine: binds and reduces drug absorption; diuretics
  • Metals (Fe, Alum) reduce the bioavailability of some antibiotics (form organometallic complexes)
  • Activated charcoal: absorbs many molecules.  Used to prevent oral overdose, must be given ASAP after ingestion




  • Parenteral Route



Drug must be sterile & non-irritant
Absorption is by simple passive diffusion

limited by solubility & area of capillary

Large proteins go via lymph channels


Subcutaneous Route
  • Parenteral



good for: poorly soluble & slow-release implants

Rate of absorption: Aqueous sltn: prompt
Repository preps: slow & sustained

Heparin & Insulin



Intramuscular Route
  • Parenteral



aqueous sltn: fast
delayed preps: slow & sustained (Ex. steroid hormones)

Good for:
moderate volumes, oily vehicles, irritating substances

Should not be made in a vessel, or contact a nerve

CI: anticoagulant therapy


Intravenous Route
  • Parenteral



Injection w/ syringe or perfusion

Good for: emergency, comatose, non-compliant
Bioavailability is 100%

Speed of administration: not too rapid or too slow

Do not use oily sltns

Chemo tx: implantable device for IV admin & long course tx.  Gives IV access w/ administration of subQ type


Intraarterial Route
  • Parenteral



Direct into artery

Bypasses: 1st pass & lungs
Rarely used

Use: vasodilator, thrombolytic, antineoplastic




Intrathecal Route
  • Parenteral



Directly into subarachnoid space

Use: local & rapid effects on meninges or cerebrospinal axis, Ex. anesthesia or to treat acute CNS infx.


Nasal Route


Used for local & general tx

Local: vasoconstrictive & antiallergic drugs (poss. of absorption & general effects)

General: polypeptide hormones (Desmopressin)

avoids 1st pass metabolism



Pulmonary Absorption (Inhalation)



Gaseous & volatile drugs

access to circulation is rapid (large SA of lungs)

+: avoids first pass metabolism, local app. to lungs
-: toxicity bc of quick absorption, rapid dissipation of effects




Topical application


Transdermal: must be lipophillic, spread over large surface area
+ absorption: high temp, lesions (burns) Ex. Scopolamine, nitroglycerin, testosterone & estrogen replacement

Mucous membrane: local app: conjunctiva, nasopharynx, oropharynx, vagina, urethra (rapid absorption)

Eye: local effects, absorption through cornea. Cons = systemic absorption through nasolacrimal canal



Rectal Route (PR)


General effect w/ limited bioavailability

1/2 bypasses the liver, so 1st pass is decreased

good if pt is unconcious, vomiting, distasteful drugs


Dose-response


response to a drug is directly proportional to the dose administered

sigmoidal curve (log dose)
if 2 drugs act on same receptor you will see 2 parallel log-dose response curves)


Sites of drug action: Specific


majority bind to specific receptors on/in cells

high structural specificity & steroselectivity



Water as a drug target


  • osmotic diuretics (mannitol), laxatives like MgSulfate



Hydrogen Ions as a drug target


ammonium chloride: orally-->liver metabolizes to urea & Cl is excreted in urine, bringing H+ with it---> acidifies the urine


Metal Ions as drug targets


chelating agents (EDTA) can bind divalent cations like Pb2+ to help in poisonings



Enzymes as a drug target


Drugs can inhibit enzymes by competitive, non-competitive, irreversible blockade

Antimicrobial drugs inhibit enzymes critical to bacterial cell function, must have some selective toxicity

Ex. Sulfonamides inhibit folate synthesis


Nucleic acids as drug target


target for antimetabolites & some antibiotics

5-fluorouracil acts as a substitute for uracil & is incorporated in faulty mRNA


Non-specific binding to a macromolecular receptor as a drug target


Thought to alter the function of membrane proteins by disordering the lipid membrane

Lack of specificity: very low chemical structural reqs

General anesthetics: nitrogen, xenon, halogenated ethers, steroids


receptor


molecule to which a drug binds to bring about a change in function of the biologic system


Spare receptor


receptor that does not bind drug when the [drug] is sufficient to produce a maximal effect

shifts the apparent potency of ligand w/o altering maximum efficacy (up-regulation)


Agonist


Agonist: binds to its receptor & produces characteristic effect
(full or partial, depending on max effect) increase the proportion of activated receptors




Inverse Agonist


stabilize receptor in inactive conformation (act similarly to competitive antagonists)


Antagonist


binds to receptor w/o causing an effect & prevents an active substance from gaining access

Competitive:can overcome by increasing [agonist], shift the dose response to agonists to the right , w/o a change in efficacy (bc there are still spare receptors) Antihistamines

Irreversible: cannot be overcome, causes downshift of efficacy, result in loss of receptor units phenoxybenzamine

Physiologic: counters the effect of another drug by binding to a different receptor & causing reverse effects

Chemical: a drug that binds to the agonist drug & inactivates it, not the receptor (Ex. Dimercaprol: chelating agent)


ED50


dose which produces a response in 50% of subjects

LD50:
if response is death
EC50: refers to [] instead of dose

Low EC50 = more potent drug


Potency (Relative)


molar [] req'd to produce a specific intensity of effect

(usually specified as ED50)
Ex. ED50 of A is 5mg & B is 10 mg, so A is 2x more potent

Only use to compare drugs acting by same mechanism (parallel dose-response curves)


Efficacy (Intrinsic Activity)


max. effect

(a low potent drug may have high efficacy, & a high potent drug can be less efficacious)

*Much more important for clinician

Full agonist: 1
Antagonist: 0
Partial agonist: 0-1

Maximal efficacy: max. effect that can be achieved, regardless of dose


Affinity


strength of binding between drug & receptor

Kd


Selectivity


separation bet. desired & undesired effects

Ideally: completely specific

Ex. Penicillin (other than allergic responses)



Therapeutic Window


Range between [Effective] & [Toxic]

Therapeutic Index = LD50/ED50
1=BAD,
want a large therapeutic window!!!




Receptor Occupancy


the more receptors occupied, the greater the response to the ligand, up to the point of saturation

2 key determinants: specificity & affinity

most ligand-receptor relationships are reversible


Concentration-Response Relationship


X-axis: Concentration
Y-axis: Measured effect (receptor occupancy)

Graded response: + [ligand], + receptor occupancy

can be saturated: more ligand will NOT increase occupancy

Linear plot: hyperbolic function
Log-linear: sigmoidal


Equillibrium Dissociation Constant (Kd)


Kd= [ligand] that produces 50% receptor occupancy @ equilibrium

High affinity = [low]-->receptor occupancy = LOW Kd
Low affinity = [high]-->receptor occupancy = HIGH Kd
Bmax= max. # of receptors bound


Intrinsic Activity


property of a drug that determines the amount of biologic effect produced/unit of drug-receptor complex formed

Ex. Morphine & meperidine are both analgesics using the opiate receptor.  Regardless of dose, max. degree of analgesia by morphine is greater than meperidine.  morphine has the greater intrinsic activity


Down-Regulation
  • Receptor Dynamics



Decreases the max. response produced-->reduction in "responding units"

Ex. Heart failure, hyperadrenergic state-->down-regulation of B-adrenergic receptors--->receptor desensitization & internalization-->decrease in B-adrenergic receptors open to interact w/ adrenergic agonists on cardiomyocytes


Up-Regulation
  • Receptor Dynamics



cells create spare receptors & only a fraction of available receptors requires engagement to provide max. response

Presence of spare receptors increases sensitivity to the agonist because there is more likelihood of an interaction


Presence of Spare Receptors


EC50 < Kd means spare receptors exist

(concentration for 50% of max. effect is less than concentration for 50% of maximal binding)


Quantal Response


differences in drug responsiveness bet. individuals across the population

administer [increasing] of drug to elicit a fixed quantal response


Cumulative frequency distribution


production of response: distributed according to log of [ligand] as a freq. distribution

Cum. freq. dist = sum. freq. @ each [] = pharmacodynamic variability w/in a population


Effector Mechanisms: Signal Transduction


ligand induces change in receptors-->initiation of effector cascades--> biologic response


Signal Transduction: transcriptional regulation


Ex. Corticosteroids & their receptors

when ligand binds, receptor acts as transcriptional regulator--> alteration of regulated genes-->altered expression of proteins


Signal Transduction: Enzyme Receptors


Ex. NSAID (aspirin) inhibit cyclooxygenase, stopping production of prostaglandins

Ligand binds enzyme-->alteration of activity


Signal Transduction: Ion channel receptors


Ex. Calcium channel blockers interrupt calcium influx, inducing sm. m. relaxation in HTN & extracellular matrix remodeling in CT diseases

ligand binds & alters ion channel conductance


Signal transduction: cell surface protein receptors


cell surface receptor-->2nd messenger--> response from cell

2nd messengers:
cAMP: through guanine nucleotide binding proteins-->adenylyl cyclase: B-adrenergic receptors

cGMP: activate guanylyl cyclase

Phos. tyrosines: kinase activators: growth factor receptors


Orally Administered Drug
  • Pharmacokinetics



what the body does to the drug
  • dissolution(stomach)
  • solubilization (dissolved particles into solution)
  • absorption across GI mucosa into portal circulation
  • first pass metabolism in liver
  • systemic circ. distribution
  • further metab. in organs
  • excretion: sweat, urinary, fecal, exhaled



Absorption of Drugs
  • Transport across cell membranes



  1. Passive diffusion: lipid cell membrane, better for unionized (more lipophillic), can NOT be limited
  2. Active transport: against [gradient], ATP-transporters (Ex. multidrug resistance p-glycoprotein)
  3. Endocytosis; large molecules



Absorption Rate
  • General determinants



dissolution, flow, SA @ absorption site, lipophillicity, [gradient] (Fick's law)

Best absorption = lipid, small, non-polar, nonionized
If oral: want weak acid


First Order Kinetics
  • absorption



rate of elimination is proportional to the amount of drug in the body

+[]=+ elim/time

  • [drug] decreases exponentially w/ time
  • rate of elim. proportional to [drug]
  • T1/2= constant regardless of [drug]



Volume of Distribution: Vd
  • 1st orer kinetics



=amt of drug in body/plasma[drug]

high lipophillicity = high Vd & high T1/2 (stays in tissues)
low lipo = low Vd= stays in blood (Neuromuscular blockers)

can exceed the total volume of the body Ex. digoxin Vd=5,000L

Completely retained in plasma: Vd=plasma vol. (4% body wght.)

high Vd can be altered by liver disease (less albumin) & kidney disease (+proteinuria)





Clearance (Cl)
  • 1st order kinetics



=rate of elim/plasma[drug]

volume of plasma from which the drug is completely removed/unit time

amount eliminated is proportional to [drug] in plasma


Zero Order Elimination


rate of elimination is constant, regardless of []

pathways rapidly saturated & work to their limit

constant amt. of drug eliminated/unit time

[drug] decreases linearly
rate elim. = constant
no true T1/2
  • EtOH (only w/ true 0 order)
At high doses
  • Phenytoin (dilantin)
  • Salicylates
  • Theophylline
  • Thiopentone (very lg. doses)
  • Warfarin
  • Herparin
  • Aspirin
  • Tolbutamide



Distribution of Drugs


Blood flow: most rapid in tissues w/ high blod flow; lungs, kidneys, liver, brain
Capillary Permeability: tissue dependent, slow into CNS bc of tight junction, liver & kidney more porous




Accounting for differences in tissue/blood @ equilibrium
  • distribution



  • Lipid solube drugs can dissolve in adipose tissue
  • Drugs can bind to intracellular sites: increase [drug] in the tissue compartment
  • Plasma protein binding: a bound drug has no effect (but if unbound they're succeptible to metabolizing enzymes)



Plasma Protein Binding
  • Distribution
  • Differences in tissue/blood @ equilibrium



most drugs bind to proteins: usually Albumin or Alpha-1-acid glycoprotein (AAG)

More highly bound= longer duration of action & lower volume of distribution

Binding: reduces free drug availabe for distribution bc of restricted diffusion out of the vascular compartment


Plasma Protein Binding
  • Distribution
  • Differences in tissue/blood @ equil.



High extraction ratio drug = high Cl (bc low protein binding)

Low extraction ratio =  Cl very dependant on amt of protein binding

Highly bound = give much higher dose to get therapeutic effect


Free Drug: Interactions w/ Plasma binding


Highly protein bound drug (warfarin, diazepam, propranolol, phenytoin) + another drug competing for binding site--> increase in amt. of free drug

Ex. Drug A is 97% bound & if 3% of it is displaced by another drug, then the free [drug] doubles, but if a drug is 70% bound & 3% is displaced, this will make little difference


% bound


% bound = bound/(bound+unbound)


Elimination of Drugs


Clearance & T1/2
Cl: depends on blood flow to the organ

T1/2 is inversely prop. to total Cl
+ total Clearance = short half-life


Half-life
  • Elimination



time req'd for amt. of drug to fall to 50% of an earlier measurement

4 T1/2 = 94% eliminated

T1/2= (0.7 x Vd)/Cl


Multicompartment Model
  • Distribution



body doesn't just contain blood (which Vd is based on), there is fat, muscle, brain tissue....

graphically [] vs time: rapid fall in [blood] (rapid redistribution)-->plateau ([blood]=[tissue])-->slower gradual fall (elimination)


Delivery of drugs to different compartments


high blood flow = quick delivery: brain, liver, spleen, kidney

low Q = slower delivery: fat, muscle
(graphically); much lower [] & longer time


Tissues involved in drug metabolism


Liver: most metabolism; smooth ER
First pass metabolism

GI: contributes to first pass clearance
Kidneys
Skin: if topical application


Biotransformation


route of drug clearance involving metabolism of lipophillic drugs-->hydrophillic derivatives (for kidney elimination)

products may have greater, lesser, or different activity from parent compound

Variation in rate: chemical exposures (drugs, diet, supplements, smoke), genetics, age, disease


Pathways of Hepatic Biotransformation


Phase I: formation of product susceptible to phase II conjugative reaction. Oxidation, reduction, deamination, hydrolysis

Phase II: synthetic reactions, conugation of subgroups to other func. groups on drug.  Generates more water soluble product that can be excreted


Phase I
  • hepatic biotransformation



Oxidation, Reduction, Deamination, Hydrolysis
  • Functionalization rxns. (can add new -OH grp. or expose a group by hydrolysis)
  • Catalyzed by oxidases in ER, mainly cytochrome P450 enzymes
  • CYP450s are mainly in hepatocytes, also in kidney, lung, intestine, skin, testes, brain
Require: 1. P450 2. P450 reductase 3. NADPH 4. Oxygen


CYP450 nomenclature


ex. P4502E1

"2": CYP family (>40% homology)
"E": subfamily (>60% homology)
"1": particular isoform


Major human cytochrome P450s (aka hepatic mono-oxygenases)


  • CYP1A2
  • CYP2C9/10 & CYP2C18/19**antiseizure
  • CYP2D6**opiates
  • CYP2E1
  • CYP3A4** 50% of drugs



CYP1A2


  • universal in liver
  • induced by: smoking, eating grilled meats
  • metabolizes: caffeine, theophylline, phenacetin by dealkylations



CYP2C9/10 & CYP2C18/19**


  • 2C family very important
  • Antiseizure meds: Phenytoin, taxol, diclofenac, piroxicam, diazepam, cycloguanil, imipramine
  • Polymorphism: 2C9 (Tolbutamide) & 2C19 (Mephenytoin)



CYP2D6**


  • expressed mainly in liver
  • Opiates: Codeine, debrisoquine, propranolol, captopril, dextromorphan, nortryptiline
  • Polymorphism: Sparteine: 10% caucasions, 2% mongoloids




CYP2E1


  • mainly in liver, also in peripheral lymphocytes
  • Induced: EtOH (role in alcoholic metabolism)
  • Industrial chemicals: benzene, styrene, vinyl chloride, carbon tetrachloride, chloroform, ethyl carbamate



CYP3A4****


metabolizes 50% of drugs
  • must abundant human isoform (liver, intestine)
  • Induced: barbituates, rifampicin, glycocorticoids
  • Most important CYP450 in drug metabolism: nifedipine, quinidine, taxol, erythromycin, contraceptives, warfarin, cyclosporin, midazolam, lidnocaine



Phase II
  • biotransformation



Synthetic Conjugation Rxns.

hydrophillic
endog cofactor + drug = more polar, cleared by kidney/bile

Mainly in liver, rxn:cofactor:substrate
  • glucuronidation:UDP-glucuronic acid:acetominophen, diazepam, morphine
  • Sulfation: PAP-sulfate:acetaminophen, estrone, methyldopa
  • Acetylation:acetyl coA:clonazepam, mescaline, sulfonamides
  • Glutathione conjugation:glutathione:ethacrynic acid (metabolite of acetaminophen)
  • Methylation:transmethylases:NT & Hormones****



Phase I & II integration
  • biotransformation



Phase I enzyme must introduce the appropriate functional group in order to be metabolized by phase II conjugation

drug in plasma-->oxidized metabolite-->conjugated metabolite

product of phase I can be excreted in urine/bile IF it is polar enough


Pharmacological Deactivation
  • Biotransformation



most drugs: action of metabolite is less than action of drug

Amphetamine: inactivated by deamination


Pharmacological Activation
  • Biotransformation



few drugs: inactive prodrugs-->active drugs

Sulindac (NSAID): phase I produces active metabolite in gut contents (NOT GUT WALL)

Codeine:req. CYP2D6-catalyzed-O-methylation-->morphine (which later)-->potent analgesic (via glucuronidation)*

It is unusual for phase II metabolites to be active


Hepatic Drug Clearance Rate


Rateelimination depends on
  • liver ability to metabolize: age, disease, gender, genetic factors*
  • presence of other drugs: Enzyme induction & inhibition, inhibitors of intestinal P-glycoprotein
  • Hepatic Blood flow



Genetic Factors affecting liver clearance
  • Elimination



  • Hydrolysis of esters
  • Acetylation of amines: 50% of white & AA people in US=slow acetylaters
  • Oxidation



Enzyme Inducers
  • Elimination:presence of other drugs



results from selective increase in synthesis of CYP450 dependent drug-oxidizing enzymes in the liver


Enzyme Inhibition
  • Elimination: presence of other drugs



most likely inhibitors involved in serious drug interactions:
  • amiodarone
  • cimetidine
  • furanocoumarins (grapefruit juice)
  • ketoconazole
  • Ritonavir (HIV protease inhibitor)




Suicide Inhibitors


drugs metabolized to products that irreversible inhibit the metabolizing enzyme


Inhibitors of intestinal P-glycoprotein
  • Enzyme inhibition



P-gp is important modulator of intestinal drug transport & typically functions to expel drugs from the mucosa into the lumen...failure = buildup


Hepatic Blood Flow
  • Affects rate of elimination



High blood flow = less time to metabolize-->extraction ratio falls, especially if intrinsic clearance is low


Low Extraction Ratio drugs


kinetics (how the body deals w/ the drug) depends on enzymatic activity

(enzyme inducer-->single apple picker w/ 4 arms!)


High Extraction Ratio Drugs


kinetics depends on blood flow
  • slower the Q, higher the extraction
  • higher the Q, the lower the extraction



Excretion


  • Elimination of drug by excretion unchanged in body fluid or breath
  • Urine: nonvolatile & metabolites. Rate: GFR (drug not bound to plasma proteins), prox. tubular active secretion, passive reabsorption
  • Bile: drugs actively transported by hepatocyte; once in SI, lipophillic are reabsorbed & cleared again by liver (enterohepatic circulation), more polar are biotransformed, unabsorbed & metabolites-->feces
  • Minor routes: sweat, tears, fluids, milk; pH-dependent passive diffusion of lipophilic drugs (Can expose infants to drugs in mother's milk)