PHARMACOLOGY OF ANTIBIOTICS

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• PHARMACOLOGY OF ANTIBIOTICS
• Introduction to Pharmacology
• A. Definitions
• 1. Pharmacology
• 2. Pharmacokinetics
• 3. Pharmacodynamics/pharmacotherapeutics
• 4. Pharmacotoxicology

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Overview of Pharmacology
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PHARMACOLOGY OF ANTIBIOTICS B. Drugs 1.
Fundamental characteristics a. drugs modify
pre-existing functions they do not
create new functions b. drugs have
multiple sites of action c.
difference between a drug and a poison is
dose
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d. access to information
about new drug development and study
sites www.centerwatch.com
clinicaltrials.gov www.fda.gov/medwatch
2. Units of drug doses a.
chemical weight of drugs mg etc. b.
international units (IU) amount of drug based
upon its biological activity
relative to a standardized response
obtained from a biological assay e.g.
minimal inhibitory
concentration of an antibiotic on bacterial
growth 3. Routes/schedule of
administration
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• schedule (frequency) of
  administration plateau principle

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II. Pharmacokinetics A. Overview

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II. Pharmacokinetics B. Absorption
Profiles 1. oral route
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2. variables obtained from an absorption
profile MEC, MTC values, onset times,
duration of action, biological
half-life 3. chemical nature of drugs vs.
absorption a. molecular weight b. lipid
solubility c. acid-base characteristics pKa
of acid/bases vs. lipid
solubility of drugs
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4. variables that influence the rates and
extent of drug absorption
G-I absorption of erythomycin delayed by
food dairy products reduce absorption of
tetracycline by forming a calcium
precipatate acid sensitive antibiotics
(erythromycin) formulated in acid-resistant
capsules
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D. Distribution
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1. Barriers to distribution a. important
barriers (1) blood brain barrier
second and third
generation
cephalosporines possess
increased permeability
to BBB b. alterations in the blood
brain barrier (1)
inflammation/infections
increase permeability of the
BBB (2) young and elderly
increased permeability of BBB
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2. Plasma binding proteins (PBP)

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a. biological importance of drugs that
bind to PBPs (1) bound drugs serve as
a reservoir, bound drugs can be
released into free states (2)
bound drugs generally have a longer
biological half-life
than drugs that do not
bind to PBPs e.g. bound sulfonamides
have a longer half-life
than sulfonamides that
bind poorly to PBPs

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(3) bound drugs are a potential site
for drug interactions, e.g.
sulfonamides displace oral anticoagulants
from PBPs and cause hemorrhage
aspirin can displace
sulfonamides from PBPs and
increase their toxicity (4) variations in
PBPs are a source of biological variation
in drug responses malnutrition, liver
or kidney diseases reduce blood levels of
PBPs and increase drug
toxicities (tetracyclines)
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3. Tissue deposits a. major
tissue deposits (1) adipose tissue 15-50 of
body wt. (2) muscle (3) bone/teeth (4)
placenta/mammary tissue, etc.
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b. biological consequences of tissue
deposits (1) deposits alter drug dosage
loading/induction/priming initial doses
designed to saturate tissue deposits AND
maintain an MEC maintenance doses designed to
maintain an MEC AFTER tissue deposits are
saturated with drug (2)
deposits are potential sites of drug toxicity
e.g. tetracycline is
deposited in developing bone and teeth
and as such should not be
administered during states of
pregnancy and early tooth development
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E. Drug Metabolism 1.
Major metabolic tissues a. liver
b. kidneys c. G-I tract d.
lungs e. blood plasma etc.
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2. Major families of metabolic enzymes
a. microsomal enzymes-formed from ER
(1) cyctochrome P-450 enzymes assoc.
with microsomes (2)
catalytic characteristics of P-450s
(a) very broad substrate specificity
(b) broad tissue distribution
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2. Major families of metabolic enzymes
(c) P-450's exist in multiple molecular
forms that provide a source of
genetic variation in drug
metabolism in different
individuals each form of P- 450
has a different substrate affinity
and product
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(d) P-450's are an inducible family of
enzymes they can also be repressed
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b. conjugation enzymes
(1) schematic example D C gt D-C
(2) conjugation molecules-glucuronic acid,
glycine, sulfate, glutathione, etc.
(3) biological consequence of conjugation
reactions inactive drugs and
increase water solubility,
increase rates of drug
elimination
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3. Phases and classification of drug
metabolism a. phases Phase I
oxidation via P-450s Phase II
conjugation metabolism b. classification
of drug metabolism first-pass
vs. systemic metabolism
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4. Biological importance of drug metabolism
a. drug biotransformation alterations
in the chemical structure of
drugs many antibiotics
are not or are incompletely
metabolized (1) drug inactivation most
drugs (2) drug (pro-drug) activation e.g.
clindamycin, loratridine,
naproxen
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4. Biological importance of drug metabolism
b. production of toxic drug metabolites
(1) acetaminophen metabolism
(a) Phase I the Phase II
metabolism formation of
toxic metabolite in phase I
metabolism which is
activated by
glutathione
conjugation in phase II
metabolism
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(b) Acetaminophen O.D. liver failure due to
glutathione depletion can be slowly replaced
by acetylcysteine therapy (2)
chloramphenicol (antibiotic) metabolism can
produce toxic metabolites that injure bone marrow
and produce aplastic anemia
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c. pharmacogenetics and drug metabolism
genetic make-up can alter the fate of drug
metabolism (1) ethnic diversity
slow and fast metabolizers of isoniazid varies
between ethnic groups and will result in differ
blood levels of drug
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(2) gender diversity drug metabolism
can vary between males and females metabolism
of benzodiazepams is higher for males compared
to females and prednisone is higher for females
than males side-effect may differ
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(3) individual genetic variability (a)
allergen production some drug metabolites are
converted to heptans than can form
complexes with cellular
proteins that induce allergic responses to this
foreign protein penicillin

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d. induction and inhibition of metabolic
enzymes (1) many drugs have been
characterized as microsomal
enzyme inducers/inhibitors
e.g. rifampin is a CYP inducer
that increases the metabolism of
estrogens and progesterone that
are components in oral
contraceptives, this effect can
result in an increased risk of pregnancy

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d. induction and inhibition of
metabolic enzymes (1) many drugs
have been characterized as
microsomal enzyme
inducers/inhibitors e.g.
erythromycin can inhibit CYP 3A4
which functions to depress the
metabolism of theophylline
(bronchiodilator), this effect increases
the probability of theophylline-induced
cardiac dysrhythmias

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e. diseases/injuries can alter drug
metabolism cirrhosis and malnutrition can
reduce liver content of microsomal
enzymes and increase drug toxicities, e.g.
tetracyclines f. drug metabolism
and its manipulation bacterial
production of beta-lactamases in
response to penicillin therapy can be
blocked by formulating penicillin with
sulbactam which is an inhibitor of beta-
lactamases
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F. Drug Elimintion 1. Major tissues of
elimination a. Kidneys most important
route of drug elimination b. enterohepatic
circulation clindamycin elim.
EHC c. sweat/saliva/lacrimation
(rifampin eliminated via
tears) d. mammary tissue via
lactation (tetracycline)
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2. Renal elimination a. major processes
associated with elimination GFR
reabsorption and secretion
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b. renal clearancevolume (ml) of blood
cleared of a drug per unit
time (ml/min). Clearance can be estimated by
dividing the rate of renal excretion of a
drug (mg/min.) by the plasma level of the
drug (mg/ml)
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c. manipulation of renal elimination (1)
actions of probenecid reduces secretion of
drugs like penicillin and indomethacin
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(2) alterations in urinary pH via ammonium
chloride (or fruit juice with Vitamin C) or
sodium bicarbonate reductions in urinary pH
increases excretion of weak bases like
amphetamines and increasing pH increases
excretion of weak acids like sulfa
drugs d. excretion vs. renal
diseases reductions in RBF or GFR increases
drug toxicities
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G. Effect of age on PK processes 1. age
related changes a. developmental changes
in young glucuronic acid
conjugation reactions are low in
neonates and chloramphenicol can
cause grey baby syndrome
(circulatory collapse) due to the
accumulation of unconjugated
chloramphenicol b. reductions of functions
in elderly 2. consequences of changes in
PK and drug responses a. young b.
elderly
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III. Pharmacodynamics pharmacotherapeutics
A. Dose-response studies developed in
animal studies and clinical trials 1.
Characteristics of dose-response curves ED100
ED50s
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• Drug potency related to ED50 values of drugs the
  lower the ED50 of a drug the higher the
  potency e.g. combining some forms of
• penicillin with probenecid can increase
  their potency

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4. Therapeutic index for drugs measures drug
safety LD50/ED50 the higher the value for the
therapeutic index the safer the drug
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B. Types of drug target tissue
interactions 1. structurally non-specific
interactions the physical presence
of a drug in a target tissue is all
that is necessary to produce its
biological effect the specific chemical
structure of the drug is not important to
its biological effects e.g. osmotic
laxative or diuretics
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B. Types of drug target tissue
interactions 2. structurally specific
interactions the chemical
structure of the drug is essential
for its biological activity because the drug
generally forms reversible chemical
bonds with some component in a target
tissue
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C. Sites of structurally specific binding
between a drug and target tissue
components 1. membrane components
hormone/neurotransmitter receptors
ion channels (calcium channel blockers)
transport proteins (sodium ATPase
inhibitorsamiloride) 2. cellular
organelles chromosomes/DNAcyclophos
amide ribosomesantibiotics, tetracycline

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C. Sites of structurally specific binding
between a drug and target tissue
components 3. enzymes some drugs are
substrates for selected
enzymes, L- DOPA some
drugs are enzymes
inhibitors, MAO inhibitors
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• Pharmacotoxicology
• A. Classification of toxic side-effects
• 1. Class A SEs 80 of SEs predictable
• and dose-dependent either these
  SEs
• cant be avoided because of the high
  
• toxicity of some drugs or it results
  from
• poor care

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• Pharmacotoxicology
• 2. Class B SEs 20 of SEs non-
• predictable and not dose
  dependent
• often idiosyncratic
  anaphylactic shock
• produced by penicillin

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• Pharmacotoxicology
• B. Mechanisms of drug toxicities
• 1. exaggerated therapeutic effects
• warfarin/methyl-DOPA
• 2. non-selective actions of drugsmultiple
• sites of action streptomycin can
  act as a
• neuromuscular blocker and cause
  muscle
• weakness

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• 3. Birth Defects
• a. Teratogens
• (1) stages of gestation
• conception to formation
• of the three germ layers
• (0-3 weeks) embryogenesis
• (3-8 weeks) formation of all
• major organ systemsmost
• susceptable stage in
• gestation to teratogens
• fetogenesis (9-38 weeks)
• maturation of all major
• systems

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(2) pregnancy
categories A (vit. B6 )
B (penicillin G) C (codeine) D
(tetracycline) X (ciprofloxacin) b.
developmental disorders (physical
evidence for these disorders may be
absent) learning and hyperkinetic
disorders fetal alcohol syndrome
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4. drug addiction a. biological basis for
drug addiction role of
dopamine and behavioral
characteristics associated with
addictive behaviors b. drug schedules used
to clarify addictive potential
of drugs Schedule I, II, III, IV 5.
carcinogens sex steroids and
antineoplastic drugs
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6. allergic reactions 28
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7. drug-drug interaction
synergistic, additive, and antagonist
effects of drug combinations e.g.
aminoglycosides and vancomycin can be
synergistic while erythromycin and
clindomycin have antagonist effects
when given in combination
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8. development of tolerance and
resistance a. tolerance can be induced by
chronic/excessive exposure to
albuterol down-regulation of
beta-2 adrenergic
receptors b. resistance can develop in
micro- organisms in response to
antibiotic therapy numerous
mechanisms e.g. beta-lactamase,
penicillin
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Antibiotics

• This class of drugs save more lives than any
  other class of drugs 60 of all antibiotics are
  NOT prescribed properly

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Overview of Antibiotic Pharmacokinetics

• Units of dosage mg/kg International units IU's
• b. Routes of administration all routes, oral
  most common
• c. Frequency of administration important for
  maintaining MEC
• d. Absorption generally good bioavailability
  often greater than 70 for most antibiotics

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Principles and Precautions for Antibiotic Therapy

• e. Assess immune functions effectiveness
• of antibiotic therapy often dependent on
• immune responses
• Review medical history for indications of
• allergies to antibiotics

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Overview of Antibiotic Pharmacokinetics

• g. Metabolism variable aminoglycoside poorly
  metabolized by the liver and are excreted
  unchanged by the kidneys cephalosporine are
  metabolized by hepatic microsomal enzymes
• h. Elimination all routes renal, EHC,
  lactation renal elimination can be manipulated
  by probenecid

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Overview of Antibiotic Pharmacodynamics
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Overview of Antibiotic Pharmacodynamics

• (1) Sulfonamides sulfamethoxazole and
  trimethaprim, often given in combination
  inhibitors of folic acid and nucleotide

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• Therapeutic effects of sulfonamides
• Treatment of acute, uncomplicated urinary
  tract infections, either alone or in
• combination with trimethaprim
• Combination therapy trimethaprim used
  to treat prostatitis, chronic bronchititis,
  sinusitis, otitis media, and travelers diarrhea

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• Therapeutic effects of sulfonamides
• Dapsone used in treatment of leprosy
  (slow growing Mycobacterium infections)

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• Bacterial Cell Wall Synthesis Inhibitors
• (a) Penicillins/Beta-lactams
• penicillins (PCN) are classified on the
• basis or their origin natural
  (penicillin
• isolated from molds)
• to synthetic forms (oxycillin) are less
  sensitive to
• metabolism by penicillinases (beta-
• lactamases) and they have a
• broader spectrum of antibiotic activity
• Penicillinase-resistant PCN's, include
• methicillin ampicillin, etc.

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• Bacterial Cell Wall Synthesis Inhibitors
• (a) Penicillins/Beta-lactams
• mechanism of action inhibits
• transpeptidation reaction
• associated with bacterial cell wall
• synthesis

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• Therapeutic effects of penicillins
• Treatment of mild infections that include
  pharyngitis and skin and soft tissue infections
  caused by Streptococcus moderate to severe
  infections that include pneumonia, meningitis,
  gonorrhea, syphilis, endocarditis, and
  septicemia.

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• Bacterial Cell Wall Synthesis Inhibitors
• (b) Cephalosporins
• classification as we move from
  the first, to
• second, to third/forth
  generation
• cephalosporins there is a
  decrease in
• sensitivity to cephalosporinases
  (beta-
• lactamases), increases in the
  spectrum of
• antibiotic activity, and
  increases in the drug
• solubility to the BBB

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• Bacterial Cell Wall Synthesis Inhibitors
• first generation cephalothin
• second generation cefaclor
• third generation cefotaxine
• fourth generation cefepime

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• Bacterial Cell Wall Synthesis Inhibitors
• (b) Cephalosporins
• mechanism of action inhibits
• transpeptidation reaction
• associated with bacterial cell wall
• synthesis

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• Therapeutic effects of cephalosporins
• Treatment of meningitis caused by gram
  negative bacteria treatment of gonorrhea when
  organisms are resistant to penicillin treatment
  of hospital acquired infections.

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• Bacterial Cell Wall Synthesis Inhibitors
• (b) Cephalosporins
• general pharmacotoxicology some
• ototoxic, some anti-vitamin K
  effects
• (include clotting disorders), some
• disulfiram activity

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• Bacterial Cell Wall Synthesis Inhibitors
• c) Vancomycins
• mechanism of action drugs bind to
  D-
• ala-D-ala terminus of nascent
• peptidoglycan that inhibits the
• transglycosylase reaction (prevents
• elongation of peptidoglycan
• chain) and utlimately inhibits
• transpeptidase activity and
  bacterial cell
• wall synthesis

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• Therapeutic effects of vancomycins
• Treatment of of severe staphylococcal and
  streptococcal infections in patients who are
  allergic or resistant to penicillin

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• (3) Inhibitors of DNA replication and RNA
• synthesis
• (a) Quinolones ciprofloxacin, DNA gyrase
• inhibitor which blocks the
  unfolding of
• DNA that is ready for replication
  pregnancy
• category X
• (b) Rifampin, inhibits RNA polymerase and
• blocks production of mRNA that is
  needed
• for protein synthesis often used
  in conjunction
• with isoniazid

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• Therapeutic effects of ciprofloxacin and
• rifampin
• Ciprofloxacin treatment of urinary tract
  infections bone and joint infections, acute
  sinusitis.
• Rifampin treatment of tuberculosis
  associated with Mycobacterium infections

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• (4) Protein Synthesis Inhibitors
• (a) Tetracycline, inhibits tRNA binding to
• ribosomes, blocks protein synthesis
• broad-spectrum antibiotics can
• interfere with tooth development and
• bone growth

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• Therapeutic effects of tetracycline
• broad spectrum, treatment of
• conjunctivitis, nongonococcal urethritis,
• rickettsial infections, typhus, syphilis,
  
• etc.

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• (4) Protein Synthesis Inhibitors
• (b) Aminoglycosides gentamicin,
• streptomycin, neomycin, inhibits the
• translocation of the ribosome along
• mRNA, blocks protein synthesis
• accumulates in ear and kidneys, may
• be ototoxic and nephrotoxic

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• Therapeutic effects of aminoglycosides
• Treatment of GI, respiratory, CNS, and
  urinary tract infections. Treatment of burns
  prophylaxis of bacterial endocarditis in
  patients undergoing operative procedures.

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• (4) Protein Synthesis Inhibitors
• (c) Microlides erythromycin inhibits
• peptide chain elongation, inhibits
• protein synthesis

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• Therapeutic effects of microlides
• Erythromycin treatment of pneumococcal
  pneumonia, intestional amebiasis, Legionnaires
  disease, rectal infections.

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• (4) Protein Synthesis Inhibitors
• (d) Clinadomycins, inhibits peptide chain
• elongation, inhibits protein synthesis
• interferes with erythromycins that bind
• to same site on bacterial ribosomes

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• Therapeutic effects of clindamycin
• treatment of acne vulgaris serious
• infections caused by Staphylococcus
• aureus and pneumococci.

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• (4) Protein Synthesis Inhibitors
• (e) Isoniazid (inhibits Mycobacterium
• cell wall formation by inhibiting
• myconic acid formation...unique to
• Mycobacterium) and PAS (para-
• amino salycilate inhibits folic
  acid
• biosynthesis and interferes with
• actions of Vitamin B6, reduces
• energy metabolism

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• Therapeutic effects isoniazid
• treatment of tuberculosis

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Overview of Antibiotic Pharmacotoxicology

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General Overview of Antibiotic Pharmacotoxicology

• Hypersensitivity responsess skin rashes to
  anaphylactic shock
• b. Superinfections clostridium, fungal
  (Candidia thrush infections
• c. Organ toxicities ototoxicity nephrotoxicity.
  cardiotoxicity CNS (seizures) hemolytic
  anemias etc.

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General Overview of Antibiotic Pharmacotoxicology

• d. Development of resistance e.g.
• Methicillin resistant Staphylococcus aureus
  (MRSA) the most wide spread MRSA strain, the so
  called vancomycin-intermediate S. aureus (VISA)
  a vancomycin-resistant S. aureus (VRSA) and
  vancomycin resistant Enterococcus (VRE) are
  several examples of multidrug resistant bacterial
  species.

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General Overview of Antibiotic Pharmacotoxicology

• d. Development of resistance e.g.
• S. aureus, a gram-positive coccus, is
  responsible for not only severe infections of the
  skin and skin structures, it also causes
  life-threatening diseases such as pneumonia,
  endocardiditis, and bacteremia.

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General Overview of Antibiotic Pharmacotoxicology

• d. Development of resistance e.g.
• S. aureus causes protracted infections of bone
  and joints and because of its abiltiy to produce
  protective biofilms on artificial materials
  (cathers/heart valves) it becomes a difficult
  infection to treat.

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General Overview of Antibiotic Pharmacotoxicology

• d. Development of resistance e.g.
• MRSA strains have developed resistance to all
  conventional antibiotics.
• Approximately 30 of healthy people carry this
  bacteria in their nostrils and skin.

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General Overview of Antibiotic Pharmacotoxicology

• d. Development of resistance
• mechanisms for drug resistance

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Mechanisms of bacterial resistance
Beta-lactam antibiotics enter gram negative
bacteria by passing through the porin
protein located in the outer membrane. A
down-regulation of porin proteins reduces
the movement of antibiotics
into bacterial cells is one mechanism of
antibiotic resistance.
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Mechanisms of bacterial
resistance altered structure of
penicillin binding proteins (PBPs
transpeptidases) is the basis of
methicillin resistance in some
bacteria
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