PHARMACOLOGY OF ANTIBIOTICS

PHARMACOLOGY OF ANTIBIOTICS

Introduction to Pharmacology

A. Definitions

1. Pharmacology

2. Pharmacokinetics

3. Pharmacodynamics/pharmacotherapeutics

4. Pharmacotoxicology



Overview of Pharmacology
















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




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

schedule (frequency) of administration; plateau principle















II. Pharmacokinetics
A. Overview
















II. Pharmacokinetics
B. Absorption Profiles
1. oral route

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






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


D. Distribution

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
2. Plasma binding proteins (PBP)











a. biological importance of
drugs that bind to PBP’s

(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



(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)
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.









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



E. Drug Metabolism








1. Major metabolic tissues
a. liver
b. kidneys
c. G-I tract
d. lungs
e. blood plasma; etc.








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





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
















(d) P-450`s are an inducible family of enzymes; they can also be repressed

b. conjugation enzymes

(1) schematic example: D + C –> 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





3. Phases and classification of drug
metabolism

a. phases: Phase I =oxidation via P-450’s;
Phase II = conjugation metabolism

b. classification of drug metabolism =
first-pass vs. systemic metabolism
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



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



(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

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













(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
(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











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
















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
















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 it’s 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
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)


2. Renal elimination
a. major processes associated
with elimination = GFR;
reabsorption and secretion




b. renal clearance=volume (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)


c. manipulation of renal elimination
(1) actions of probenecid=
reduces secretion of drugs like penicillin and indomethacin

(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
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







III. Pharmacodynamics –pharmacotherapeutics













A. Dose-response studies: developed in animal studies and clinical trials

1. Characteristics of dose-response curves: ED100; ED50s

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

4. Therapeutic index for drugs = measures drug safety= LD50/ED50; the higher the value for the therapeutic index the safer the drug
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


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


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
inhibitors=amiloride)

2. cellular organelles:
chromosomes/DNA=cyclophosamide; ribosomes=antibiotics, tetracycline





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







Pharmacotoxicology

A. Classification of toxic side-effects

1. Class A SE’s = 80% of SE’s predictable
and dose-dependent; either these SE’s
can’t be avoided because of the high
toxicity of some drugs or it results from
poor care




Pharmacotoxicology

2. Class B SE’s = 20% of SE’s = non-
predictable and not dose dependent;
often idiosyncratic; anaphylactic shock
produced by penicillin


Pharmacotoxicology

B. Mechanisms of drug toxicities:

1. exaggerated therapeutic effects;
warfarin/methyl-DOPA

2. non-selective actions of drugs=multiple
sites of action: streptomycin can act as a
neuromuscular blocker and cause muscle
weakness


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 systems=most
susceptable stage in
gestation to teratogens;
fetogenesis (9-38 weeks) =
maturation of all major
systems




(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


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
6. allergic
reactions



28




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




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






Overview of Antibiotic Pharmacodynamics
Overview of Antibiotic Pharmacodynamics

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




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 traveler’s diarrhea






Therapeutic effects of sulfonamides:

Dapsone used in treatment of leprosy (slow growing Mycobacterium infections)

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.






Bacterial Cell Wall Synthesis Inhibitors

(a) Penicillins/Beta-lactams:

mechanism of action: inhibits
transpeptidation reaction
associated with bacterial cell wall
synthesis









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.
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:



Bacterial Cell Wall Synthesis Inhibitors



first generation: cephalothin
second generation: cefaclor
third generation: cefotaxine
fourth generation: cefepime


Bacterial Cell Wall Synthesis Inhibitors

(b) Cephalosporins;

mechanism of action: inhibits
transpeptidation reaction
associated with bacterial cell wall
synthesis








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.
Bacterial Cell Wall Synthesis Inhibitors

(b) Cephalosporins;

general pharmacotoxicology: some
ototoxic, some anti-vitamin K effects
(include clotting disorders), some
disulfiram activity

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





Therapeutic effects of vancomycins:

Treatment of of severe staphylococcal and streptococcal infections in patients who are allergic or resistant to penicillin
(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




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


(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




Therapeutic effects of tetracycline:

broad spectrum, treatment of
conjunctivitis, nongonococcal urethritis,
rickettsial infections, typhus, syphilis,
etc.

(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






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.

(4) Protein Synthesis Inhibitors


(c) Microlides: erythromycin inhibits
peptide chain elongation, inhibits
protein synthesis





Therapeutic effects of microlides:

Erythromycin: treatment of pneumococcal pneumonia, intestional amebiasis, Legionnaires’ disease, rectal infections.

(4) Protein Synthesis Inhibitors


(d) Clinadomycins, inhibits peptide chain
elongation, inhibits protein synthesis;
interferes with erythromycins that bind
to same site on bacterial ribosomes






Therapeutic effects of clindamycin:

treatment of acne vulgaris; serious
infections caused by Staphylococcus
aureus and pneumococci.
(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





Therapeutic effects isoniazid:

treatment of tuberculosis







Overview of Antibiotic Pharmacotoxicology

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.
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.
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.
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.
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.
General Overview of Antibiotic Pharmacotoxicology

d. Development of resistance:

mechanisms for drug resistance


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.




Mechanisms of bacterial resistance:

altered structure of penicillin binding
proteins (PBP’s; transpeptidases) is the
basis of methicillin resistance in some
bacteria