2. Learning Objectives
• Define and differentiate between pharmacokinetics and clinical
pharmacokinetics
• Define pharmacodynamics and relate it to pharmacokinetics
• Describe the concepts of pharmacokinetics and pharmacodynamics
• Identify factors that cause interpatient variability in drug disposition and drug
response
• Describe situations in which routine clinical pharmacokinetic monitoring
would be advantageous (Applied pharmacokinetics and pharmacodynamics)
4. Definitions
•Pharmacokinetics (PK)
• Process by which a drug enters and leaves the body
• Based on absorption, distribution, metabolism, and excretion to define
systemic exposure
•Clinical pharmacokinetics
• Application of pharmacokinetic principles to the safe and effective
therapeutic management of drugs in an individual patient.
• Primary goals of clinical pharmacokinetics include enhancing efficacy and
decreasing toxicity of a patient’s drug therapy
• The right drug against the right pathogen must be administered at the right
dose and at the right time to be safe and effective.
7. Kinetic Homogeneity principle
• A drug’s effect is often related to its concentration at the site of
action, so it would be useful to monitor this concentration.
• Changes in the plasma drug concentration reflect changes in
drug concentrations at the receptor site, as well as in other
tissues.
• .
8. Bioavailability
The ratio of the systemic exposure by oral (or extravascular) absorption to that
of intravenous administration. It is the fraction of administered drug that
reaches the systemic circulation.
• Absolute bioavailability means that the amount of drug absorbed by the
extravascular route of administration has been compared with the
intravenous route.
• Relative bioavailability means that two different extra vascularly
administered dosage forms have been compared
11. Drug Transportation
• Drug molecules can cross cell membrane by:
– Passive Diffusion
– Protein – mediated transport (carrier mediated)
• Facilitated Transport
• Active transport
– Primary
– Secondary
12. Passive transport
• Most important Mechanism for most of the Drugs
• Majority of drugs diffuses across the membrane in the direction of
concentration gradient
• Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of the
membrane
• Characteristics
– Not requiring energy
– Having no saturation
– Having no carriers
13. Remember !
The drugs which
are ionized, high
polarity and lower
lipid solubility are
difficult to permeate
membrane
The drugs which
are Unionized, low
polarity and higher
lipid solubility are
easy to permeate
membrane
14. Effect of pH
• Acidic drugs, e.g. aspirin are largely unionized at acid gastric pH and are
absorbed from stomach, while bases, e.g. atropine are largely ionized
and are absorbed only when they reach the intestines
• The unionized form of acidic drugs which crosses the surface
membrane of gastric mucosa cell, reverts to the ionized form within
the cell and then only slowly passes to the extracellular fluid. This is
called ion trapping, i.e. a weak electrolyte crossing a membrane to
encounter a pH from which it is not able to escape easily. This may
contribute to gastric mucoal cell damage caused by aspirin.
15. Effect of pH
• Basic drugs attain higher concentration intracellularly (pH 7.0 vs 7.4
of plasma).
• Acidic drugs are ionized more in alkaline urine- do not back diffuse
in the kidney tubules and are excreted faster. Accordingly, basic
drugs are excreted faster if urine is acidified.
• Lipid-soluble nonelectrolytes (e.g. ethanol, diethyl-ether) readily
cross biological membranes and their transport is pH independent.
16. Pharmacokinetics- Absorption
• Absorption: It describes the movement of drug from an extravascular space to
an intravascular space
• The amount of drug that reaches the systemic circulation is expressed as a
percentage of the total amount that could have been absorbed- bioavailability
17. Factors Influencing Absorption
1. Factors Related To Drug
a) Physicochemical properties
# Degree of ionization, Degree of solubility, Chemical nature,
valence
# High lipid / water partition coefficient increases absorption
b) Pharmaceutical form of drug
For example Absorption of solutions is better than suspensions or
tablets.
18. Factors Influencing Absorption
2. Factors Related To The Patient
a) Route of administration
b) Area and vascularity of absorbing surface
c) State of absorbing surface
d) Rate of general circulation
e) Presence of other drugs and other Specific factors
19. Factors Influencing Absorption
2. Factors Related To The Patient
a) Route of
administration:
absorption is faster from
i.v. > inhaled > i.m. > oral > i.d.
20. Factors Influencing Absorption
b) Area and vascularity of absorbing surface
Absorption is directly proportional to both area and vascularity. Thus
absorption of the drug across the intestine is more efficient than across the
stomach, as Intestine has more blood flow and much bigger surface area than
those of the Stomach.
c) State of absorbing surface
For e.g. atrophic gastritis and mal-absorption syndrome
decrease rate of absorption of drugs.
21. Factors Influencing Absorption
d) Rate of general circulation
For e.g. in shock, peripheral circulation is reduced and
I.V. route is used.
e) presence of other drugs and Specific factors
For e.g. intrinsic factor of the stomach is essential for vitamin B12
absorption from lower ileum and adrenaline induces vasoconstriction so
delay absorption of local anesthetics.
22. Factors Influencing Absorption
3. First Pass Effect (pre-systemic metabolism): where drugs must pass
through gut mucosa and liver before reaching systemic circulation.
i)Gut first pass effect : e.g. benzyl penicillin is destroyed by gastric acidity,
insulin by digestive enzymes
ii)Hepatic first pass effect: e.g. lidocaine (complete destruction so not
effective orally) and propranolol (extensive destruction)
23. Liver
First pass
metabolism
through liver
via hepatic
portal vein
Metabolism of
drugs by liver
enzymes
Excretion of metabolites and
intact drugs in urine
Kidney
Orally ingested
drugs
hepatic
vein
Pharmaco-
dynamic
activity in
body
Parenteral / IV
drugs etc.
Renal artery
GIT
Ureter
24. Liver P450 systems
• Cytochrome P450 (microsomal) enzymes are a large family of enzymes
found in the liver that are part of the body’s defence mechanism against
toxic substances
• The body treats drugs as foreign, potentially toxic substances
• Microsomal enzymes change drugs by biochemical reactions
• The various cytochromes have specific affinities for particular drugs
• This is why there is so much variation in the metabolism of drugs – half
life etc
25. Liver P450 systems
• Liver enzymes inactivate some drug molecules
• First pass effect (induces enzyme activity)
• P450 activity is genetically determined:
• Some persons lack such activity leads to higher drug plasma
levels (adverse actions)
• Some persons have high levels leads to lower plasma levels (and
reduced drug action)
• Other drugs can interact with the P450 systems
• Either induce activity (apparent tolerance)
• Inactivate an enzyme system
26. Liver P450 systems
• Sometime the activity of the P450 enzymes activates the drug but
mostly it deactivates drugs.
• Drugs that are inactive until activated by the liver are called pro-drugs
and include enalapril (an ACE inhibitor), clopidogrel and aspirin. (many
other drugs are inactive until activated in the tissues or cells)
• Some drugs can induce P450 enzymes, increasing their metabolic activity
and other drugs can inhibit them, so reducing their metabolic activity.
This is the basis for many drug interactions
27. Interactions
Drugs that inhibit drug
metabolising enzymes
Drugs affected by inhibition
(concentration increased)
Cimetidine Amiodarone, phenytoin, pethidine,
warfarin
Corticosteroids Tricyclic anti-depressants
Ciprofloxacin Theophylline
MOA inhibitors e.g. phenelzine Pethidine
28. Interactions
Drugs that induce drug
metabolising enzymes
Drugs affected by induction
(concentration decreased)
Phenobarbital
Warfarin
Oral contraceptives
Corticosteroids
Ciclosporin
Simvastatin
Rifampicin
Griseofulvin
Phenytoin
Ethanol
Carbamazepine
St John’s wort
(Hypericum perforatum)
29. Absorption kinetics
For some drugs poor absorption is beneficial because their target is
further along the digestive tract.
The anti-bacterial vancomycin is poorly absorbed so is useful to treat
the gut bacterium Clostridium difficile.
Other drugs can be packed in capsules that resist absorption until the
capsules degrade in the colon. Colpermin used to treat irritable bowel
syndrome is an example.
31. Volume of Distribution (V)
• Definition: Apparent Volume of distribution is defined as the
volume that would accommodate all the drug in the body,
if the concentration was the same as in plasma
• Expressed as: in Litres
V =
Dose administered IV
Plasma concentration
33. Volume of Distribution (V)
• A drug with a high Vd has a propensity to leave the plasma and enter
the extravascular compartments of the body, meaning that a higher
dose of a drug is required to achieve a given plasma concentration.
(High Vd -> More distribution to other tissue)
• Conversely, a drug with a low Vd has a propensity to remain in the
plasma meaning a lower dose of a drug is required to achieve a given
plasma concentration. (Low Vd -> Less distribution to other tissue)
34. Pharmacokinetics- Factors affecting the
physiologic distribution
• Lipophilic molecules are more likely to pass through lipid bilayers and
therefore more likely to leave the bloodstream and distribute to areas with
high lipid density (adipose) and therefore have a higher Vd.
• Hydrophilic molecules are less likely to pass through lipid bilayers and
therefore more likely to remain in the bloodstream and therefore have
a lower Vd.
• Partition coefficient of the drug between different types of tissues, blood
flow to tissues.
• pH
• Binding affinity to plasma proteins relative to tissue components
35.
36. Clinical Significance of Volume of Distribution
• From the clinical perspective, the single most important utility of Vd
is calculating the loading dose of a drug
• Loading dose (mg) = [Cp (mg/L) x Vd (L)] / FCp represents the
desired plasma concentration of drug
• Vd represents the volume of distribution
• F represents the bioavailability of drug (IV administration = 1)
• Maintenance dose rate (mg/hr) = [Cp (mg/L) x Cl (L/hr)] / F
• Cp represents the desired plasma concentration of drug
• Cl represents the clearance rate of drug
• F represents the bioavailability of drug (IV administration = 1)
37. Clinical Significance of Volume of Distribution
• The loading dose is only required for a few drugs in certain
situations while maintenance doses are required for most drugs to maintain
the steady-state plasma concentration.
• Loading doses are usually indicated in clinical scenarios where a drug needs
to reach steady-state rapidly
• Ex, antiepileptic administration during an active seizure or aspirin loading
during a suspected myocardial infarction
• Loading dose rarely needs to be modified while maintenance doses need to
be adapted depending on various characteristics of the patient.
38. Clinical Significance of Volume of Distribution
• Obesity vs. Normal BMI – The loading doses of drugs such as
anesthetics may be dosed based on different weight scalars such as
total body weight vs. ideal bodyweight depending on the
pharmacokinetics of specific drugs to prevent over or underdosing
• Pediatric vs. adult dosing – Body composition changes with aging
and therefore, drug distribution will be affected meaning that loading
doses will vary between pediatrics and adults
39. Brain and CSF Penetration
• BBB is lipoidal and limits the entry of non-lipid soluble drugs
(amikacin, gentamicin, neostigmine etc.).
(Only lipid soluble unionized drugs penetrate and have action on
the CNS)
• Efflux carriers like P-gp (glycoprotein) present in brain capillary
endothelial cell (also in intestinal mucosal, renal tubular, hepatic
canicular, placental and testicular cells) extrude drugs that enter
brain by other processes.
(Inflammation of meaninges of brain increases permeability of
BBB)
• In t/t of parkinsonism, Dopamine (DA) does not enter brain, but
its precursor levodopa does
40. Plasma Protein Binding
• Plasma protein binding (PPB): Most drugs possess
physicochemical affinity for plasma proteins. Acidic drugs
bind to plasma albumin and basic drugs to α1-glycoprotein
• Extent of binding depends on the individual compound.
Increasing concentration of drug can progressively saturate
the binding sites
41. Plasma Protein Binding
Significant clinical implications:
a) Highly PPB drugs are largely restricted to the vascular compartment and
tend to have lower Vd
b) The PPB fraction is not available for action – acts as storage - equilibrium
with free drug in plasma
c) High degree of protein binding makes the drug long acting, because bound
fraction is not available for metabolism as well as excretion, unless it is
actively excreted by liver or kidney tubules
d) The drugs with high physicochemical affinity for plasma proteins (e.g.
aspirin, sulfonamides, Chloramphenicol) can replace the other drugs(e.g.
acenocoumarol, warfarin) or endogenous compounds (bilirubin) with lower
affinity – kernicterus sulfonamide-bilirubin
43. What is Biotransformation?
• Chemical alteration of the drug in the body
• Aim: to convert non-polar lipid soluble compounds to polar
lipid insoluble compounds to avoid reabsorption in renal
tubules
• Most hydrophilic drugs are less biotransformed and excreted
unchanged – streptomycin, neostigmine and pancuronium
etc.
• Biotransformation is required for protection of body from
toxic metabolites
44. Results of Biotransformation
1. INACTIVATION: Active drug and its metabolite to inactive
metabolites – most drugs (ibuprofen, paracetamol,
chlormphenicol etc.)
2. ACTIVE DRUG TO ACTIVE PRODUCT (phenacetin –
acetminophen or paracetamol, morphine to Morphine-6-
glucoronide, digitoxin to digoxin etc.)
3. INACTIVE DRUG TO ACTIVE/ENHANCED ACTIVITY (PRODRUG) –
levodopa - carbidopa, prednisone – prednisolone and enalpril –
enalprilat)
4. NON TOXIC OR LESS TOXIC DRUG TO TOXIC METABOLITES
(Isonizide to Acetyl isoniazide)
(Mutagenicity, teratogenicity, carcinogenicity, hepatotoxicity)
45. Biotransformation - Classification
2 (two) Phases of
Biotransformation:
• Phase I or Non-synthetic –
metabolite may be active or
inactive
• Phase II or Synthetic –
metabolites are inactive
(Morphine – M-6 glucoronide is
exception)
46. Phase I (Non-synthetic)
Reactions
Introduction or unmasking of functional group by oxidation, reduction
hydrolysis, Cyclization, Decyclization
These reactions may result in
1.Drug inactivation (most of drugs)
2.Conversion of inactive drug into active metabolite (cortisone→ cortisol)
3.Conversion of active drug into active metabolite (phenacetin→
paracetamol)
4.Conversion to toxic metabolite (methanol → formaldehyde)
47. Phase II (Synthetic) reactions
• Functional group or metabolite formed by phase I is masked by
conjugation with natural endogenous constituent as glucuronic acid ,
glutathione, sulphate , acetic acid, glycine or methyl group.
• These reactions usually result in drug inactivation with few exceptions
e.g. morphine-6-conjugate is active
• Most of drugs pass through phase I only or phase II only or phase I then
phase II.
• Some drugs as isoniazid passes first through phase II then phase I
(acetylated then hydrolyzed to isonicotinic acid).
48. Factors affecting drug metabolism
1. Drugs
2. Genetic variation
3. Nutritional state
4. Dosage
5. Age
49. Factors affecting drug metabolism
1.Drugs
One drug can competitively inhibit the metabolism of another if it
utilizes the same enzyme or cofactors either by Enzyme induction or by
Enzyme inhibition
i) Enzyme induction - Some drugs increase the synthesis of microsomal
enzyme protein, or decrease degradation of enzymes.
ii)Enzyme inhibition (drugs that inhibit drug metabolism): it occurs faster
than enzyme induction and causes serious drug interactions
50. Factors affecting drug metabolism
2.Genetic variation
The most important factor is genetically determined polymorphisms.
(Ex) Isoniazid is metabolized in the liver via acetylation. There are two forms
(slow and fast) of the enzyme responsible for acetylation (N-acetyl
transferase ), thus some patients metabolize the drug quicker than others.
Slow acetylators are prone to peripheral neuritis while fast acetylators are
prone to hepatic toxicity
3.Nutritional state
Conjugating agents are sensitive to body nutrient level. For
example, low protein diet can decrease glycine.
51. Factors affecting drug metabolism
4.Dosage
High dose can saturate metabolic enzyme leading to drug
accumulation. If metabolic pathway is saturated due to high dose or depletion
of endogenous conjugate, an alternative pathway may appear e.g.
paracetamol may undergo N-hydroxylation to hepatotoxic metabolite.
5.Age
Drug metabolism is reduced in extremes of age (old patients and
infants).
53. Organs of Excretion
• Excretion is a transport procedure which the prototype drug (or parent
drug) or other metabolic products are excreted through excretion organ
or secretion organ
• Hydrophilic compounds can be easily excreted.
• Routes of drug excretion
• Kidney
• Biliary excretion
• Sweat and saliva
• Milk
• Pulmonary
54. Hepatic Excretion
• Drugs can be excreted in
bile, especially when the are
conjugated with – glucuronic
Acid
Organic Bases – OCT
Others – Pgp
Larger molecules are eliminated
• Drug is absorbed glucuronidated or sulfatated in the liver and
secreted through the bile glucuronic acid/sulfate is cleaved off by
bacteria in GI tract drug is reabsorbed (steroid hormones, rifampicin,
amoxycillin, contraceptives)
• Anthraquinone, heavy metals – directly excreted in colon
Portal
vein
Bile duct
Intestines
55. Renal Excretion
All water soluble substances
Amount of Drug in urine is
Net Renal Excretion = (GFR + Tubular secretion) – Tubular
Reabsorption
• Glomerular Filtration
• Tubular Reabsorption
• Tubular Secretion
57. Kinetics of Elimination
• First Order Kinetics (exponential): Rate of elimination
is directly proportional to drug concentration, CL
remaining constant
• Constant fraction of drug is eliminated per unit time
• Zero Order kinetics (linear): The rate of elimination
remains constant irrespective of drug concentration
• CL decreases with increase in concentration
• Alcohol, theophyline, tolbutmide etc.
59. Excretion –
The Plateau Principle
Repeated dosing:
• When constant dose of
a drug is repeated before
the expiry of 4 half-life –
peak concentration is
achieved after certain
interval
• Balances between dose
administered and dose
interval
60. Target Level Strategy
• Low safety margin drugs (anticonvulsants, antidepressants, Lithium,
Theophylline etc. – maintained at certain concentration within
therapeutic range
• Drugs with short half-life (2-3 Hrs) – drugs are administered at
conventional intervals (6-12 Hrs) – fluctuations are therapeutically
acceptable
• Long acting drugs: Prolonged half-life
• Loading dose: Single dose or repeated dose in quick succession – to
attain target conc. Quickly
• Loading dose = target Cp X V/F
• Maintenance dose: dose to be repeated at specific intervals
• Dose Rate =
target Cpss x CL
F
61. Monitoring of Plasma concentration
• Useful in
• Narrow safety margin drugs – digoxin, anticonvulsants,
antiarrhythmics and aminoglycosides etc
• Large individual variation – lithium and antidepressants
• Renal failure cases
• Poisoning cases
• Not useful in
• Response measurable drugs – antihypertensives, diuretics etc.
• Drugs activated in body – levodopa
• Hit and run drugs – Reserpine, MAO inhibitors
• Irreversible action drugs – Orgnophosphorous compounds
63. Therapeutic Index
• Therapeutic index = toxic dose/effective dose
• This is a measure of a drug’s safety
• A large number = a wide margin of safety
• A small number = a small margin of safety
64. Drug Concentrations may be
Useful when there is:
• An established relationship between
concentration and response or toxicity
• A sensitive and specific assay
• An assay that is relatively easy to perform
• A narrow therapeutic range
• A need to enhance response/prevent
toxicity
65. Why Measure Drug
Concentrations?
• Lack of therapeutic response
• Toxic effects evident
• Potential for non-compliance
• Variability in relationship of dose and
concentration
• Therapeutic/toxic actions not easily
quantified by clinical endpoints
66. Potential for Error when using TDM
•Assuming patient is at steady-state
•Assuming patient is actually taking the drug
as prescribed
•Assuming patient is receiving drug as prescribed
•Not knowing when the [drug] was measured in
relation to dose administration
•Assuming the patient is static and that changes in
condition don’t affect clearance
•Not considering drug interactions
67. Therapeutic Window
•Useful range of concentration over which a drug is
therapeutically beneficial. Therapeutic window
may vary from patient to patient
•Drugs with narrow therapeutic windows require
smaller and more frequent doses or a different
method of administration
•Drugs with slow elimination rates may rapidly
accumulate to toxic levels….can choose to give one
large initial dose, following only with small doses
70. Pharmacodynamics
• “What the drug does to the body”
• Includes physiological and biochemical
effects of the drug & MOA
• Integrates : organism susceptibility +
patient pharmacokinetics
71. Pharmacodynamics
Pharmacodynamics refers to the relationship between drug
concentration at the site of action and the resulting effect, including
the time course and intensity of therapeutic and adverse effects.
The effect of a drug present at the site of action is determined by that
drug’s binding with a receptor.
The concentration at the site of the receptor determines the intensity of
a drug’s effect
81. Bacteriostatic vs Bactericidal activity
• Bacteriostatic and bactericidal agents are
equivalent for treatment of most infectious
disease in immunocompetent hosts
• Bactericidal agents should be selected
over bacteriostatic ones in circumstances
of impaired local or systemic host
defenses
82. Concepts of MIC & MBC
MIC (minimum inhibitory concentration)
• Defined as the minimal concentration
of antibiotic that prevents the
clear suspension of
105 CFU/ ml from becoming turbid
after overnight incubation
• Turbidity signifiesat least 10 times increasein
bacterial density
MBC (minimal bactericidal concentration)
• For Bactericidal drugs : same as MIC or
upto 4 times MIC
• For Bacteriostatic drugs : many fold higher
than MIC
87. Determinants of antibiotic action
• Response of an anti infective agents is dependent on the peak concentration
(C max) or the total exposure (area under the concentration-time curve
[AUC])
90. Clinical Significance
• Antibiotics with a long post-antibiotic effect can be administered at
longer dosing intervals than would be predicted by their
pharmacokinetic half-life
• Longer dosing intervals (fewer tablets/day) can reduce blood levels &
side effects, yet maintain clinical efficacy
• Fewer doses per day tends to increase adherence to therapy
• Example: this characteristic is responsible for the efficacy of “once-
daily” dosing of aminoglycosides.
91. Time Kill Assay
The Time-kill kinetics assay is used to study the
activity of an antimicrobial agent against a bacterial
strain and can determine the bactericidal or
bacteriostatic activity of an agent over time.
CLSI Methods of Determining Bactericidal Activity of Antimicrobial Agents
92. Basics of the Time-Kill Kinetics
• Bactericidal activity is defined as greater than 3 log10 -fold
decrease in colony forming units (surviving bacteria), which
is equivalent to 99.9% killing of the inoculum.
• The time kill analysis can monitor the effect of various
concentrations of an antimicrobial agent over time in
relation to the stages of the growth of the bacteria (lag,
exponential, stationary phase)
93. Basics of the Time-Kill Kinetics
• Time-kill kinetics assays for agents such as antiseptics
require a shorter time-kill kinetics study and follow different
methodology.
• In contrast to the multiple time points in a time-kill kinetics
assay, the minimal bactericidal concentration (MBC) test is
defined as a 99.9% or greater killing efficacy at a specified
time.
94. Post-antibiotic effect (PAE)
• A persistent antibacterial effect after a brief antibiotic
exposure that occurs even in the absence of host defenses is
termed PAE
• The organism may become more susceptible to phagocytes –
post antibiotic leucocyte enhancement
• Concentration below MIC can alter bacterial morphology,
slows bacterial growth rate and prolongs PAE
95. Mechanism of PAE
• Slow recovery after reversible nonlethal
damage to cell structures
• Persistence of the drug at a binding site or
within the periplasmic space
• The need to synthesize new enzymes before
growth can resume
96. PAE (cont.)
• Most antibiotic possess significant in vitro
PAE against susceptible gram-positive
cocci
• Antibiotics with significant PAEs against
susceptible gram-negative bacilli are
limited to carbapenems and the agents
that inhibit protein or DNA synthesis
97. PAE (cont.)
• In vivo PAEs usually much longer than in
vitro PAEs
• Due to post-antibiotic leukocyte
enhancement (PALE) and exposure of
bacteria to subinhibitory antibiotic
concentrations
• Efficacy of once-daily dosing regimens is
in- part due to PAE
98. PAE (Cont.)
In vitro PAE
• Period of suppression of bacterial growth after
short exposure of organisms to antibiotic
Sub MIC effect
• Any effect of antibiotic with concentration below
MIC
Post antibiotic sub-MIC effect
• Effect of sub MIC drug concentration on bacterial
growth following serial exposure to drug
concentration exceeding MIC
Post MIC effect
• The difference in time for number of antibiotic
exposed bacteria vs controls to increase 1 log
values after drug concentration falls below the
MIC
99. Antimicrobial drug combinations
Rationale for combination antibiotic
therapy
• To provide broad-spectrum empiric
therapy in seriously ill patients
• To treat polymicrobial infections
• To decrease the emergence of resistant
strains
• To decrease dose-related toxicity
• To obtain enhanced inhibition or killing
101. Mechanism of Synergistic Action
• Blockade of sequential steps in a
metabolic sequences
– E.g. Trimethoprim-sulfamethoxazole
• Inhibition of enzymatic inactivation
– E.g. β lactamase inhibitor drugs
(Sulbactam)
• Enhancement of antimicrobial agent
uptake
– E.g. Penicillin can increase the
uptake of aminoglycosides by a
102. Mechanism of Antagonistic Action
• Inhibition of cidal activity by static agents
• Bacteriostatic agents can antagonize the action of
bactericidal cell wall-active agents as cell wall-
active agents require that the bacteria be actively
growing and dividing
• Induction of enzymatic inactivation
– Some gram-negative bacilli possess inducible β
lactamase
– β lactam
antibiotics
are potent inducers of
β
lactamase production
– If an inducing agent is combined with an
intrinsically active but hydrolysable β lactam such
as piperacillin, antagonism may result
104. β-lactams
• β-lactams (penicillins, cephalosporins and carbapenems) are
time-dependent and PD effect on the pathogen is affected by the
cumulative percentage of time that the free drug concentration exceeds
the MIC (fT > MIC)
• To improve PK/PD target attainment, β-lactams can be administered at
increased doses, increased frequency or by an extended or continuous
infusion, along with an initial loading dose.
• In renally impaired patients, reduction in dose instead of frequency is
the optimal strategy in reducing drug accumulation, but ensuring the fT
> MIC is maintained.
105. Vancomycin
• Vancomycin is a classic example of an antimicrobial that exhibits
killing when AUC/MIC is maximized
• A PK/PD target of AUC/MIC ≥400 has been advocated to achieve
clinical improvement and microbiologic eradication of
Staphylococcus aureus pneumonia and bacteraemia
• A 2- to 4-fold reductions in mortality were observed with attainment
of these AUC/MIC thresholds
• Trough serum concentration is often used as a surrogate marker for
AUC and is recommended as the most accurate and practical method
to monitor the efficacy of vancomycin
106. Fluoroquinolones
• AUC/MIC ratio is the major PK/PD parameter determining efficacy and
outcomes of fluoroquinolones, and targets range from 125–250.
• A study of ciprofloxacin for the treatment of Enterobacteriaceae
bloodstream infections demonstrated that an AUC/MIC ≥250 was
associated with a significantly greater treatment success rate
• In patients with renal impairment, dose adjustments are made by
prolonging the dosing interval rather than altering the dose as
fluoroquinolones have predominant concentration dependence with
time-dependence
107. Aminoglycosides
• Optimal clinical efficacy in the treatment of Gram-negative infections
occurs with a ratio ≥8–10
• the PAE for Gram-negative organisms was between 10 hours (for
Pseudomonas aeruginosa) to >12 hours (for Klebsiella pneumoniae
• The third PD property of aminoglycosides is the phenomenon of
adaptive resistance, which is a period of reversible resistance to
bactericidal action after initial exposure.
• The combination of concentration-dependent killing, PAE and
adaptive resistance provides the theoretical basis for higher doses
given less frequently.
108. Aminoglycosides
• Meta-analyses have shown either equivalence or superiority for
once-daily dosing in clinical efficacy, bacteriologic efficacy and
nephrotoxicity.
• PK/PD dosing has revolutionised how aminoglycosides are prescribed –
from thrice to once daily dosing, and has also improved their safety and
efficacy. As such, extended interval dosing for aminoglycosides is widely
considered the standard of care.
• AdjBW = IBW + 0.4 (ABW − IBW) should be used to avoid overdosing
obese patients
• Trough levels have been used as a measure of the potential for
development of toxicity
109. Conclusion
• Suboptimal dosing of antimicrobials has been attributed to poorer
clinical outcomes
• Dosing optimisation requires a good knowledge of PK/PD principles
• With the rising rates of antimicrobial resistance and a limited drug
development pipeline, PK/PD concepts can foster more rational and
individualised dosing regimens, improving outcomes while
simultaneously limiting the toxicity of antimicrobials.
