Pharmacokinetics
[Ma. Fidelis Espiritu-Quiza, MD, FPCP]
2 branches of Pharmacology
 Pharmacokinetics
- “what the body does to the drug”
 Pharmacodynamics
- “what the drug does to the body”
Pharmacokinetics: The Dynamics of Drug Absorption,
Distribution, Metabolism and Elimination
 Physiochemical factors in transfer of drugs across
membranes
 Drug absorption, bioavailability and routes of
administration
 Extent and rate of bioavailability
 Distribution of drugs
 Metabolism of drugs
 Excretion of drugs
 Clinical pharmacokinetics
 Design and optimization of drug regimens
 Therapeutic drug monitoring
Pharmacokinetics Overview
 Routes of drug administration
 Absorption of drugs
 Drug distribution
 Drug clearance through metabolism
 Drug clearance by the kidney
 Clearance by other routes
 Design and optimization of dosage regimen
Drug Movement or Transfer
 Paracellular diffusion through intercellular gaps
 Transmembrane transfer
 Passive membrane transport
 Carrier-mediated membrane transport
Physiochemical Factors in Drug Transfer Across
Membranes
 All drug movement with the body requires
passage of drugs cell across membranes
 Determinants to drug transfer:
- Physiochemical properties of drugs
- Physiochemical properties of the
membranes
Drug Characteristics that Determine Drug Transfer and
Availability at Sites of Actions
 Molecular size
 Molecular shape
 Degree of ionization
 Relative lipid solubility of ionized and unionized
forms
 Binding to serum and tissue proteins
Barriers to Drug Movement
 Single layer of cells
 Several layers of cells with extracellular protein
 Plasma membrane
- Common barrier to drug distribution
Cell Membrane Characteristics that Affect Drug Transfer
 Fluidity
 Flexibility
 Highly organized
 High electrical resistance
 Impermeable to highly polar molecules
 Relatively permeable to water
- by diffusion
- by flow resulting from hydrostatic or osmotic
differences across the membrane pressure
- Bulk flow of water can carry drug molecules
- Most large lipophilic drugs pass through cell
membrane
 Most large lipophilic drugs pass through cell
membrane
 Transmembrane movement is limited to
unbound drug (free drug)
 Proteins with bound drug are too polar and too
large for simple diffusion
 Presence of membrane proteins
 May provide selective targets for drug
actions
- Receptors Passive Membrane Transport
- Ion channels  Ion Trapping
- Transporters - An acidic drug will accumulate on the
more basic side of the membrane
- A basic drug will accumulate on the more
acidic side of the membrane
- Clinical implication: enhance absorption
and excretion of drugs

Passive Membrane Transport

 Drug molecules penetrate by diffusion along a
concentration gradient due to solubility in the
lipid bilayer (Fick’s Law of Diffusion)
 Directly proportional to:
- Magnitude of concentration gradient across
the membrane
- Lipid-water partition coefficient of the drug
- Membrane surface are exposed to the drug
 For ionic substances depend on:
- Electrochemical gradient for the ion
- Differences in pH across the membrane
 Transmembrane distribution of weak electrolytes
determined by:
- pKa of substance
- pH gradient across the membrane
Carrier- Mediated Membrane Transport
 Facilitated diffusion
- Carrier-mediated transport not requiring
energy
- Moves along electrochemical gradient
- Highly selective for specific
conformational structure
- Mediate either drug uptake or drug efflux
(P-glycoprotein)
- Ex. Glucose entry across muscle
membrane facilitated by presence of
insulin-sensitive glucose transporter
protein

 Active transport
- Direct requirement for energy
- Movement against an electrochemical
gradient
- Saturability
- Selectivity
- Competitive inhibition by co-transported
compounds
- Subtypes:
o Primary active transport
 One type of substance is
transported
o Secondary active transport (co-
transporter)
 more than one type of
substance id transported
 Same direction (symport)
 Opposite direction
(antiport)
- Examples: Na , K +, -ATPase
+

- Na+- Ca2+ exchange protein

- Na+ dependent glucose transporters
(SGLT1 and SGLT2 in GIT and renal
epithelium)
  First-pass effect
- Reduction in bioavailability due to
inactivation or diversion of a fraction of
the administered and absorbed dose of
drug before it reaches the general
circulation and be distributed to its sites
of action
 A function of the anatomical site from which
absorption takes place
Picture
 Sites of first-pass metabolism:
- Intestinal microbial flora
- Gastrointestinal epithelium
- Liver
- Lungs Kidneys
 Pharmaceutical Equivalence
- Products contain the same active
ingredients and are identical in strength
or concentration, dosage form and route
of administration
 Bioequivalence
- Rate and extent of bioavailability of the
active ingredient of 2 products are not
much different under stable conditions
 Factors that affect bioavailability
- Differences in crystal form ad particle
size
- Conditions that alter the rate of
dissolution or disintegration of the
dosage form
- Different excipients or vehicles that may
alter pharmacokinetic properties of the
active ingredient

Pharmacokinetic Processes
 Drug Absorption
 Drug Distribution
 Drug Metabolism (Biotransformtation)
 Drug Elimination (Excretion)

Drug Absorption and Bioavailability

 Absorption
- The movement of a drug from its site of
administration into the central
Measurable site
compartment and the extent to which
this occurs
 Bioavailability Preferred is 1 or 100 percent
Iv administration

- The fractional extent to which a dose of

a drug reaches its site of action or a
biological fluid from which the drug has
access to its site of action

Picture
  Enteric coating of drugs:
- To prevent destruction or rapid
dissolution by gastric secretions
- To minimize local gastric irritation

Controlled-Release Preparations
 Controlled-release (CR), sustained- release (SR),
extended-release (XR), prolonged-action
 Potential advantages:
- Reduced losing frequency (favors
compliance)
- Sustained maintenance of therapeutic
effect over time
- Elimination of peaks and troughs of
plasma levels of the drug
 “Dose-dumping”
- Sudden release of all contents at one
time due to destruction of controlled-
release mechanism
- Resulting in toxicity due to higher dose
content than regular formulations
Picture
Major Routes of Drug Administration Major disadvantages of Oral route of Administration
 Oral (enteral) - Limited absorption due to physical
- Most common, safest, economical, and characteristics of the drug
convenient method - Emesis as a result of irritation to the GIT
 Parenteral mucosa
- More rapid availability to site of action - Destruction by digestive enzymes or low
- Utilized for emergency therapy, gastric pH
unconscious and/or uncooperative - Irregularities in absorption or propulsion
patients or those patients that cannot due to food or other drugs
retain anything by mouth - Need for patient cooperation
(compliance)
Oral Route of Drug Administration
 Absorption from GIT governed by:
- Surface area for absorption
- Blood flow to site of absorption
- Physical state of the drug (solid,
solution, suspension)
- Water solubility
- Drug concentration at site of absorption
 Most drug absorption from GIT is by passive
diffusion
 Absorption preferentially favored when drug is
non-ionized and more lipophilic
 Major site of drug absorption is in the small
intestine due to greater surface area regardless
of degree of ionization of the drug
 Factors that alter gastric emptying time will
affect rate of absorption in the SI:
- Presence of food
- Certain drugs with prokinetic activity of
the GIT
- Physiological state due to hormonal
effect (estrogen slowing of GIT transit
Sublingual Route of Administration - Avoidance of hepatic first-pass loss
 Venous drainage (plexuses of veins under the - Local application of the drug at the site of
tongue) from mouth direct to superior vena cava action especially for pulmonary diseases
 Circumvents first - pass metabolism in the GIT  Examples:
and the liver - Beta-agonists inhalation for treatment of
 Rapid drug absorption with rapid onset of action asthma
 For non-ionic and highly lipid soluble substances - Anesthetic gases
 Examples: - Corticosteroids as anti-inflammatory
- Nitroglycerin for angina or chest pain of agents for bronchial hyper-reactivity
cardiac origin
- Nifedipine for rapid decrease in BP Topical Route of Administration
 For local effects with ideally minimal systemic
Transdermal Route of Administration distribution
 Dependent on surface area and lipid solubility  Applied to mucous membranes of the following:
 Epidermis behaves as a lipid barrier - Conjunctiva
 Dermis is freely permeable - Nasopharynx
 Systemic absorption occurs more readily through - Oropharynx
abraded, burned, inflamed or denuded skin - Vagina
 Rate and extent of absorption is affected by rate - Colon
of subcutaneous blood flow or perfusion - Urethra
 Absorption may be enhanced by: - Urinary bladder
- Occlusive dressing  Sometimes used intentionally for systemic
- Hydration of skin absorption such as intranasal- insulin, ADH
- Suspending drug in oily vehicle  Sometimes associated with systemic toxicity due
 Controlled release preparations: to site characteristics which favor enhanced
- Nicotine for tobacco smoking withdrawal absorption
- Scopolamine for motion sickness  For the eyes, the site of absorption for local
- Hormonal replacement therapy effects is the cornea.
- Birth control preparations
Novel Routes of Administration
 Inserts or implants
- Ocular inserts
- Estrogen implants for prolonged release
 Drug
- Eluting stents in cardiac grafts
 Pumps
- Insulin pump

Pulmonary Route of Administration

 Inhalational for gaseous or volatile substances or
aerosolized particles
 Rapid access to circulation due to large surface
area of the lung
 Minimizes systemic distribution when in the right Parenteral Route of Administration
dose  Major routes
 Potential toxicity due to inhalation of toxic - Intravenous (IV)
chemical fumes - Subcutaneous (SC)
 May also result to local irritation of the - Intramuscular (IM)
respiratory tract - Intradermal (ID)
 Advantages include the following: - Intra-arterial
- Almost instantaneous absorption of drug - Intra-thecal
into the blood
  May be subject to first-pass elimination in the
lungs (except intra-arterial)
 Subcutaneous, intramuscular and intradermal
rate of absorption limited by:
- Area of absorbing capillaries
- Solubility of substance in the interstitial
fluid
Intravenous (IV) Route of Administration
 100% bioavailability (complete and rapid)
- Drug delivery is immediate and controlled
and achieved with accuracy
- Ideal for irritating substances due to
dilution by blood
- High risk for acute adverse effects of the
drug due to rapidity of onset
- May be given as bolus or drip by “piggy-
back”
 Drug characteristics that contraindicate use of IV
route
- Oily vehicle
- Can precipitate blood constituents
- Can hemolyze blood elements
 Once administered, can no longer be withdrawn
 Warrants close monitoring during administration
and some period immediately after
administration
Intra-arterial and Intrathecal Route
 Intra-arterial
- For direct access to a specific organ
- Localized effects
- Treatment of organ tumors
- Bypass first-pass effect of lungs
 Intrathecal
- Into the meninges of the CNS
- For direct access to the CNS especially
since the CNS has tight junctions
Major disadvantages of Parenteral Route of
Administration
 Need for maintenance of asepsis
 Pain in injection site
 Difficulty of self-administration by the patient
 High risk for acute adverse effects of the drug
 Less chances of drug removal once absorbed

Subcutaneous (SC) Route of Administration

 For drugs not irritating to the tissue
 May cause pain, necrosis and sloughing off
 Constant and sustained release
 May be given as pellets under the skin
 May be given with vasoconstrictor agent to
retard absorption (epinephrine with lidocaine)

Intramuscular (IM) Route of Administration

 Drugs in aqueous solution
 Rate and extent of absorption may be influenced
by the following:
- Local heat applied to the area
- Activities that increase blood supply
(exercise/massage)
- Amount of fat tissue in the surrounding
area
 May be used for irritant substances
Drug Distribution
 Factors that affect the rate and extent of drug
distribution in the body:
- Physiochemical properties of the drug
- Physiological and pathological conditions
of the body
o Cardiac output
o Regional blood flow
o Capillary permeability
o Tissue volume
  Two phases of drug distribution
1) First (rapid) phase
 Well-perfused organs (liver,
kidney, brain and heart)
2) Second (slower) phase
 Muscles, viscera, skin, fat
 Potential for alteration in intensity of drug effects
due to changes in plasma protein binding and/or
competition of binding sites
 Increase plasma protein may result in decreased
therapeutic efficacy due to increased binding
 Decrease plasma protein (liver disease, renal
losses of albumin) may result in increased
therapeutic efficacy due to decreased binding
 Tissue binding of drugs
- Generally reversible
- Binding to cellular components
 Proteins
 Phospholipids
 Nuclear proteins

Drug Distribution in the CNS

 Drug penetration is transcellular rather than
paracellular due to presence of “tight junctions”
 Utilizes membrane transport proteins (influx and
efflux transporters)
 Blood-brain barrier
- Brain capillary endothelial cells and
pericapillary glial cells
 Lipid solubility of non-ionized and unbound drug-
clinical implication:
- Modification of ability to penetrate CNS
to limit adverse side effects of certain
drugs
 Meningeal and encephalic inflammation increase
local permeability
Drug Distribution
 Other clinically significant sites of drug
 Determinants of tissue distribution:
distribution
- Relative binding of drug to plasma
- Fat
proteins and tissue macromolecules -
- Bones and teeth
more important determinant
- Placenta
- Partitioning of drug between blood and
 Fetal plasma is slightly more acidic
tissue
than that of the mother – ion
- Lipid solubility
trapping of basic drugs
- Transmembrane pH gradients
- Milk
 Plasma protein binding is usually reversible
- Hair
 Occasional covalent binding
- Saliva, sweat
 Plasma proteins with which drugs bind:
o Albumin
Drug Metabolism (Biotransformation)
 For acidic drugs
 Major site of drug metabolism: LIVER
o ꭤ1- acid glycoprotein
 Other sites of drug metabolism
 For basic drugs
- GIT epithelium
o Specific proteins especially for hormones
- Lung endothelium
 Sex hormone-binding globulin
- Renal tubular cells
 Thyroid hormone-binding
 Lipophilic characteristics of drugs that promote
globulin
access to sites of action hinder their excretion
 Only unbound drug crosses membranes, are from the body
metabolized and excreted
 Main purpose: conversion of hydrophobic
 Only unbound drug binds to receptors substances to more hydrophilic substances in
 Fraction bound is a function of number of binding preparation for elimination from the body and
sites and drug concentration
 Plasma protein binding is nonlinear and saturable
 termination of biological and pharmacological
activity
 In general: biotransformation reactions generate
more polar, inactive metabolites

 Maybe altered due to age, gender, genetic

variability, disease and xenobiotics
 Phases of drug metabolism
- Phase 1 (functionalization phase)
- Phase 2 (biosynthetic phase)
 PHASE 1 (functionalization phase)
- Introduce or expose functional group on
parent compound
- Generally, results in loss of
pharmacologic activity Drug Metabolism (Biotransformation)
- Enzyme systems primarily involved  Result of drug biotransformation
reside in the endoplasmic reticulum - Altered pharmacologic activity
- Enzymes groups  Active substance to inactive moiety
 Cytochrome P450 isozymes  Inactive drug (prodrug) to active
 Transferases molecule
 PHASE II (biosynthetic phase)  Toxic product to non-toxic
- Conjugation reactions metabolite
- Lead to formation of covalent linkages  Conversion of non-toxic substance
between a functional group on parent to toxic metabolite
compound or on results of phase I
reactions
- Glucuronic acid, sulfate, glutathione,
amino acids, or acetate
- Results to highly polar substances
- Enzyme systems primarily located in the
cytosol
 PHASE I (functionalization phase)
- Activity may be enhanced or inhibited
- Enzyme inducers
 Anticonvulsants (phenytoin,
barbiturates, diazepam)
 Rifampicin
- Enzyme inhibitors
 Metronidazole, erythromycin,
ketoconazole
 Cimetidine
Termination of Drug Effect  ABC transporters
 Metabolism - Organic cationic drugs (organic bases)
 Excretion  Tubular reabsorption – drug is passively
 Redistribution of drug from its site of action into reabsorbed back into the blood
other tissues or sites - Mostly by non-ionic diffusion
Excretion of Drugs - Some through action of membrane
 Drugs are eliminated either as unchanged form transporters
or as metabolites  Ion trapping
 Except from lungs, excretion of polar compounds
from excretory organs is more efficient than for Biliary and Fecal Excretion
substances with high lipid solubility  Active transporter secretion into the bile
 Most lipid soluble drugs are not readily excreted canaliculi
 Excretory organs:  Active transporter secretion from enterocytes of
 Kidney: major organ of excretion systemic circulation directly into the intestinal
 Lungs: importantly mainly for anesthetic lumen
gases  Enterohepatic recirculation
 GIT: unabsorbed orally ingested drugs or - Reabsorption of substances from the GIT
drug metabolites excreted either in bile lumen into the systemic circulation
or secreted directly into GIT and not - Responsible for prolonging duration of
reabsorbed action of a drug
 Skin - Ezitimibe:
 Breast milk  Reduces intestinal absorption of
cholesterol by interfering with the
Renal Excretion sterol transporter system in the
 3 major processes: intestinal epithelial cell- prolong
- Glomerular filtration duration of action
- Active tubular secretion - Toxicity potential:
 Predominantly in the  Reabsorption of toxic substances
proximal tubule already excreted into the GIT
- Passive tubular reabsorption lumen resulting in prolonged or
 Non-ionized forms of repeated manifestations of
weak acid and bases in toxicity
proximal and distal - Ex. Organophosphates (insecticide)
tubules  Enterohepatic recirculation
 Determinants to amount of drug entering renal responsible for intermittent
tubular lumen: recurrence of cholinergic toxicity
- Glomerular filtration rate  Repeat dose activated charcoal
- Extent of plasma binding of the drug; for adsorption with eventual
only unbound drug is filtered excretion into the feces
 Tubular secretion Excretion by Other Routes
- Drug is actively secreted mostly in the  Sweat, Saliva and Tears
proximal tubule  Depends mainly on:
 Active carrier-mediated process - Diffusion of the non-ionized lipid soluble
 Transporters: form of drugs through the epithelial cells
 P glycoprotein (P-gp) - pH
 Multi-Drug-Resistance-  Milk is more acidic than plasma
Associated Protein Type - Traps basic drugs, resulting to increased
2 (MRP2) delivery of basic drugs to infants
 ATB-binding cassette  Some excretion in hair and skin
(ABC) transporters
 P-gp and MRP2 Transporters
- Amphiphatic cations
- Conjugated metabolites (glucuronides,
sulfates and glutathione adducts
Clinical Pharmacokinetics
 Fundamental tenet:
- Relationship exists between the
pharmacological effects of a drug and an
accessible concentration of the drug
(blood or plasma)
 Attempts to provide both a quantitative
relationship between dose and effect and a
framework within which to interpret
measurements of concentrations of drugs in
biological fluids and adjustment through changes
in dosing for the benefit of the patient
 Importance in patient care: Clearance
- Improvement in therapeutic efficacy  Most important concept in designing a regimen
- Avoidance of unwanted effects can be for long term administration
attained by application of principles
 Refers to elimination of drug from systemic
when dosage regimens are chosen and
circulation
modified
 Important in assuring maintenance of drug levels
 Dose adjustment for individualization of patient
within steady-state within the therapeutic
therapy is dependent on physiological and window during the entire course of treatment
pathophysiological variables which affect
 Steady-state concentration:
pharmacokinetic parameters
- rate of drug elimination equals rate of
 4 most important parameters that govern drug
drug absorption
disposition:
 The amount of plasma cleared of 100% of the
 Clearance
drug per given unit of time (ml/min)
 Measure of body’s efficiency
 Indicates the volume of biological fluid (blood or
eliminating the drug
plasma) from which drug is completely removed
 Volume of distribution (Vd)
 Measure of apparent space
 Total systemic clearance:
in the body available to
CL= CL renal + CL hepatic + CL other
contain the drug
 Dosing Rate (maintenance):
 Elimination half-life (T 1/2)
Dosing rate = (CL * Target C ss)/ F
 Measure of rate of removal
 C ss refers to drug concentration in the body at
of the drug from the body
steady state
 Bioavailability
 First - order kinetics:
 Fraction of the drug
- Constant fraction of drug in the body is
absorbed in the systemic
eliminated per unit time
circulation
o Governs elimination of drugs
through non-saturable
mechanisms (enzymes and
transporters involved in
elimination are not saturated)
 Zero – order kinetics:
- Constant amount of drug is eliminated
per unit time
o Occurs when mechanisms of drug
elimination become saturated
FIRST ORDER ELIMINATION
 The decline in Cp varies with the concentration
 The term “first order” reflects the fact that the
rate of elimination is dependent on
concentration
 The concentration declines ‘exponentially’ with
time
ZERO ORDER ELIMINATION
 Rate of elimination is constant with time
 Constant amount of drug is eliminated with time
Clearance
 Rate of drug elimination of a particular organ is
the product of blood flow and the difference
between the arterial drug concentration entering
the organ and the venous drug concentration
exiting from the organ
 Extraction ratio:
- An expression of clearance of the drug
by a specific organ
(CA-CV)/ CA
- CA = arterial concentration of the drug
- CV = venous concentration of the drug
Hepatic Drug Clearance:
 Determinants of hepatic drug clearance:
1) The intrinsic clearance (Cl int.)
2) Hepatic blood flow
 Extraction Ratio:
- Refers to the combined effect of the
intrinsic clearance and rate of hepatic
blood flow – proportion of administered
drug that is removed by the liver
 Intrinsic Clearance (Cl int.)
- Refers to the liver’s inherent ability to
metabolize the drug
- Dependent on enzymatic activity
- Activity may be decreased or increased
by the use of either the following:
o CYP 450 enzyme inhibitors
(cimetidine, metronidazole,
erythromycin)
o enzyme inducers
(phenobarbital, rifampicin)
 Hepatic blood flow
- Affects rate at which drugs can be
transported in the blood to the liver
- Affected by physiologic and disease
conditions
Faster flow  decreased rate of removal
Slower flow  increased rate of removal
Volume Distribution
 Relates the amount of drug in the body to the
concentration of the drug in the blood or plasma
 Does not refer to a real physiologic space
 Merely an apparent space or volume of fluid that
would be required to contain all the drug in the
body
Vd= amount of drug in the body (dose)/ Co
Initial dose = C * Vd
 Often provided by the drug developer
- Often provided as volume per kg body
weight (L/kg)
 Factors that determine the volume of distribution
of any given drug
- Degree of plasma protein binding vs.
tissue protein binding
- Degree of binding to high-affinity
receptor sites
- Extent or rate of blood flow or perfusion
to storage site
- Lipid solubility
- Body mass: fat content vs. body water
- Amount of drug in other body storage
compartment
- Age, gender
- Disease
HALF-LIFE (T1/2)
 The time it takes for the plasma concentration or
the amount of the drug in the body to be
reduced by half (50%)
 Half-life of absorption
 Half-life of elimination
 T1/2 = 0.693* (Vss/CL) THERAPEUTIC DRUG MONITORING
 Major use of measured concentrations of drugs
 Often provided by the drug developer for normal at steady state is to refine estimate of CL/ F for
physiologic conditions the patient being treated
 Affected by volume of distribution and clearance  Sampling time is important issue
parameters  If measurement is to determine attainment of
peak plasma concentrations within the
therapeutic window- soon after administration of
drug
----------------------------------------------------------------------------
 Loading dose: (oral) Target Cp * Vss/F
 Loading dose: (IV) Target Cp * Vss

 Dosing rate (oral): Target Cp * CL/F

----------------------------------------------------------------------------
 It takes four (4) half-lives of absorption for near
attainment of steady state
 It takes five (5) half-lives of elimination for near
100% removal of the drug from the body
 Provides basis for dosing interval in the
administration of maintenance doses
T1/2 = 0.693 * (Vss/ CL)
 Directly proportional to volume of distribution
and inversely proportional to clearance
 Half-lives constitute the basis for dosing interval
 Half-lives constitute the basis for time to achieve
steady-state
 Half-lives constitute the basis for time for
elimination of drug from the body
 Dosing rate (IV): Target Cp * CL/F
 A 40-year-old male patient (70 kg) was recently
diagnosed with infection. He received 2,000 mg
vancomycin as IV loading dose. The peak plasma
concentration of vancomycin was reported to be
28.5mg/L. What is the apparent V4?
Vd = dose/C
 2,000 mg / 28.5 mg/L
 70.1 L
 Because the patient is 70 kg, the apparent
volume of distribution in L/kg will be
approximately 1L/kg (70.1 L/ 70kg).

CHARACTERISTICS OF DRUGS ASSOCIATED WITH TDM

 Narrow therapeutic range
 Unpredictable dose/response relationship
 Significant consequences from toxicity
 Correlation between SDCs and efficacy or toxicity
 Readily available assays

INFUSION LENGTH
 The length of infusion has a significant effect
upon the peak serum level.
 If we were to administer the same dose to the
same patient at different infusion rates, the peak
levels would differ significantly

Infusion Dose Interval Peak level

(mins) (mg) (hrs) (mg/dl)
30 500 8 26.8
60 500 8 25.3
120 500 8 22.5
APPLIED PHARMACOKINETICS: Practical Considerations

 Choose practical, convenient doses and

administration schedules.
- Odd doses and schedules may lead to
errors in administration
 Consider a loading dose
- Some drugs, which are usually
administered without a loading dose,
may require a loading dose in order to
quickly attain therapeutic levels

Some reasons for variation of CL

Low CL
Normal variation
Renal impairment
Genetic poor metabolism
Liver impairment
Enzyme inhibition
Old age/ neonate
High CL
Normal variation
Increased renal blood
flow
Genetic
hypermetabolism
Enzyme induction
Drugs with pH-dependent renal elimination

ACIDS BASES
 Elimination  Elimination
enhanced by enhanced by acid
alkaline diuresis diuresis
Amphetamines
Methadone
Phenobarbitone Mexiletine
Phencyclidine
Phenylpropanolamines,
Salicylates e.g. ephedrine,
pseudoephedrine
Quinidine