16/02/2024 Y.

Obirikorang 1
BASICS/FUNDAMENTALS OF
PHARMACOLOGY
PHARMACOKINETICS
 LEARNING OBJECTIVES
By the end of this session we should be able to;

· Define and understand the pharmacokinetic process of

drug excretion

· Identify the relationship between drug metabolism and

excretion

· Define and calculate elimination half life and understand

its clinical importance

· Understand and describe the factors that affect drug

excretion and how alterations in these factors influence
excretion.
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https://youtu.be/VZRVt9r4oSM
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 EXCRETION OF DRUGS
• Excretion is defined as the process where by drugs or
drug metabolites are irreversibly transferred from
internal to external environment through renal or non
renal routes.

• The principal organ of excretion are kidneys. The drugs

are transported unaltered or altered out of the body –
termination of the pharmacological action of the drug.

• Excretion, along with metabolism and tissue

redistribution, is important in determining both the
duration of drug action and the rate of drug elimination.
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 EXCRETION OF DRUGS
• The drug that is excreted slowly, the concentration
of drug in the body is maintained and the effects of
the drug will continue for longer period and vice-
versa.

• The major processes of excretion include renal

excretion, hepatobiliary excretion and pulmonary
excretion.

• The minor routes of excretion are saliva, sweat,

tears, breast milk, vaginal fluid, nails and hair.
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 EXCRETION OF DRUGS
• Patients with kidney disease may require a dosage
reduction and careful monitoring of kidney function.

• Children have immature kidney function and may

require dosage reduction and kidney function tests.

• Similarly, older adults have diminished kidney

function and require careful monitoring and lower
dosages

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 DIFFERENT ROUTES OF DRUG EXCRETION
• Renal excretion: A major part of excretion of
chemicals is metabolically unchanged or changed. The
excretion of drug by the kidney involves.
I. Glomerular filtration, e.g. digoxin
II. Active tubular secretion; occurs in proximal tubule of
nephron e.g. benzyl penicillin, pethidine
III. Passive tubular reabsorption.

• The function of glomerular filtration and active

tubular secretion is to remove drug out of the body,
while tubular reabsorption tends to retain the drug.

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 DIFFERENT ROUTES OF DRUG EXCRETION

• Hepatobiliary excretion: the conjugated drugs are

excreted by hepatocytes in the bile.

• Excretion of drugs through bile provides a back up

pathway when renal function is impaired.

• After excretion of drug through bile into intestine,

certain amount of drug is reabsorbed into portal vein
leading to an enterohepatic cycling which can
prolong the action of drug e.g. chloramphenicol,

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 DIFFERENT ROUTES OF DRUG EXCRETION
• Gastrointestinal excretion: when a drug is
administered orally, a part of the drug is not absorbed
and excreted in the faeces.

• The drugs which do not undergo enterohepatic cycle

after excretion into the bile are subsequently passed
with stool

• E.g. Aluminium hydroxide Changes the stool into

white colour, ferrous sulfate changes the stool into
black and Rifampicin into orange red.
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 DIFFERENT ROUTES OF DRUG EXCRETION

• Pulmonary excretion: Drugs that are readily

vaporized, such as many inhalation anaesthetics
and alcohols are excreted through lungs. E.g.
alcohol

• The rate of drug excretion through lung depends

on the volume of air exchange, depth of
respiration, rate of pulmonary blood flow and the
drug concentration gradient.
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 DIFFERENT ROUTES OF DRUG EXCRETION
• Sweat: A number of drugs are excreted into the
sweat either by simple diffusion or active secretion
e.g. rifampicin.

• Excretion of drugs through skin may lead to

urticaria and dermatitis.

• Compounds like benzoic acid, salicylic acid, alcohol

and heavy metals like lead, mercury and arsenic are
excreted in sweat.
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 DIFFERENT ROUTES OF DRUG EXCRETION
• Mammary excretion: Many drugs mostly weak basic
drugs are accumulated into the milk.

• Therefore lactating mothers should be cautious about

the intake of these drugs because they may enter into
baby through breast milk and produce harmful effects
in the baby

• e.g. ampicillin, aspirin, chlordiazepoxide, coffee,

diazepam, furosemide, morphine, streptomycin

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 DIFFERENT ROUTES OF DRUG EXCRETION -
SALIVARY EXCRETION
• The pH of saliva varies from 5.8 to 8.4. Unionized lipid
soluble drugs are excreted passively.

• The bitter after taste in the mouth of a patient is

indication of drug excreted.

• Some basic drugs inhibit saliva secretion and are

responsible for mouth dryness.

• Compounds excreted in saliva are Caffeine, Phenytoin,

Theophylline.
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 Elimination – What is it?
• Process whereby body terminates drug action

• Combination of metabolism (biotransformation) and

excretion

• Elimination of a drug from the body will require eliminating

the drug from several sites
– Lung, liver, muscle, kidney etc.
– In the liver and muscle typically involves biotransformation
– In the kidney typically involves excretion

• Rate of elimination is called clearance

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 Clearance
• It may be defined as a function of clearance from
each elimination site; CL = Rate of elimination
Concentration (C)
• CLkidney = Rate of eliminationkidney
C
• CLliver = Rate of eliminationliver
C
• CLother = Rate of eliminationother
C

• CLsystemic = CLkidney + CLliver + CLother

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 CLEARANCE OF DRUGS
• FIRST – ORDER ELIMINATION KINETICS

• ZERO – ORDER ELIMINATION KINETICS

• https://youtu.be/T3964Ha6AKI

• https://youtu.be/GPgWdGsxyOM
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 Clearance
• For most drugs the rate of elimination is
directly proportional to the
concentration of the drug attained in
clinical settings – if the drug is 1, the rate
of elimination is 1.

–Elimination is not saturable

–This is called First Order kinetics

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 First Order Kinetics
• With most drugs, there is a rapid fall in drug levels, as
most drugs are readily metabolized, and there is an
excess of enzyme available for the metabolism. Thus, the
enzyme never becomes saturated with drug. This is
known as first order kinetics.

• In first order kinetics, increasing the concentration of the

drug increases the metabolism of the drug.

• First order kinetics is also observed with drugs that are

eliminated unchanged.
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 Clearance

• A few drugs exhibit capacity limited elimination

– Elimination is saturable after which time a constant

amount of the drug is metabolized per unit time

– This is called Zero Order kinetics

– Important examples in human pharmacology

include alcohol, phenytoin

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 Alcohol Metabolism - an example of zero
order kinetics
• 150 lb male college student drinks 5 pints of beer
(140 grams) over a three hour period of time and
goes to bed with a Blood Alcohol Concentration of
approximately 250 mg/dl

• If first order kinetics were to apply the t1/2 would be

1 hour

– Halve the BAL each hour

– BAL @ 8am <1mg/dl
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 Alcohol Metabolism
• But in reality Zero Order kinetics applies once the
metabolizing enzymes become saturated

– Alcohol metabolized at rate of approximately 8 grams/hour

– After 8 hours 64 grams will be metabolized

– 76 grams remain in the body

– BAC will be > 120 mg/dl

• This is the most important example of zero order

kinetics in human pharmacology
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 Elimination Half life
• Time required to eliminate half of the amount of drug in
the body or to reduce the plasma concentration by 50%
– Denoted as T1/2

• It is calculated from the plasma concentration curve

following administration of a single dose of a drug

• Only used for drugs that follow first order kinetics

• It will be affected by anything that changes the volume of

distribution or the clearance
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 An Example – How long will it take for the body to
eliminate 100 mg of drug X?
• 100 mg of drug in plasma at time zero and the drug’s half life
is 4 h

• 50% of drug is eliminated in one half life

• 50 mg of drug remains in plasma after 4 h (1 half life)
• 25 mg of drug remains in plasma after 8 h (2 half lives )
• 12.5 mg of drug remains in plasma after 12 h (3 half
lives)
• 6.25 mg of drug remains in plasma after 16 h (4 half
lives)

• Thus for drugs that are eliminated via first order kinetics
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 Continuous and multiple dose kinetics
• When a drug that exhibits first order kinetics is
administered continuously/ intermittently it accumulates
until it reaches a plateau or steady state concentration
• When initially administered the rate of administration is
far greater than the rate of elimination
• As the drug continues to be administered, the rate of drug
elimination gradually increases whereas as the rate of
administration remains constant.
• Eventually the rate of administration will equal the rate of
elimination
– This is the definition of steady state concentration
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Drug Accumulation to the Steady State

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 Time required to reach steady state concentration
• Because the time to reach steady state is dependent on
the time it takes for the rate of elimination to equal rate
of administration, the time to reach steady state is a
function of the elimination half life of the drug
• First order processes requires 4-5 half lives to be
completed
– the time to reach steady state takes 4-5 half lives

• If half life changes the time required to reach steady state

will also change

• The time required to reach steady state is independent of

drug dose or rate/frequency of dosing
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 Steady State Concentration
• The steady state concentration reached is directly
proportional to the drug dose administered per unit of
time and the elimination half life
– If the dose is doubled the steady state concentration is
doubled
– If the elimination half life is doubled the steady state
concentration is doubled

• A drug administered by continuous infusion will reach

steady state at the same rate as a drug administered
intermittently.
– The plasma level of the latter will fluctuate

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 Oral Dosing of Medication
• In most cases a single dose of a drug is insufficient to cause the
desired therapeutic effect

• Repeated doses are required to attain a steady state

concentration and a therapeutic concentration

• A sufficient number of equivalent doses are given at regular

intervals so that the amount given equal the amount eliminated
– The half life helps guide the frequency of dosing
– If the dosing interval is shorter than 4 half lives drug
accumulation will occur

• This results in peaks in concentration after drug administration

and trough right before the next dose
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 Loading Dose vs. Maintenance Dose

• Loading dose is used when it is necessary to rapidly

achieve a therapeutic plasma concentration
– Commonly used with antibiotics and anticoagulants

• Maintenance dose is given to establish or maintain a

desired steady state concentration

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Drug Half-Life and Clearance

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 Elimination Half life
and Clearance

• https://youtu.be/gqpchVWTA4A

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Clinical scenarios that can change Pharmacokinetics
• Disease states
Liver disease reduced phase 1 metabolism and
reduced albumin
Renal failure – reduced GFR and secretion
Heart failure – volume expansion, reduced circulation
Pulmonary fibrosis - absorption
• Post surgical states
– Gastric bypass surgery
• Poly pharmacy
Drug-drug or drug - food interactions
Enzyme induction or saturation
• Enzyme polymorphisms
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 The importance of Age Factors Affecting Drug movement
Age Group
Process of
Drug Neonates and Infants Children Elderly Adults
movement
Absorption Altered absorption of No major changes. No major changes.
some drugs.
Distribution Incomplete blood-brain No major changes. Higher Vd for fat-soluble
barrier; higher volumes drugs and drugs bound
of distribution for water- to plasma proteins.
soluble drugs.
Lower Vd for water-
soluble drugs
Metabolism Lower rate of oxidative Biotransformation rate for Reduced oxidative
reactions and some drugs higher than metabolism;
glucuronate in adults.
conjugation.
Excretion Reduced capacity to No major changes. Reduced capacity to
excrete drugs. excrete drugs.
• Reduced GFR
• Reduced secretion
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