Learning Objectives

1. Discuss the onset of drugs and magnitude of drug action are related to the rate and extent of
absorption
2. Discuss the factors affecting the drug absorption from GIT
3. Discuss how ionization of drug influences the absorption
4. Discuss the first pass effect of drug and how to overcome it
5. State the factors influencing the bioavailability of drug distribution
6. Discuss how plasma protein binding influences drug actions – onset and magnitude of drug
action, erratic drug action
7. List the processes of termination of drug activity
8. Understand the redistribution and uptake processes
9. Discuss the enzyme induction and enzyme inhibition with examples
10. State phases and outcomes of biotransformation with examples
11. Outline the determinants of biotransformation
12. List different routes of drug excretion
13. List processes of renal excretion
14. Discuss the factors that influence biotransformation and renal excretion
15. Discuss the enterohepatic circulation
16. Understand the basic concept of clinical pharmacokinetics
17. Understand single dose kinetic and multiple dose kinetics
18. Understand the parameters: C0, Cmax, Css, Tmax, Vd, T1/2, Kel, CL and their clinical
significances

Pharmacokinetics means movement of drugs in the body.

Involves 4 important stages

Absorption → Distribution → Metabolism → Excretion (ADME)

 Significance of Pharmacokinetics
✓ Depends on patient-related factors
✓ Depends on drug’s chemical properties
✓ Allows practitioners the flexibility to prescribe and administer medications
o Provide greatest benefit with lower risk
o Allow adjustment as necessary
o Physiology and lifestyles of patients are varied

Absorption
✓ Movement of drugs across the cell membrane into the blood stream
✓ Has to be in a solution form before crossing cell membrane
o Any dosage form (except IV injection, oral solutions, enema and eye drops)
▪ Integrated before absorption

Movement of Drugs
across Cell Membrane

Passive diffusion Facilitated diffusion Active diffusion Endocytosis

high to low high to low any concentration

engulfement of drug
concentration concentration gradient

lipid soluble drugs need carrier proteins need energy from ATP large drug molecules

small water soluble

require energy
drugs
 Factors Affecting Absorption

Surface Area,
pH Blood Flow
Contact Time

p- Presence of Patient's
Glycoproteins Food Condition

Formulation of
the Drug

pH ✓ Drugs in an ionized form

o Low lipid solubility
▪ Ions (hydrophilic) and oil (hydrophobic)
o harder to infiltrate cell membranes
o Ionization depends on
1. pH of the environment
2. pKa (equilibrium constant) of a drug
o pKa is the pH at which the drug is 50% ionized
✓ Weak acids
 o 𝐴𝐻 ⇋ 𝐴− + 𝐻 +
o 𝐴𝐻 is non polar
▪ Non-ionized
▪ Absorbed easily
o 𝐻 + is polar
▪ Ionized
▪ Difficult to absorb
o Acidic drugs placed in acidic environment produce more AH
▪ Can be absorbed more easily
✓ Weak base
o 𝐵𝐻 + ⇋ 𝐵 + 𝐻 +
o 𝐵𝐻 + is polar
▪ Ionized
▪ Difficult to be absorbed
o B is non-polar
▪ Non-ionized
▪ Easily absorbed
o Basic drugs in basic environment produces more B
▪ Can be absorbed more easily
Blood Flow ✓ Increased blood flow to drug administration site
o Increases absorption
✓ Decreased blood flow
o Such as
1. Shock
2. Decreases blood flow to GI
✓ IV routes is the best option
Surface Area, ✓ Diarrhea
Contact Time o Reduce contact time
o Reduces absorption
✓ Drugs affect gastric motility
o Example: metoclopramide
▪ Metoclopramide is a dopamine receptor antagonist and has
been approved by the FDA to treat nausea and vomiting in
patients with gastroesophageal reflux disease or diabetic
gastroparesis by increasing gastric motility.
▪ Result in durg interacrions
✓ Diseases like IBD, gastroenteritis
o Reduce villi surface area
o Reduce absorption
p- ✓ Transporters on cell membranes
Glycoproteins ✓ Push drug out after going through the cell membrane
✓ Mechanism: multi-drug resistance
Presence of ✓ Chelation of drugs (like quinolones with milk)
Food o Reduces drug absorption
✓ Alter gastric emptying
Patient’s ✓ Gastrectomy
Condition ✓ GI diseases
Formulation ✓ Syrups
of the Drug ✓ Suspensions
✓ Powders
 ✓ Capsules
✓ Tablet
✓ SR

Bioavailability (F)
✓ Extent of absorption
✓ Some amount of drug is lost
o During absorption
o Hence, less than 100% of the drug reaches
circulation
✓ Definition: percentage or fraction of unchanged
drug reaching the systemic circulation following
administration by any route
✓ To get a bioavailability of 100% - IV injection is
preferred
✓ Why?
o Orally administered drugs
▪ Examples
1. Syrups
2. Tablets
3. Capsules
4. Powders
 oAbsorbed from the GIT into the postal circulation
oSome drug may be metabolized before reaching the systemic circulation
oAnother reason: First-Pass Effect
▪ Besides passing through intestinal mucosa
▪ Orally administered drug need to pass through liver as well
• Before accessing the systemic circulation
▪ Drug is metabolized or destroyed before reaching the systemic circulation
• Reduce the amount of drug reaching to the systemic circulation
✓ Example of First-Pass Effect
o Dose is 100mg (in tablet)
o 20mg is not absorbed
o First-pass effect with 60mg metabolized
o Hence, 100𝑚𝑔 − 60𝑚𝑔 − 20𝑚𝑔 = 20𝑚𝑔 (𝑟𝑒𝑚𝑎𝑖𝑛𝑖𝑛𝑔)
20
o Bioavailability is = 0.2
100
o Amount of drug absorbed/ reaching the systemic circulation is the bioavailability
multiplies with does (F * dose)
▪ 𝐴𝑚𝑜𝑢𝑛𝑡 = 0.2 × 100𝑚𝑔 = 20𝑚𝑔
 How to Overcome or Bypass First Pass Effect
✓ Use other formulations
1. Injection
• IV
• IM
• SC
• Intrathecal-spine
• Intravitreal-fine needle into the eye
2. Sublingual/ buccal administration
• Direct absorption into systemic circulation
• E.g. GTN tablets
3. Rectal (cream, suppository etc.), pessary-devices/ tablets/ capsules
• By pass the liver
• Gives a local effect
• Rapid response
o Suitable for vomiting patients – they cannot take drugs orally
• E.g.
1. Mesalazine to treat
a. inflammatory bowel disease
b. ulcerative colitis/ Crohn’s disease
4. Cutaneous
• Local effect
• Can reach systemic circulation on long term use
5. Nasal sprays/ Inhalation
• Large surface area of lung
• Rapid blood flow
• Local effects to the lungs
o Minimizing systemic effects
o Glucocorticoids and bronchodilators
• Lung itself may have a first-pass effect
o By excretion and possible mechanism
6. Prodrugs
• Metabolized to its inactive form to active metabolites in the liver
• Enalapril (enalaprilat)
• Prednisone (prednisolone)
• Codeine (morphine)
• Clopidogrel (thiol-CTM)
 Rate of Absorption
✓ How fast the drug is absorbed into circulation?

Rate of
Absorption

First Order Zero Order

Kinetics Kinetics
First Order Kinetics Zero Order Kinetics
✓ Absorbed at a constant fraction ✓ Drug is absorbed at a constant amount
o Constant fraction per unit time o Constant amount per unit time
✓ Rate of absorption is propotional to the ✓ 100mg→80mg→60mg→40mg→20mg→
concentration of drug at the site of 0mg
inflammation o Absorbed 20mg each time
✓ Examples: most drugs ✓ Examples :
1. Controlled released drugs
2. Depot injection
3. Long action injection

✓ IV drugs give the fastest onset

o 100% bioavailability
✓ Rate of absorption
o Affect the onset of action
o Oral drugs are slower due to factor of absorption
▪ Bioavailability is determined by factors of absorption and the first pass effect
✓ Extent of absorption determines how much drug reaches the circulation
✓ Systemic drug absorption from GI depends on
1. Chemical properties of drug
2. Dosage form
3. Anatomy or physiology of absorption site
 Drug Distribution
✓ Distribution is the movement of drugs from the circulation to the tissues and organs
✓ Factors

Plasma
Tissue
Protein
Binding
Binding

Blood Flow or
Capillary
Supply to
Permeability
Organs
Plasma ✓ Plasma protein (albumin) mostly associated with drug binding
Protein ✓ Inactive form of a drug: bind to albumin
Binding o Cannot cross the blood plasma
o Cannot be distributed to other compartments
✓ Free drug: not binded to albumin
o Active for distribution
✓ Protein binding is saturable
o More drug is added, more free drug is available
✓ Drug can displace the protein binding of another drug
o Making free form
o Increases the activity
✓ Free form (unbound) escapes the blood stream
o Distributed to other sites
o Free form is pharmacologically active
✓ Protein bound form is inactive
o Not available for metabolism and excretion
✓ How does the protein binding influence drug action?
1. Duration of action: released into the free form
2. Magnitude of drug action: higher bondage, less active
3. Erratic drug action: drugs with larger binding capacity may displace
first
Tissue ✓ Accumulate in the tissue
Binding ✓ Can lead to toxicities
Blood Flow ✓ Heart, brain, liver and kidneys have more blood flow
or Supply to ✓ Skin and adipose tissues have less flow
Organs
Capillary ✓ Leakage from circulation to other compartments
Permeability ✓ Many drugs do not cross blood brain barrier
o Permeability can increase in meningitis
▪ Breaching of the blood brain barrier during the initial viral
infection
✓ Placental transfer of drugs
o Small molecules or lipophilic drugs crosses the placenta
o Possibility of adverse effects to fetus

Volume of Distribution

✓ Definition: volume of drug distributed to tissues and fluids

✓ Alteration of plasma protein binding will change volume distribution (L/kg)
𝐵𝑖𝑜𝑎𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦 (𝐹)×𝐷𝑜𝑠𝑒 𝑜𝑓 𝑡ℎ𝑒 𝐷𝑟𝑢𝑔
✓ 𝑉𝑜𝑙𝑢𝑚𝑒 𝐷𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑖𝑜𝑛 (𝑉𝑑) = 𝑃𝑙𝑎𝑠𝑚𝑎 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑡ℎ𝑒 𝐷𝑟𝑢𝑔 (𝐶)
✓ Loading dose is a large initial dose of a substance or series of such doses given to rapidly achieve
a therapeutic concentration in the body.
𝑉𝑑 ×𝐶
o 𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝐷𝑜𝑠𝑒 = 𝑆 ×𝐹
✓ A: administration of a drug into the body produces a specific plasma concentration
o Vd is the volume that accounts for the total dose administration
o Based on the observed plasma concentration
✓ B: any factor that decreases the drug plasma concentration
o E.g. decreased plasma protein binding
o Increase the apparent volume of distribution
✓ C: any factor that increases the drug plasma concentration
o E.g. decreased tissue binding
o Decrease the apparent Vd
 Metabolism
✓ Ways how a liver metabolizes a drug
✓ Possibilities
1. Active → Inactive Form
2. Prodrug → Active Drug
3. Active Form → Toxic Metabolites
• Toxic metabolites can lead to liver failure
• Liver can either metabolize to activate the drug or get rid of the drug
✓ Biotransformation (chemical alterations to drug molecules) happens in 2 phases

Biotransformation

Phase 1 Phase 2

heme containing responsible for the

transferase
enzyme in the metabolism of CYP450 system
enzymes
hepatocytes drugs

CYP2C19

CYP2D6

CYP3A4
 ✓ CYP450 (cytochrome P450) system
o CYP3A4 is the most common
o 40 to 50%
✓ Idea of hydrophilic and hydrophobic
o Hydrophobic
▪ Lipid-soluble
o Hydrophilic
▪ Water soluble
▪ Easier to excrete

Phase I
Non-polar Lipophilic → Oxidation, Reduction, Hydrolysis → Polar, Hydrophilic, Water Soluble

*water-soluble drug can be removed easily

✓ Factors for Phase I Metabolism

Enzyme
Patient Factors Polymorphism Inhibitors and
Inducers
Patient Factors ✓ Liver disease
o Reduces the ability to biotransform the drugs
o Lead to increased active form of the drug
o Result: toxicities
✓ Age of patients
o Elderly, adult, adolescent and babies are given different drugs
Polymorphism ✓ How readily the drug is metabolized (fast/ slow)
✓ Can be genetic effect
✓ Rapid metabolizers
o Active drug is biotransformed rapidly into inactive form
o Reduces concentration of active drug
o Reduce the therapeutic effect
✓ Slow metabolizers
o Active drug is biotransformed slowly into inactive form
o Increases the concentration of active drug
o Lead to toxicities
o Example:
▪ Codeine in babies
▪ Increase somnolence
• Somnolence, defined as a state of drowsiness or
strong desire to fall asleep
▪ Lead to respiratory depression
Enzyme ✓ Polypharmacy increases the likelihood of drug interactions
Induction and o Polypharmacy means eat too many drugs
Inhibition ✓ Enzyme inducers
o Increases the metabolism of drugs
o Result: lower active drug concentration
o E.g.
▪ Warfarin (blood thinner)
▪ Give with an enzyme inducer
▪ Therapeutic levels of warfarin drops
▪ Patient is at risk of blood clotting as the drug can’t work
effectively
o Examples
1. Rifampicin – TB
2. Phenytoin – Anti-epileptic
3. Phenobarbitone – Anti-epileptic
4. Carbamazepine – Anti-epileptic
✓ Enzyme inhibitors
o Increases the metabolism of drugs
o Result: higher active drug concentration
o E.g.
▪ Warfarin
▪ Therapeutic levels increase
▪ At risk of bleeding
▪ Drug concentration increases at toxic level
o Examples
1. Azoles – antifungal
2. Omeprazole – gastric
3. Erythromycin – antibiotics
4. Ritonavir – anti-HIV
 ✓ Metabolism mainly occurs in the liver
o May occur in
1. Lungs
2. Kidneys
3. Intestines

Clinical Significance of
Enzyme Induction &
Inhibition

Drug interactions
(therapeutic effects & Drug autoinduction
toxicities)

Drug Interactions ✓ Oral contraceptives

(therapeutic effects o Rifampicin will decrease the level of contraceptives
and toxicities) o Causing decreased effectiveness
✓ Clopidogrel
o Rifampicin is enzyme inducer
o Clopidogrel is a prodrug
o Rifampicin increases the levels of clopidogrel
o Increases antiplatelet effect
o Increased bleeding
✓ Clopidogrel
o Omeprazole is enzyme inhibitor
o Affects the conversion of inactive form to active form
o Reducing the effectiveness
Drug Autoinduction ✓ Autoinduction is a phenomenon that can occur anytime a drug
induces an enzyme which is also predominately involved in its own
metabolic clearance.
✓ Can induce liver enzymes
o Increase its own metabolism (carbamazepine and phenytoin)
o Lead to decreased levels leading to drug tolerance
o Measure the levels of this drug
▪ To ensure its efficacy in patients
 Phase II
✓ Conjugation
o Drug is metabolized into a more polar and water soluble metabolite
▪ This can ease excretion
✓ Involves transferase
✓ Reactions
1. Glucurodination
2. Acetylation
3. Methylation
4. Sulphation
5. Glutathione conjugation

Excretion
✓ Elimination of the drug from the body is majorly through the kidneys and liver
o Kidney: urine
o Liver: bile and feces
✓ Other ways
o Exhalation
o Sweat
o Saliva
✓ Factors that affect kidney/ renal excretion of drugs

Glomerular Tubular
Filtration Reabsorption

Tubular
Secretion
Glomerular ✓ Drug filtration through the glomerulus into the bowman capsule
Filtration ✓ Glomerular filtration depends on
1. Plasma protein binding of the drug
• Highly protein bound drugs is difficult to be filtered
• Can increase drug concentration
o Leading to toxicities
2. Glomerular filtration rate (GFR)
• Patients with renal impairment/ kidney disease
o Reduced GFR
o Can result accumulation of the drug
o Adjustment of dose
Tubular ✓ Some drugs are not filtered
Secretion o Through the glomerulus
✓ Secretion occurs at proximal tubule
✓ Depends on
1. Solubility of the drug
2. Concentration gradient across the blood and proximal tubule
✓ Non-polar, hydrophobic drugs and higher concentration in blood ease the
secretion
o Compared to low concentration
✓ Polar, hydrophilic and lower concentration in blood need active transport into
the tubules
o Compared to higher concentration
✓ Site potential for drug interactions
o Through transporter competition
✓ E.g.
1. Probenecid
• Increases penicillin levels
• By competing for these transporters
2. Cimetidine
• Increases TMP-SMX levels
Tubular ✓ Small, non-polar and hydrophobic drugs are easily reabsorbed
Reabsorption o Back into the circulation by passive diffusion
✓ Once reabsorbed
o Goes into the liver
o Metabolized into a more polar, water soluble form
o Easier excretion
✓ Drug overdose
1. Aspirin, phenobarbitone (weak acid)
2. Amphetamines (weak bases)
3. Ion trapping
✓ Manipulation of urinary pH through ionization
o Important in drug poisoning
o E.g.
▪ Sodium bicarbonate is given to treat salicylate and barbiturate
overdose
 Biliary Excretion
✓ Important route of excretion
o Drugs that are highly polar and high molecular weight
✓ Enterohepatic Circulation: a repeated processes where the active form of the drug is released back
into the circulation after metabolism

✓ Hydrophilic drug conjugates

o Mainly glucuronides
▪ Hydrolysed by intestinal or bacterial enzymes
▪ Releases the active form of the drug
▪ Reabsorbed into the circulation
o Concentrates in the bile
o Get released into the intestines
✓ Clinical significance
 Clinical
Significance

Can prolong an Drug

effect of a drug interaction
Can prolong a effect of a drug Drug interaction
✓ Oral contraceptives ✓ Certain antibiotics can affect normal flora
✓ Morphine o Retarding hydrolysis of a
✓ Rifampicin conjugate
o Affect its reabsorption
✓ Can affect gastric motility
o E.g. antidiarrheal drugs
▪ Reduces gastric motility
▪ Reduce enterohepatic
circulation of morphine
leading to decreased
effect

Application of Clinical Pharmacokinetics

✓ To ensure the efficacy and safety of patient’s drug therapy
✓ Individualization of drug dose
o To account for patient variation
o Example: dosage adjustments in neonates, elderly, hepatic and renal impairment
✓ Pharmacokinetic interactions
o Example: drugs that interfere drug metabolism (inhibit drug tubular reabsorption)
✓ Explain toxicities
1. Pharmacokinetic drug interactions
2. Changes in drug metabolism (liver impairment)
3. Changes in drug excretion (renal impairment)
4. Highly protein binding drugs (warfarin, phenytoin)
✓ Effect of drug depends on the drug concentration
 o Optimal therapeutic effect is reached when the target concentration of a drug in the
plasma is achieved
✓ To measure concentration of drug in plasma
1. Withdraw blood/ take the blood samples
2. Know when it is indicated and when to take the sample
3. Do not withdraw from the same line
✓ Estimation of drug concentration
o Through laboratory analysis
1. Spectrophotometry
2. Chromatography
✓ Therapeutic drug monitoring
o Management of patient’s drug therapy based on monitoring drug concentrations in the
plasma
✓ Durg has a defined therapeutic range and a narrow therapeutic index/ therapeutic window

✓ Examples
o Anti-leptic drug (AED) monitoring
▪ Provide a “benchmark” level
▪ When seizure control worsens or toxicity develops
▪ Assist in investigating breakthrough seizures
▪ Loading dose required in status epilepticus
• A seizure that lasts longer than 5 minutes, or having more than 1 seizure
within a 5 minutes period, without returning to a normal level of
consciousness between episodes is called status epilepticus.
▪ To guide dosage adjustments
• Switching btw generic and brand
o Vancomycin monitoring
▪ Severe infections, critically ill, obese patients (BMI>40)
▪ Renal impairment and unstable renal function
▪ No clinical response within 3-5 days
▪ Serum levels to determine frequency of administration (8-24 hourly)
o Digoxin monitoring
▪ Narrow therapeutic index
• Prone to drug interactions and patient comorbidities
▪ Levels need to be check
• 1 week after starting
• Regularly afterwards
• When there is a change in medication

Case Study Example

Dosage Regimens
 Dosage
Regimens

Continuous
Single Dose Multiple Dose
Infusion

Steady
Concentration

Maintenance
Dose

Loading Dose

✓ Single dose

o Given one off

▪ Example like painkiller to induce sleep
o C0: concentration of drug at zero time
o Cmax: maximum peak concentration
o Tmax: time to achieve peak concentration, Cmax
✓ Multiple Dose

o Dose is given repeatedly

o Results in accumulation
o For disease that lasts longer than drug in plasma
o Second peak plasma concentration higher then previous
▪ Due to concentration
1. Steady Concentration, Css
• Concentration of the drug in the body stays consistent
• Rate of administration = rate of elimination
• After 4 – 5 half-lives of administered drug
2. Maintenance Dose, MD
• Needed to maintain steady state concentration
3. Loading Dose, LD
• Needed in cases of emergency
• To achieve the target concentration rapidly
✓ Example
o Dosage for IV phenytoin in status epilepticus
o Loading dose: 10 – 15 mg/kg
o Maintenance: 100mg for 6 – 8 hourly
𝑡𝑎𝑟𝑔𝑒𝑡 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 ×𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 ×𝑑𝑜𝑠𝑖𝑛𝑔 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙
✓ 𝑀𝐷 = 𝐹
o CL (clearance rate) defines serum drug levels at a steady state
▪ Reduce maintenance dose
▪ Reduce dosing interval frequency
✓ Continuous infusion

o Durg enter the circulation at a constant rate

o Steady state occurs when the rate of administration equals to the rate of elimination
o Drug concentration remains stable and constat
o Css: steady state concentration
o Take 4 – 5 half-lives to reach steady state
 Pharmacokinetic Parameters

Pharmacokinetic
Parameters

Absorption Distribution Elimination

Absorption ✓ Drugs with faster absorption have faster onset

o Faster to reach the circulation
✓ Bioavailability (F): fraction of unchanged drug reaching the systemic
circulation
o Bioavailability of 1 is 100%
o 0.8 is 80%
o Used as the calculation of required dose to achieve target
concentration
Distribution ✓ Volume of distribution, Vd
o Volume of drug distributed to tissues and fluids
𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝐷𝑟𝑢𝑔 𝑖𝑛 𝑡ℎ𝑒 𝐵𝑜𝑑𝑦
✓ 𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝐷𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑖𝑜𝑛 = 𝑃𝑙𝑎𝑠𝑚𝑎 𝐷𝑟𝑢𝑔 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛
o 𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝐷𝑟𝑢𝑔 𝑖𝑛 𝑡ℎ𝑒 𝐵𝑜𝑑𝑦 = 𝐷𝑜𝑠𝑒 × 𝐵𝑖𝑜𝑎𝑣𝑎𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦
✓ Clinical significance of Vd
o Heavier person has higher Vd
▪ Higher dose is needed
o Person with high Vd is difficult to dialyse during drug poisoning
o Loading dose can be calculated in emergency cases
𝑡𝑎𝑟𝑔𝑒𝑡 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 ×𝑉𝑑
o 𝐿𝐷 =
𝐹
o Relationship
▪ High Vd needs higher loading dose
▪ Low Vd needs lower loading dose
Elimination ✓ Drug clearance is the volume of plasma cleared of a drug over a specified time
period
✓ Clearance is the rate of which a drug is removed from plasma (mg/min)
divided by the concentration of that drug in the plasma (mg/mL)
✓ 𝑡𝑜𝑡𝑎𝑙 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 = 𝑟𝑒𝑛𝑎𝑙 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 + ℎ𝑒𝑝𝑎𝑡𝑖𝑐 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 +
𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝑓𝑟𝑜𝑚𝑚 𝑎𝑙𝑙 𝑜𝑡ℎ𝑒𝑟 𝑡𝑖𝑠𝑠𝑢𝑒𝑠
✓ Clinical significance
o Essential: determining the dosing of medications
o Patients with renal or hepatic disease
▪ Necessary to adjust dosages
𝑡𝑎𝑟𝑔𝑒𝑡 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 ×𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 ×𝑑𝑜𝑠𝑖𝑛𝑔 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙
o 𝑀𝑎𝑖𝑛𝑡𝑒𝑛𝑎𝑛𝑐𝑒 𝐷𝑜𝑠𝑒 = 𝐹
o Decreased Cl
▪ In renal and hepatic impairment
▪ Reduce maintenance dose
▪ Reduce dosing interval frequency
✓ Drug can follow first order elimination or zero order elimination

Elimination

First-Order Second-Order
Elimination Elimination
 ✓ Half-life
o Time needed for drug concentration to droop by 50%
o Usually takes 4 – 5 half-lives
▪ To eliminate the drug from the body
✓ First order elimination
o Most drugs

✓ Zeo order elimination

First-Order Elimination Zero-Order Elimination

✓ Concentration of drug decreases ✓ Concentration of drug decreases linearly
exponentially with time with time
✓ Rate of elimination is proportional to ✓ Rate of elimination is constant
concentration of drug o Independent of concentration of
✓ Graph log [drug] vs time is linear drug
✓ Half-life is constant regardless of the ✓ No constant half-life
concentration of drug ✓ Prone to toxicities
 o Accumulation or when
elimination process is saturated

✓ Elimination rate constant, Kel

o Fraction of drug in the plasma being eliminated per unit time
o Can be calculated from concentration data (the slope)
✓ Drugs thar follow first-order elimination kinetics
o Kel is used to calculate half-life
▪ Inversely proportional to half-life
o Used to calculate clearance as well
𝑛𝑎𝑡𝑢𝑟𝑎𝑙 log 2 0.693
o 𝐾𝑒𝑙 = 𝑇1/2
= 𝑇1/2
o 𝐶𝑙 = 𝑉𝑑 × 𝐾𝑒𝑙

Clinical Significance of Hald-Life

✓ Predict when the drug is fully eliminated
o When to initiate drug during switching
o Avoid acute poisoning
✓ Determine dose regimens
o Drugs with short-life would need more frequent dosing
✓ During TDM (therapeutic dose monitoring)