pharmacokinetics pharmacokinetics. drug site of action effects blood systemic circulation
TRANSCRIPT
PharmacokinetiPharmacokineticscs
DRUGSITEOF
ACTION
EFFECTS
BLOOD
SYSTEMICCIRCULATION
DRUGSITEOF
ACTION
EFFECTS
BLOOD
SYSTEMICCIRCULATION
Drug must have necessary properties
to be transported From:
its site of administration To:
its site of action
The drug must be The drug must be capable of reaching capable of reaching
the site of actionthe site of actionmust remain at the site must remain at the site
of action long of action long enoughenough
The drug must
achieve
these
criteria without
inducing
unacceptable
toxicity in the patient
Definitions
• Pharmacokinetics is the study of the time course of the drug concentration in the body, i.e., "what the body does to the drug".
• Therapeutic drug monitoring is the measurement of the serum level of a drug and the coordination of this serum level with a therapeutic range.
• The therapeutic range is that range of serum drug concentrations which have been shown to be efficacious without causing toxicity in the majority of patients.
• Clinical pharmacokinetics deals with the application of pharmacokinetic principles to the safe and effective therapeutic management of drug dosage in an individual patient.
L = Liberation, the release of the drug from it's dosage form.
A = Absorption, the movement of drug from the site of administration to the blood circulation.
D = Distribution, the process by which drug diffuses or is transferred from intravascular space to extravascular space (body tissues).
M = Metabolism, the chemical conversion or transformation of drugs into compounds which are
easier to eliminate. E = Excretion, the elimination of unchanged drug or metabolite from the body via renal, biliary, or pulmonary processes.
Routes of Drug DeliveryRoutes of Drug DeliveryParenteral
(IV)Inhaled
Oral
Transdermal
Rectal
Topical
Parenteral(SC, IM)
Drug Absorption
Orally Rectually (drug embedded in a
suppository, which is placed in the rectum) Parenterally (given in liquid form by
injection with a needle and syringe) Inhaled –thru the lungs as gases, as
vapors, or as particulars carried in smoke or in an aerosol
Absorbed through the skin Absorbed through mucous membranes
Drug Absorption -caveats
OrallyDrug must be soluble and stable in
stomach fluid (not destroyed by gastric acids), enter the intestine, penetrate the lining of the stomach or intestine, and pass into the blood stream.
Drug Absorption -disadvantages May occasionally lead to
vomiting and stomach distress.
How much of the drug will be absorbed into the bloodstream cannot always be accurately predicted because of the genetic differences between people and because differences in the manufacture of the drugs.
The acid in the stomach destroys some drugs.
Drug Absorption -caveats
Rectually Rarely used unless patient is vomiting,
unconscious, or unable to swallow
Rectually Often irregular, unpredictable, and
incompleteMany drugs irritate the membranes
that line the rectum.
Drug Absorption -disadvantages
Drug Absorption
Parenterally Intravenous –directly into a veinIntramuscular –directly into muscleSubcutaneous –just under the skin
Drug Absorption
Parenterally Often produces a more prompt
response than does oral administration because absorption is faster.
Permits a more accurate dose because the unpredictable processes of absorption are bypassed.
Drug Absorption -disadvantages Parenterally Leaves little time to respond to an
unexpected drug reaction or accidental overdose.
Requires the use of sterile techniques.Once a drug is administers by injection, it
cannot be recalled.
Drugs that cannot become completely soluble before injection, cannot be injected intravenuously.
Drug Absorption
Inhaled Lung tissues have a large surface area
with large blood flow, allowing for rapid absorption of drugs.
Drug Absorption
Absorbed through the skinProvides continuous, controlled release of a drug from a reservoir through a
semipermeable membrane. Potentially minimizes side effects
associated with rapid rises and falls in plasma concentration of the drug contained in the patch.
Dose• Dose is the amount of a chemical that
gets inside of your body.
• Measured in mg of chemical/kg of weight
The Dose Makes The Poison
Who took the largest dose of Tylenol?
65 kg 75 kg 10 kg 2.5 kg 300 mg 600 mg 100 mg 50 mg
Calculating Dose:
300 mg 62.5 kg = 4.8 mg/kg
50 mg 2.5 lb = 20 mg/kg
Dose - Response
• Effective dose
ED50 - the dose producing the desired (therapeutic) effect in 50% of the test animals
• Toxic dose
TD50 - the dose toxic to the specified organ in 50% of the test animals administered by the stated
route
• Lethal dose
LD50 - the dose lethal to 50% of test animals when administered by stated route
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
Warfarin:A Small Therapeutic Index
Per
cent
of
Pat
ient
s
0
50
100
0 Log Drug Concentration
DesiredTherapeutic
Effect
UnwantedAdverseEffect
Penicillin:A Large Therapeutic Index
Per
cent
of
Pat
ient
s
0
50
100
0 Log Drug Concentration
DesiredTherapeutic
Effect
UnwantedAdverseEffect
NSAID (IBUPROFEN) Wide TI
Normal dose = 400-3200 mg/day
(THEOPHYLLINE) BLOOD CONC = 10-20 µg/ml
below this conc (not much effect )above
20 µg/ml (serious toxicities)
Drug Concentrations in the Plasma
Drug Concentration in Plasma (Cp)
mcg/mL
50
40
30
20
10
Time since administration of drug(hours)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
But what’s missing here
that is needed for this info to be of any use?
Drug Concentrations in the Plasma
Drug Concentration in Plasma (Cp)
mcg/mL
50
40
30
20
10
Time since administration of drug(hours)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Therapeutic Concentrations
(Therapeutic Range)
Subtherapeutic Concentrations
Toxic Concentrations
0 2 4 6 8 10 12Time (hour)
Dru
g co
ncen
trat
ion
in b
lood
Onset and duration of drug action
0 2 4 6 8 10 12Time (hour)
Dru
g co
ncen
trat
ion
in b
lood
MEC
Onset and duration of drug action
0 2 4 6 8 10 12Time (hour)
Dru
g co
ncen
trat
ion
in b
lood
MTC
MEC
Onset and duration of drug action
0 2 4 6 8 10 12Time (hour)
Dru
g co
ncen
trat
ion
in b
lood
MTC
MEC
Onset and duration of drug action
Example: Oral Dose
• A single oral dose will give you a single peak plasma concentration
• The drug concentration then continuously declines
• Repeated doses result in oscillations in plasma concentration
Pla
sma
Con
cent
rati
on
Time
CONCEPT OF DRUG CLEARANCE:INTRODUCTION TO Cl
[D]PSS
Toxic Threshold
Therapeutic Threshold
Time (hrs)
[D] P
(m
g/L
) (Therapeutic Window)
Single Dose
Multiple Doses
[D]PSS = [D]P at steady state
0
1
2
3
4
5
6
7
0 5 10 15 20 25
Time
plasma conc
toxic
effective
0
1
2
3
4
5
6
7
0 5 10 15 20 25
Time
plasma conctoxic
Cumulation and use ofloading doses
effective
Loading Dose = Vd x plasma conc
Multiple dosing
• In a medical/dental context some drugs are given as single doses but this is unusual.
•
• Most are given as a course of therapy, one or more doses per day for several days or
weeks
Multiple dosing
• On multiple dosing plasma concentration will rise and fall with each dose and body
load will increase until
Rate in = Rate out administration = elimination
i.e. steady state is reached.
At Steady StateRate in = Rate out
F x Dose / Dosing Interval = SSC x CL
Dosage Plasma level
F = fraction of dose administered
Question
• What maintenance dose is required for drug A if;
• Target average SS concentration is 10 mg/L
• CL of drug A is 0.015 L/kg/hr• Patient weighs 75 kg
• Answer on next slide.
Answer
• Maintenance Dose = CL x CpSSav
• CL = 0.015 L/hr/kg x 75 = 1.125 L/hr
• Dose = 1.125 L/hr x 10 mg/L = 11.25 mg/hr
• So will need 11.25 x 24 mg per day= 270 mg
Example: Maintenance Dose Calculations
A target plasma theophylline concentration of 10 mg/L is desired to relieve acute bronchial asthma in a patient.
mean clearance = 2.8 L/h/70 kg. Since the drug will be given as an intravenous infusion, F = 1.
Dosing rate = CL × TC = 2.8 L / h / 70 kg × 10 mg / L = 28 mg / h / 70 kg
Therefore, in this patient, the proper infusion rate would be28 mg/h/70 kg.
If the asthma attack is relieved, the clinician might want to maintain this plasma level using oral theophylline, which might be given every 12 hours using an extended-release formulation to approximate a continuous intravenous infusion. Foral = 0.96
When the dosing interval is 12 hours, the size of each maintenance dose would be:
Maintenance dose =Dosing rate/F × Dosing interval
= 28 mg / h/ 0.96 × 12 hours
= 350 mg
If an 8-hour dosing interval was used, the ideal dose would be 233 mg; and if the drug was given once a day, the dose would be 700 mg.
Question
• What is the loading dose required for drug A if;
• Target concentration is 10 mg/L
• VD is 0.75 L/kg
• Patients weight is 75 kg
• Answer is on the next slide
Answer: Loading Dose of Drug A
• Dose = Target Concentration x VD• VD = 0.75 L/kg x 75 kg = 56.25 L• Target Conc. = 10 mg/L• Dose = 10 mg/L x 56.25 L• = 565 mg• This would probably be rounded to 560 or
even 500 mg.
A young child given an intramuscular injection might ask "How will that 'ouch' get from there to my sore throat"?
The answer to this question is the basis of
pharmacokinetics. Drug is given into : eg: GUT (one body
Compartment) to move to its site of action
eg: Brain (another compartment)
HOW?
Pharmacokinetics
Absorption –the process by which the drug moves into the body from external source
Distribution –the drug is distributed throughout the body (including fetus)
Metabolism –detoxification or breakdown of the drug into metabolites that no longer exert any effect
Elimination –metabolic waste products are removed from the body
PharmacokineticsPharmacokinetics in its simplest form describes the time course of a particular drug’s actions: the time to onset and the duration of effect.
Pharmacokinetics
PK/PD
Time
Co
nc
PK PD
Time
Eff
ect
Dose
Drug BodyDrug Body
Molecular size
Lipid solubility
Ionization
Absorption
Distribution
Elimination
DRUG THERAPY
Goal :
To Rapidly Deliver and Maintain therapeutic
(non toxic) levels of drugs in the target tissues.
The drug will appear at the target organ :
•How rapidly?
• In what concentration?
•For how long?
53
“7 Rights” of Safe Medication Administration
Right Drug Right Dose Right Time Right Route Right Patient Right Reason Right Documentation
WHY BE CONCERNED ABOUT HOW DRUGS GET INTO BODY?
• Bioavailability - % of dose that gets into body
• Bioequivalence - similarity between two formulations of same drug
• Speed of Drug Onset - how long it takes the drug to begin working
• Dosing Interval - how often the drug should be given
• Site of Action - whether the drug stays local or acts systemically
This issue importantly affects:
WHAT IS DRUG ABSORPTION?
The movement of drug molecules across biologicalbarriers (mostly layers of cells) from the site of
administration to the blood stream.
BIO
LO
GIC
AL
BA
RR
IER
Vascular SystemSite of Administration
DRUG
• Weak acids aspirin in intestines are mostly ionized(intestinal pH ranges from 6.6 to 7.5)
• Weak bases atropine in stomach are mostly ionized(stomach pH ranges from 1 to 2)
Many drugs are weak organic acids or bases (weak elctrolytes)
Weak acids Weak bases DISSOCOATER-COOH = R-COO- + H+
R-NH2 + H+ = R- NH3+
Degree of Ionization depends on : pH of Medium
pKa of the molecule
What is pKa?
• non-ionized forms of drugs are more soluble in lipids and absorbed better
than water-soluble, ionized forms of drugs
IONIZATION decreases membrane permeability
Ionized forms of compounds have low lipid solubility
Why?
Acidic drugs are ionized in basic environmentBasic drugs are ionized in acidic environment
Henderson Hasselbach
• pH = pKa + Log ---------------- [A-] [HA]
pKa = pH at which 50% of a substance Is ionized
pH = pKa + log [A-]
Henderson-Hasselbach equation
[HA]
WEAK acid
pH = pKa + log [B]
[BH+]WEAK
base
pKa = pH at which 50% of a substance is ionized
Henderson Hasselbach
---------------- [I]
[U]WEAK ACID
10pH - pKa
=
Benzoic Acid
Henderson Hasselbach
---------------- [I]
[U]WEAK BASE
10pKa - pH
=
Aniline
Moral of the story...Moral of the story...Moral of the story...Moral of the story...
Acidic drugs are best absorbed from acidic environments
Acidic drugs are best absorbed from acidic environments
Basic drugs are best absorbed from
basic environments
Basic drugs are best absorbed from
basic environments
WHAT AFFECTS DRUG ABSORPTION?
• Rate of release of drug from pharmaceutical preparation
• Membrane permeability of drug
• Surface area in contact with drug
• Blood flow to site of absorption
• Destruction of drug at or near site of absorption
The rate of drug absorption will be affected by:
WHAT DETERMINES RATE OFRELEASE OF DRUG FROM
PHARMACEUTICALPREPARATION?
• Solutions: No Delay, Immediate Release
• Capsules & Tables: Delay (Dissolution) Followed by Rapid Release
• Creams, Ointments & Suppositories: No Delay, but Slow Release
A: DOSAGE FORM
WHAT DETERMINES RATE OFRELEASE OF DRUG FROM
PHARMACEUTICALPREPARATION?
Decrease Rate ofDissolution
• Binders• Lubricants
• Coating Agents
B: ADDITIVES (EXCIPIENTS)
Increase Rate of Dissolution
• Disintegrants
Variable Effects onRate of Dissolution
• Diluents• Coloring Agents• Flavoring Agents
WHAT DETERMINES RATE OFRELEASE OF DRUG FROM
PHARMACEUTICALPREPARTAION?
• Tablet Compression - Hard tablets dissolve more slowly
• Tablet Shape - Round tablets dissolve more slowly
•Tablet Size - Large tablets dissolve more slowly
C: MANUFACTURING PARAMETERS
WHAT DETERMINES RATE OFRELEASE OF DRUG FROM
PHARMACEUTICALPREPARATION?
• Enteric Coating - Dissolve in intestines, not stomach
D: DELAYED RELEASE PREPARATIONS
WHAT DETERMINES RATE OFRELEASE OF DRUG FROM
PHARMACEUTICALPREPARATION?
• Reservoir Diffusion Products - Drug diffuses from pill corethrough membrane shell
• Matrix Diffusion Products - Drug diffuses through matrixin which it is embedded
• Matrix Dissolution Products - Drug released as matrix dissolves• Osmotic Tablets - Drug pumped out of tablet by osmotic forces
• Ion-Exchange Products - Drug bound to resin exchanges with endogenous ions
E: SUSTANED RELEASE PREPARATIONS
WHAT DETERMINES MEMBRANEPERMEABILITY OF DRUGS?
• Presence of Aliphatic and Aromatic Structures
•Absence of Polar Groups
A: LIPOPHILICITY increases membranepermeability
WHAT DETERMINES MEMBRANEPERMEABILITY OF DRUGS?
• Weak acids in intestines are mostly ionized(intestinal pH ranges from 6.6 to 7.5)
• Weak bases in stomach are mostly ionized(stomach pH ranges from 1 to 2)
B: IONIZATION decreases membranepermeability
WHAT DETERMINES SURFACEAREA FOR ABSORPTION?
• Low Surface Area: eyes, nasal cavity, buccal cavity, rectum, stomach, large intestines
• High Surface Areasmall intestines, lungs
ANATOMY
WHAT DETERMINES WHETHER A DRUG IS DESTROYED
AT OR NEAR SITE OF ADMINISTRATION?
• Liver - hepatic enzymes (“first pass” effect)
• Colon - intestinal microflora
•Stomach - digestive enzymes and acids
BIOCHEMISTRY
WHAT ARE THE ROUTES OFADMINISTRATION FOR DRUGS?
• Oral
•Sublingual
•Rectal
ENTERAL
• Intravenous (IV)• Intra-arterial (IA)• Subcutaneous (SC)• Intradermal (ID)
• Intramuscular (IM)• Intraperitoneal (IP)• Lungs (Inhalation)
• Skin (Topical)
PARENTERAL
•Nose (Intranasal)• Eye (Opthalmic)
• Ear (Otic)• Vagina
• Urinary Bladder• Directly Into Target Tissue
High
WHAT ARE THE ADVANTAGES AND DISADVANTAGES OFORAL, IV, IM AND SC ADMINISTRATION?
SAFETYHigh Low Oral > SC > IM > IV
Oral > SC > IM > IV
CONVENIENCELow
DelayedImmediate
WHAT ARE THE ADVANTAGES AND DISADVANTAGES OFORAL, IV, IM AND SC ADMINISTRATION?
BIOAVAILABILITYHigh and Reliable Low and/or Variable IV > IM = SC > ORAL
IV > IM > SC > Oral
ONSET OF ACTION
LowHigh
LowHigh
WHAT ARE THE ADVANTAGES AND DISADVANTAGES OFORAL, IV, IM AND SC ADMINISTRATION?
INTERACTIONS WITH FOODRisk No Risk Oral > IV = IM = SC
Oral > IM = SC = IV
COMMERCIAL AVAILABILITY OF DOSAGE FORMS
VOLUME OF DRUG Oral = IV > IM > SC
WHY CONSIDER OTHER ROUTES OFADMINISTRATION?
• Sublingual - Rapid absorptionthat bypasses liver
• Rectal - Great for patient thatis vomiting or cannot (will not)
swallow medication
Pharmacokinetic Parameters
----------------------------
ClearanceVolume of distribution
Half – lifeBioavailability
DRUG CLEARANCE:
Example:
CL = 10 mg/hr
4 mg/L= 2.5 L/hr
Rate of Drug Elimination (Excretion rate) = 10 mg/hr[D]P (Concentration) = 4 mg/L
Is the volume of body fluid cleared of drug per time unit (L/h, mL/min)
Clearance (CL)Blood, Plasma, Serum
Which Particular fluid assay ?----------------------------------------
Serum Clearance (CL) of 200 ml/min
In one minute all of the drug could have been eliminated from 200 ml of serum
Total Body Clearance (CL)
-------------------------------------• CL = (CLliver + CLg.i. tract + CLkidney + CLlung
+ ...)
Dose / Area under the curve (AUC)e.g. mg / (mg.h /L) = L/h
Clearance
Clearance also plays a role in determining
the steady-state concentration of a drug or toxicant:
Csteady-state = Rate of administration/ CL
Cl is a major determinant of [D]P at STEADY STATE ([D]P
SS)
INPUT
OUTPUT
STEADY STATE LEVEL
(Kidney & Liver)
Elimination
Drugs leave the body through: Kidneys Lungs Bile Skin
Elimination
Drugs leave the body through: Kidneys:1) Excrete most of the products of body
metabolism2) Closely regulate the levels of most of
the substances found in body fluids• Psychoactive drugs are often reabsorbed out of the kidneys, so the liver has to enzymatically transform the drugs so with minimal reabsorption they can exit in urine.
Elimination
Drugs leave the body through: Lungs
Only occurs with highly volatile or gaseous agents
Elimination
Drugs leave the body through: Skin
Small amounts of a few drugs can pass through the skin and be excreted in sweat.
Pharmacokinetics
Distribution –the drug is distributed throughout the body
Drug Distribution Body Membranes that Affect Drug
Distribution1. Cell membranes2. Walls of the capillary vessels in
the circulatory system3. Brain-blood barrier4. Placental barrier
Drug Distribution1st Body Membrane that Affects
Drug Distribution Cell membranes
Permeable to small lipid (fatty) molecules
Drug Distribution2nd Body Membrane that Affects
Drug Distribution Walls of the capillary vessels in
the circulatory systemDoes not depend on lipid solubility
Only drugs that do not bind to plasma proteins
pass through capillary pores.
Drug Distribution3rd Body Membrane that Affects
Drug Distribution Brain-blood barrier
The rate of passage of a drug into the
brain is determined by two factors:
(1) the size of the drug molecule and
(2) its lipid (fat) solubility.
Drug Distribution4th Body Membrane that Affects
Drug Distribution Placental barrier
Oxygen and nutrients travel from the
mother’s blood to that of the fetus,
while carbon dioxide and other waste
products travel from the blood of the
fetus to the mother’s blood.
Fat-soluble substances (including all
psychoactive drugs) diffuse rapidly and
without limitation.
Distribution
Distribution is the process by which a drug diffuses or is transferred from intravascular space toextravascular space (body tissues). These spaces are described mathematically as volume(s) ofdistribution.
In the simplest of terms, a drug's volume of distribution is that volume of bodily fluid into which a drugdose is dissolved.
Volume of distribution = Dose / drug concentration
Central volume (Vc)
The central volume of distribution (Vc) is a hypothetical volume into whicha drug initially distributes
upon administration. This compartment can be thought of as the blood in vessels and tissues whichare highly perfused by blood.
Drug Distribution• At any given time, only a very small
portion of the total amount of a drug that is in the body is actually in contact
with its receptors. Most of the administered drug is found in areas of
the body that are remote from the drug’s site of action.
Drug Distribution
• Wide distribution often accounts for many of the side effects of a
drug
• It takes time for a drug to distribute in the body• Drug distribution is affected by elimination
THE BODY AS COMPARTMENTS--------------------------
1. Highly Vascular PLASMA, RED CELLS
LUNGS
LIVER, BRAIN & SPLEEN
THE BODY AS COMPARTMENTS--------------------------
2. Low Vascular FAT DEPOSITS
One, two, and three compartment pharmacokinetic models. Fortunately many of the processes involved in drug movement around the body are not saturated at normal therapeutic dose levels. The pharmacokinetic - mathematical models that can be used to describe plasma concentration as a function of time can then be much simplified. The body may even be represented as a single compartment or container for some drugs. For other drugs a two or three compartment model is found to be necessary.
Body before and after a rapid I.V. bolus injection, considering the body to behave as a single compartment. In order to simplify the mathematics it is often possible to assume that a drug given by rapid intravenous injection, a bolus, is rapidly mixed. This slide represents the uniformly mixed drug very shortly after administration.
Oral curve and beakers. We can picture oral administration as water flowing from one bucket (representing the GI tract) into a second beaker (representing the body). At first drug flows into the 'body' beaker and the level rises, as drug concentration rises, then after peaking the levels start to fall as elimination overtakes absorption.
Intravenous bolus injection with a two compartment model. Often a one compartment model is not sufficient to represent the pharmacokinetics of a drug. A two compartment model often has wider application. Here we consider the body is a central compartment with rapid mixing and a peripheral compartment with slower distribution. The central compartment is uniformly mixed very shortly after drug administration, whereas it takes some time for the peripheral compartment to reach a pseudo equilibrium.
WHY BE CONCERNED ABOUT WHERE DRUGS GO?
Where drugs go determines Where Drugs Act:
• Ciprofloxacin [Cipro®] penetrates the prostate gland andtherefore is effective in bacterial prostatitis, whereas
most antibiotics do not enter the prostate andare therefore ineffective in prostatitis.
• Fexofenadine [Allegra®] is largely excluded from the brainand therefore is a “nonsedating” antihistamine, whereas
most antihistamines freely enter the brain andcause marked drowsiness.
WHY BE CONCERNED ABOUT WHERE DRUGS GO?
Where drugs go influences Where Drugs Are Eliminated:
• Penicillin is actively transported into the proximal tubules andis therefore rapidly excreted by the kidneys.
• Inhalation anesthetics distribute to alveolar spaces andtherefore are eliminated by the lungs.
WHY BE CONCERNED ABOUT WHERE DRUGS GO?
Where drugs go influences How Long Drugs Last In the Body :
• Raloxifene [Evista®]) (for treatment of osteoporosis in postmenopausal women) is transported by the liver into the
intestines where it is reabsorbed (enterohepatic recirculation).This greatly increases the time raloxifene lasts in the body.
Pharmacokinetic Parameters
----------------------------
ClearanceVolume of distribution
Half – lifeBioavailability
Volume of Distribution (Vd)
The ‘apparent’ volume of distribution:A theoretical volume only:
NO PHYSICAL BASE NO PHYSIOLOGICAL BASE
Volume in which drug appears to distributeVd not physical volume.Vd is proportionality constantVd = Dose(known)/Cp(known)
Volume of Distribution (Vd)
Vd = D / C- Quantifies Distribution
- Drug Concentration (C) mg/L
Amount of drug in the body (D) mg
VOLUME OF DISTRIBUTION OF DRUGS:DETERMINANTS OF VD
Plasma Protein Binding
CP
VD
CP
=A
VOLUME OF DISTRIBUTION OF DRUGS:DETERMINANTS OF VD
Distribution into Fat
Cp
VD
CP
=A
Volume of Distribution
• Gives information on HOW the drug is distributed in the body
• Used to calculate a loading dose
Plasma Protein Binding
• Many drugs bound to circulating plasma proteins such as albumin
• Only free drug can act at receptor site
Protein-bound drug
Free Drug
Receptor Site
A bound drug has no effect!
Binding % of some BDZs
• Flurazepam 10 %
• Alprazolam 70 %
• Lorazepam 90 %
• Diazepam 99 %
No generalization for a pharmacological or chemical class
Pharmacokinetic Parameters
----------------------------Clearance
Volume of distributionHalf – life
Bioavailability
Half Life
Half-life is the time taken for the concentration of drug in blood to fall by a half
0
10
20
30
40
50
60
70
80
90
100
110
0 1 2 3 4 5 6 7 8 9
Time (hours)
Co
nce
ntr
atio
n (
mg
/L)
Half - Life (t1/2)
t1/2 = ----------------0.693 . Vd
CLBoth Vd and CL may change independently.Therefore t1/2 is not an exact index of drug
elimination.
Secondary pharmacokinetic parameter and depends on CL & Vd
Half - Life (t1/2)
t1/2 = ----------------0.693 . Vd
CLIs the time it takes for the concentration to fall to half
of its previous value
Secondary pharmacokinetic parameter and depends on CL & Vd
A drug has a half life of A drug has a half life of 10 seconds10 seconds. You . You give a patient a dose of give a patient a dose of 6mg6mg. After . After 30 30 secondsseconds how much of the drug remains? how much of the drug remains?
A drug has a half life of A drug has a half life of 10 seconds10 seconds. You . You give a patient a dose of give a patient a dose of 6mg6mg. After . After 30 30 secondsseconds how much of the drug remains? how much of the drug remains?
TimeTime AmountAmount
0 sec0 sec 6 mg6 mg
10 sec10 sec 3 mg3 mg
20 sec20 sec 1.5 mg1.5 mg
30 sec30 sec 0.75 mg0.75 mg
Time Course of drug action
• Distribution Half Life: • time for drug to reach 50% of its peak concentration
• Elimination Half Life:
• time for drug concentration to fall 50%
• Steady State Concentration:
• the level of drug achieved in blood with repeated, regular-interval dosing
Time to Steady State• Time to steady state depends on half life
Tss = 4 x t½
Steady-state occurs after a drug has been given
for approximately 4-5 elimination half-lives.
C
t
Cpav
Four half lives to reach steady state
Pharmacokinetic Parameters
----------------------------Clearance
Volume of distributionHalf – life
Bioavailability
Bioavailability
Dose
Destroyed in gut
Notabsorbed
Destroyed by gut wall
Destroyedby liver
tosystemiccirculation
0
10
20
30
40
50
60
70
0 2 4 6 8 10
Pla
sma
con
cen
trat
ion
Time (hours)
i.v. route
oral route
BioavailabilityBioavailabilityExtent of absorption of a drug following its
administrationby routes
other than IV injection
BioavailabilityBioavailability 100 mg Oral , 70 mg absorbed 100 mg Oral , 70 mg absorbed
unchangedunchangedBioavailability = 70 % Bioavailability = 70 %
Iv admin = 1Iv admin = 1Oral admin < 1 Oral admin < 1
lidocaine bioavailability 35% due to lidocaine bioavailability 35% due to destruction in gastric acid and liver destruction in gastric acid and liver metabolismmetabolism
Gut wall, gut, liver metabolismGut wall, gut, liver metabolism Incomplete absorptionIncomplete absorption Enterohepatic cyclingEnterohepatic cycling & elimination into & elimination into
the bilethe bile
BiequivalenceBiequivalenceDrugs with comparable Drugs with comparable
BioavailabilityBioavailability
Therapeutic equivalenceTherapeutic equivalence
Drugs with comparable Drugs with comparable Efficacy & SafetyEfficacy & Safety
Bioavailability Affected by:
Dosage form Dissolution and absorption of drug Route of administration Stability of the drug in the GI tract (if oral
route) Extent of drug metabolism before reaching
systemic circulation Presence of food/drugs in GI tract
Example – same drug, 3 different formulations could have same
bioavailability
Time
Plasma conc
IV
Oral – not S/R
Oral - SR
bioequivalent
Two drug products are said to be bioequivalent if they
are pharmaceutical equivalent or pharmaceutical
alternatives, and if their rates and extents of
absorption do not show a significant difference.
Purpose of BE
Therapeutic equivalence (TE) Bioequivalent products can be
substituted for each other without any adjustment in dose or other additional therapeutic monitoring.
The most efficient method of assuring TE is to assure that the formulations perform in an equivalent manner.
Fundamental Bioequivalence
Assumption
When a generic drug is claimed bioequivalent to a
brand-name drug, it is assumed that they are
therapeutically equivalent.
Safety Concern
Generic Drugs
They’re cheaper, but do they work as well?
Safety Concern
Generic and brand-name drugs do exactly the same thing and are
completely interchangeable.
I would hesitate to substitute a generic for a brand-name drug for those patients who have been on the drug for years. However, I would not hesitate to suggest a doctor start a new patient on
the generic version.
Drug Switchability
The switch from a drug (e.g., a brand-name drug or its generic
copies) to another (e.g., a generic copy) within the same patient whose concentration of the drug has been titrated to a steady, efficacious and
safe level Individual Bioequivalence (IBE)
Post-approval meta-analysis for BE review
DRUG METABOLISMDRUG METABOLISM
Drug MetabolismDrug Metabolism(we’re still talking about (we’re still talking about
Pharmacokinetics)Pharmacokinetics)
CYP450
Biotransformation
Potentially toxic xenobiotic
Inactive metabolite
Relatively harmless
Reactive intermediate
DetoxificationMetabolic activation
Converting lipophilic to water soluble compounds
Xenobiotic
Reactive intermediate
Conjugate
Phase I - Activation
Phase II - Conjugation
Excretion
Lipophilic
(non-polar)
Water soluble(polar)
Metabolism –detoxification or breakdown of the drug into metabolites that no longer exert any effect
How Drug go out from body ?
Drug Elimination
Metabolism:conversion of one chemical
entity to another.
Excretion:Loss of drug or its
metabolites
DRUG METABOLISMDRUG METABOLISM
BiotransformationBiotransformationXenobiotic Xenobiotic metabolismmetabolism
Phase I Phase IIDRUG METABOLITE CONJUGATE
Expose or introduce a Conjugate the functional functional group that groups exposed or introduced can be conjugated by during Phase I biotransformation Phase II enzymes
Small in water solubility Large in water solubility
• Termination of Pharmacological activity or introduce toxicity
• The rate and extent to which a drug is metabolized determines the dose of the drug and the duration of the effect of the drug
Rate limiting/Affected by genetic and
environmental factors
Active/Inactive/Toxic/Mutagenic/Carcinogen
OH OGlucuronide
Two-phase biotransformation
Phase I (functionalization) reactions: Oxidation, Reduction, and hydrolytic reactions
(makes the drug more polar, but not necessarily inactive)
Phase II (conjugation) reactions: Conjugation to polar groups: glucuronidation,
sulfation, acetylation (most of these result in drug inactivation)
•Ultimate effect is to facilitate elimination
Phase I
• introduction of functional group
• hydrophilicity increases slightly• may inactivate or activate original compound• major player is CYP or mixed function oxygenase
(MFO) system in conjunction with NAD(P)H• location of reactions is smooth endoplasmic reticulum
Phase II
• conjugation with endogenous molecules(GSH, glycine, cystein, glucuronic acid)
• hydrophilicity increases substantially• neutralization of active metabolic intermediates• facilitation of elimination • location of reactions is cytoplasm
BIM
M11
8
Drug Metabolism - Phase II
• Conjugation reactions– Glucuronidation by UDP-Glucuronosyltransferase:
(on -OH, -COOH, -NH2, -SH groups)
– Sulfation by Sulfotransferase:
(on -NH2, -SO2NH2, -OH groups)
– Acetylation by acetyltransferase:
(on -NH2, -SO2NH2, -OH groups)
– Amino acid conjugation
(on -COOH groups)– Glutathione conjugation by Glutathione-S-transferase:
(to epoxides or organic halides)– Fatty acid conjugation
(on -OH groups)– Condensation reactions
Cytochrome P450 (CYP) Mixed Function Oxidases (MFO)
• Located in many tissues but highly in liver ER• Human: 16 gene families• CYP 1,2,3 perform drug metabolism• >48 genes sequenced• Key forms: CYP1A2, CYP2C9, CYP2C19, CYP2D6,
CYP2E1, and CYP3A4• Highly inducible
– Alcohol CYP2E1– Dioxin/PCBs CYP1A– Barbiturates CYP2B
• CYP genes have multiple alleles (2D6 has 53, and 2E1 has 13)
METABOLISM (BIOTRANSFORMATION)------------------------------------
The processes by which foreign molecules (Xenobiotics) are
chemically altered by a living organism.
Result------------
• Water soluble metabolites
• Increased Excertion
• Reduced Biological Half-life
• Minimum Toxicity
Result------------
• More polar metabolites is formed
• Possible Increase in M. wt and Size
• Excretion & Elimination
Result------------
• Exposure time is shortened
• Possibility of accumulation is reduced
• Probable change in Biological activity
• Change in the duration of the biological activity
Metabolism
the major mechanism for terminating xenobiotic activity,
and is frequently the single most important determinant of the
duration and intensity of toxic responses to a xenobiotic.
Enzymatic, chemical, or stereo chemical change to an administered drug;
conversion of substance
Active to Less Active or Inactive (Most cases):» Hydroxylation of Pentobarbital
Active to Equivalent Activity:» Codeine to Morphine
Inactive to Active:
Carbon Tetrachloride - carcinogen
IMPLICATIONS FOR DRUG METABOLISMIMPLICATIONS FOR DRUG METABOLISM
1. Termination of drug action
2. Activation of prodrug
3. Bioactivation and toxication
4. Carcinogenesis
5. Teratogenesis
Transformation of Xenobiotics by Biological Systems
Sites of biotransformation
• where ever appropriate enzymes occur; plasma, kidney, lung, gut wall and
LIVER
• the liver is ideally placed to intercept natural ingested toxins (bypassed by injections etc) and has a major role in biotransformation
Skin BloodBrain
MetabolismMetabolism
• Amitriptylline is metabolized by CYP1A2
• Cimetidine inhibits CYP1A2
• Coadministration results in elevated Amitriptylline levels
Cimetidine, Ritonavir, amiodarone, diltiazem, ketoconazole
Inhibit CYP3A4
Cimetidine, Fluoxetine, amiodarone
Inhibit CYP2D6
Cimetidine, Ketoconazole, Omeprazole
Inhibit CYP2C19
Barbiturates, Carbamazepine, Phenytoin, pioglitazone, glucocorticoids, …
Induce CYP3A4 & 3A5
Phenobarbital, dexamethasone
Induce CYP2A6 & 2B6 & 2C9
Smoking , Omeprazole
Induce CYP1A1 &1A2
Aspirin, Ethanol
Phenytoin
Metabolism rate is constant
Drug Elimination Kinetics
Time
Log Concentrati
on100
12.5 6.25
3.13
1.56
0.78
0.39
25
50
• Most drugs are eliminated according to a First-Order Rate Process:– A constant fraction of drug is eliminated per unit of time –
– rate of elimination is proportional to the plasma concentration
– Blood concentration declines in linear fashion over time
First order kinetics
A constant fraction of drug is eliminated per unit of time.
When drug concentration is high, rate of disappearanceis high.
First order kinetics First order kinetics
First order kinetics First order kinetics
• The half life is independent of The half life is independent of dosedose
• The rate of elimination is directly The rate of elimination is directly proportional to the amount of proportional to the amount of chemical in the bodychemical in the body
Zero order kinetics
Rate of elimination is constant.
Rate of elimination is independent of drug concentration.
Constant amount eliminated per unit of time.
Example: Alcohol
Velocity Of Metabolism Of A Drug
0 5 10 15 20 25 30 35 40 45 50 55 600
10
20
30
40
50
60
70
80
first order metabolism
zero order metabolism
[Drug] mM
Vel
ocity
(ng/
g tis
sue/
min
)
Kmx2.pzm
Velocity Of Metabolism Of A Drug
0 5 10 15 20 25 30 35 40 45 50 55 600
10
20
30
40
50
60
70
80
first order metabolism
zero order metabolism
[Drug] mM
Vel
ocity
(ng/
g tis
sue/
min
)
Kmx2.pzm
Aspirin, Ethanol
Phenytoin
Metabolism rate is constant
Zero order kinetics Zero order kinetics Why?Why?
Paracetamol Metabolism
N-acetylcysteine
• Supplies glutathione
• Dosage for NAC infusion - ADULT– (1) 150mg/kg IV infusion in 200ml 5% dextrose over 15 minutes,
then– (2) 50mg/kg IV infusion in 500ml 5% dextrose over 4 hours, then– (3) 100mg/kg IV infusion in 1000ml 5% dextrose over 16 hours
• Side-effects– Flushing, hypotension, wheezing, anaphylactoid reaction
• Alternative is methionine PO (<12 hours)
Metabolism
Factors affecting drug metabolism
• Drug metabolism can be affected by:
– First pass effect
– Hepatic blood flow
– Liver disease
– Drugs which alter liver enzymes
Main site of drug metabolism = LIVER
The phenomenon of
“first pass effect”
or
“first pass metabolism”
and its clinical relevance
Some drugs are ineffective when given orally – examples: nitroglycerine, nor-adrenaline, insulin
Drug Admin: Formulation
• First Pass EffectBlood from the gastrointestinal tract passes through the liver before entering any other
organs. During this first pass through the liver, a fraction of the drug (in some cases nearly all) can
be metabolized to an inactive or less active derivative. The inactivation of some drugs is so
great that the agents are useless when given orally.
(e.g.. lidocaine)
Factors affecting drug metabolism
• Genetic factors– e.g acetylation status
• Other drugs– hepatic enzyme inducers– hepatic enzyme inhibitors
• Age– Impaired hepatic enzyme activity
• Elderly• Children < 6 months (especially premature babies)
Factors affecting biotransformation
• age (reduced in aged patients & children)
• sex (women slower ethanol metabilizers)
• species (phenylbutazone 3h rabbit, 6h horse, 8h monkey, 18h mouse, 36h man); biotransformation route can change
• clinical or physiological condition
• other drug administration (induction (not CYP2D6 ) or inhibition)
• food (grapefruit juice --CYP3A)
• first-pass (pre-systemic) metabolism
Factors Influencing Activity and Level of CYP Enzymes
Nutrition 1A1;1A2;2E1; 3A3; 3A4,5
Smoking 1A1;1A2
Alcohol 2E1
Drugs 1A1,1A2; 2A6; 2B6; 2C; 2D6; 3A3, 3A4,5
Environment 1A1,1A2; 2A6; 1B; 2E1; 3A3, 3A4,5
Genetic Polymorphism
1A; 2A6; 2C9,19; 2D6; 2E1
Red indicates enzymes important in drug metabolism
Pharmacogenetics
–drug transporters
–drug metabolizing enzymes
Succinylcholine
● Used during anesthesia to induce muscle Used during anesthesia to induce muscle paralysisparalysis
● Paralysis usually lasts minutes, but in some Paralysis usually lasts minutes, but in some individuals, it may last up to one hourindividuals, it may last up to one hour
● Due to altered kinetics of Due to altered kinetics of pseudocholinesterase pseudocholinesterase
Isoniazid
● Used in the treatment of tuberculosisUsed in the treatment of tuberculosis● Observed variation in the amount of unchanged Observed variation in the amount of unchanged
isoniazid in the urineisoniazid in the urine● Differences were due to an individuals ability to Differences were due to an individuals ability to
convert isoniazid to acetylisoniazid.convert isoniazid to acetylisoniazid.● Caused by mutations in the Caused by mutations in the N-acetyltransferase-2 N-acetyltransferase-2
enzyme (NAT2) on chromosome 8enzyme (NAT2) on chromosome 8● Some individuals develop isoniazid toxicity Some individuals develop isoniazid toxicity
manifested as peripheral neuropathymanifested as peripheral neuropathy