BASIC PHARMACOKINETICS

FATE OF DRUGS IN BODY

DRUG ADMINISTERED

INTENDED EFFECTS

(ABSORPED)

ENTER SYSTEMICCIRCULATION

REACH SITE OFACTIONDISTRIBUTED

METABOLISED

ELIMINATED

Pharmacokinetics and pharmacodynamics

• Pharmacokinetics is the study of how a drug reaches its target in the body and how it is affected on that journey, i.e; effect of the body on the drug. – the study of how is the drug absorbed,

distributed, metabolized and excreted in the body

• Pharmacodynamics is the study of how drugs interact with a molecular target, i.e; effect of the drug on the body.

3

ADMINISTRATION

• Aim of drugs administration is to achieve therapeutic level at site of action.

• Route of drugs administration : First category – drugs must pass

through a barrier to reach systemic circulation.1. Oral

2. Inhalational3. Injection into the body but not the vascular system

(IM,SC)4. Through natural orifices (rectal, nasal & vaginal)

ADMINISTRATION

Second category – drugs injected directly into the

systemic circulation (IV)

Third category – Topicals through skin (stratum corneum)

Fourth category – Drug administered by these specialized routes of administration achieve

local and targeted therapy. A portion may reach systemic circulations (SA. Epidural, intraocular)

ADMINISTRATION

1. Oral Administration• Most convenient, most economical • Disadvantages:

– emesis (drug irritation of the gastrointestinal mucosa)

– digestive enzymes/gastric acidity destroys the drug

– unreliable or inconsistent absorption due to food or other drug effects

– metabolism of the drug by gastrointestinal flora

• Factors determining rate of drug effect onset

1. Dissolution

2. Absorption

3. Significant first pass effects

4. The mucosal surface area

5. Gastric emptying

6. Perfusion to the gut mucosa

ADMINISTRATION2. Transdermal Administration• The delivery of drugs through an intact skin.• The stratum corneum is the main barrier to the

diffusion of drugs, especially polar compounds.• Potent drugs with high lipid solubility can be

absorbed transdermally to produce systemic effects (e.g. fentanyl, GTN, ethinylestradiol, hyoscine).

• The stratum corneum will also act as a reservoir for lipid soluble drugs for several days after the drug has been stopped.

Advantages: – sustained, therapeutic plasma levels

(reduced peaks/valleys associated with intermittent drug administrations)

– avoids continuous infusion technique difficulties

– low side effect incidence (smaller doses)

ADMINISTRATION

• Factors contributing to reliable transdermal drug absorption: – molecular weight < 1000 – pH range 5-9 in aqueous medium – no histamine-releasing action – daily drug requirement <10 mg

• Example of drugs available for transdermal delivery: fentanyl, GTN

ADMINISTRATION

3. Rectal Administration• Proximal rectum administration

Absorption into superior hemorrhoidal veins then enters the portal venous system then to the liver (possible first pass hepatic effect) and finally into the systemic circulation

• Low rectal administration of drug may allow the drug to enter the systemic circulation without passing through the liver

• Generally unpredictable pharmacological responses for the above reasons

• Rectal mucosal irritation possible

ADMINISTRATION4. INTRAMUSCULAR• Less painful than subcutaneous injection• Muscle less prone to chemical injury and infection

than SC fat• Irritating substances may be given• Uptake of drugs following IM injection is more

rapid, especially for water-soluble drugs• Duration of action shorter following IM than SC

injection.• Absorption is dependent on perfusion• Unpredictable in the very emaciated and obese• Complications – Sterile abscess, Sciatic nerve

injury, Pain

ADMINISTRATION4. SUBCUTANEOUS

• Advantages – absorption is slow and sustained

• Improve by i) hyaluronidase

ii) implanting insoluble pellets – contraceptive

iii) dissolving in oil – penicillin

• Time of onset – 30 mins, peak – 60 mins

• Skin blood flow – 12.8 ml/100g/min

• Decreases absorption when vasoconstricted

ADMINISTRATION5. INTRAVENOUS• No absorption required, bypass liver• Accurate and predictable• Fast: able to titrate in ill and old patient• Irritating substance may be used (endothelium relatively insensitive) Disadvantages

- No retreat- IV access required- Unfavourable reactions secondary to high plasma

concentration

ABSORPTION

Absorption : passage of a drug from an external site of administration across

body tissues to the systemic circulation / site of action. Absorption occurs through :

1. passive diffusion2. special carrier mechanism3. pinocytosis

Pinocytosis is the ingestion of dissolved materials by endocytosis. The cytoplasmic membrane invaginates and pinches off placing small droplets of fluid in a pinocytic vesicle. The liquid contents of the vesicle is then slowly transferred to the cytosol.

ABSORPTION

• Absorption occurs mainly by passive non-ionic diffusion and is therefore dependent on factors such as

1. Lipid solubility2. Molecular size3. Ionisation*

ABSORPTION

– Fick’s law of diffusion– Rate of diffusion A x D x (P1-P2)

T

» A = surface area» D = diffusion coefficient = solubility/ MW» T = thickness» P1-P2 = concentration gradient

ABSORPTION

IONIZATION• Drug ionization reduces a drug's ability to cross a

lipid bilayer• Amount of ionization depends on pKa (dissociation

constant)• Numerically equal to the pH of a solution in which

the drug is 50% ionised

• pKa of a drug is the measure of the acid strength, e.g. an acid with a pKa of 2 is 10X as strong as an acid with pKa of 3

• The basic strength of drugs increases with the pKa, a basic drug of pKa of 9 is 10X as strong as base with pKa of 8.

The equilibrium constant K is defined as the fraction of H+ and A-  to the HA. K = ([H+] [A-] ) /  [HA] for this equilibrium K is called Ka  for acid dissociation constant.  

Since we are interested in the amount of H+ we need to arrange the equation to just have [H+] in one side. [H+] = Ka ([HA]/[A-] )  

Taking the logarithm of each side gives:log [H+]  = log Ka  + log ([HA]/[A-] )  

Now we can multiple by -1.-log [H+]  = -log Ka  - log ([HA]/[A-] )  Which is the same as:-log [H+]  = -log Ka  + log ([A-] /[HA])  

Traditionally, -log is substituted with a lower case p, so the equation becomes (known as the Henderson-Hasselback equation:

pH = pKa + log ([A-] /[HA])

So if we know the pH of a solution and the pKa we can determine how much [A-] and [HA] we have in solution, using the rearranged equation below.[A-] /[HA] = exp (pH -  pKa)

This means that when pH is equal to pKa, [A-]

= [HA], or that the acid is 50% ionized.  

pHpKa  Ratio [A-] /[HA]

3 4 0.1

4 4 1

5 4 10

6 4 100

Ionization - Weak Acids

• eg Aspirin (pKa 3.5)• RCOOH RCOO- + H+

• pH = pKa + log [ionized]

[unionized]• Weak acid;

– >acidic; > unionized– >basic; >ionized

Ionization - Weak Bases

• eg Ephidrine (pKa 9.6)

• RNH3+ RNH2 + H+

• pH = pKa + log [unionized] [ionized]

• Weak base;– >basic; >unionized– >acidic; >ionized

Non-ionic diffusion of weak acid, pKa = 6

Non-ionic diffusion of weak base, pKa = 7

ION TRAPPING

• A phenomenon whereby drugs are kept in

environments of altered pH, by the change in equilibrium brought about

by the change in pH

Placental Transfer Of Basic Drugs

•e.g local anesthetics -fetal pH is lower than maternal pH -lipid-soluble, nonionized local anesthetic crosses the placenta converted to poorly lipid soluble ionized drug-gradient is maintained for continual transfer of local anesthetic from maternal circulation to fetal circulation-in fetal distress, acidosis contributes to local anesthetic accumulation

• Kidney - Nearly all drugs filtered at the glomerulus - Most drugs in a lipid-soluble form will be

reabsorbed by passive diffusion. - To increase excretion: change the urinary pH to

favor the charged form of the drug since charged form cannot be readily reabsorbed (they cannot readily pass through biological membranes)

– Weak acids: excreted faster in alkaline pH (anion form favored)

– Weak bases: excreted faster in acidic pH (cation form favored)

Bioavailability

• The proportion of intact/unchanged drug that is available to the systemic circulation, after oral/intramuscular administration.

• Affected by:– Extent of absorption– First Pass metabolism

Bioavailability = AUCPO X 100%

AUCIV

PO

IV

Quantifies Absorption

First Pass Metabolism• Proportion of drug that is removed or

metabolised by an organ before it reaches the systemic circulation during the initial single transit– Liver

• High ER (>0.7) eg Propanolol, Lignocaine• Low ER (<0.3) eg Warfarin, Thiopentone

– Gastrointestinal eg; L-dopa, Chlorpromazine– Pulmonary eg; Lignocaine, Propanolol,

opiods

DISTRIBUTION

• After gaining access to the systemic circulation, drugs distribute in different tissues and organs of the body.

• Factors affecting;– Physicochemical char. of the drugs

• Lipid solubility• Degree of ionization

– Cardiac output & regional blood flow to various organs: VRG, MG, FG

– Binding: Plasma protein / Tissues

Volume of Distribution• Quantifies distribution.• Volume of distribution (Vd) of a drug is a

mathematical expression of the sum of the apparent volumes of the compartments that constitute the compartmental model.

• This value depicts the distribution characteristics of a drug in the body.

• The volume in which the amount of drug in the body would need to be uniformly distributed to produce the observed plasma concentration.

• Volume of distribution is calculated as the dose of drug administered intravenously divided by the resulting plasma concentration of drug before elimination starts.

Vd = Amount of Drug in the Body Plasma Drug Concentration

• Indicates the extent of extravascular tissue uptake of the drugs

Volume of DistributionFactors determining Vd1. Physicochemical characteristics of the drug

– Lipid solubility of drug– Degree of ionisation (function of drug

pKa and ambient pH)

– Molecular weight2. Degree of plasma protein binding (acidic

and neutral drugs to albumin and basic drugs to 1-acid glycoprotein)3. Tissue binding4. Regional blood flow to tissues (affected by

age and disease states eg CRF, CCF)

Volume of DistributionClinical Significants

Drugs with small Vd (5-20 litres) are predominantly localized in plasma/ECF (muscle relaxants) or are extensively bound to plasma proteins (warfarin, phenytoin, tolbutamide). These are typically highly polar, water-soluble drugs.

Drugs with Vd equal to TBW (30-45 L in adults) are evenly distributed throughout TBW (examples are alcohol, urea and some sulphonamides)

Drugs with Vd larger than TBW have extensive tissue penetration and binding to tissues or sequestration in fats. In these circumstances, the concentration in tissues may be higher than in plasma. These are typically highly lipid soluble drugs for example digoxin, fentanyl, thiopentone, most phenothiazines a most anti-depressants.

Protein Binding

• Drugs are bound to plasma protein in a reversible

manner• Saturable process• 3 main types of carrier proteins for drugs:

1. Albumin – bound mainly to acidic drugs e.g diazepam, digoxin, warfarin, barbiturates2. α1-acid glycoprotein – bound mainly to basic

drugs e.g. opioids, β-Blockers, Tricyclic anti-

depressants, LA, antiarrhythmics3. Globulins – Steroid hormones, Thyroid hormone

Protein Binding

• fraction unbound (fU) = unbound [drug] total [drug]

• fU is determined by

i) The affinity of the drug for proteinii) The concentration of the binding

proteiniii) The concentration of the drug

relative to that of binding protein

Protein BindingImplication1. Distribution2. Clearance - bound and free drug can be cleared by liver and kidney

- in liver, ↑ ER (> 0.7) insensitive to protein binding

but for ↓ ER (<0.3), dependent on [free drug] - in kidney, glomerular filtration dependent on

protein binding3. Disease Process - altered in renal or liver diseases4. Drug interaction

METABOLISM

• Role of metabolism or biotransformation is to convert pharmacologically active, lipid-soluble drugs into water soluble and often pharmacologically inactive metabolites.

• Increased water solubility decreases the Vd and enhance its excretion.

• Main site liver, others are kidney, lung, plasma

• Drug biotransformation mechanisms are described as either phase I or phase II reaction types.

Phase I Metabolism (non synthetic reactions)

• Usually result in drug oxidation, reduction or hydrolysis.

• Most phase 1 reactions are carried out by the liver cell in the smooth ER or microsomes

• A non-specific enzyme system in the ER (Cytochrome P-450 or mixed function oxidase system) is responsible for most drug oxidations and reductions and for some hydrolytic reactions

Cytochrome 450 System

oxidation-reduction process

Involves two important microsomal enzymes

1. Cytochrome P450

2. Flavoprotein

Gain of electron (e-) result in reduction

Loss of e- results in oxidation

InduceInhibited

Inactivated

Phase II metabolism (synthetic or conjugation reactions)

• Combinaton of unchanged drugs or phase I metabolites with other chemical group (eg; glucuronide, sulphate, acetate etc)

• The most important reaction is conjugation of drugs to glucuronides

• Conjugates are often polar and inactive

• Occurs both in microsomes or cytosol

Phase II Metabolism

Adapted from Table 4-3, Correia, M.A., Drug Biotransformation. in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 57.

Some Phase II Reactions

Type of Conjugation Endogenous Reactant Transferase (Location) Types of Substrates Examples

Glucuronidation UDP glucuronic acidUDP glucuronosyl transferase

(microsomal)

phenols, alcohols, carboxylic acids, hydroxylamines,

sulfonamides

morphine, acetaminophen, diazepam, digitoxin,

digoxin, meprobamate

Acetylation Acetyl-CoA N-Acetyl transferase (cytosol) Aminessulfonamides, isoniazid,

clonazepam, dapsone, mescaline

Glutathione conjugation glutathioneGSH-S-transferase (cytosolic,

microsomes)epoxides, nitro groups,

hydroxylaminesethycrinic acid, bromobenzene

Sulfate conjugationPhosphoadenosyl

phosphosulfateSulfotransferase (cytosol)

phenols, alcohols, aromatic amines

estrone, 3-hydroxy coumarin, acetaminophen,

methyldopa

Methylation S-Adenosyl-methionine transmethylases (cytosol)catecholamines, phenols,

amines, histamine

dopamine, epinephrine, histamine, thiouracil,

pyridine

METABOLISM

Rate of metabolism is determined by:• drug concentration at the site of

metabolism• Intrinsic rate of metabolism process

(enzyme activity)

Rate of metabolism best described by first-order

and zero-order kinetics.

First-Order Kinetics

Definition•A constant percentage of drug is eliminated from the body per unit time.•As the drug concentration increases, proportionally more drug is removed. •Fraction of drug metabolized is independent of concentration •Elimination half-life remains constant •Most drugs obey first order kinetics

ZERO ORDER KINETICS Definition

• A constant amount of drug is eliminated from the body per unit time. Also known as Michaelis Menten Kinetics

• Occurs when [drug] exceeds capacity of enzymes (saturated)

• Intrinsic activity of enzymes determines the amount of drug metabolised

• Aspirin, theophylline and warfarin examples for drugs that follow zero order at normal doses (higher doses → thiopentone)

ZERO ORDER KINETICS

Enzymes are no longer saturated therefore drugs undergo 1st order kinetics

CLEARANCE

• Volume of blood which is irreversibly cleared of a substance per unit time.

• Quantifies elimination

Clsystemic = Clhepatic + Clrenal + Clothers

CLEARANCE

• Two physiological variables control the

clearance:i) Efficiency of the eliminating organ ii) Blood flow to the organ

ELIMINATION

Sites– Renal– Hepatobiliary– Pulmonary– Saliva– Sweat– Breast milk– Tears– Vaginal secretions– GIT

RENAL CLEARANCE

• Most low MW compounds and their metabolites are excreted in urine

• When total clearance is predominantly by renal (ClR > 0.7), accumulation will occur in renal failure e.g aminoglycosides, digoxin

• If ClR < 0.3, renal disease have little effect on drug elimination

RENAL HANDLING OF DRUGSThe renal elimination of drugs is dependent onthree separate processes that take place atdifferent sites of the nephron:

1. Glomerular Filtration 2. Active Tubular Secretion3. Distal Tubular Reabsorption

GLOMERULAR FILTRATION

• Only the free or unbound fraction in plasma

water is available for filtration by the renal

glomerulus.

• Affected by drug molecular size,

electrical charge of drug molecule and the

number of functioning nephrons present.

ACTIVE TUBULAR SECRETION• Active secretion of drugs by the

proximal tubules occurs via an active carrier transport mechanism→ requires cellular energy and may go against concentration gradient.

• So active with some drugs that even bound drugs can be stripped of plasma proteins in one pass of the blood.

• Dependent on renal perfusion.

• Independent of protein binding.

ACTIVE TUBULAR SECRETION• Acidic and basic drugs are secreted by 2

separate and distinct transport systems.

• Acidic drugs may compete with each other for tubular secretion; conversely basic drugs may interfere with the elimination of other bases or cations.

• Examples are:

Acidic drugs: penicillins, cephalosporins, salicylates,

thiazide diuretics, furosemide

Basic drugs: dopamine, morphine, neostigmine,

lignocaine

PASSIVE TUBULAR REABSORPTION

• In the distal renal tubules passive reabsorption of drugs occurs by non-ionic diffusion.

• The urine here is normally acidic, but can range from pH 4.5 to 8.0, and therefore a considerate gradient of H+ exists between urine and plasma.

• Drugs secreted at prox. tubules are ionised form. As urine becomes > acidic, acidic drugs will exist in non ionised form and can readily diffuse back into plasma → ↓ elimination

PASSIVE TUBULAR REABSORPTION

• Dependent on - Urine pH determines non-ionized

fraction in urine - Flow rate through the tubules

determines transit time and concentration gradient developed in tubules• Weak acids are excreted more rapidly in

alkaline urine.

• Alkalinization result more ionized drug and resulting less passive reabsorption of the drug.

DRUGS WITH CLINICALLY IMPORTANT URINE PH-DEPENDENT ELIMINATION

Weak acids (Alkaline urine increases excretion):

Phenobarbitone Salicylates

Sulphonamide derivatives

Weak bases (Acid urine increases excretion): Amphetamine

Ephedrine Quinine

DOSE ADJUSTMENT IN RENAL DYSFUNCTION

• Renal clearance is reduced in proportion with the reduction in creatinine clearance.

• Adjustment is usually only necessary when a drug is more than 50% cleared by renal elimination and when renal function is reduced to half of normal or less.Creatinine Clearance = (140 – Age) X

Weight X constant

(Cockcroft Gault) Serum Creatinine (mol/L)

(Constant = 1.23 for men , 1.04 for female)

HEPATIC CLEARANCE

• At steady state, the removal of drugs by the liver can be expressed by the extraction ratio (ER).

• extraction ratio is an overall measure of the ability of the liver to remove drugs from the hepatic capillaries and reflects drug metabolism.

ER = Ca – Cv Ca where

Ca = [drug] in mixed portal venous and hepatic arterial blood

Cv = [drug] in hepatic venous blood.

HEPATIC CLEARANCE

HEPATIC CLEARANCE

Hepatic clearance is dependent on 3 biologic

factors:

1. Hepatic blood flow

2. Intrinsic metabolising capacity of the

liver (reflects the activity of drug

metabolising enzymes)

3. The proportion of unbound drug in blood,

which is affected by plasma drug binding.

INTRINSIC HEPATIC CLEARANCE • Represents the rate at which liver water is cleared of

drug in ml/min.

• Represents the maximum ability of the liver to irreversibly eliminate drugs by metabolism or biliary excretion.

• Is independent of liver blood flow.

• ClH = Q x ClI x fU

Q + (ClI x fU)

ClI = intrinsic hepatic clearance

fU = fraction of unbound drug

FLOW OR PERFUSION LIMITED DRUGS

• When intrinsic hepatic clearance is high relative to HBF, then hepatic clearance determined by liver blood flow.

• Most of drug is extracted by liver on one passage high ER (> 0.7).

• NOT affected by protein binding or enzyme activity level.

• First pass effect is high.

• Sensitive only to factors that affect hepatic blood flow.

• Examples are lignocaine, tricyclic antidepressants, opioids and some ß-blockers.

ENZYME LIMITED DRUGS (CAPACITY LIMITED)

• When intrinsic hepatic clearance is low relative to HBF.

• Low ER (i.e. < 0.3); hepatic clearance is dependent on intrinsic clearance (i.e. enzyme activity) and the fraction of drug unbound in blood.

• Sensitive to liver enzyme activity profoundly affected by enzyme induction or inhibition.

• Hepatic clearance NOT affected by changes to HBF.

• Low first pass effect after oral administration.

• Examples are phenytoin, warfarin, theophylline, most barbiturates and benzodiazepines.

ENZYME LIMITED DRUGS (CAPACITY LIMITED)

• Enzyme limited, binding insensitiveDrugs with low binding to plasma proteins (< 20-30%) may be unaffected by changes in protein binding

• Enzyme limited, binding sensitiveDrugs that are extensively bound to plasma proteins (> 85%), hepatic clearance will be affected by changes in protein binding.

BILIARY EXCRETION OF DRUGS

• Biliary excretion is usually the major route of elimination for compounds with MW > 400-500 Da.

• This active mechanism via Na/K/ATPase transport system is able to concentrate drugs to even 100 times their plasma levels.

• Drugs with high clearance in bile

- Acidic drugs: ampicillin, rifampicin, radiographic

contrast

- Basic drugs: Vecuronium, pancuronium, alcuronium,

glycopyrrolate

CLEARANCE: CLINICAL USAGE1. One of the determinants of half-life.

t½ = 0.693 Vd

Cl 2. Determines the amount of drug needed to for

maintenancedose.

Elimination Rate = Clearance X Plasma Concentration

Steady state is defined as the situation at which the rate of drug

administration is equal to the rate of drug elimination so that plasma drug concentration remains equal.

Therefore, Elimination Rate = Maintenance Rate Maintenance Dose = Clearance X Desired Cpss

HALF-LIFE (t½)

• Half-life is the time taken for the plasma concentration to fall by half its initial value.

• Depends on clearance and volume of distribution.

• 1 t ½ = 50% elimination 2 t ½ = 75% elimination 3 t ½ = 87.5% elimination 4 t ½ = 93.75% elimination → requires 4-5 half lives to eliminate drug

FACTORS AFFECTING T½

• t1/2 = 0.693 Vd Cl• An in the t½ may be due to Vd or Cl• Differentiating the primary change is

important as one will require increasing loading dose while the other requires lowering dosing rate

a. Decrease dose (smaller Vd)b. Increase dosing interval (decreased clearance)c. Reduce infusion rate (decreased clearance)

CLINICAL APPLICATIONS T½

• Predicts time taken to reach steady-state conditions following initiation of therapy (4-5 half lives).

• Predicts time taken for attainment of new steady state following increase or decrease of drug dose

• Determines the dosing interval• Predicts time taken for termination

of drug effect in some drugs

CONTEXT-SENSITIVE HALF-TIME

• Context-sensitive half-time, in contrast to elimination half-time, considers the combined effects of distribution and metabolism as well as duration of continuous IV administration on drug pharmacokinetics.

• Depending largely on the lipid solubility of the drug and the efficiency of its clearance mechanisms, the context-sensitive half-time increases in parallel with the duration of continuous IV administration

COMPARTMENT MODEL

Why Model Data?♦ A successful model allows one to

summarize large amounts of data into a few values that describe the whole data set.

♦ Allows us to make prediction and therefore calculate dose regimens

Compartment Models• One Compartment Model

– Distributed into a single compartment in the body

– From which a constant proportion of drug in the body is eliminated within a specific time period

compartmentDrug Dose

Elimination

Compartment Models

• Two Compartmental Model– Following administration, the drug is

rapidly distributed in the central compartment and then slowly equilibrates with another(peripheral) compartment

• 2 distinct phases;– Distribution phase– Elimination phase

Drug Dose

Elimination ()

Distribution ()

Central compartment

Peripheral compartment

Represented by intravascular fluids and highly prefused organs

Compartment Models3 Compartment Models

• After IV injection of some drugs, the initial rapid distribution is followed by a second slower distribution phase before the elimination phase

• The decline in the plasma concentration of many opioid drugs, muscle relaxants and IV anaesthetics can be resolved into three components

• Drug is injected into and eliminated from central compartment and reversibly transferred between central and two peripheral compartments

THE END