Aznan Lelo

Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran Universitas Sumatera Utara

18 November 2011, Magister PPDS, FK USU

Pharmacokinetics (PK) & pharmacodynamics (PD)

PK - What the body does to the drug?
Absorption; distribution, metabolism, excretion (ADME)

PD - What the drug does to the body?

Drug concentration at the site of action or in the plasma is related to a magnitude of effect

Pharmacokinetics (PK) and pharmacodynamics (PD)

Dose

Plasma Site Concenof tration Action

Effects

PK

PD

Pharmacokinetics
Area of pharmacology dealing with, "the absorption, distribution, biotransformation and excretion of drugs Factors
Route of administration Absorption and distribution Inactivation Elimination

Half-Life
Half-Life determined by the time required to reduce by one-half the amount of the drug present in the body Drugs have different & distinct half-lives Comparison for drug elimination rates Determines frequency with which multiple doses of a drug can be safely administered Half-life does not change with the drug dose

Pharmacokinetic properties
the route(s) of administration, dose, latency of onset, time of peak action, duration of action, and frequency of drug administration. (KD Tripathy, 2007).

Routes of administration
Oral (peroral, p.o., via digestive system) Parenteral injection (through the skin)

Subcutaneous (s.c.) Intramuscular (i.m.) Intravenous (i.v.) Intraperitoneal (i.p.)

Pulmonary absorption (inhalation) Topical application

All pharmacokinetics processes involve transport of the drug across biological lipid membrane.
Passive diffusion Filtration through lipid Carrier transport

Mechanism of transport Passive transport

Passive diffusion Filtration

Specialized transport
Carrier transport Active transport Facilitated diffusion Pinocytosis etc.

Mechanism of transport
Passive diffusion
Limits:
size and shape of drug molecule lipid solubility of drug degree of ionized drug

Passive (simple) diffusion

The lipid soluble unionized drug diffuse across the lipid biomembrane in the direction of their concentration gradient. It does not need energy. Most drugs are week electrolytes. Their ionization is pH dependent. The ionization of a week acid (AH) is given by the equation of HendersonHasselbalch:

[AH] pKa = pH + log10 ------] [A

Lipid solubility
Ionization is the major factor:
When drugs are ionized (charged) they become much less lipid soluble, and drugs tend to become ionized when dissolved in solution

More ionized > less lipid soluble > less absorption > less effect

Carrier transport
by combination with a carrier molecule which acts as a ferry-boat across the lipid region of the membrane. Carrier transport is saturable and competitively inhibited by analogues which utilize the same carrier. a) Active transport is a movement against the concentration gradient. It needs energy and is inhibited by metabolic poisons.
Levodopa and methyldopa are actively absorbed from the gut by aromatic amino acid transport.

Carrier transport
b) Facilitated diffusion. This proceeds more rapidly than passive (simple) diffusion and translocates even nondiffusible substrates, but along their concentration gradient, therefore, does not need energy. Example: Facilitated transport of glucose. cell membrane and trapping within the cell of a small vesicle containing extracellular constituents. The vesicle contents can than be released within the cell, or extruded from the other side of the cell. Pinocytosis is important for the transport of some macromolecules (e.g. insulin through BBB).

Pinocytosis involves the invagination of a part of the

Absorption
It is the passage of drug from the site of administration into the circulation. Aqueous solubility
If a drug given as water solution, it is absorbed faster

Concentration.
Drug given as concentrated solution is absorbed faster.

Area of absorbing surface.

If the area is larger, the absorption is faster.

Vascularity of absorbing surface.

Increased blood flow hastens drug absorption.

Oral absorption
Unionized lipid soluble drugs (e.g. ethanol) are readily absorbed from GIT.
Highly ionized drugs, e.g. amikacin, gentamicin, neostigmine, are poorly absorbed

Acid drugs (aspirin, barbiturates etc.) are predominantly unionized in the acid gastric juice and are absorbed from stomach.
Acid drugs absorption from stomach is slower, because the mucosa is thick, covered with mucus and the surface is small.

Basic drugs (e.g. atropine, morphine etc.) are largely ionized and are absorbed only from the duodenum.

Oral absorption
Presence of food dilutes the drug and retards absorption.
Food delays gastric emptying. The most drugs are absorbed better if taken in empty stomach. Certain drugs form poorly absorbed complexes with food constituents, e.g. tetracyclines with calcium present in milk.

Certain drugs are degraded in the GIT,

e.g. penicillin G by acid, insulin by peptidases, and are ineffective orally. Enteric coated tablets (having acid resistant coating) and sustained released preparations can be used to overcome acid ability, gastric irritancy and brief duration of action.

Oral absorption
Drugs can also alter absorption by gut wall effect:
altering motility (atropine, amitriptyline, pethidine, methoclopramide) or causing mucosal damage (neomycin, methotrexate, reserpine, vinblastine).

Alteration of gut flora by antibiotics may disrupt the enterohepatic recirculation of oral contraceptives and digoxin. Intestinal absorption:
duodenum (B1, Fe2+) ileum (B12, A, D, E, K) large intestine (water, Na+, Cl-, K+)

A = Enterohepatic circulation

Systemic effect
Liver A Kidney

Small Intestine Pancreas

PIROXICAM : long t1/2 (> 45 hr) enterohepatic cycle

Routes of administration
Concentration of Cocaine in plasma

Drug half-life varies as a function of route of administration Half-life = time for plasma drug conc. to fall to half of peak level

Routes of administration
Effects of route of administration on rate of absorption are due to many factors:
Surface area available for absorption Blood circulation at the site of administration Amount of drug destroyed immediately Extent of binding to inert substances

Bioavailability
refers to the rate and extent of absorption of a drug from dosage form as determined by its concentration-time curve in blood or by its excretion in urine.
It is a measure of the fraction (F) of administered dose of a drug that reaches the systemic circulation in the unchanged form.

Bioavailability of drug injected iv. is 100%, but is frequently lower after oral ingestion, because:
The drug may incompletely absorb The absorbed drug may undergo first pass metabolism in intestinal wall and/or liver or be excreted in bile.

Plasma concentration (mcg/ml)

AUC area under the curve F bioavailability

AUC p.o. F = ------------ x 100% AUC i.v.

(i.v. application)
(p.o. application)

Time (h)

10

15

Plasma concentration time curves of the three preparations of a drug which containing the same amount. Formulation B is more slowly absorb than A and may not produced therapeutic effect. Formulation C is absorbed to lesser extent (it has lower bioavailability).

Drug distribution
It is the passage of drug from the circulation to the tissue and site of its action.
Drug must pass through many cell membranes (Cells in gut, blood vessels, glial cells, neurons)

Most important factor in achieving active dose at site of action (e.g., brain) The extent of distribution of drug depends on :
its lipid solubility, ionization at physiological pH (dependent on pK), extent of binding to plasma and tissue proteins and differences in regional blood flow, disease like CHF, uremia, cirrhosis.

Movement of drug proceeds until an equilibration is established between unbound drug in plasma and tissue fluids.

Route of Administration

Drug Distribution
Intramuscular or Subcutaneous Injection Tissue Depots
DRUG DRUG

Local activity only

Oral Gastrointestinal tract

Intravenous Injection

Topical Administration

DRUG

DRUG DRUG First Pass Effect

Systemic circulation
Serum Albumin
Drug Metabolites
Enterohepatic Recirculation

Drug
+

Lipid Membranes

Drug Metabolites

Primarily the Liver produces Drug

Metabolites

Bile Duct

Intestinal Tract Feces

Kidney

Receptors for desired effects

Receptors for undesired effects

Pharmacology
Urine: Drug & Drug Metabolite

Route of Metabolism

Route of Elimination

Drug Distribution

1. 2. 3. 4. 5.

The total body water as a percentage of body mass varies from 50% to 70%, being rather less in women than in man. Body water is distributed into the follow main compartments: plasma (5% of body mass) intestinal fluid (16%) intracellular fluid (35%) transcellular fluid (2%) fat (20%)

Apparent volume of distribution (Vd) It is accept that the body behaves as a single homogeneous compartment with volume (Vd) which drug gets immediately distributed:

Vd = ----------------------------Plasma concentration

Dose administered i.v.

Volume of Distribution
An abstract concept Gives information on HOW the drug is distributed in the body Used to calculate a loading dose

Volume of Distribution, Clearance and Elimination Rate Constant

V

Volume 100 L
Clearance 10 L/hr

V2 Cardiac and Skeletal Muscle

V

Volume 100 L (Vi)

Clearance 10 L/hr

Volume of Distribution = Dose_______ Plasma Concentration

V2 Cardiac and Skeletal Muscle

V

Volume 100 L (Vi)

Clearance 10 L/hr

Clearance = Volume of blood cleared of drug per unit time

V2 Cardiac and Skeletal Muscle

V

Volume 100 L (Vi)

Clearance 10 L/hr

Clearance = 10 L/hr Volume of Distribution = 100 L What is the Elimination Rate Constant (k) ?

CL = kV k = 10 Lhr -1 = 0.1 hr -1 100 L

10 % of the Volume is cleared (of drug) per hour k = Fraction of drug in the body removed per hour

CL = kV
If V increases then k must decrease as CL is constant

Loading Dose
Dose = Cp(Target) x VD

Apparent volume of distribution (Vd)

Drugs extensively bound to plasma proteins are largely restricted to the vascular compartment and have low Vd
e.g. warfarin 99% bound and its Vd is 0,1 L/kg.

Drugs sequestrated in other tissues may have Vd much more than total body water or even body mass,
e.g. digoxin (6 L/kg) and propranolol (3 to 4 L/kg).

Therefore, in case of poisoning, drugs with large Vd are not easily removed by haemodialysis.

Redistribution. Highly lipid soluble drugs given i.v. or by inhalationally get distributed to organs with high blood flow (brain, heart, kidney, liver). Later they get distributed to less vascular tissues (muscles and fat) and the drug-plasma concentrations falls. Greater the lipid solubility of the drug hastens its redistribution. Anaesthetic action of thiopentone (thiopental) is terminated in few minutes due to redistribution. However, when the same drug is given repeatedly or continuously over long periods the low perfusion high capacity sites get progressively filled up and the drug becomes longer acting.

Thiopental redistribution in muscle and fat (long postNarcotic sleep)

Blood-Brain Barrier
Limits the ability of drugs to reach the brain, even when they can reach other tissues

BBB is lipoidal and limits the entry of non-lipid soluble drugs (amikacin, gentamicin, neostigmine etc.). Only lipid soluble unionized drugs penetrate and have action on the CNS. Efflux carriers like P-gp (glycoprotein) present in brain capillary endothelial cells (also in intestinal mucosal, renal tubular, hepatic canicular, placental and testicular cells) extrude drugs that enter brain by other processes Inflammation of meanings of brain increases permeability of BBB. Dopamine (DA) does not enter brain, but its precursor levodopa does. This is used latter in parkinsonism.

GIT
L-DOPA
(levodopa)

Blood and peripheral tissues

DDC

Brain

1-5%
DDC

COMT

85-90%

9%

DDC DOPA-decarboxilase; COMT catechol--methyltransferase

Plasma protein binding (PPB)

Most drugs possess physicochemical affinity for plasma proteins.
Extent of binding depends on the individual compound. Increasing concentration of drug can progressively saturate the binding sites. The clinical significant implications of PPB are:
Highly PPB drugs are largely restricted to the vascular compartment and tend to have lower Vd. The PPB fraction is not available for action. There is an equilibration between PPB fraction of drug and free molecules of drug. acidic drugs bind to plasma albumin and basic drugs to 1-glycoprotein.

Plasma protein binding (PPB)

The drugs with high physicochemical affinity for plasma proteins (e.g. aspirin, sulfonamides, chloramphenicol) can replace the other drugs (e.g. acenocoumarol, warfarin) or endogenous compounds (bilirubin) with lower affinity. High degree of protein binding makes the drug long acting, because bound fraction is not available for metabolism, unless it is actively excreted by liver or kidney tubules. Generally expressed plasma concentrations of the drug refer to bound as well as free drug. In hypoalbuminemia, binding may be reduced and high concentration of free drug may be attained (e.g. phenytoin).

Tissue Distribution
Tissue storage. Drugs may also accumulate in specific organs or get bound to specific tissue constituents, e.g.: Heart and skeletal muscles digoxin (to muscle proteins) Liver chloroquine, tetracyclines, digoxin Kidney digoxin, chloroquine Thyroid gland iodine Brain chlorpromazine, isoniazid, acetazolamide Retina chloroquine (to nucleoproteins) Iris ephedrine, atropine (to melanin) Bones and teeth tetracyclines, heavy metals (to mucopolysaccharide of connective tissue) Adipose tissues thiopental, ether, minocycline, DDT

METABOLISM (BIOTRANSFORMATION)
Metabolism includes chemical alteration of the drugs in the body. Most hydrophilic drugs (amikacin, gentamycin, neostigmine, mannitol) are not biotransformated and are excreted unchanged. Mechanism which metabolize drugs is developed to protect the body from toxins. The primary site for drug metabolism is liver, other sites are kidney, intestine, lungs and plasma. Metabolism of drugs may lead to the following:
Inactivation. Active metabolite from an active drug. Activation of inactive drug (PRODRUG)

Biotransformation reactions can be classified into two phases: I (no synthetic) and II (synthetic, conjugation).

Phase I (no synthetic reactions)

a) Oxidation is the most important drug metabolizing reaction. Various oxidation reactions are hydroxylation; oxygenation at C-, N- or S-atoms; N or 0-dealkylation, oxidative deamination, etc. Oxidative reactions are mostly carry out by a group of monooxygenases in the liver, which in the final step involve cytochrom P450 reductase and O2. There are more than 200 cytochrom P450 isoenzimes, differing in their affinity for various substances (drugs). They are grouped into >20 families.

Biotransformation reactions
can be classified into two phases: I (no synthetic) and II (synthetic, conjugation).

Phase I (no synthetic reactions)

a) Oxidation b) Reduction. c) Hydrolysis.
d) Cyclization e) Decyclization

Substrates:
Cumarins Mephenytoin Omeprazole

Tolbutamide Warfarin Phenytoin

Midazolam Nifedipine Erythromycin Cyclosporine

Caffeine Theophylline Tacrine

Chlorzoxazone

Dextrometorphan Sparteine Debrisoquine

CYP2B6

CYP2A6 <5%

CYP2C19 <5%

CYP2C8/9/18 ~20%

CYP3A4/5 (3050%)

CYP1A2 ~15%

CYP2E1 ~10%

CYP2D6 <5%

CYP1A1

Inhibitors:
Methoxsalen Fluconazole Sulphaphenazole Ketoconazole Gestodene Furafylline Fluvoxamine Tetrahydro- Quinidine furane

Inducers:
Phenobarbital Phenobarbital Phenobarbital Rifampicin Rifampicin Phenobarbital Rifampicin Dexamethasone Carbamazepine Omeprazole Nicotine Ethanol Isoniazid

Phase II synthetic (conjugation) reactions

Conjugation reactions have high energy requirements. (1) Glucoronide conjugation is the most important synthetic reaction. Examples: chloramphenicol, aspirin, morphine, metroniazole, GCS, bilirubin, thyroxine. The liberated drug is reabsorbed and undergoes the same fate. This enterohepatic recirculation of some drugs (e.g. chloramphenicol, phenolphthalein, oral contraceptives) prolongs their action. (2) Acetylation. e.g. sulfonamides, isoniazid. Multiple genes control the acetyltransferases and rate of acetylation shows genetic polymorphizm (slow and fast acetylators). (3) Sulfate conjugation. e.g. chloramphenicol, adrenal and sex steroids. (4) Methylation. e.g: adrenaline, histamine, nicotinic acid. (5) Ribonucleoside/nucleotide synthesis

(6) Only a few drugs are metabolized by enzymes of intermediary metabolism. Examples:
alcohol by dehydrogenases allopurinol by xanthine oxidase succinylcholine and procaine by plasma cholinesterase adrenaline by monoamine oxidase (MAO)

Drug Metabolism
Genetic polymorphism Extensive & poor metabolizers Cytochrome P450
Smooth microsomes - oxidative drug metabolism enzymes. Cytochrome p450 - hemoprotein . Cyp450 heme reduction a rate limiting step in hepatic drug oxidation

FIRST PASS (PRESYSTEMIC) METABOLISM This refers to metabolism of a drug during its passage from the site of absorption into systemic circulation. All orally administered drugs are exposed to drug metabolism in the intestinal wall and liver in different extent. High first pass metabolism: propranolol, verapamil, pethidine, salbutamol, nitroglycerine, morphine, lidocaine. Orally dose of these drugs is higher than sublingual or parenteral dose. There is individual variation in the oral dose due to differences in the extent of first pass metabolism. Oral bioavailability is increased in patients with severe liver disease.

IV. EXCRETION
Excretion is the passage out of systematically absorbed drug.
Drug and their metabolites are excreted in:

urine (through the kidney) bile and faeces exhaled air saliver and sweat milk

The kidney is responsible for excreting of all

water soluble substances.
Glomerular filtration. Glomerul capillaries have large pores. All nonprotein bound drugs (lipid soluble or insoluble) presented to the glomerulus are filtrated. Glomerular filtration of drugs depends on their plasma protein binding and renal blood flow. Glomerular filtration rate (g.f.r.) declines progressively after the age of 50 and is low in renal failure. Tubular reabsorption. Lipid soluble drugs filtrated at the glomerulus back diffuse in the tubules because 99% of glomerular filtrate is reabsorbed, but nonlipid soluble and highly ionized drugs are unable to do so.

Thus, rate of excretion of such drugs, e.g. aminoglycoside (amikacin, gentamicin, tobramycin) parallels g.f.r. Changes in urinary pH affect tubular reabsorption of partially ionized drugs: Weak bases ionize more and are less reabsorbed in acidic urine. Weak acids ionized more and are less reabsorbed in alkaline urine. This principle is utilized for facilitating elimination of drugs in poisoning: Urine is acidified in morphine and atropine poisoning. Urine is alkalized in barbiturate and salicylate poisoning.

The effect of changes in urinary pH on drug excretion is greatest for drug having pKa values between 5 to 8, because only in these case pH dependent passive reabsorption is significant.

Tubular secretion is the active transfer of organic acid and bases by two separate nonspecific mechanism, which operated in the proximal tububules: Organic acid transport for penicillins, probenecid, salicylates, uric acid, sulfinpyrazones, nitrofurantoin, methotrexate, drug glucuronides etc. Organic base transport for thiazides, quinine, procainamide, cimetidine, amiloride etc.

Many drug interactions occur due to competition for tubular secretion, e.g.: Aspirin blocks uricosuric action of probenecid and sulfinpyrazone and decreases tubular secretion of methotrexate. Probenecide decreases the urine concentration of nitrofurantoin, increases the duration of penicillin action and impairs secretion of methotrexate. Quinidine decreases renal and biliary clearance of digoxin by inhibiting efflux carrier P-gp.
Tubular transport mechanisms are no well developed at birth. Duration of action of many drugs (penicillins, cephalospoins, aspirin etc.) is longer in neonates. These systems mature during infancy.

aminoglycosides beta-lactams sulfonamides quinolones nitrofurans polymyxins

macrolides lincosamines rifampicin tetracyclines (p.o.)

General inhalation anaesthetics Potassium iodide Bronchoantiseptic oils Alcohol

sulfonamides barbiturates reserpine alcohol coffeinum

Saliva excretion

oleandomycin spiramycin
phenytoin

zalcitabine verapamil

Morphine
(10% stomach excretion)

morphine pKb: 7.9 stomach pH: 12 plasma pH: 7.36

KINETICS OF ELIMINATION (elimination = metabolism + excretion)

Clearance (Cl) of a drug is the theoretical volume of plasma from which the drug is completely removed in unit time: Cl = Rate of elimination/Plasma concentration Renal (Clr) or creatinine clearance (Clcr): Curine x Vurine Clrenal = -------------------Cplasma

First order (exponential) kinetics. For majority of drugs the processes involved in elimination are not saturated over the clinically obtained concentrations. These drugs have first order kinetics. Their rate of elimination is directly proportional to drug concentration and their clearance remains constant.

Semilog plasma concentration-time plot of a drug eliminated by first order kinetics after i.v. injection.

Zero order (linear) kinetics.

In a few cases where the drugs are inactivated by metabolic degradation (such as ethanol, phenytoin, theophylline, salicylates and warfarin), the time-course of disappearance of drug from the plasma does not follow the exponential or biexponential pattern, but is initially linear. These drugs are removed at a constant rate which is independent of plasma concentration. This is often called zero order kinetics.

Plasma half live (t1/2) is the time in which the plasma

concentration of a drug declines by one half. Drug with long t1/2 can accumulate. Plasma t1/2 of some drugs:

Adenosine < 2 sec Dobutamine 2 min Benzylpenicillin 30 min Amoxicillin 1 h Paracetamol 2 h Atenolol 7 h Diazepam 40 h Ethosuccimide 54 h Digitoxin 168 h

From the peak plasma concentration the drug is virtually eliminated from the plasma in 5 t1/2 periods:

(1)

(2)

(3)

(4)

(5)

Half-Life
Half-Life determined by the time required to reduce by one-half the amount of the drug present in the body Drugs have different & distinct half-lives Comparison for drug elimination rates Determines frequency with which multiple doses of a drug can be safely administered Half-life does not change with the drug dose

Clearance
Ability of organs of elimination (e.g. kidney, liver to clear drug from the bloodstream Volume of fluid which is completely cleared of drug per unit time Units are in L/hr or L/hr/kg Pharmacokinetic term used in determination of maintenance doses

Maintenance Dose Calculation

Maintenance Dose = CL x CpSSav
CpSSav is the target average steady state drug concentration The units of CL are in L/hr or L/hr/kg Maintenance dose will be in mg/hr so for total daily dose will need multiplying by 24

Half-Life and k
Half-life is the time taken for the drug concentration to fall to half its original value The elimination rate constant (k) is the fraction of drug in the body which is removed per unit time.

Integrating:

Cp2 = Cp1

-kt .e

Logarithmic transform:
lnC2= lnC1 - kt

logC2 = logC1 - kt/2.303

Elimination Half-Life:
t1/2 = ln2/k

t1/2 = 0.693/k

Steady-State
Steady-state occurs after a drug has been given for approximately five elimination half-lives. At steady-state the rate of drug administration equals the rate of elimination and plasma concentration - time curves found after each dose should be approximately superimposable.

Accumulation to Steady State 100 mg given every half-life

194 187.5 175 150 100 87.5 75 50 94 97 100 200

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