Pharmacokinetics

Nur Permatasari

Dosage

Plasma Site of Concen. Action

Effects

PHARMACOKINETICS Pharmacokinetics

Pharmacodynamics PHARMACODYNAMICS
The drug acts on the body,

the body work on the drug

Systemic Availability

Therapeutics index

When a drug enters the body, the body begins immediately to work on the drug:

Absorption Distribution Metabolism (biotransformation), Excretion

These are the processes of pharmacokinetics.

Therapeutics site of action RECEPTORS

TISSUE RESERVOIRS

Bound

Free

Free

Bound Unwanted of site of action

FREE BOUND

ABSORPTION/ LIBERATION

Free Drug

EXCRETION

Bound Drug

METABOLITE
SYSTEMIC CIRCULATION

BIOTRANSFORMATION

In order to reach their site of action, drugs have to pass through several membranes transmembrane transport AND the plasma membrane represents the common barrier to drug distribution.

Structure of the plasma membrane

The plasma membrane consists of a bilayer and membrane proteins embedded in the bilayer

Mechanisms of transmembran transport

Passive diffusion: passage of drugs through the lipid surface (major mechanism of drug absorption) directly proportional to the magnitude of the concentration gradient across the membrane
Lipid-soluble

drugs Small water-soluble drugs Noncharged form of weak electrolytes

Drug absorption is depend on physico chemical properties of drug

The rate of absorption is related to the oil:water partition coefficient

The greater the partition coefficient, the higher the lipid-solubility of the drug, and the greater its diffusion across membranes or the faster its absorption

Water-soluble drugs
Cell membranes are relatively permeable to water either by diffusion or by flow resulting from hydrostatic or osmotic differences across the membrane, but bulk-flow transport is limited when the molecular mass of the solute exceeds 100 to 200 daltons

Weak electrolytes and membrane permeability

Most drugs are small (MW < 1000) weak electrolytes (acids/bases). In solution exist in a non-ionized and an ionized forms of drugs .
The fraction of drug that is non-ionized depends on its chemical nature, its

pKa, and the local biophase pH...

Henderson-Hasselbach equation

base pH - pKa = log acid

For an acidic drug: acid = HA; base = AFor a basic drug: acid = BH+; base = B

% Ionized vs. pH

For HA acids: % ionization = 100/(1 + 10(pKa pH)) For BH+ acids: % ionization = 100/(1 + 10(pH pKa))

Example: Percentage ionized pseudoephedrine HCl (pKa 9.9) in the small intestine at pH 8.0?

Acids are increasingly ionized with increasing pH (basic environment),

whereas Bases are increasingly ionized with decreasing pH (acidic environment).

Other transmembrane transport

Filtration: bulk flow of water-soluble drugs through pores (glomerular, capillary) Facilitated diffusion: carrier-mediated, ATP not required (e.g., glucose) Active transport: carrier-mediated, ATP required (e.g., Na+, K+, Ca++) Endocytosis and exocytosis: (e.g., for very large compounds)

Routes of Administration

Per oral is a major route of drug administration .. Why ??

Relatively Fast Painless (usually) Easy Safe No need for equipment or help Most drugs can be given orally

But. Some physiologic factors determined the drug absorption

ORAL INGESTION , governed by:

surface

area for absorption, blood flow, physical state of drug, concentration. via passive process.

occurs In

theory: weak acids optimally absorbed in stomach, weak bases in intestine. reality: the overall rate of absorption of drugs is always greater in the intestine (surface area, organ function).

In

Unique characteristics of the oral route

Influences of gastric emptying (accelerates gastric emptying increase the rate of absorption) Small intestine usually most important because of large surface area (folds of Kerckring, villi, microvilli) The motility of the small intestine Drug inactivation important for oral route

stomach (acid), small intestine (ester/other enzyme), distal small intestine/colon (gut bact)

Ingestion of a solid dosage form with a glass of cold water, fasting, lying on the right side, hyperthyroidism accelerate gastric emptying

Ingestion with a fatty meal, acidic drink, or with another drug with anticholinergic properties, lying on the left side, hypothyroidism, sympathetic output (as in stress) retard gastric emptying.

First-Pass Metabolism

Extent of metabolism occurring before drug enters systemic circulation Main site: Liver Decrease in drug efficacy (orally) can be overcome by using a greater dose Example: Propranolol (5 mg vs. 100 mg) Extensive metabolism may render oral admin. impossible Example: Lidocaine

The fraction of drug eliminated from portal blood during absorption hepatic extraction ratio (ERH) ERH = ClH/ QH

Bioavaibilty (F) F = 1- ERH

Drug Absorption & Route of administration

Absorption describes the rate and extent at which a drug leaves its site of administration. Bioavailability (F) is the extent to which a drug reaches its site of action, or to a biological fluid (such as plasma) from which the drug has access to its site of action.

AUC = area under the curve

plasma concentration of drug

AUC oral Bioavailability = AUC injected i.v. X 100

AUC injected I.v.

AUC oral

time

Important Properties Affecting Drug Absorption

Chemical properties acid or base degree of ionization polarity molecular weight lipid solubility or... partition coefficient

Physiologic variables gastric motility pH at the absorption site area of absorbing surface blood flow pre absorptive hydrolysis ingestion w/wo food

Advantage

Relatively Fast Painless (usually) Easy Safe No need for equipment or help Most drugs can be given orally E.g., medications in pill form, barbiturates, LSD, caffeine, alcohol

Disadvantage

Not very fast Some drugs dont withstand stomach/GI conditions (insulin, cocaine) Drug absorption more variable May cause GI distress Not suitable for uncooperative, vomiting, unconscious FIRST PASS through liver

INJECTION

subcutaneous, intramuscular absorbed by diffusion and affected by blood flow intravenous, intraarterial injection avoids absorption
Other

Intraperitoneal = (I.P.) into stomach cavity (between

organs). Faster than P.O. Intrathecal = into subdural spaces of the spinal cord; bypasses blood- brain barrier but invasive Intracerebroventricular = into the ventricles (where cerebrospinal fluid is produced) in the brain; bypasses blood- brain barrier but extremely invasive Intracerebral = into the brain itself

Injection types

Injection, in general
Advantage Disadvantage

Fast Bypasses first pass Bypasses digestion More accurate dose Can be done by person with training

Painful Too fast to respond if bad reaction or overdose Potential for infection Unless planning IV, must be careful to avoid veins No recall of drug

LUNG

Inhalation: passive diffusion, rapid absorption, dependent on particle size (6 m cutoff)

Disadvantage Potential harm to lungs Short term = pneumonia Long term = cancer Exacerbation of abuse liability Only viable for volatile forms of drugs or that can be in very tiny particles Drug is sometimes destroyed in process

Advantage Painless and quick Easy and discreet Very rapid; 5 - 8 sec to brain Intense effects Smoke Examples: metapmphetamine Vapor examples: anasthetics

MUCOUS MEMBRANE sublingual, buccal, nasal, vaginal or rectal mucosa: passive diffusion
Advantage Quick absorption Easy and discreet Little chance of infection or tissue harm (except with vasoconstrictors) Disadvantage Can taste bad or irritate membranes Not all drugs absorbed readily Ease and speed exacerbate abuseliable drugs potential for abuse

SKIN Transdermal
Advantage Easy Not painful Slow, sustained release Bypasses GI tract & first pass Only have to change every few days / weeks Disadvantage Can fall off Potential toxicity to children and pets Very few drugs absorbed sufficiently, low permeability of skin Local irritation possible Toxicity if additional drug consumed

Distribution
Only that fraction of drug which is non-protein-bound

can bind to cellular receptors and pass across tissue membranes, thus being distributed to other body tissues, metabolized, and excreted.

The actual pattern of drug distribution reflects various

physiological factors (blood perfusing organ, capillary permeability ) and physicochemical properties (protein plasma binding, lipid solubility) of the drug.

Phases of Distribution

first phase reflects cardiac output and regional blood flow. Thus, heart, liver, kidney & brain receive most of the drug during the first few minutes after absorption. next phase delivery to muscle, most viscera, skin and adipose is slower, and involves a far larger fraction of the body mass.

Central nervous system: permeable to lipid-soluble drugs only; limited permeability to water-soluble drugs when inflamed, that are highly bound to plasma proteins , that are weak acids (are highly ionized at the pH of blood, 7.4) The view that the placenta is an absolute barrier to drugs is, however, completely inaccurate (in part because a number of influx transporters are also present.The fetus is to some extent exposed to all drugs taken by the mother.

Plasma protein

albumin - binds many acidic drugs a1-acid glycoprotein for basic drugs

The fraction of total drug in plasma that is bound is determined by : * its concentration, * its binding affinity, * and the number of binding sites
Binding of drugs to plasma proteins such as albumin is nonselective

Drug Reservoirs
Body compartments where a drug can accumulate are reservoirs. They have dynamic effects on drug availability.

GIT plasma proteins as reservoirs (bind drug) cellular reservoirs Adipose (lipophilic drugs) Bone (crystal lattice) Transcellular (ion trapping)

Bone Reservoir
Tetracycline antibiotics (and other divalent metal ion-chelating agents) and heavy metals may accumulate in bone. They are adsorbed onto the bone-crystal surface and eventually become incorporated into the crystal lattice. Bone then can become a reservoir for slow release of toxic agents (e.g., lead, radium) into the blood.

Adipose Reservoir
Many lipid-soluble drugs are stored in fat. In obesity, fat content may be as high as 50%, and in starvation it may still be only as low as 10% of body weight.
70% of a thiopental dose may be found in fat 3 hr after administration.

GI Tract as Reservoir
Weak bases are passively concentrated in the stomach from the blood because of the large pH differential. Some drugs are excreted in the bile in active form or as a conjugate that can be hydrolyzed in the intestine and reabsorbed.
In these cases, and when orally administered drugs are slowly absorbed, the GI tract serves as a reservoir.

Redistribution
Termination of drug action is normally by biotransformation/excretion, but may also occur as a result of redistribution between various compartments. Particularly true for lipid-soluble drugs that affect brain and heart.

Redistribution of thiopental after intravenous injection

100

Thiopental concentration (as percent of initial dose)

blood

brain
50

muscle

adipose

0 1 10 100 1000

minutes

Drug Biotransformation
Usually inactivates the drug. Can generate active metabolite

Can generate toxic metabolite (isoniazid).

Often generates polar, highly ionized metabolites.

Conversion rate influences pharmacological activity.

Some drugs are eliminated unchanged (digoxin).

Phase I and Phase II Metabolic Reactions

These are general categories of reactions and occur in no particular order.

Phase I functionalization reactions (oxidation, reduction, hydrolysis) introduce or expose a functional group on the parent compound result in loss of pharmacological activity Phase II conjugation reactions lead to covalent linkage of a functional group on the parent drug or phase I metabolite with endogenously derived glucuronic acid, sulfate, methyl, glutathione, amino acids, acetate, acetylate etc result in highly polar conjugates

Biotransformation of Major Functional Groups

(-OH) oxidation, methylation, glucuronide conjugation, sulfate conjugation.

(-COOH) oxidation, glucuronide conjugation, glycine conjugation.

(-NH2) deamination (and aldehyde formation), glucuronide conjugation, methylation.

Phase I and Phase II Metabolic Reactions

Absorption Metabolism Excretion

Phase I
Metabolite with modified activity Inactive metabolite

Phase II
Conjugate
Conjugate

Drug

Lipophilic

Hydrophilic

Some Drugs Stimulate and Some Inhibit the drug metabolizing enzymes

Stimulation is via induction, which means an increase in enzyme synthesis (oxidation, reduction, glucoronide formation). Phenobarbital and polycyslic aromatic hydrocarbon (cigarette smoke) inducers Inhibition is via competition, prodrug inhibition or a decrease in the activity of existing enzyme. Cimetidine inhibitor

Enzyme Induction
100 Plasma Level Zoxazolamine (mg/ml)

No induction Phenobarbital induction

(Classic barbiturate effect)

10

Benzopyrene induction
1

(Generated from grilling meat)

Time (hrs)

ACETAMINOPHEN METABOLISM
1. 2. Oxidation Reactive Intermediate

3.
4.

Glutathione Conjugation
Hepatic Cell Death

Acetominophen Metabolism
Ac-glucuronide Ac Ac-sulfate Cytochrome P-450 Reactive electrophilic compound (Ac*)

Good

GSH GS-Ac* Ac*-protein

Bad

Ac-mercapturate

Hepatic cell death

Elimination Of Drugs

Metabolism: Excretion:

Liver Kidney Liver (bile) Lungs

Others : Feces, Saliva, Sweat, Milk

Renal Excretion of Drugs

Filtration

(Glomerulus)

Secretion - Active Transport (Tubule)

Transporter for Organic Acids Transporter for Organic Bases Reabsorption - Passive Transport (Tubule)

Glomerular Filtration

Only unbound drug is filtered. Plasma Protein Binding of drug prevents filtration: Thyroxine is 99% bound. Molecular Size:
Albumin

(70,000) is not filtered.

Inulin

(5,500) is freely filtered; can be used to estimate GFR.

Tubular Secretion
Active Transport Organic Acids (inhibited by probenecid)

Organic Bases No effect of protein binding on this process The clearance of drug eliminated by tubular secretion is a function of renal blood flow

Tubular Reabsorption

Passive Transport:
pH,

concentration, size, lipid solubility, ionization.

acid

urine favors reabsorption of weak acid, basic urine favors reabsorption of weak base.
urine is affected by diet,drugs, diurnal, condition of patients (respiratory and metabolic acidosis)

pH

Enterohepatic Cycle

Liver
2

Portal vein
1

Common bile duct

4

Small intestine

Factors affecting drug metabolism

reversible binding to plasma proteins localization of drugs (e.g., fat) hepatic blood flow Age genetics-related deficiency or alteration in drug metabolizing enzyme (e.g., acetylator, pseudocholinesterase deficiency and succinylcholine) pathology inhibition / inductionof drug metabolizing enzyme (e.g., by erythromycin, phenobarbital) Diet (carb-protein, vegetables, charcoal-broiled beef) Enviromental chemicals (alcohol, cigarette smoking, other chemicals)