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GENERAL PHARMACOLOGY

PHARMACOKINETIC PRINCIPLES

Usman iftikhar tararPcol-Mphil 611

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DEFINITION

• Pharmacology embraces the knowledge of the history, source, physical and chemical properties, compounding, biochemical and physiological effects, mechanisms of action, absorption, distribution, biotransformation excretion, therapeutic and other uses of drugs.

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DEFINITION

• Pharmacology is the study of the effects of chemicals and the mechanism of these effects on living organisms(Pharmacodynamics), and the effects of the living organisms on the chemicals including absorption, distribution, metabolism and excretion(pharmacokinetics).

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PHARMACOKINETICS

• After a drug is released from its dosage form, the drug is absorbed in to the surrounding tissue.

• Pharmacokinetics is the science of the kinetics of drug absorption, distribution and elimination(i.e. excretion and metabolism).The description of drug distribution and elimination is often termed drug disposition.

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Figure:The interrelationship of the absorption, distribution, binding, metabolism, and excretion of a drug and its concentrationat its sites of action.

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Transfer of drugs across membranes

• Before an administered drug can arrive at its site of action in effective concentrations, it must surmount a number of barriers.

• These barriers are chiefly a succession of biological membranes.

• A biological membrane or cell membrane consist of bilayer of amphipethic lipids, with their hydrophobic ends oriented inward and hydrophilic ends outward.

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Transfer of drugs across membranes

• Drugs are thought to penetrate these biological membranes in three general ways.

i) By passive diffusion.ii) Through specialized transport mechanisms.iii) Vesicular transport.iv) Other methods

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i)Passive diffusion• Passive diffusion process is driven

by concentration gradient across the membrane.

• Passive diffusion is described by Fick’s law, which states that the rate of diffusion across a membrane(dc/dt) is proportional to the difference in drug concentration on both sides of the membrane(C1-C2), with P as permeability coefficient.

• -dc/dt=P(C1-C2)

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Influence of pH• Most drugs are weak acids or

bases that are present in solution as both the non-ionized and ionized species.

• The non-ionized molecules usually are more lipid-soluble and can diffuse readily across the cell membrane. In contrast, the ionized molecules usually are unable to penetrate the lipid membrane because of their low lipid solubility.

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Influence of pH

• Acc. To Handerson hasselbalch equation:

at steady state, an acidic drug will accumulate on the more basic side of the membrane and a basic drug on the more acidic side—a phenomenon termed ion trapping.

• The ratio of ionized to unionized drug is governed by the pKa of the drug and the pH of that compartment

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Influence of pH on the distribution of a weak acid

between plasma and gastric juice separated by a lipid barrier.

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Some acidic and basic drugs

ACIDIC DRUGS• Acetylsalicylic

acid• Benzylpenicillin• Boric acid• Warfarin• Sulfanilamide• Theophylline• Thiopental

BASIC DRUGS• Amphetamine • Caffeine• Atropine• Morphine• Procaine• Reserpine • Chlordiazepoxide

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ii)Through specialized transport mechanisms

• Active transport is characterized by a direct requirement for energy, movement against an electrochemical gradient.

• Active transport is a specialized process requiring a carrier that binds the drug to form a carrier–drug complex that shuttles the drug across the membrane and then dissociates the drug on the other side of the membrane.

• A few lipid-insoluble drugs that resemble natural physiologic metabolites (such as 5-fluorouracil) are absorbed from the gastrointestinal tract by this process

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Specialized transport mechanisms

• Facilitated diffusion describes a carrier mediated transport process in which there is no input of energy, and therefore, enhanced movement of the involved substance is down an electrochemical gradient.

• As in the permeation of glucose across a muscle cell membrane mediated by the insulin-sensitive glucose transporter protein GLUT4.

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iii) Vesicular Transport

• Vesicular transport is the process of engulfing particles or dissolved materials by the cell.

• Pinocytosis refers to the engulfment of small solutes or fluid.

• Phagocytosis refers to the engulfment of larger particles or macromolecules, generally by macrophages.

• Endocytosis and Exocytosis are the processes of moving specific macromolecules into and out of a cell, respectively.

• Vesicular transport is the proposed process for the absorption of orally administered Sabin polio vaccine and various large proteins.

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Other methods

• Pore (Convective) Transport: Very small molecules (such as urea, water, and sugars) are able to cross cell membranes rapidly, as if the membrane contained channels or pores.

• A certain type of protein called a transport protein may form an open channel across the lipid membrane of the cell.

• Ion-Pair Formation: Strong electrolyte drugs maintain their charge at all physiologic pH values and penetrate membranes poorly. When the ionized drug is linked up with an oppositely charged ion, an ion pair is formed in which the overall charge of the pair is neutral. This neutral drug complex diffuses more easily across the membrane. For example,propranolol, a basic drug that forms an ion pair with oleic acid.

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Drug absorption

• Absorption may be defined as the process by which a compound penetrates one or more biological membranes to gain entry into the body.

• Absorption is not to be confused with bioavailability, which describes entry of administered compounds into the systemic circulation. For some drugs and dosage routes, absorption and bioavailability may be identical.

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Choice of route of administration

• Oral ingestion• Controlled release preparation• Sublingual• Transdermal• Rectal• Parenteral• Intravenous• Subcutaneous• Intramuscular• Intrarterial• Intrathecal• Pulmonary absorption.• Topical application.• Novel methods

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Drug absorption depends on

• Physicochemical properties of the drug.Surface areaCrystal or amorphous drug formSalt formState of hydration

• The dosage form used.• Anatomy and physiology of the

absorption site

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Other factors influencing absorption

I. Blood flow to absorption site:E.g. in shock blood flow to cutaneous tissue is

reduced, so absorption is decreased after sub-cutaneous administration.

II. Total surface area:e.g. in intestine rich in microvilli, surface area is

increased to 1000 folds.

III. Contact time:Contact time is decrease in most drugs are

absorbed in duodenum so drugs that prolong gastric emptying decrease absorption.

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Distribution of drug• Following absorption or systemic

administration into the bloodstream, a drug distributes into interstitial and intracellular fluids.

• This process reflects a number of physiological factors and the particular physicochemical properties of the individual drug.

• The more important determinant of blood–tissue partitioning is the relative binding of drug to plasma proteins and tissue macromolecules.

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A- Plasma proteins

• An average subject(70 kg) has about 5 L of blood, which is equivalent to 3 L of plasma.

• Many drugs circulate in the bloodstream bound to plasma proteins.

• Albumin is a major carrier for acidic drugs.• α1-acid glycoprotein binds basic drugs. • Nonspecific binding to other plasma proteins

generally occurs to a much smaller extent. • The binding is usually reversible.

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A-Plasma proteins

• The concentration of drug in the plasma or tissues depends on the amount of drug systemically absorbed and the volume in which the drug is distributed. The apparent volume of distribution, V D in a model, is used to estimate the extent of drug distribution in the body.

• Vd=conc. of drug in the body/plasma conc.

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Tissue Binding.

• Many drugs accumulate in tissues at higher concentrations than those in the extracellular fluids and blood.

• E.g. during long-term administration of the antimalarial agent quinacrine, the concentration of drug in the liver may be several thousand folds higher than that in the blood. Such accumulation may be a result of active transport or, more commonly tissue binding.

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Tissue binding

• Tissue binding of drugs usually occurs with cellular constituents such as proteins, phospholipids, or nuclear proteins and generally is reversible.

• A large fraction of drug in the body may be bound in this fashion and serve as a reservoir that prolongs drug action in that same tissue or at a distant site reached through the circulation. Such tissue binding and accumulation also can produce toxicity.

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Fat as a Reservoir• Many lipid-soluble drugs are stored

by physical solution in the neutral fat.• In obese persons, the fat content of

the body may be as high as 50%, and even in lean individuals it constitutes 10% of body weight; hence fat may serve as a reservoir for lipid-soluble drugs.

• For example, as much as 70% of the highly lipid-soluble barbiturate thiopental may be present in body fat 3 hours after administration

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Erythrocytes, or red blood cells (RBCs),

• RBCs consist of about 45% of the volume of the blood.• Phenytoin, pentobarbital, and amobarbital are known to have a

preferential binding of drug to the erythrocytes over plasma. Penetration into RBC is dependent on the free concentration of the drug.Increased drug binding to plasma albumin reduces RBC drug concentration.

• With most drugs, however, binding of drug to RBC generally does not significantly affect the volume of distribution, because the drug is often bound to albumin in the plasma. Even though phenytoin has a great affinity for RBC, only about 25% of the blood drug concentration is present in the blood cells, and 75% is present in the plasma because the drug is also strongly bound to albumin.

• For drugs with strong erythrocyte binding, the hematocrit will influence the total amount of drug in the blood.

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Redistribution

• Termination of drug effect after withdrawal of a drug usually is by metabolism and excretion but also may result from redistribution of the drug from its site of action into other tissues or sites.

• E.g. intravenous anesthetic thiopental, a highly lipid-soluble drug. Because blood flow to the brain is so high, the drug reaches its maximal concentration in brain within a minute of its intravenous injection.

• After injection, the plasma concentration falls as thiopental diffuses into other tissues, such as muscle. The concentration of the drug in brain follows that of the plasma because there is little binding of the drug to brain constituents. Thus, the onset of anesthesia is rapid, but so is its termination.

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Central Nervous System and

Cerebrospinal Fluid.• The distribution of drugs into the CNS from the blood is

unique. One reason for this is that the brain capillary endothelial cells have continuous tight junctions; therefore, drug penetration into the brain depends on transcellular rather than paracellular transport. The unique characteristics of brain capillary endothelial cells and pericapillary glial cells constitute the blood–brain barrier.

• At the choroid plexus, a similar blood–CSF barrier is present except that it is epithelial cells that are joined by tight junctions rather than endothelial cells. The lipid solubility of the nonionized and unbound species of a drug is therefore an important determinant of its uptake by the brain; the more lipophilic a drug is, the more likely it is to cross the blood–brain barrier.

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Placental Transfer of Drugs

• The transfer of drugs across the placenta is of critical importance because drugs may cause anomalies in the developing fetus. Lipid solubility, extent of plasma binding, and degree of ionization of weak acids and bases are important general determinants in drug transfer across the placenta.

• The fetal plasma is slightly more acidic than that of the mother (pH 7.0 to 7.2 versus 7.4), so that ion trapping of basic drugs occurs.

• As in the brain, P-gp and other export transporters are present in the placenta and function to limit fetal exposure to potentially toxic agents.

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References

• Goodman & Gilman’sThe Pharmacological Basis of THERAPEUTICS. 11th ed.

• Rang & Dales Pharmacology 6th ed.• Basic and clinical pharmacology 11th ed.• Pharmacology principles and practice by Miles Hacker.• Appleton & lange’s review of pharmacy(Mcgraw Hill).• Encyclopedia of PHARMACEUTICAL TECHNOLOGY 3rd

ed. Vol. 1.• Applied biopharmaceutics & pharmacokinetics 11th ed.• Pharmaceutical dosage forms and drug delivery

system 8th ed.

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