Pharmacokinetics, Overview

Definition: The study of the movement of drugs in the body, including the processes of absorption, distribution, localization in tissues, biotransformation and excretion. The actions of the body on the drug are called pharmacokinetic processes

Pharmacokinetic processes govern the absorption, distribution, metabolism and elimination of drugs Learning pharmacokinetics is of great practical importance in the choice and administration of a particular

drug for a particular patient, e.g., one with impaired renal function

Absorption: It is the process of entry of drug from site of administration into systemic circulation.

Drug should be at an adequate concentration at its site of action to produce its effect The two fundamental processes that determine the concentration of a drug at any moment

and in any region of the body are:– translocation of drug molecules– chemical transformation by drug metabolism and other processes involved in drug elimination

These are critically important for choosing appropriate routes of administration

Pharmacokinetics, Absorption

Translocation of drug molecules: drug molecules move around the body in two ways: bulk flow transfer (i.e. in the bloodstream) The chemical nature of a drug makes no difference

to its transfer by bulk flow. diffusional transfer (i.e. molecule by molecule, over short distances)

Diffusional transfer (transmembrane movement of the drugs): ability to cross hydrophobic diffusion barriers is strongly influenced by lipid solubility. delivering drug molecules to and from the non-aqueous barriers is influenced by water solubility

Absorption, The Movement of Drug Molecules Across Cell Barriers

Cell membranes form the barriers between aqueous compartments in the body. The most universal function of cell membrane is to act as a selective barrier to the passage of

molecules, allowing some molecules to cross while excluding others. The cell membrane consists of a bimolecular lipid sheet (hydrophobic) interspersed with protein

molecules (hydrophilic), and contains minute aqueous pores which allow passage of small hydrophilic substances.

Passage of drugs through the blood brain barrier (in the CNS) and placental barrier: There are tight junctions between the cells the endothelium is enclosed in an impermeable layer of periendothelial cells (pericytes). These features prevent potentially harmful molecules from leaking from the blood into these

organs and have major pharmacokinetic consequences for drug distribution

The Movement of Drug Molecules Across Cell Barriers

Passage of drugs across cell membranes1) Simple diffusion: The majority of drugs gain access to the body through this mechanism.

Drugs must be first in aqueous solution to gain access to the lipid membrane Drugs pass along concentration gradient No energy or carrier is required It is not saturable. It depends on:

concentration gradient lipid solubility: Acidic drugs are lipid soluble in acidic environment, so they may be absorbed in the stomach. Basic drugs are lipid soluble in basic

environment, so they are absorbed in the intestine degree of ionization, thickness of membrane molecular size of the drug

Concentration gradient is maintained by removal of the drug from other side of the membrane. Lipid solubility is measured by lipid/water partition coefficient (ratio of drug concentration in lipid phase and water phase when shaken in one immiscible

lipid/water system). Ionized drugs generally have low lipid/water coefficient.

The Movement of Drug Molecules Across Cell Barriers, contd.

2) Specialized transport: - Substances that are too large or poorly lipid soluble as amino acids and glucose are carried by specialized

carriers.

- a. Facilitated diffusion: is similar to simple diffusion but requires a carrier and it is saturable.

A carrier molecule is a transmembrane protein which binds one or more molecules or ions, changes conformation and releases them on the other side of the membrane.

Carrier molecules facilitate entry and exit of physiologically important molecules, such as sugars, amino acids, neurotransmitters and metal in the direction of their electrochemical gradient

The Movement of Drug Molecules Across Cell Barriers, contd.

b. Active transport: where drugs pass against concentration gradient, so it requires: energy, carrier (thus it is saturable) Example: many drugs, especially weak acids (e.g., penicillin, uric acid) and weak bases (e.g., histamine), are actively secreted into the renal tubule, and thus more rapidly excreted

Mechanism Direction Energy required Carrier Saturable

Passive diffusion Along gradient No No No

Facilitated diffusion Along gradient No Yes Yes

Active transport Against gradient Yes Yes Yes

The Movement of Drug Molecules Across Cell Barriers, contd.

c. Pinocytosis: It involves invagination of part of the cell membrane and the trapping of a small vesicle containing extracellular

constituents within the cell

The vesicle contents can then be released within the cell, or extruded from its other side

Examples: Pinocytosis of vitamin B12 (complexed with intrinsic factor).

It is important for the transport of some macromolecules (e.g. insulin, which crosses the blood–brain barrier by this process)

Routes of Administration

A route of a drug administration is the path by which a drug is brought into contact with the body

The pharmacokinetic properties of a drug are critically influenced by the route of administration

Drug must be transported from the site of entry to the part of the body where its action is desired to take place

The administration of a drug is a fundamental responsibility of the nurse. An understanding of the basic concepts of administering drugs is critical if the nurse is to perform this task safely and accurately

The nurse must have factual knowledge of each drug given, the reasons for its use, the drug’s general action, the more common adverse reactions of the drug, special precautions in administration, and the normal dose ranges.

It also is important for the nurse to take patient considerations, such as allergy history, previous adverse reactions, patient comments, and change in patient condition, into account before administering the drug.

The nurse should Always check the label of the drug three times:

1. when the drug is taken from its storage area,

2. immediately before removing the drug from the container, and

3. before returning the drug to its storage area.

I. Parenteral: desired effect is systemic. Drug is given by injection

Routes of Administration, Classification

Classification:I. Enteral (any form of administration that involves any part of the GIT): desired effect is systemic

(non-local). Drug is given via the digestive tract

II. Parenteral: desired effect is systemic. Drug is given by injection

III.Topical: desired effect is local. Drug is applied directly where its action is desired

I. Enteral:

I. by mouth (orally): many drugs such as tablets, capsules, liquids Widely used, convenient Some capsules and tablets contain sustaine-drelease drugs, which dissolve over an extended

period of time. Administration of oral drugs is relatively easy for patients who are alert and can swallow (can

not be used in unconscious patients). Certain drugs are given by the sublingual (placed under the tongue) route. These drugs must

not be swallowed or chewed and must be dissolved completely before the patient eats or drinks. Nitroglycerin is commonly given sublingually.

II. by gastric feeding tube: many drugs and for enteral nutrition

III. Rectally: various drugs in suppository or enema form The effect of digestive enzymes is avoided Useful for unconscious patients and in vomiting cases

Routes of Administration, Classification

II. Parenteral: The most common routes of parenteral drug administration the subcutaneous (SC),

intramuscular (IM), intravenous (IV), or intradermal routes.

The most common routes of parenteral drug administration the subcutaneous (SC), intramuscular (IM), intravenous (IV), or intradermal routes.

Rapid response obtained

Useful in emergencies, vomiting, and unconsciousness

The drug should be in a sterile dosage form (the nurse should pay attention to keep the drug sterile)

Routes of Administration, Classification

III. Topical: epicutaneous (application onto the skin), e.g. allergy testing, antifungal creams

inhalational, e.g. asthma medications

enema, e.g. contrast media for imaging of the bowel

eye drops (onto the conjunctiva), e.g. antibiotics for conjunctivitis

ear drops - such as antibiotics and corticosteroids for otitis externa

intranasal route (into the nose), e.g. decongestant nasal sprays

vaginal, e.g. antifungals creams

Routes of Administration, Summary

Plasma level curve

Cmax = maximal drug level obtained with the dose.

tmax = time at which Cmax occurs. Lag time = time from administration to appearance in blood. Onset of activity = time from administration to blood level reaching minimal effective concentration

(MEC). Duration of action = time plasma concentration remains greater than MEC. Time to peak = time from administration to Cmax.

2-Distribution

Distribution: Movement of drug from the central compartment (tissues) to peripheral compartments (tissues) where the drug is present.

Distribution of a drug from systemic circulation to tissues is dependent on lipid solubility , ionization, molecular size, binding to plasma proteins, rate of blood flow and special barriers

Drugs in vascular spaceDrugs are present in blood in :

1-Free form: active, diffusible, available for biotransformation and excretion.

2-Bound form (mainly to albumin): inert, non-diffusible, not available for metabolism and excretion. It acts as a reservoir for drug.Binding to plasma proteins is reversibleDrugs highly bound to plasma proteins are in general expected to persist in body longer than those less bound and are expected

to have lower therapeutic activity, less efficient distribution and less available for dialysis in poisoning.

3-Biotransformation (Metabolism) The conversion of a substance from one form to another by the actions of organisms or enzymes. Phases of biotransformation:

Phase I (Non-synthetic) reactions: introduction or unmasking of functional group by oxidation, reduction or hydrolysis. These reactions may result in :

1-Drug inactivation (most of drugs)

2-Conversion of inactive drug into active metabolite (cortisone→ cortisol)

3- Conversion of active drug into active metabolite (phenacetin→ paracetamol)

4-Conversion to toxic metabolite (methanol → formaldehyde)

Phase II (Synthetic) reactions: Functional group or metabolite formed by phase I is masked by conjugation with natural endogenous constituent as glucuronic acid, glutathione, sulphate, acetic acid, glycine or methyl group. These reactions usually result in in drug inactivation with few exceptions e.g. morphine-6- conjugate is active Most of drugs pass through phase I only or phase II only or phase I then phase II. Some drugs as isoniazid passes first through phase II then phase I (acetylated then hydrolyzed to isonicotinic acid).

4- Excretion of drugs

It is the process by which a drug or metabolite is eliminated from the body

Routes of excretion1- Renal Excretion: It is the result of three processes:

Passive glomerular filtration, active tubular secretion in proximal tubules and passive tubular reabsorption.

2-Gastrointestinal Tract:

a. Salivary glands

b. Stomach

c. Large intestine

d. Liver through bile

3-Sweat

4-Lungs

5-Milk