PHARMACOKINETICS

INTRODUCTION:

The scope of pharmacy practice includes more traditional roles such as compounding and

dispensing medications, and it also includes more modern services related to health care,

including clinical services, reviewing medications for safety and efficacy, and providing drug

information. Pharmacists, therefore, are the experts on drug therapy and are the primary health

professionals who optimize medication use to provide patients with positive health outcomes.

The word pharmacy is derived from its root word pharma which was a term used since the 15th–

17th centuries. In addition to pharma responsibilities, the pharma offered general medical advice

and a range of services that are now performed solely by other specialist practitioners, such as

surgery and midwifery. The pharma (as it was referred to) often operated through a retail shop

which, in addition to ingredients for medicines, sold tobacco and patient medicines. The pharmas

also used many other herbs.

In its investigation of herbal and chemical ingredients, the work of the pharma may be regarded

as a precursor of the modern sciences of chemistry and pharmacology, prior to the formulation of

the scientific method.

An establishment in which pharmacy (in the first sense) is practiced is called a pharmacy,

chemists or drug store.

The etymological roots are: pharmakon (Greek), “drug;” and vigilare (Latin), “to keep awake or

alert, to keep watch.”

TERMINOLOGY:

Pharmacy is the health profession that links the health sciences with the chemical sciences and it

is charged with ensuring the safe and effective use of pharmaceutical drugs. The word derives

from the Greek word (pharmakon), meaning "drug" or "medicine”

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Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic

variation on drug response in patients by correlating gene expression or single-nucleotide

polymorphisms with a drug's efficacy or toxicity.

Pharmacogenomics is the whole genome application of pharmaco genetics, which examines the

single gene interactions with drugs.

Pharmacogenomics is being used all critical illnesses like cancer, cardio vascular disorders, HIV,

tuberculosis, asthma, and diabetes.

Pharmacodynamics is the study of the physiological effects of drugs on the body or on

microorganisms or parasites within or on the body and the mechanisms of drug action and the

relationship between drug concentration and effect.

Pharmacovigilance (abbreviated PV or PhV) is the pharmacological science relating to the

detection, assessment, understanding and prevention of adverse effects, particularly long term

and short term side effects of medicines with a view to:

identifying new information about hazards associated with medicines

preventing harm to patients.

Pharmacognosy is the study of medicines derived from natural sources.

The American Society of Pharmacognosy defines pharmacognosy as "the study of the physical,

chemical, biochemical and biological properties of drugs, drug substances or potential drugs or

drug substances of natural origin as well as the search for new drugs from natural sources.

The terms pharmacogenomics and pharmacogenetics tend to be used interchangeably.

DEFINITION:

Pharmacokinetics, sometimes abbreviated as PK, (derived from Ancient Greek pharmakon

"drug" and kinetikos "to do with motion";) is a branch of pharmacology dedicated to the

determination of the fate of substances administered externally to a living organism.

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Pharmacokinetics is the study of the fate of a pharmaceutical product (drug) when administered

to a living organism. The word is derived from the term "pharmacon", meaning drug or the

science of preparing and dispensing medicines, and "kinetics", meaning motion.

The study of the action of a drug in living cells or organisms can include the rate of absorption,

which organs it migrates to, whether or not it is metabolized or simply excreted/eliminated. This

is the main focus of Phase I clinical trials, which use healthy volunteer test subjects to study the

pharmacokinetics of a new drug. These studies also evaluate the consequences of ingestion,

injection, absorption or other modes of exposure to the drug, since some pharmaceuticals can

interfere with normal metabolic processes, through various modes of action that include inducing

or inhibiting biochemical reactions, competing with enzymes for active sites, or binding to DNA

to initiate or prevent transcription.

Pharmacokinetics is often studied in conjunction with pharmacodynamics. Pharmacokinetics

includes the study of the mechanisms of absorption and distribution of an administered drug, the

rate at which a drug action begins and the duration of the effect, the chemical changes of the

substance in the body (e.g. by enzymes) and the effects and routes of excretion of the metabolites

of the drug.

Pharmacokinetics is the study of what the body does to a drug.

Pharmacodynamics is the study of what a drug does to the body.

PHARMACOKINETIC PROCESS:

All pharmacokinetic process involves transport of the drug across biological membranes. Drugs

are transported across the membranes by:

Passive diffusion and filtration.

Specialized transport.

PASSIVE DIFFUSION:

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The drug diffuses across the membrane in the direction of its concentration gradient, the

membrane playing no active role in the process. Lipid soluble drugs acts through this process.

FILTRATION:

It is passage of drugs through aqueous pores in the membrane or through paracellar spaces. Lipid

insoluble drugs takes place through this action.

SPECIALISED TRANSPORT:

This can be carrier mediated or by pinocytosis.

Carrier mediated: the drug combines with a carrier present in the membrane and the complex

then translocates from one face of the membrane to another. The carriers for polar molecules

appear to form a hydrophobic coating over the hydrophilic groups and thus facilitate passage

through the membrane. This is of two types:

Active transport

Facilitated diffusion.

Active transport: movement occurs against the concentration gradient, needs energy and is

inhibited by metabolic poisons. It results in selective accumulation of the substance on one side

of the membrane. Eg: levodopa.

Facilitated diffusion: this proceeds more rapidly than simple diffusion and translocates even non

diffusible substrates, but along their concentration gradient, therefore, does not need energy.

Pinocytosis: it is the process of transport across the cell in particulate form by formation of

vesicles.

ABSORPTION:

Absorption is the movement of drug from its site of administration into the circulation. Except

when given through IV the drug has to cross biological membranes. Factors affecting absorption

are:

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Aqueous solubility: drugs given in solid form must dissolve in the aqueous biophase before they

are absorbed. Obviously a drug given as watery solution is absorbed faster than from dilute

solution.

Concentration: passive transport depends on concentration gradient. Drug given a concentrated

solution is absorbed faster than the diluted solution.

Area of absorbing surface: larger it is faster the absorption.

Vascularity of the absorbing surface: blood circulation removes the drug from the site of

absorption and maintains the concentration gradient across the membrane. Increased blood flow

hastens drug absorption.

Route of administration: this affects drug absorption, because each route has its own

peculiarities.

ORAL: the effective barrier to orally administered drugs is the epithelial lining of the

gastrointestinal tract, which is lipoidal. Acidic drugs eg: salicylates are predominantly unionized

in the acid gastric juice and are absorbed from stomach, while basic drugs eg: morphine are

largely ionized and are absorbed only on reaching the duodenum. However even for acidic drugs

absorption from stomach is slower, because the mucosa is thick covered with mucus and the

surface area is small. Thus faster gastric emptying accelerates drug absorption in general.

SUBCUTANEOUS AND INTRAMUSCULAR: By these routes the drug is deposited directly in

the vicinity to the capillaries. Lipid soluble drugs pass readily across the whole surface of the

capillary endothelium. Capillary highly porous do not obstruct absorption of even large lipid

insoluble molecules or ions. Very large molecules are absorbed through lymphatics. Thus many

drugs not absorbed orally are absorbed parenterally.

TOPICAL SITES: (SKIN, CORNEA MUCOUS MEMBRANES):

Systemic absorption after topical application depends primarily on lipid solubility of the drugs.

However only few drugs significantly penetrate intact skin.

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Eg: corticosteroids applied over extensive areas can produce systemic effects and pituitary

adrenal suppression. Cornea is permeable to lipid soluble, unionized but not to highly ionized

drugs.

Mucous membranes of mouth, rectum, and vagina absorb lipophilic drugs.

CLASSIFICATION:

ADME

Pharmacokinetics is divided into several areas including the extent and rate of absorption,

distribution, metabolism and excretion. This is commonly referred to as the ADME scheme.

However recent understanding about the drug-body interactions brought about the inclusion of

new term Liberation. Now Pharmacokinetics can be better described as LADME.

Liberation - the process of release of drug from the formulation.

Absorption - the process of a substance entering the blood circulation.

Distribution - the dispersion or dissemination of substances throughout the fluids and

tissues of the body.

Metabolism - the irreversible transformation of parent compounds into daughter

metabolites.

Excretion - the elimination of the substances from the body. In rare cases, some drugs

irreversibly accumulate in body tissue.

Pharmacokinetics describes how the body affects a specific drug after administration.

Pharmacokinetic properties of drugs may be affected by elements such as the site of

administration and the dose of administered drug. These may affect the absorption rate.

Parameters

The following are the most commonly measured pharmacokinetic parameters:

Variable DescriptionExample

valueAbbreviation(s) Formula

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Dose

loading dose (LD), or steady

state /maintenance dose

(MD)

1000 mg

Volume of

distribution

The apparent volume in

which a drug is distributed

immediately after it has been

injected intravenously and

equilibrated between plasma

and the surrounding tissues.

25 L

Concentration

initial or steady-state

concentration of drug in

plasma

40.0 mg/L

Biological

half-life

The time required for the

concentration of the drug to

reach half of its original

value.

14 hr

Elimination

rate constant

The rate at which drugs are

removed from the body.0.05 /hr

Elimination

rate

rate of infusion required to

balance elimination50 mg/hr

Area under the

curve

The integral of the plasma

drug concentration (Cp) after

it is administered.

0.1

mg/mL×hr

Clearance

The volume of plasma

cleared of the drug per unit

time.

1.25 L/hr

BioavailabilityThe fraction of drug that is

absorbed.1

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Cmax

The peak plasma

concentration of a drug after

oral administration.

40.0 mg/Ldirect

measurement

Cmin

The lowest (trough)

concentration that a drug

reaches before the next dose

is administered.

1.0 mg/Ldirect

measurement

Analysis

Pharmacokinetic analysis is performed by non compartmental (model independent) or

compartmental methods. Noncompartmental methods estimate the exposure to a drug by

estimating the area under the curve of a concentration-time graph. Compartmental methods

estimate the concentration-time graph using kinetic models.

Population pharmacokinetics

Population pharmacokinetics is the study of the sources and correlates of variability in drug

concentrations among individuals who are the target patient population receiving clinically

relevant doses of a drug of interest. Certain patient demographic, pathophysiological, and

therapeutical features, such as body weight, excretory and metabolic functions, and the presence

of other therapies, can regularly alter dose-concentration relationships. For example, steady-state

concentrations of drugs eliminated mostly by the kidney are usually greater in patients suffering

from renal failure than they are in patients with normal renal function receiving the same drug

dosage.

Population pharmacokinetics seeks to identify the measurable pathophysiologic factors that cause

changes in the dose-concentration relationship and the extent of these changes so that, if such

changes are associated with clinically significant shifts in the therapeutic index, dosage can be

appropriately modified.

Software packages used in population pharmacokinetics modeling include NONMEM.

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Routes of Drug Administration:

1. Intravenous

2. Oral

3. Buccal

4. Sublingual

5. Rectal

6. Intramuscular

7. Transdermal

8. Subcutaneous

9. Inhalational

10. Topical

Of all of these routes most likely to be asked about the transdermal, as it is fashionable.

Otherwise, most other basic pharmacology questions tend to concern the pharmacology of

intravenous agents; that is what is discussed below.

First Order Kinetics:

A constant fraction of the drug in the body is eliminated per unit time. The rate of elimination is

proportional to the amount of drug in the body. The majority of drugs are eliminated in this way.

 

The Volume of Distribution (Vd) is the amount of drug in the body divided by the concentration

in the blood. Drugs that are highly lipid soluble, such as digoxin, have a very high volume of

distribution (500 litres). Drugs which are lipid insoluble, such as neuromuscular blockers, remain

in the blood, and have a low Vd.

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The Clearance (Cl) of a drug is the volume of plasma from which the drug is completely

removed per unit time. The amount eliminated is proportional to the concentration of the drug in

the blood.

The fraction of the drug in the body eliminated per unit time is determined by the elimination

constant (kel).

Rate of elimination = clearance x concentration in the blood.

Elimination half life (t1/2): the time taken for plasma concentration to reduce by 50%. After 4

half lives, elimination is 94% complete.

It can be shown that the kel = the log of 2 divided by the t1/2 = 0.693/t1/2.

Likewise, Cl = kel x Vd, so, Cl = 0.693Vd/t1/2.

And t1/2 = 0.693 x Vd / cl

The rate of elimination is the clearance times and the concentration in the plasma

Roe = Cl x Cp

Fraction of the total drug removed per unit time = Cl/Vd.

If the volume of distribution is increased, then the kel will decrease, the t1/2 will increase, but the

clearance won't change.

Example: You have a 10ml container of orange squash. You put this into a litre (990ml) of water.

The Vd of the orange squash is 1000ml. If, each minute, you empty 10ml of the orange liquid

into the 10ml container, discard this, and replace it with 10ml of water. The clearance is 10 ml

per minute. The elimination half life is: 70 minutes . The kel is Cl/Vd = 10/1000 = 0.01.

If the volume of the container is increased to 2000ml, then the clearance remains the same, but

the Vd, and consequently the t1/2, increases (to 140 minutes).

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What is described above is a single compartment model, what would occur if the bloodstream

was the only compartment in the body (or if the Vd = the blood volume). But the human body is

more complex than this: there are many compartments: muscle, fat, brain tissue etc. In order to

describe this, we use multicompartment models.

Multicompartment Models:

Why does a patient wake up after 5 minutes after an injection of thiopentone when we know that

it takes several hours to eliminate this drug from the body? What happens is that, initially the

drug is all in the blood and this blood goes to "vessel rich" organs; principally the brain. After a

few minutes the drug starts to venture off into other tissues (fat, muscle etc) it redistributes, the

concentration in the brain decreases and the patient wakes up! The drug thus redistributes into

other compartments.

If you were to represent this phenomenon graphically, you would follow a picture of rapid fall in

blood concentration, a plateau, and then a slower gradual fall. The first part is the rapid

redistribution phase, the alpha phase, the plateau is the equilibrium phase (where blood

concentration = tissue concentration), and the slower phase, the beta phase, is the elimination

phase where blood and tissue concentrations fall in tandem. This is a simple two compartment

model.

 

An couple of interesting pieces of information can be derived from the log concentration versus

time graph. If you extrapolate back the elimination line to the y axis, then you get to a point

called the CP0 - a theoretical point representing the concentration that would have existed at the

start if the dose had been instantly distributed (dose/Vd). From this new straight line you can

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figure out how long it takes for the concentration to drop by 50%: the elimination half life.

Likewise, a similar procedure can be performed on the phase: the redistribution half life.

Bioavailability

This is the fraction of the administered dose that reaches the systemic circulation. Bioavailability

is 100% for intravenous injection. It varies for other routes depending on incomplete absorption,

first pass hepatic metabolism etc. Thus one plots plasma concentration against time, and the

bioavailability is the area under the curve.

Zero Order Elimination

When a patient had ethyl alcohol before midnight he will fail a breath analyzer test at 8 am the

following morning. What happens is that the metabolic pathways responsible for alcohol

metabolism are rapidly saturated and that clearance is determined by how fast these pathways can

work. The metabolic pathways work to their limit. This is known as zero order kinetics: a

constant amount of drug is eliminated per unit time. This form of kinetics occurs with several

important drugs at high dosage concentrations: phenytoin, salicylates, theophylline, and

thiopentone (at very large doses). Because high dose this is very slow to clear, we no longer use it

in infusion for status epileptic us

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Dosage regimens

The strategy for treating patients with drugs is to give sufficient amounts that the required

therapeutic effect arises, but not a toxic dose.

The maintenance dose is equal to the rate of elimination at steady state (i.e.at steady state, rate of

elimination = rate of administration):

Dosing rate = clearance x desired plasma concentration.

Drugs will accumulate within the body if the drug has not been fully eliminated before the next

dose. Steady state concentration is thus arrived at after four half lives.

The loading dose = the volume of distribution x the desired concentration (i.e. the

concentration at steady state).

Hepatic Drug Clearance

Many drugs are extensively metabolized by the liver. The rate of elimination depends on 1) The

liver's inherent ability to metabolize the drug, 2) the amount of drug presented to the liver for

metabolism. This is important because drugs administered orally are delivered from the gut to the

portal vein to the liver: the liver gobbles up a varying chunk of the administered drug (pre-

systemic elimination) and less is available to the body for therapeutic effect. This is why you

have to give a higher dose of morphine, for example, orally, than intravenously.

Hepatic drug clearance (i.e. the amount of each drug gobbled up by the liver) depends on:

1) The Intrinsic clearance (Cl int).

2) Hepatic blood flow.

These two factors are independent of one another, and their combined effect is the proportion of

drug gobbled up: the extraction ratio.

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For drugs that have a low intrinsic clearance, this effect can be increased by giving a second

agent that boosts the effect of the liver's enzyme system; these are enzyme inducers. Examples of

such drugs are antiepileptic (carbamazepine & phenytoin), rifampicin, alcohol and spironolactone

[also barbiturates]. Enzyme inhibitors have the opposite effect: examples are flagyl, allopurinol,

cimetidine, and erythromycin.

Likewise, if the blood flow increases, the liver has less chance to gobble up the drug, and the

extraction ratio falls. This is particularly the case, as you would expect, of the intrinsic clearance

is low.

Drug distribution

Once a drug has gained access to the blood stream, it gets distributed to other tissues that initially

had no drug, concentration gradient being in the direction of plasma to tissues.

Apparent volume of distribution (V);

V= dose administered i.v

-----------------------------

Plasma concentration.

Redistribution: highly lipid soluble drugs given iv or by inhalation initially get distributed to

organs with high blood flow eg. Brain, heart, kidney etc. later, less vascular but more bulky

tissues (muscle, fat) take up the drug- plasma concentration falls and the drug is withdrawn from

these sites.

Penetration into brain and CSF: the capillary endothelial cells in brain have tight junctions and

lack large intercellular pores. Further an investment of neural tissue covers the capillaries.

Together they constitute so called blood brain barrier. A similar blood CSF barrier is located in

the choroid plexus. Both these barriers are lipoidal and limit the entry of entry of non lipid

soluble drugs. Eg: streptomycin, neostigmine. Only lipid soluble drugs are therefore are able to

penetrate and have action on the central nervous system.

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Passage across placenta: placental membranes are lipoidal and allow free passage of lipophilic

drugs, while restricting hydrophilic drugs. The placental efflux P-glycoprotein also serves to limit

fetal exposure to maternally administered drugs.

TISSUE STORAGE:

Drugs may also accumulate in specific organs or get bound to specific tissue constituents.

organ Drug

Skeletal muscle, heart Digoxin,emetine (to muscle proteins)

liver Chloroquine, digoxin.

kidney Chloroquine, digoxin.

thyroid Iodine

brain Isoniazid, chlorpromazine.

retina Chloroquine

iris Atropine, ephedrine.

Bone and teeth Tetracyclines, heavy metals.

Adipose tissue Thiopentone, ether.

When a drug is introduced into the body, where it ends up depends on a number of factors:

1) blood flow, tissues with the highest blood flow receive the drug first,

2) protein binding, drugs stuck to plasma proteins are crippled, they can only go where the

proteins go

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3) lipid solubility and the degree of ionization, this describes the ability of drugs to enter tissues

(highly lipid soluble / unionized drugs can basically go anywhere).

Protein Binding

Most drugs bind to proteins, either albumin or alpha-1 acid glycoprotein (AAG), to a greater or

lesser extent. Drugs prefer to be free, it is in this state that they can travel throughout the body, in

and out of tissues and have their biological effect. The downside of this is that they are easy prey

for metabolizing enzymes.

The amount of albumin does not appear to be hugely relevant. In disease states such as sepsis, the

serum albumin drops drastically, but the free drug concentration does not appear to increase.

Degree of ionization

This is really important with regard to local anesthetics. The essential fact to know is that highly

ionized drugs cannot cross lipid membranes (basically they can't go anywhere) and unionized

drugs can cross freely. Morphine is highly ionized, fentanyl is the opposite. Consequently the

latter has a faster onset of action. The degree of ionization depends on the pKa of the drug and

the pH of the local environment. The pKa is the pH at which the drug is 50% ionized. Most drugs

are either weak acids or weak bases. Acids are most highly ionized at a high pH (i.e. in an

alkaline environment). Bases are most highly ionized in an acidic environment (low pH). For a

weak acid, the more acidic the environment, the less ionized the drug, and the more easily it

crosses lipid membranes. If you take this acid, at pKa it is 50% ionized, if you add 2 pH points to

this (more alkaline), it becomes 90% ionized, if you reduce the pH (more acidic) by two units, it

becomes 10% ionized. Weak bases have the opposite effect.

Local anesthetics are weak bases: the closer the pKa of the local anesthetic to the local tissue pH,

the more unionized the drug is. That is why lignocaine (pKa 7.7) has a faster onset of action than

bupivicaine (pKa 8.3). If the local tissues are alkalinized (e.g. by adding bicarbonate to the local

anesthetic), then the tissue pH is brought closer to the pKa, and the onset of action is hastened.

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BIOTRANSFORMATION:The primary site for drug metabolism is liver; others are kidney, intestine, lungs and plasma. Bio

transformation of drugs may lead to the following:

Inactivation: most drugs and their active metabolites are rendered inactive or less active. Eg:

morphine.

Active metabolite from an active drug: many drugs have been found to be partially converted

to one or more active metabolite. The effects observed are the sum total of that due to the parent

drug and its active metabolites.

Activation of inactive drug: few drugs are inactive as such and need conversion in the body to

one or more active metabolites. Such a drug is called a pro drug.

Bio transformation reactions can be classified into:

Non synthetic /phase I reactions- metabolite may be active or inactive.

Synthetic/conjugation/phaseII reactions-metabolite is mostly inactive.

Non synthetic reactions:

Oxidation: this reaction involves addition of oxygen / negatively charged radical or removal of

hydrogen/positively charged radical. Oxidations are the most important drug metabolizing

reactions.

Ex:paracetamol, phenothiazines.

Reduction: this reaction is the converse of oxidation and involves cytochrome P-450 enzymes

working in the opposite direction. Ex: halothane.

Hydrolysis: this is cleavage of drug molecule by taking up a molecule of water. It occurs in liver,

intestines, plasma and other tissues.

Cyclization: this is formation of ring structure from a straight chain compound. Eg: proguanil.

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Decyclization: this is opening up of ring structure of the cyclic drug molecule ex: barbiturates.

SYNTHETIC REACTIONS:

These involve the conjugation of the drug or its phase I metabolite with an endogenous substrate,

generally derived from carbohydrate or amino acid, to form a polar highly ionized organic acid

which is easily excreted in the urine or bile.

Glucuronide conjugation: compounds with a hydroxyl or carboxylic group are easily

conjugated with a glucuronic acid which is derived from glucose. Ex: Morphine.

Acetylation: compounds having amino or hydrazine residues are conjugated with the help of

acetyl coenzyme. Ex: sulphonamides.

Methylation: the amines and phenols can be methylated Ex: adrenaline

Sulphate conjugation: the phenolic compounds and steroids are suphated by the suphokinases.

Ex: chloramphenicol.

Glycine conjugation: salicylates and other drugs having carboxylic acid group are conjugated

with glycine, but this is not a major pathway of metabolism.

Ribo nucleoside or nucleotide synthesis: it is important for the activation of many purine and

pyrimidine antimetabolites used in cancer chemotherapy.

EXCRETION:

Excretion is the passage out of systematically absorbed drug. Drugs and their metabolites are

excreted in

Urine

Faeces

Exhaled air

Saliva

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Sweat

Milk

Urine: it is the most important channel of excretion of most drugs.

Renal excretion: the kidney is responsible for all water soluble substances. The amount of drug

or its metabolites ultimately present in urine is the sum total of glomerular filtration, tubular re

absorption and tubular secretion.

Glomerular filtration: Glomerular capillaries have pores larger than usual; all protein bound

drug (whether lipid soluble or insoluble) presented to the glomerulus is filtered. Thus it depends

on the plasma protein binding and renal blood flow.

Tubular re absorption: this depends upon the lipid solubility and the ionization of the drug at

the existing urinary PH. Lipid soluble drugs filtered at the glomerulus diffuse back in the tubules

because 99% of glomerular filtrate is re absorbed, but lipid insoluble and highly ionized drugs are

unable to do so. Thus rate of excretion of drug such as amino glycoside antibiotics parallels

GFR.

Tubular secretion: this is the active transfer of organic acids and bases by two separate non

specific mechanisms which operate in the proximal tubules.

Organic acid transport: penicillin, salicylates.

Organic base transport: thiazides, cimetidine.

Both transport process are bi directional i.e they can transport their substrates from blood to

tubular fluid and vice versa.

Faeces: apart from unabsorbed fraction, most of the drug present in faeces is derived from bile.

Liver actively transports into bile organic acids (especially glucoranides), organic bases and

steroids by separate non specific active transport mechanisms. Relatively larger molecules are

eliminated in the bile most of the drug including that released by deconjugation of glucoranides

by bacteria in the intestine is reabsorbed.

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Ex: erythromycin, ampicillin.

Certain drugs excreted directly in the colon. Eg: purgatives.

Exhaled air: gases and volatile liquids are eliminated by lungs, irrespective of their lipid

solubility. Alveolar transfer of the gas/vapour depends on its partial pressure in the blood.

Saliva and sweat: these are of minor importance for drug excretion. Lithium, heavy metals and

rifampicin are excreted through these secretions.

Milk: the excretion of drug is not important for the mother, but the suckling infant inadvertently

receives the drug. Most drugs enter breast milk by passive diffusion. Lipid soluble and less

protein bound drugs cross better.

Ex: morphine, monteleukast, theophylline.

PROLONGATION OF DRUG ACTION:

It is sometimes advantageous to modify a drug in such a way that it acts for a longer period. By

doing so,

Frequency of administration is reduced.

Improved patient compliance.

Large fluctuations in plasma concentration.

Drug effect could be maintained overnight without disturbing sleep.

By prolonging absorption from site of administration:

Oral: by administering sustained release tablets.

Parenteral: subcutaneous and intramuscular injections in insoluble form (ex: lente insulin) or as

oily solution (depot progestin) and inclusion of vasoconstrictor with the drug (adrenaline with

local anesthetics).

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Transdermal: the drugs impregnated in adhesive patches, strips or as ointment applied on the skin

ex: nitroglycerine.

By retarding rate of metabolism: small chemical modification markedly affects the rate of

metabolism without affecting the biological action. Ex : addition of ethinyl group to estradiol

makes it longer acting and suitable for use as oral contraceptive.

By retarding renal excretion: the tubular secretion of drug being an active process can be

suppressed by a competing substance ex: probenecid prolongs the action of penicillin and

ampicillin.

EXAMPLE FOR AMLODIPINE:

Amlodipine is a dihydropyridine calcium antagonist drug with distinctive pharmacokinetic

characteristics which appear to be attributable to a high degree of ionisation. Following oral

administration, bioavailability is 60 to 65% and plasma concentrations rise gradually to peak 6 to

8h after administration. Amlodipine is extensively metabolised in the liver (but there is no

significant presystemic or first-pass metabolism) and is slowly cleared with a terminal

elimination half-life of 40 to 50h. Volume of distribution is large (21 L/kg) and there is a high

degree of protein binding (98%). There is some evidence that age, severe hepatic impairment and

severe renal impairment influence the pharmacokinetic profile leading to higher plasma

concentrations and longer half-lives. There is no evidence of pharmacokinetic drug interactions.

Amlodipine shows linear dose-related pharmacokinetic characteristics and, at steady-state, there

are relatively small fluctuations in plasma concentrations across a dosage interval. Thus, although

structurally related to other dihydropyridine derivatives, amlodipine displays significantly

different pharmacokinetic characteristics and is suitable for administration in a single daily dose.

ROLE OF NURSE:

1.Rightclient

2.right drug

3.right dose

4.right time

5. Right route

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5 Additional Rights

1. right assessment

2. right documentation

3. client’s right to education

4. right evaluation

5. client’s right to refuse

A. Right Client

Nurse must do:

verify client check ID bracelet & room number

have client state his name

distinguish between 2 client’s with same last names

B. Right Drug

Components of a drug order:

1.date & time the order is written

2.drug name (genericpreferred)

3.drug dosage

4.frequency & duration of administration

5.any special instructions for withholding or adjusting dosage.

6.physician or other health care provider’s signature or name.

7.signature of licensed practitioner.

Nurse must do:

• check medication order is complete & legible.

• know general purpose or action, dosage & route of drug

• compare drug card with drug label three times.

1. at time of contact with drug bottle/ container

2. before pouring drug

3. after pouring drug

4 Categories of Drug Orders:

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Standing Order / Routine Order

ongoing order

may have special instructions to base administration

include PRN orders

ex. digoxin 0.2 mg PO q.d., maintain blood level at 0.5 – 2.0 ng/ml

2.One-time (single) order

given only once, at a specific time

ex. Cefixime 2mg IM at 7 AM on 12-1-05

3. PRN order

given at client’s request & nurse’s judgement for need & safety

ex Mefenamic Acid 500mg q 4h PRN for pain

4. STAT order

given once, immediately

ex. Morphine 2mg IV STAT

C. Right Dose

Nurse must do:

Calculate and check drug dose accurately.

Check PDR, drug package insert or drug handbook for recommended range of

specific drugs.

D. Right Time

Nurse must do:

Administer drugs at specified times.

Administer drugs that are affected by foods, before meals.

Administer drugs that can irritate stomach, with food.

Drug administration may be adjusted to fit schedule of client’s lifestyle, &

activities. & diagnostic procedures.

Check expiration date.

Antibiotics should be administered at even intervals. 23

E. Right Route

Nurse must do:

assess ability to swallow before giving oral meds.

Do not crush or mix meds in other substances before consultation with

physician or pharmacist

Use aseptic technique when administering drugs.

Administer drug at appropriate sites.

Stay with client until oral drugs have been swallowed.

F. Right Assessment

Get baseline data before administration.

Assess the colour of the urine, sweat etc.

Check blood urea , creatinine level for nephrotoxic drugs.

Investigate for liver function if the drug is acting through liver.

Check for any adverse reactions.

G. Right Documentation

Immediately record appropriate information

• Name, dose, route,time & date, nurse’s initial or signature

Client’s response:

• narcotics

• analgesics

• antiemetics

• sedatives

unexpected reactions to medications.

Use correct abbreviations & symbols.

H. Right to Education

Client teaching :

• therapeuticpurpose

• side-effects

• diet restrictions or requirements

• skill of administration

• laboratory monitoring

Principle of Informed Consent 24

I. Right Evaluation

client’s response to medications.

effectiveness

extent of side-effects or any adverse reactions.

J. Right to Refuse

Nurse must do:

determine, when possible, reason for refusal.

explain risk for refusing medications & reinforce the reason for medication.

Refusal should be documented immediately.

Head nurse or health care provider should be informed when omission pose

Reference:biotech.about.com/od/.../g/pharmacokin.htm

http://www.4um.com/tutorial/science/pharmak.htm

25

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