PK,PD and fate of drug.

Drug action in the body

Dr. Tosi
 Definitions
• Pharmacokinetics
– The process by which a drug is absorbed,
distributed, metabolized and excreted
by the body
– Is a study of what the body does to a
drug
-In Pharmacokinetics an attempt is made to
quantify the various dispositional
parameters regarding;
• Absorption
• Distribution ADME
• Metabolism
• Excretion
 ABSORPTION
• In general, for a drug to reach its intended target, the
drug must be present in the bloodstream (an
exception is application of drug for local effects such
as local anesthesia).
• Thus, absorption of drugs refers to the process
where by an amount of a drug reaches the general
circulation from its site of administration.
• The fraction of unchanged drug reaching the
systemic circulation is expressed as the
bioavailability.
Figure 2-3 Factors affecting bioavailability of drugs.
 Routes of Administration
• Routes of administration greatly affect bioavailability
by changing the number of biologic barriers a drug
must cross or by changing the exposure of drug to
pumping and metabolic mechanisms.
• Enteral administration involves absorption of the drug
via the GI tract and includes oral, gastric or duodenal
(e.g., feeding tube), and rectal administration
• Parenteral administration refers to any routes of
administration that do not involve drug absorption via
the GI tract (par = around, enteral = gastrointestinal),
including the IV, intramuscular (IM), subcutaneous (SC
or SQ), and transdermal routes.
Figure 1-2 Drugs administered sublingually and rectally avoid
"first-pass metabolism" in the liver.
• The first-pass effect(first- pass metabolism or
pre systemic metabolism) is a phenomenon of
drug metabolism whereby the concentration
of a drug is greatly reduced before it reaches
the systemic circulation.
 DISTRIBUTION
• After absorption into the bloodstream, drugs
are distributed to the tissues via blood flow
and diffusion and/or filtration across the
capillary membranes of various tissues.
• Initial distribution is determined by cardiac
output and regional blood flow.
– ▴ Drugs are initially distributed to tissues with the
highest blood flow (e.g., brain, lungs, kidney, and
liver).
– ▴ Tissues with lower blood flow (e.g., fat) receive
drugs later.
• Distribution to some tissue compartments is
restricted by barriers.
– ▴ The blood-brain barrier restricts distribution of
hydrophilic drugs into the brain.
Drug Redistribution
• After the initial distribution to high-blood flow
tissues, drugs redistribute to those tissues for
which they have affinity.
• Drugs may sequester in tissues for which they have
affinity.
• These tissues may then act as a sink for the drug
and increase its apparent volume of distribution
(see later).
• In addition, as plasma concentrations of drug fall,
the tissue releases drug back into the circulation,
thus prolonging the duration of action of the drug.
• In addition to specific molecular targets, drugs
show varying degrees of binding to different
components in body compartments.
• This type of binding can play an important role
in a drug's pharmacokinetic profile and in drug
interactions.
 Plasma Protein Binding
• Plasma proteins, such as albumin, α-
glycoprotein, and steroid hormone binding
globulins, exhibit affinity for a number of
drugs.
• Binding to plasma protein is generally
reversible
• Plasma protein binding greatly reduces the
amount of drug free in the plasma.
• Only free drug in the plasma is able to diffuse
to its molecular site of action.
• Thus plasma protein binding can greatly
reduce the concentration of drug at the sites
of action and necessitate larger doses.
• For highly protein-bound drugs, a small change in
plasma protein binding can lead to a large change
in the proportion of free drug in the plasma and
may lead to toxicity.
– ▴ For a drug that is 99% bound to plasma protein, only
1% is free in the plasma. Reduction of plasma protein
binding to 98% results in a doubling of free drug and
drug effect.
• Changes in plasma protein binding can occur as a
result of:
– ▴ Disease
– ▴ Competition between drugs for the same binding site
– ▴ Saturation of binding sites
 Tissue Binding
• Similarly to binding to plasma proteins, drugs
may also bind to individual components of
tissues.
• Binding to tissues results in sequestration of
drug in the tissue.
 ELIMINATION
• Drugs are eliminated from the body via two
basic mechanisms: biotransformation
(metabolism) and excretion.
• These processes are initiated as soon as the
drug reaches the systemic circulation.
 METABOLISM
• Many drugs are lipophilic molecules that
resist excretion via the kidney or gut because
they can readily diffuse back into the
circulation.
Figure 2-6 Renal mechanisms in drug excretion .
• Biotransformation is an essential step in
eliminating these drugs by converting them to
more polar water-soluble compounds.
• There are several different biotransformation
pathways that drug molecules may follow
Figure 2-5 Drug biotransformation pathways.
 Biotransformation:

• May convert drugs to inactive metabolites, thus

terminating their actions
• May convert drugs to active metabolites that may have the
same or different beneficial actions as the parent drug
• May convert inactive drug molecules (prodrugs) to active
drugs
• May convert drugs to reactive intermediates that exert toxic
effects
• Occurs in many tissues including the kidney, gut, and lungs,
but for most drugs the liver is the major site of
biotransformation
• Two major processes contribute to
biotransformation of drugs.
– Phase I Reactions
– Phase II Reactions
 Phase I Reactions
• Phase I reactions are also called oxidation-
reduction reactions or handle reactions.
• These reactions uncover or add a reactive
group to the drug molecule through oxidation,
reduction, or hydrolysis.
• They make the drug molecule more polar and
more reactive, which facilitates excretion or
further biotransformation of the drug through
phase II reactions.
• Oxidation accounts for a large proportion of
drug metabolism.
• It is mediated primarily by mixed function
oxygenases (monooxygenases; microsomal
mixed function oxidases) located in
endoplasmic reticulum, which include the
following:
– ▴ Cytochrome P-450 (CYP) family of enzymes
– ▴ Flavin monooxygenase family of enzymes
– ▴ Hydrolytic enzymes (e.g., epoxide hydrolase)
 Phase II Reactions
• Phase II reactions are also called conjugation
reactions.
– These reactions add a polar group, such as
glucuronide, glutathione, acetate, or sulfate, to the
drug molecule.
– They increase the water solubility of compounds to
facilitate excretion.
– Generally they inactivate the drug but in some cases
can produce active metabolites (e.g., conversion of
procainamide to N-acetylprocainamide).
• Conjugation reactions can occur:
– ▴ Directly with the parent drug molecule or
– ▴ With a reactive intermediate generated by phase
I reactions.
 Drug Excretion
• Drug excretion refers to the removal of drug from
the body.
• Generally, only hydrophilic molecules are
excreted effectively.
• Accordingly, drugs may be excreted as
unchanged parent molecules if they are
sufficiently hydrophilic.
• Lipophilic drugs must be biotransformed to
hydrophilic drug metabolites to be excreted.
• Drug may be excreted via a number of routes,
such as the kidney or in bile, sweat, and breast
milk.
• The lungs are an excretion route by which
volatile lipophilic substances (e.g., inhaled
general anesthetics) can be excreted.
• Changes in excretion rates will affect the
plasma concentration of drugs and their
metabolites and thus play an important role in
the design of drug regimens.
 RENAL EXCRETION
• Renal excretion is quantitatively the most
important route of excretion for most drugs
and drug metabolites.
• Renal excretion involves three processes:
glomerular filtration, tubular secretion,
and/or tubular reabsorption.
• The sum of these processes determines the
extent of net renal drug excretion.
Figure 2-6 Renal mechanisms in drug excretion .
 DRUG ACTION IN THE BODY
• Pharmacodynamics
– The interactions of a drug and the receptors
responsible for its action in the body
– Is a study of what the drug does to the body
• Drug molecules must be ‘bound’ to
particular constituents of cells and tissues
inorder to produce an effect
• The sites where drug molecules are bound
are called drug targets
• Most drug targets are protein molecules
• Other targets include DNA (antimicrobial
and antitumour drugs) and calcium salts
(biphosphonates)
 Protein targets for drug binding
• Four main kinds of regulatory protein
commonly involved as primary drug targets
– Receptors
– Enzymes
– Carrier molecules (transporters)
– Ion channels
 Drug receptors
• Definition in pharmacology: target molecule
through which soluble physiological mediators
(hormones, neurotransmitters, inflammatory
mediators, e.c.t) produce their effects.
• Other macromolecules with which drugs
interact to produce their effects are known as
drug targets
 Drug specificity

• To be useful as either a therapeutic or scientific tool,

a drug must act selectively on particular cells and
tissues (show high degree of binding site specificity)
• Proteins that function as drug targets generally show
a high degree of ligand specificity – will ignore closely
related molecules
• Example: angiotensin acts strongly on vascular
smooth muscle and kidney tubules but very little
effect on other kinds of smooth muscle or intenstinal
epithellium
• However, no drug acts with complete specificity
• In general, the lower the potency of a drug, and the
higher the dose needed, the more likely is that sites
of action other than the primary one will assume
significance
 Drug receptor interactions
• When drug molecule occupies a receptor, the
receptor may or may not be activated
• Receptor activation: the bound drug molecule
influences the receptor to elicit a tissue
response
• Binding and activation are two distinct steps of
the receptor-mediated tissue response
 Concepts used to characterise drug
effects
• Receptor agonist: a drug which upon binding to
a receptor causes its activation
• Receptor antagonist: a drug which binds to a
receptor without causing activation thereby
preventing the agonist from binding
• Affinity of a drug: something which governs the
tendency of the drug to bind to the receptors
• Efficacy of a drug: something governing the tendency
to for the drug, once bound, to activate the receptor
• Drugs of high potency: generally have high affinity to
the receptors occupying a significant proportion of the
receptors even at low concentration
• Agonists possess high efficacy
• Antagonists have, in the simplest case, zero efficacy
• Partial agonists: drugs with intermediate level of
efficacy, even at 100 % receptor occupancy the tissue
response is submaximal
• Full agonists: drugs with sufficient efficacy that they
can elicit a maximal tissue response
• Full agonists: can produce a maximal response
(the largest response that the tissue is capable
of giving)
• Partial agonists: can produce only a
submaximal response
• The difference between full and partial
agonists lies in the relationship between
receptor occupancy and response
• The response at any given occupancy is much
smaller for the partial agonist (cannot produce
maximal response even at 100 % occupancy)
 Measurement of drug effects
• Biological response measured by varying drug
concentration and observing tissue response
in an organ or tisssue bath
• This is often plotted as a concentration-effect
or dose-response curve
 Uses of the dose-response curve

• Estimation of the maximal response that the

drug can produce (Emax)
• Estimation of the concentration or dose needed
to produce 50 % of maximal response (EC50 or
ED50)
• These parameters are useful in comparing
potencies of different drugs that produce
qualitatively similar effect
Figure 2-3 Experimentally observed concentration-effect curves. Although the lines, drawn according to the binding equation 2.5, fit the points well, such curves do not give correct
estimates of the affinity of drugs for receptors. This is because the relationship between receptor occupancy and response is usually non-linear.
 DRUG ANTAGONISM
• Drugs interfere each other’s action
• Frequently, the effect of one drug is diminished or
completely abolished in the presence of another
• The mechanisms through which drugs do this may be
classified as follows
– Chemical antagonism
– Pharmacokinetic antagonism
– Antagonism by receptor block
– Non-competitive antagonism (block of receptor-effector
linkage)
– Physiological antagonism
Antagonism by receptor block
Physiological antagonism
 Desensitisation and Tachyphylaxis
• Synonymous terms used to describe the
phenomenon whereby the effect of a drug
diminishes when it is given continously or
repeatedly.
• Desensitisation often develops within few
minutes
• Tolerance, conventionally describe a more
gradual decrease in responsiveness taking
days or weeks to develop
• Drug resistance, describe the loss of
effectiveness of antimicrobial or antitumour
drugs
• Mechanisms through which desensitasation
develops include
– Change in receptors
– Loss of receptors
– Exhaustion of mediators
– Increased metabolic degradation of the drug
– Physiological adaptation
– Active extrusion of drug from cells (mainly
relevant in cancer chemotherapy
The End!!