This document discusses the key concepts of pharmacokinetics including absorption, distribution, metabolism, and excretion of drugs in the body. It describes how drugs move across cell membranes via passive diffusion or active transport. Factors like a drug's molecular properties, route of administration, blood flow, and first-pass metabolism affect its absorption and bioavailability. Distribution of drugs is determined by tissue perfusion and solubility. Metabolism and excretion occur mainly in the liver and kidneys and allow elimination of drugs from the body.

1. DR. RANIA ABDULLAH

2. PHARMACOKINETICS
Pharmacokinetics defines the relationships
among
drug dosing, drug concentration in body fluids
and tissues, and time.
It consists of four linked processes:
 Absorption
Distribution
Biotransformation
Excretion

3. TRANSFER OF DRUGS ACROSS
MEMBRANES
Drug absorption, distribution, metabolism, and
excretion of drugs all require transfer of
drugs across cell membranes. Most drugs must also
traverse cell membranes to reach their sites of action.
Biologic membranes consist of a lipid bilayer with a
nonpolar core and polar elements on their surfaces.
The nonpolar core hinders the passage of water-
soluble molecules, so that only lipid soluble
molecules easily traverse cell membranes.

4. Transport Processes
Drugs can cross cell membranes either by passive
processes or by active transport. Passive
diffusion occurs when a concentration gradient
exists across a membrane. The rate of passive
transfer is directly proportional to the
concentration gradient and the lipid solubility of
the drug.
Passage of water-soluble drugs is restricted to small
aqueous channels through the membrane.

5. Effects of Molecular Properties
Almost all drugs are either weak acids or weak
bases, and are present in both ionized and
nonionized forms at physiologic pH.
The nonionized form is more lipid
soluble and able easily to traverse cell membranes..

6. Absorption
Absorption defines the processes by which a drug
moves from the site of administration to the
bloodstream.
There are many possible routes of drug
administration:
oral, sublingual, rectal, inhalational, transdermal,
transmucosal, subcutaneous, intramuscular, and
intravenous.

7. Except after intravenous (iv) injections, drugs must be
absorbed into the circulation before they
can be delivered to their sites of action. Therefore,
absorption is an important determinant of both
the intensity and duration of drug action. Incomplete
absorption limits the amount of drug reaching the site
of action, reducing the peak pharmacologic effect.
Rapid absorption is a prerequisite for rapid onset of
action.
The speed of absorption depends on the solubility and
concentration of drug. All drugs must dissolve in water
to reach the circulation.

8. Consequently,
Drugs in aqueous solutions are absorbed faster
than those in solid formulations, suspensions, or
organic solvents.
A high concentration of drug facilitates
absorption.
Increased blood flow to the site of injection
increases the rate of absorption.
Decreased blood flow secondary to hypotension,
vasoconstrictors, or other factors slows drug
absorption.

9. Oral drug administration is convenient, inexpensive,
and relatively tolerant of dosing errors.
However, it requires cooperation of the patient,
exposes the drug to first-pass hepatic metabolism,
and permits gastric pH , enzymes , motility , food, and
other drugs to potentially reduce the predictability
of systemic drug delivery.
Nonionized (uncharged) drugs are more readily
absorbed than ionized (charged) forms . Therefore,
an acidic environment (stomach) favors the absorption
of acidic drugs (A – + H + → AH), whereas a more
alkaline environment (intestine) favors basic drugs
(BH + → H + + B).

10. All venous drainage from the stomach and small
intestine flows to the liver. As a result, the
Bioavailability of highly metabolized drugs may be
Significantly reduced by first-pass hepatic metabolism.
Because the venous drainage from the mouth and
Esophagus flows into the superior vena cava rather than
into the portal system, sublingual or buccal drug
Absorption bypasses the liver and first-pass
metabolism.
Rectal administration partly bypasses the portal system,
and represents an alternative route in small children.

11. Parenteral routes of drug administration
include subcutaneous, intramuscular, and
Intravenous injection. Subcutaneous and
Intramuscular absorption depend on drug
diffusion from the site of injection to the
bloodstream. The rate at which a drug enters the
bloodstream depends on both blood
flow to the injected tissue and the injectate
formulation.

12. Bioavailability
Bioavailability is defined as the fraction of the total
dose that reaches the systemic circulation.
Bioavailability is reduced by factors such as
incomplete absorption from the site of injection or
GI tract, the first-pass effect, or pulmonary uptake
of drugs.
Even after iv injection, the bioavailability of drugs
formulated in lipid suspensions may be less
than 100%. These suspensions contain small lipid
droplets.

13. Distribution
Once absorbed, a drug is distributed by the
Bloodstream throughout the body. Highly perfused
Organs (the so-called vessel-rich group such as the
brain, heart, lungs, liver, and kidneys, receive most of
the drug soon after injection.) .
Therefore, these tissues receive a disproportionate
amount of drug in the first minutes following drug
administration. These tissues approach
Equilibration with the plasma concentration more
quickly than less well perfused tissues (muscle, skin, fat
)

14. due to the differences in the rate of rise in drug
concentration . In an organ , is determined by that
organ’s perfusion and the relative drug solubility in
the organ compared with blood.
Only free, unbound drug can cross capillary
membranes. The extent of tissue uptake of drugs
depends on the affinity of drug binding to blood
constituents, relative to the overall affinity of
binding to tissue components .

15. Lipophilic molecules can readily transfer
between the blood and organs. Charged molecules
are able to pass in small quantities into most
organs.
However, the blood–brain barrier is a special case.
Most drugs that readily cross the blood–brain
barrier (eg, lipophilic drugs like hypnotics and
opioids) are avidly taken up in body fat.
So distribution of highly lipid-soluble drugs into
the CNS is limited only by cerebral blood flow.

16. Following intravenous bolus administration, rapid
Distribution of drug from the plasma into
peripheral tissues accounts for the profound
decrease in plasma concentration observed in the
first few minutes.
For each tissue, there is a point in time at which the
apparent concentration in the tissue is the same as
the concentration in the plasma.

17. The redistribution
The rapid entry and equally rapid egress of
lipophilic drugs from richly perfused organs such
as the brain and heart is referred to as
redistribution phase (for each tissue) follows this
moment of equilibration.
During redistribution, drug returns from
peripheral tissues back into the plasma. This
return of drug back to the plasma slows the rate of
decline in plasma drug concentration.

18. The volume of distribution, V d ,
is the apparentvolume into which a drug has
“distributed” (ie, mixed). This volume is calculated by
dividing a bolus dose of drug by the plasma
concentration at time Zero.
All intravenous anesthetic drugs are better
modeled with at least two compartments: a
central compartment and a peripheral
compartment.

19. The central compartment may be thought of as
including the blood and the lungs.
The peripheral compartment is composed of the other
body tissues.
A small V dss implies that the drug has high aqueous
solubility and will remain largely within the
intravascular space.

20. Biotransformation
Biotransformation is the chemical process
by which the drug molecule is altered in the
body. The liver is the primary organ of metabolism
for drugs.
The end products of biotransformation are often
(but not necessarily) inactive and water soluble.
Water solubility allows excretion by the kidneys.

21. Metabolic biotransformation is frequently
divided into phase I and phase II reactions. Phase
I reactions convert a parent compound into more
polar metabolites through oxidation, reduction, or
hydrolysis. Phase II reactions couple (conjugate) a
parent drug or a phase I metabolite with an
Endogenous substrate (eg, glucuronic acid) to form
Water soluble metabolites that can be eliminated in
The urine or stool.

22. Although this is usually a sequential
process, phase I metabolites may be excreted
Without undergoing phase II biotransformation,
And a phase II reaction can precede or occur
without a phase I reaction.
Hepatic clearance is the volume of blood or
Plasma cleared of drug per unit of time.

23. Excretion
The liver and kidneys are the most important organs
for drug elimination. The liver eliminates drugs
primarily by metabolism to less active compounds
and, to a lesser extent, by hepatobiliary excretion of
drugs or their metabolites. The primary role of the
kidneys is the excretion of water-soluble, polar
compounds.
Some drugs and many drug metabolites are excreted
by the kidneys.
.

24. The nonionized (uncharged) fraction of drug is
reabsorbed in the renal tubules, whereas the
ionized (charged) portion is excreted in urine. The
fraction of drug ionized depends on the pH; thus
renal elimination of drugs that exist in ionized and
nonionized forms depends in part on urinary pH.
The term “drug clearance,” or “elimination
clearance,” describes the ability to remove drug
From the blood. Drug clearance is the theoretical
volume of blood from which drug is completely and
irreversibly removed in a given time interval.