Basic course

)Pharmaco kinatic(

Presented by
D.Tagwa alfadel
 Defined as the study of the time course of drug
absorption distribution metabolism and excertion.

 OR refers to what the body does to a drug,

 Pharmacodynamics
 describes what the drug does to the body
 pharmaco kinetic is important because knowledge of
kinetic and effect (dynamic) of drug is necessary for
correct use of drug in therapy choice of the best route
of administration choice of the best dose regimen

 . Four pharmacokinetic properties determine the

 onset, intensity, and the duration of drug action
 absorption
 indicate passage of the drug moleculs from site of
administration across the membrane into blood stream

 Distribution:
 Indicate passage of drug molecules from blood to tissues
 Metabolism:
 , the drug may be biotransformed by metabolism by
 the liver, kidney or other tissues. The process of
metabolism transform lipophilic drug into more polar
hydrophilic readily excreatable product

 Elimination:
 May occur through biotransformation and by the
passage of molecules from the blood to the out side of
the body through urine, bile,or other route
 The route of administration is determined by the
properties of the drug (for example, water or lipid
solubility, ionization and by the therapeutic
objectives (for example, the desirability of a rapid
onset, the need for long-term treatment

 Major routes of drug administration

 1/ enteral (oral)

 2/, parenteral(I,V- I,A - I,M- s/C)

 3/ topical, through other

 1/Enteral administration (administering a drug by
 mouth)

 is the safest and most common, convenient, and

economical method of drug administration. The drug
may be swallowed, allowing oral delivery, or it may
be placed under the tongue (sublingual), or between
the gums and cheek (buccal), facilitating direct
absorption into the bloodstream

 Oral route
 Advantages
 . Oral drugs are easily self-administered
 toxicities and/or overdose of oral drugs may be
overcome with antidotes, such as activated charcoal.
 A wide range of oral preparations is available
including
 enteric-coated and extended-release preparations
 Sublingual/buccal
 Placement under the tongue allows a drug
 to diffuse into the capillary network and enter the
systemic circulation directly.
 advantages,
 1/including ease of administration,
 2/ rapid absorption,
 3/ bypass of the harsh gastrointestinal (GI)
environment, and avoidance of first-pass metabolism
.
 The buccal route
 (between the cheek and gum)
 2/parenteral

 The parenteral route introduces drugs directly into

the systemic circulation. Parenteral administration is
used for drugs that are poorly absorbed from the GI
tract (for example, heparin) or unstable in the GI tract
(for example,insulin). is also used if a patient is
unable to take oral medications (unconscious
patients) and in circumstances that require a rapid
onset of action.
 Advantage

 , parenteral routes have the highest

bioavailability100%
 are not subject to first-pass metabolism or the harsh
GI environment.
 provides the most control over the actual dose of
drug delivered to the body

 disadvantage
 irreversible and may cause pain, fear, local tissue
damage, and infections.
 Impolism of forigen particle air or thrombosis are
possible
 The three major parenteral routes are
 intravascular (intravenous or intra-arterial),
intramuscular, and subcutaneous


 Intravenous (IV):
 IV injection is the most common parenteral route. It
is useful for drugs that are not absorbed orally.IV
delivery permits a rapid effect and a maximum
degree of control over the amount of drug delivered

 I,V bolus injection

 That mean, the full amount of drug is delivered to
the systemic circulation almost immediately.
 IV infusion
 , the drug is infused over a longe period of time,
resulting in lower peak plasma concentrations and
an increased duration of circulating drug levels


 Intramuscular (IM)


 Drugs administered IM can be in aqueous solutions,

which are absorbed rapidly, or in specialized depot
preparations, which are absorbed slowly. ( consist of
a suspension of the drug in a nonaqueous vehicle
 Advantage
 Could be used for oily vehicle or irritatin substantces


 Dis advantage
 Pain full especially when large volume are injected
 Sciatica nerve pulsy could be avoided by injection in
outer gluteal quadrand of the buttock
 Sterial abscess
 Increasethe serum level of critinine phosphokinase
released from damaged muscle cell and may obscure
diagnose of myo cardial infaction
 Subcutaneous (SC):
 Like IM injection, but slow than it SC injection
provides absorption via simple diffusion

 advantage
 sutiable for insoluble suspention and implanted solid
pellet

 disadvantage
 not sutiable for inj of large volume
 possible necrosis or pain of irritating substance
 3/ Rectal:
 Because 50% of the drainage of the rectal region
 bypasses the portal circulation, the biotransformation
of drugs by the liver is minimized with rectal
administration.
 Advantage
 Acidity and gastric enzyme are avoided
 Portal circulation will be by passed
 It can be used in pt unable to swallow
 Duration of action may be prolonged
 Dis advantage

 Absorption usually irregular and incomplete

 Some drug may irritate the mucosa
 4/Oral inhalation:
 Inhalation routes, both oral and nasal provide rapid
delivery of a drug across the large surface area of the
mucous membranes of the respiratory tract and
pulmonary epithelium.
 Drugs that are gases (for example, some anesthetics)
or aerosol are administered via inhalation.
 This route is effective and convenient for patients
with respiratory disorders (such as asthma or chronic
obstructive pulmonary disease), because the drug is
delivered directly to the site of action, thereby
minimizing systemic side effects. Examples -
 (bronchodilator)
 5/Nasal inhalation:
 This route involves administration of drugs directly
into the nose


 6/Intrathecal/intraventricular:
introduce drugs directly into the cerebrospinal fluid
 7/Topical:

 Topical application is used when a local effect of the

drug is desired.ex skine

 8/Transdermal:
This route of administration achieves systemic
effects by application of drugs to the skin, usually via a
transdermalpat
 ABSORPTION OF DRUGS

 The rate and extent of absorption depend on

 the environment where the drug is absorbed,
 chemical characteristics of the drug,
 route of administration (which influences
bioavailability). Routes of administration other than
intravenous may result in partial absorption and
lower bioavailability

 Mechanisms of absorption of drugs from the GI
tract

 Depending on their chemical properties, drugs may

be absorbed from the GI tract by
 passive diffusion,
 facilitated diffusion,
 active transport,
 endocytosis or exocytosis
 Passive diffusion:

 The driving force for passive absorption of

a drug is the concentration gradient across a membrane
separating two body compartments.
 the drug moves from a region of high concentration
to one of lower concentration
 . Passive diffusion does not involve a carrier, is not
saturable, and shows a low structural specificity.
majority of drugs are absorbed by this mechanism.
 Facilitated diffusion:

 Other agents can enter the cell through specialized

transmembrane carrier proteins that facilitate the
passage of large molecules These carrier proteins
undergo conformational changes, allowing the
passage of drugs or endogenous molecules into the
interior of cells and moving them from an area of
high concentration to an area of low concentration.

 It does not require energy, can be saturated, and

may be inhibited by compounds that compete for the
carrier
 Active transport:


 drug entry involves specific carrier proteins that

span the membrane. .
 Energy-dependent active transport is driven by
 the hydrolysis of adenosine triphosphate. It is
capable of moving drugs against a concentration
gradient, from a region of low drug
 concentration to one of higher drug concentration.
The process is saturable. Active transport systems are
selective and may be competitively inhibited by
other cotransported substances

 Endocytosis and exocytosis:

 This type of absorption is used to transport drugs of

exceptionally large size across the cell membrane.

 Endocytosis
 involves engulfment of a drug by the cell membrane
and transport into the cell by pinching off the drug-
filled vesicle.
 Exocytosis
 is the reverse of endocytosis. Many cells use
exocytosis to secrete substances out of the cell
through a similar process of vesicle formation.
Vitamin B12is transported across the gut wall by
endocytosis, whereas certain neurotransmitters (for
example, norepinephrine) are stored in intracellular
vesicles in the nerve terminal and released by
exocytosis.
 Factors influencing absorption
1/gastric pH

2/Blood flow to the absorption site

3/Total surface area available for absorption

4/Contact time at the absorption surface

5/Expression of P-glycoprotein: Expression of P- 

glycoprotein
 P-glycoprotein
 is a transmembrane transporter protein responsible
for transporting various molecules, including drugs,
across cell membranes
 It is expressed in tissues throughout the body,
including the liver, kidneys, placenta, intestines, and
brain capillaries, and is involved in transportation of
drugs from tissues to blood. That is, it
“pumps” drugs out of the cells. Thus, in areas of high
expression,
P-glycoprotein reduces drug absorption 
 Bioavailability

 is the rate and extent to which an administered drug

 reaches the systemic circulation

 Determination of bioavailability:
 is determined by

1/ comparing plasma levels of a drug after a particular

route of administration ( ex) oral –IV.
2/ After IV administration, 100% of the drug rapidly 
enters the circulation. When the drug is given orally,
only part of the administered dose appears in the
plasma
 plotting plasma concentrations of the drug versus
time, the area under the curve (AUC) can be
measured.
 The total AUC reflects the extent of absorption of the
drug

 Factor affect bioavailbility

 1/First-pass hepatic metabolism:

When a drug is absorbed from the GI tract, it enters the

portal circulation before entering the systemic
circulation If the drug is rapidly metabolized in the
liver or gut wall during this initial passage, the
amount of unchanged drug entering the systemic
circulation is decreased
 2/physical properities such as lipid and water
solubility

 3/chamical instability
4/Nature of the drug formulation:
 5/gastric transiat time

 6/absorption site(blood flow—surface area)

 7/disease(thyrotoxicosis –malabsorption)

 Bioequivalence
Two drug formulations are bioequivalent if they show
comparable bioavailability and similar times to
achieve peak bloodconcentrations
 Dru distribution
 is the process by which a drug reversibly leaves the
 bloodstream and enters the interstitium (extracellular
fluid) and the tissues.

 distribution of a drug from the plasma to the

interstitium depends on
 1/cardiac output and local blood flow,
 2/ capillary permeability, the tissue volume,
 3/ degree of binding of the drug to plasma and
tissue proteins,
 4/relative lipophilicity of the drug
 Pharmacokinetic parameter

 Half- life(t1/2)
 Is time requird to reduce plasma concentration to on half
it,s initial value

 T1/2 of adrug increased by

1/low renal or hepatic blood flow ex in cardiogenic shock
heard failure or heamorrhage
2/ decreased metabolism in hepatic insufficiency

 T1/2 decrease by
1/ increased hepatic blood flow
2/decreased protein binding
3/increased metabolism
 Volume of distribution
 Is ahypothetical volum of fluid into which adrug is
disseminated

 It is calculated by dividing the dose that ultimately

gets into the systemic circulation by the plasma
concentration
 V=D/C0
 Although Vdhas no physiologic or physical basis, it
can be useful to compare the distribution of a drug
with the volumes of the water compartments in the
body
 Once drug enters the body, it has the potential to
distribute into any one of the three functionally
distinct compartments of body water or to
become sequestered in a cellular site
.
 If a drug has low V that maen adrug has a high
molecular weight or is extensively protein bound, it
is too large to pass through the slit junctions of the
capillaries trapped within the plasma (vascular)
compartment.

 Large V the more likely that the drug is found in the

tissue of the body
 Drug clearance(CL)

 Volume of plasma in vascular compartment cleared

of drug per unit time by processes of metabolism and
excertion

 Drug can be cleared by renal excertion or by

metabolism or both

 CL(total)=CL(renal)+CL(non renal)
 Absorption rate constant(Ka)
 Is the proportionality constant that relates the rate
of drug absorped into the body

 Elimination rate constant(Ke)

 Is first order rate constant describing drug
elimination from the body
 DRUG CLEARANCE THROUGH METABOLISM

 Once a drug enters the body, the process of

elimination begins. these elimination processes
decrease the plasma concentration . That is, a
constant fraction of the drug present is eliminated in
a given unit of tim

 drugs are eliminated according to first-order kinetics

(inear), or zero-order or non linear kinetics
 Kinetics of metabolism
 1./First-order kinetics:

 The metabolic transformation of drugs is catalyzed

by enzymeThat is, the rate of drug metabolism and
elimination is directly prportional to the
concentration of free drug, and first-order kinetics
is observed.
 This means that a constant fraction of drug is
metabolized per unit of time (that is, with each half-
life, the concentration decreases by 50%)
. First-order kinetics is also referred to as linear kinetics
 Zero-order kinetics

 The enzyme is saturated by a high free drug

concentration, and the rate of metabolism remains
constant over time. This is called zero-order kinetics
(also called nonlinear kinetics).

 aconstant amount of drug is metabolized per unit of

time. The rate of elimination is constant and does not
depend on the drug concentration.ex aspirine –
phenytoin
 Reactions of drug metabolism

 Liver is major site of metabolism but can occur in

other tissue
 The kidney cannot efficiently eliminate lipophilic
drugs that readily cross cell membranes and are
reabsorbed in the distal convoluted tubules.
Therefore, lipid-soluble agents are first metabolized
into
 polar (hydrophilic) substances in the liver via two
sets of reactions, called phase I and phase 2
 phase 1

 non synthetic reaction

 such as cleavage (e.g oxidation reduction hydrolysis
)formation and modification of function group the
most important metabolic enzyme involved in this
phase cytochromeP450(CYP450) superfamily of
enzymes this group of enzyme act as catalyst for
oxidation for many drug it con also be induced or
inhibited by many drugs and other other substances
 Phase II:

 This phase consists of conjugation reactions many

phase I metabolites are still too lipophilic to be excret
 A subsequent conjugation reaction with an
endogenous substrate, such as glucuronic acid,
sulfuric acid, acetic acid, or an amino acid, results in
polar substances
 DRUG CLEARANCE through THE KIDNEY

 Renal elimination of a drug

 Elimination of drugs via the kidneys into urine
involves the processes
 of glomerular filtration, active tubular secretion, and
passive tubular reabsorption.
 DESIGN AND OPTIMIZATION OF DOSAGE
REGIMEN


 drugs are continually administered, either as an IV

infusion or in oral fixed-dose/fixed-time interval
regimens (for example, “one tablet every 4 hours”).
 Continuous or repeated administration results in
accumulation of the drug until a steady state occurs
 Steady-state concentration


 is reached when the rate of drug elimination is equal to

the rate of drug administration, such that the plasma and
tissue levels remain relatively constant


 Influence of the rate of infusion on steady-state

concentration:
 The steady-state plasma concentration (Css) is directly
proportional to the infusion rate. For example, if the
infusion rate is doubled, the Cssis double the Cssis
inversely proportional to the clearance of the drug. Thus,
any factor that decreases clearance, such as liver or
kidney disease, increases the Cssof an infused drug
 . Factors that increase clearance, such as increased
metabolism, decrease the Css


 Time required to reach the steady-state drug

concentration:
 The concentration of a drug rises from zero at the
start of the infusion to its ultimate steady-state level,
Css
 The rate constant for attainment of steady state is the
rate constant for total body elimination of the drug.
Thus, 50% of Cssof a drug is observed after the time
elapsed, since the infusion, t, is equal to t1/2, where
t1/2(or half-life) is the time required for the drug
concentration to change by 50%. After another half-
life, the drug . reaches steady state in about four to
five half-lives

 Optimization of dose
 The goal of drug therapy is to achieve and maintain
concentrations within a therapeutic response
window while minimizing toxicity and/or side
effects.

 Theraputic concentration range (therapeutic

window)
 is the concentration range from the minimal effective
concentration (MEC) to the minimal toxic
concentration(MTC)

 . Drug regimens are administered as a maintenance

dose OR loading dose
 Maintenance dose:
 Drugs are administered to maintain a Css within the
therapeutic window. It takes four to five half-lives
for a drug to achieve Css

 Loading dose:
 “loading dose” of drug is administered to achieve
the desired plasma level rapidly, followed by a
maintenance dose to maintain the steady state