Transcript 8th Lecture 1433

Pharmacology PHL 211
Eighth Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Pharmacokinetics, Overview
 Pharmacokinetics: the study of the movement of drugs in the body, including the processes of
absorption, distribution, localization in tissues, biotransformation and excretion
 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
Pharmacokinetics, Introduction
 Drugs need to achieve an adequate concentration in their target tissues
 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
 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
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.
The Movement of Drug Molecules Across Cell Barriers
 Gaps between endothelial cells are packed with a loose matrix of proteins that act as filters,
retaining large molecules and letting smaller ones through.
 Aqueous Diffusion: It occurs within the larger aqueous
compartments of the body (interstitial space, cytosol,
etc) and across epithelial membrane tight junctions and
the endothelial lining of blood vessels through aqueous
pores
 It is important also in the transfer of gases such as carbon
dioxide
 In other organs, especially in the CNS (blood brain barrier, BBB) and the placenta
(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 membranes
1) Passive transfer:
a. Simple diffusion: The vast majority of drugs gain access to the body through this mechanism.
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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 inhibited by metabolic inhibitors
It is not saturable
It depends on:
 concentration gradient
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

lipid solubility
degree of ionization,
thickness of membrane
molecular size
 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,
Lipid solubility: weak acids and weak bases/Clinical Significance
 In drug poisoning, renal elimination of drugs can be enhanced by changing urinary
pH to increase drug ionization and inhibits tubular reabsorption.
 Alkalinization of urine by NaHCO3 increases excretion of acidic drugs e.g. aspirin.
 Acidification of urine by vitamin C or NH4Cl increases excretion of weak base drugs e.g.
amphetamine.
The Movement of Drug Molecules Across Cell Barriers,
contd.
b. Filtration: In capillaries, pores have large size and so nearly all free drugs in plasma can
be filtered. It depends on hydrostatic and osmotic pressure, so it is limited by blood flow but
not by lipid solubility and it is not saturable
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 metals
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)
Plasma level curve

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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.
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 target tissue
 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 sustained-release 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 are the intravenous (IV),
intramuscular (IM), the subcutaneous (SC) and intradermal routes.
 Rapid response obtained
 Useful in emergencies, vomiting
and unconsciousness
 The drug should be in a sterile
dosage form
III. Topical:
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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. vaginal antifungal creams
1- Absorption
 It is the process of entry of drug from site of administration into systemic circulation.
 Factors influencing absorption
 A- Factors related to drug
a) Physicochemical properties:
1-Degree of ionization: highly ionized drugs are poorly absorbed.
2-Degree of solubility: High lipid/water partition coefficient increases absorption.
3-Chemical nature: inorganic iron is better absorbed than organic iron.
4-Valency: ferrous salts are more absorbed than ferric,
-so vitamin C increases absorption of iron.
b) Pharmaceutical form of drug:
Absorption of solutions is better than suspensions or tablets.
1- Absorption
 B- Factors related to the patient:
1-Route of administration:
absorption is faster from i.v. > inhaled > i.m. > oral > dermal administration
seconds
minutes
hours
2-Area and vascularity of absorbing surface:
absorption is directly proportional to both area and vascularity. Thus absorption of
the drug across the intestine is more efficient than across the stomach, as intestine
has more blood flow and much bigger surface area than those of the stomach
3-State of absorbing surface: e.g. atrophic gastritis and mal-absorption syndrome
decrease rate of absorption of drugs.
4-Rate of general circulation: e.g., in shock, peripheral circulation is reduced and
I.V. route is used.
5-Specific factors and presence of other drugs: e.g. intrinsic factor of the stomach
is essential for vitamin B12 absorption from lower ileum and adrenaline induces
vasoconstriction so delay absorption of local anesthetics.
Bioavailability
 It is the percentage of drug that reaches systemic circulation in an unchanged form and
becomes available for biological effect following administration by any route. It is 100%
after IV administration.
 It is calculated by comparison of the area under the plasma concentration time curve
(AUC) after IV dose of a drug with that observed when the same dose is given by another
route e.g. oral.
Area under the curve (AUC) oral x 100
Oral bioavailability =
Area under the curve (AUC) I.V.
 Oral bioavailability depends on amount absorbed
and amount metabolized before reaching systemic
circulation (first pass metabolism)
2-Distribution
 Distribution: Movement of drug from the central compartment (blood) 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
 The body compartments include extracellular (plasma, interstitial) and intracellular which
are separated by capillary wall and cell membrane
The major compartments are:
—plasma (5% of body weight)
—interstitial fluid (16%)
—intracellular fluid (35%)
—transcellular fluid (2%)
—fat (20%)
2-Distribution
 Selective distribution: Some drugs have special affinity for specific tissue. e.g. calcium in
bones, iodide in thyroid gland and tetracycline in bone and teeth.
 Volume of Distribution:
 The volume of distribution (Vd) , also known as apparent volume of distribution, is a
pharmacological term used to quantify the distribution of a medication between plasma
and the rest of the body after oral or parenteral dosing.
 Vd, is defined as the volume of fluid required to contain the total amount, Q, of drug in
the body at the same concentration as that present in the plasma, Cp.
 Vd is not a real volume, small volume indicates extensive plasma protein binding, but
large volume indicates extensive tissue binding
 Vd is increased by increased tissue binding, decreased plasma binding and increased
lipid solubility
Drugs in vascular space
 Drugs 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 reversible
 Significance of binding to plasma proteins:
* Two drugs may have affinity for plasma protein binding sites, thus compete with each
other leading to drug interactions
* An example: Phenylbutazone and salicylates can displace warfarin (oral
anticoagulant) and oral hypoglycemics from plasma proteins
* Drugs 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.
2.
3.
4.
Drug inactivation (most of drugs)
Conversion of inactive drug into active metabolite (cortisone→ cortisol)
Conversion of active drug into active metabolite (phenacetin→ paracetamol)
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 drug inactivation with few exceptions e.g. morphine-6conjugate 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).
3-Biotransformation (Metabolism)
 Sites of biotransformation and types of enzymes
1. Microsomal enzymes: they are present in smooth endoplasmic reticulum of cells especially liver
 Microsomal enzymes catalyze:
-Glucuronide conjugation
-Oxidation by microsomal cytochrome P450 enzymes (CYP450)
-Hydroxylation
-Dealkylation
-Reduction
-Hydrolysis
 They are affected by drugs and age
2. Non-microsomal enzymes: present in liver, kidney, plasma, skin and GIT…etc
 They catalyze:
-Conjugations rather than glucuronic acid
-Oxidation by soluble enzymes in cytosol or mitochondria of cells e.g. MAO (monoamine
oxidase) and alcohol dehydrogenase
-Reduction
-Hydrolysis
 Their activity is stable throughout life.
3-Biotransformation (Metabolism)
 Factors affecting drug metabolism
1-Drugs: They can stimulate (induce) or inhibit microsomal metabolizing enzymes.
* Enzyme induction: Some drugs increase the synthesis or decrease degradation of
enzymes.
 Examples: testosterone, phenobarbitone, phenytoin, carbamazepine, rifampicin, some
glucocorticoids, tobacco smoking, ethyl alcohol (chronic)
 Importance of enzyme induction:
a) It decreases effect of other drugs
b) Tolerance is sometimes explained by a drug inducing its own metabolism, e.g. ethyl alcohol,
phenobarbitone
c) It is a mechanism of adaptation to environmental pollutants (pollutants induce their own
metabolism reducing their toxic effects)
* Enzyme inhibition (drugs that inhibit drug metabolism): it occurs faster than enzyme
induction and causes serious drug interactions.
 Examples: oestrogen, progesterone, cimetidine, chloramphenicol, erythromycin, sodium
valproate, cotrimoxazole, ketoconazole and ciprofloxacin
2.Genetic variation: The most important factor is genetically determined polymorphisms.
 Example: Isoniazid is metabolized in the liver via acetylation. There are two forms (slow and
fast) of the enzyme responsible for acetylation (N-acetyl transferase), thus some patients
metabolize the drug quicker than others
3-Biotransformation (Metabolism)
3. Nutritional state: Conjugating agents are sensitive to body nutrient level. For example,
low protein diet can decrease glycine.
4. Dosage: High dose can saturate metabolic enzyme leading to drug accumulation.
5. Age: Drug metabolism is reduced in extremes of age (old patients and infants).
6. Gender: testosterone induces CYP450, whereas estrogen inhibits it.
7. Disease state:
-Liver disease decreases the ability to metabolize drugs.
-In cases of heart failure and shock, reduced hepatic flow will increase the effect of
rapidly metabolized drugs whose hepatic clearance is blood flow dependent e.g.
lidocaine, morphine, propranolol, verapamil….
-Kidney disease reduces the excretion of drugs.
8. Route of administration: 1st pass effect occurs for drugs administered orally
4- Excretion of drugs
 It is the process by which a drug or metabolite is eliminated from the body
 Routes of excretion
1- Renal Excretion: It is the result of three processes:
Passive glomerular filtration, active tubular secretion in proximal tubules and passive
tubular re-absorption.
 Factors affecting renal excretion:
1-Glomerular filtration rate. Only free unbound water soluble drugs with low
molecular weight are filtered.
2-Change in urinary pH affects excretion of weak acid and base drugs. Thus:
*Alkalinization of urine by NaHCO3 increases excretion of acidic drugs e.g.
aspirin
*Acidification of urine by NH4CL or vitamin C increases excretion of base drugs
e.g. amphetamine
3-Active tubular secretion e.g., probenecid, penicillin, …...
4- Excretion of drugs
2-Gastrointestinal Tract:
a. Salivary glands: e.g., iodides, rifampicin
b. Stomach: e.g., morphine
c. Large intestine: e.g., tetracycline, streptomycin
d. Liver through bile, e.g.:
-Ampicillin and rifampicin are excreted in active form so can be used in biliary infection
and ampicillin in typhoid carriers
3-Sweat: e.g., rifampicin, vitamin B1.
4-Lungs: e.g., gases and volatile anesthetics.
5-Milk: basic drugs are trapped and excreted in acidic milk, e.g., morphine,
amphetamine
Also many other drugs e.g. chloramphenicol, oral anticoagulants and
phenolphthalein can be excreted in milk