This document provides definitions and key concepts related to clinical pharmacology. It defines pharmacology as the study of how drugs interact with living systems, and related terms like pharmacokinetics, pharmacodynamics, xenobiotics, and toxicology. The document outlines different drug classifications and names. It describes the goals of drug therapy to prevent, control or cure disease. The main concepts of pharmacokinetics involving absorption, distribution, metabolism and excretion of drugs in the body are introduced. Different mechanisms of drug permeation like diffusion, active transport and endocytosis are also summarized.

1. Clinical Pharmacology 1
Sept, 2022

2. Introduction
Definitions:
• Pharmacology:
– Pharmacology: from Greek; pharmakon, "poison or drug in
modern Greek"; and logia "Study of“
– the study of substances that interact with living systems
through chemical processes, especially by binding to
regulatory molecules and activating or inhibiting normal
body processes.
– the study of actions of drugs on the body
(pharmacodynamics) and the fate of drugs in the body
(pharmacokinetics).
– study of how chemical agents affect living processes.
• chemical agents that affect living processes: hormones,
neurotransmitters, growth factors, drugs (pharmaceuticals), toxic
agents in the environment

3. Terms
• Drug:
• a chemical agent/substance of known structure which when administered
to a living organism, produces a biological effect.
• Any substance that interacts with a molecule or protein that plays a
regulatory role in living systems
• Note: nutrients/essential dietary ingredients are not regarded
as drugs
• Drugs may be chemicals administered to achieve a beneficial
therapeutic effect on some process within the patient or for
their toxic effects on regulatory processes in parasites
infecting the patient
Introduction cont’

4. • Medicine:
• A chemical preparation, which usually contains one or more drugs,
administered with the intention of producing a therapeutic effect.
• Medicines usually contain other substances (excipients, stabilisers,
solvents, etc.) besides the active drug, to make them more convenient
to use
• For a substance to count as a drug, the substance must be
administered as such, but not released endogenously through
physiological mechanisms
• e.g. insulin or thyroxine are regarded as drugs only when administered
intentionally
Introduction cont’

5. • Xenobiotics: (Gr. xenos - stranger)
• Chemicals that are not synthesized by the body, but introduced into it
from outside
• Xenobiotics are substances that are foreign to the body
• Most drugs are xenobiotics
• Poisons: drugs that have almost exclusively
harmful effects
• Toxins: Poisons of biologic origin, usually
synthesized by plants or animals
Introduction cont’

6. • Sources of drugs :
• Chemicals obtained from plants, animal tissues or microbes:
• Alkaloids- substances derived from plants, containing nitrogen groups and which
give an alkaline reaction in aqueous solution e.g. morphine, cocaine, atropine and
quinine
• Antibiotics: obtained from numerous micro-organisms including Penicillium and
Streptomyces
• Synthetic chemicals- newly synthesized compounds or modification
of naturally occurring drugs. Aspirin, barbiturates among the first
drugs to be synthesized
• or products of genetic engineering
Introduction cont’

7. • Chemical nature of drugs:
– Drugs exist in various chemical forms- ions,
carbohydrates, lipids, or proteins.
• They vary in size from lithium (MW 7) to
proteins (MW 50,000)
• Most drugs however range between MW
100 and 1000
• Most drugs are weak acids or weak
bases, i.e. they incompletely dissociate in
water
Introduction cont’

8. • Drug preparations:
• Crude drug preparations
• Pure drug compounds
• Pharmaceutical preparations:-
• drug products in their finished dosage
form that can be administered to a
patient at a predetermined dose and
via a specific route of administration
Introduction cont’

9. Introduction cont’

10. • Important characteristics of drugs:
– Specificity (size, charge and shape to fit in a
particular receptor);
– Be absorbed
– Be delivered to the site of action
– Route/mechanism of elimination should be
known
Introduction cont’

11. • Drug Names:
– A drug often has several names:
• Chemical name- specifies the chemical structure, uses
standard nomeclature e.g. acetylsalicyclic acid
• Nonproprietary/generic name- derived from the
chemical names of drugs e.g. oxacillin which belongs to
the penicillin group
• Proprietary/trade/brand name: a registered
trademark belonging to a particular company e.g.
Panadol (paracetamol)
Introduction cont’

12. Drug groups/classification
• Most of drugs currently available have been arranged
into several classes; about 70 groups
– the drugs within each group are very similar in
pharmacodynamic actions and in their pharmacokinetic
properties as well.
• For most groups, one or more prototype drugs can be
identified that typify the most important
characteristics of the group.
– This permits classification of other important drugs in the
group as variants of the prototype, so that only the
prototype must be learned in detail and, for the remaining
drugs, only the differences from the prototype
Introduction cont’

13. • Clinical pharmacology: study of drugs as applied in
prevention, diagnosis and treatment of disease
• Pharmacotherapeutics:
– medical science concerned with the use of drugs in the
treatment of disease.
– Pharmacology provides a rational basis for
pharmacotherapeutics by explaining the mechanisms and
effects of drugs on the body and the relationship between
dose and drug response.
• Toxicology: the study of poisons and organ
toxicity
– It focuses on the study of "undesirable/harmful" effects of
drugs and other chemicals on biological processes
Introduction cont’

14. • Pharmacokinetics: what the body does to the drug
(actions of the body on the drug); comprises of:
– A: Absorption
– D- Distribution
– M: Metabolism
– E: Excretion
• Pharmacodynamics: what the drug does to the body
(actions of a drug to the body); deals with mechanisms
of action and drug effects in the body;
• receptor binding, postreceptor effects, and chemical
interactions
Introduction cont’

15. • In therapeutics the primary goal is to achieve a
desired beneficial effect with minimal adverse
effects
– For any prescribed medicine, the clinician determines
the dose that closely achieves this goal
• Thus the need to study the pharmacokinetic and
pharmacodynamic principles to understand the dose-effect
relationship of drugs
– Pharmacokinetics: dose-concentration
– Pharmacodynamics: concentration-effect
Introduction cont’

17. Purpose of Drug Therapy
• Drug therapy aims to prevent, control or cure
various disease states.
• To achieve this, the right drug dose must be
delivered to the tissues
• The following should be taken into
consideration:
– Speed of onset of drug action
– Intensity of drug effect
– Duration of drug action

20. Pharmacokinetics:
• What the body does to the drug
• The movement of drug into, through, and out of the
body—
– the time course of its absorption, bioavailability,
distribution, metabolism, and excretion
• Pharmacokinetic processes:
– ADME-absorption, distribution, metabolism, excretion
– In drug development, calculation of loading and
maintenance doses is achieved by appropriate
application of pharmacokinetic data
Pharmacokinetics-Introduction

22. • Plasma drug concentration:
– a function of the rate of input of the drug (by
absorption) into the plasma, the rate of
distribution to the peripheral tissues (including
the target organ), and the rate of elimination, or
loss, from the body.
• Effective drug concentration
– the concentration of a drug at the receptor site.
Pharmacokinetics-Introduction

23. • For a drug to bring about its intended therapeutic
effect, it must move from the site of administration to
the site of action (receptor)
– Except in only a few cases where drugs may be
administered directly into the site of action (e.g. topical
application of an anti-inflammatory agent), the site of
administration of a drug is usually a different
compartment from the site of action;
• In other words, the drug must be absorbed into the blood and
distributed into the site of action
– Hence, the drug should move across a number of biologic
barriers (permeate) to reach its site of action
Pharmacokinetics-Introduction

26. • Mechanisms of drug permeation:
– Diffusion:
• Passive- aqueous and lipid
• Facilitated
– Active transport
– Endocytosis, Pinocytosis
Pharmacokinetics-Introduction

27. • Passive diffusion:
– Drugs diffuse across a cell membrane down a concentration gradient; from a
region of high concentration (e.g., GI fluids) to one of low concentration
(e.g., blood)- refer to Fick’s law of diffusion
– Aqueous diffusion: the movement of molecules through the
aqueous/watery pores in capillaries. Organs like the brain and testes do not
have these pores, therefore being highly protected from circulating drugs
– Lipid diffusion: passive movement of molecules through cell membranes
and other lipid structures; it’s a major drug permeability limiting factor due
to the large number of lipid barriers (cell membrane) between body
compartments
Pharmacokinetics-Introduction

28. • Facilitated diffusion:
– A carrier mediated form of transport , usually for
substances that are too large or lipid insoluble to
diffuse
• Glucose is an example of substances transported via
this mechanism
– The process is independent of energy, hence
cannot transport substances against a
concentration gradient
Pharmacokinetics-Introduction

30. • Active transport
– An energy dependent selective process, requiring
energy expenditure, to transport substances
against a concentration gradient.
– Its mostly limited to drugs structurally similar to
endogenous substances (e.g., ions, vitamins,
sugars, amino acids).
Pharmacokinetics-Introduction

31. Endocytosis, exocytosis:
• Endocytosis: a process whereby a cell engulfs a molecule,
– the substance attaches to a cell surface receptor, the cell
membrane invaginates, encloses the fluid or particles, then fuses
again, forming a vesicle that later pinches off and moves to the
cell interior.
– Energy expenditure is required in endocytosis
– Pinocytosis:
– a mode of endocytosis for small particles and surrounding fluids
– Also referred to as cell drinking or fluid endocytosis.
• Through endocytosis, very large (e.g. protein molecules) or
very lipid-insoluble chemicals can enter cells e.g.
• vitamin B12 and iron (small and polar) combine with special proteins
(B12 with intrinsic factor and iron with transferrin), and the complexes
enter cells by this mechanism.
• Exocytosis is the reverse of endocytosis
Pharmacokinetics-Introduction

32. Pharmacokinetic processes
• Absorption
• Distribution
• Metabolism
• Excretion

33. Absorption
Absorption: Process of movement of drugs from the site of
administration to the bloodstream
• Several factors determine the rate and extent of drug absorption-
• Drug factors/physicochemical properties:
• Nature of drug formulation/dosage form and route of administration;
disintegration/dissolution of a drug
• Lipid solubility: (hydrophillic vs lipophillic properties): lipid-water
partion coefficient
• pH of the media
• Particle size/molecular weight
• Drug-drug interaction
• Host factors/biological factors:
• Surface area at the site of absorption
• Blood flow at the absorptive area
• GI motility for orally administered drugs
• Presence of food

34. Absorption cont’
• A key parameter used in describing absorption
of drugs is Bioavailability – see next slides

35. Bioavailability:
• The proportion of unchanged drug reaching the systemic
circulation (thereby accessing its site of action) following
administration by any route.
• Bioavailability of a drug may depend on:
1) Route of administration
2) Dosage form
Note: factors influencing the rate of absorption also affect
bioavailability
Absorption cont’

36. 1) Route of administration
– Drugs administered intravenously have 100% bioavailability
– Other routes of administration have less than 100% bioavailability:
– Orally administered have lower bioavailability due to:
a. Extent of absorption:
- Incomplete absorption of a drug after oral administration may lower the
level of the drug reaching systemic circulation
- e.g. only 70% of digoxin is absorbed PO
b. First pass metabolism:
- The elimination of drug that occurs following administration but before it
reaches the systemic circulation (e.g. during passage through the gut wall,
portal circulation, liver for an orally administered drug)
- Some drugs may undergo extensive biotransformation (metabolism),
- thus reducing the amount of active drug being released to the systemic circulation
Absorption cont’

37. Routes of drug administration
• Oral:
– Involves ingestion of drugs into the GI
– Drugs given orally are subject to first pass effect
• Buccal (between the gum and cheek) and Sublingual (under the
tongue)
– Both routes avoid the first pass effect
• Rectal (Suppository)
– Offers partial avoidance of first pass effect; some drugs may move
higher in the rectum where there is absorption to portal circulation
– Suitable for large amounts of drug or drugs with unpleasant tastes
– Also appropriate in patients who are vomiting
Absorption cont’

39. • Intravenous:
– offers instantaneous and complete absorption i.e. 100% bioavailability
– The route is however potentially more dangerous,
• Owing to the high blood levels reached when the dose is large or administration
is too rapid.
• Intramuscular
– Absorption through this route is often faster and more complete (higher
bioavailability) than with oral administration
• This route may be contraindicated for some drugs:
• e.g. Heparin is not administered through this route due to risk of hematoma
– First pass effect avoided
• Subcutaneous
– Rate of absorption slower than the intramuscular route.
– Not appropriate for large-volume bolus doses,
• Heparin does not cause hematomas when administered by this route.
– First-pass metabolism is avoided.
Absorption cont’

40. • Inhalation
– Drug administered in gaseous, vaporized or aerosol form
– offers delivery closest to the target tissue in treatment of
respiratory diseases
– The large and thin alveolar surface area allows for rapid
absorption
• Topical
– application to the skin or to the mucous membrane of the eye,
ear, nose, throat, airway, or vagina for local effect
• Transdermal
– application across the skin for systemic effect.
– Absorption occurs very slowly
– first-pass effect is avoided.
Absorption cont’

42. Bioavailability in relation to route of administration
ROUTE BIOAVAILABILITY COMMENTS
IV 100% Most rapid onset
IM ≤100% May be painful; larger volumes may
be given compared to SC route
SC ≤100% Less painful than IM; smaller
volumes than IM
Oral <100% Most convenient; first pass effect
may be significant
Rectal <100% First pass effect lower than oral
Inhalation <100% Very rapid onset
Transdermal ≤100% Usually very slow absorption; used
for lack of first pass effect; has
prolonged duration of action

43. Absorption cont’
2) Dosage properties
• Bioavailability of a drug is largely determined by the
properties of the dosage
• The extent and rate absorption of a drug is determined by
the physicochemical characteristics of the preparation
containing the drug
• Some drug preparations may posses characteristics that
make them to have better absorption and bioavailability
than others
• Differences in bioavailability among formulations of a
given drug can have clinical significance;
– thus, knowing whether drug formulations are equivalent is
essential.
• Terms used in describing equivalence:
– Chemical equivalence
– Bioequivalence
– Therapeutic equivalence

44. Absorption cont’
• Chemical/pharmaceutical equivalence
– indicates that drug products contain the same compound
in the same amount and meet current official standards;
• however, inactive ingredients in drug products may differ
• Bioequivalence
– indicates that the drug products, when given to the same
patient in the same dosage regimen, result in equivalent
concentrations of drug in plasma and tissues.
• Therapeutic equivalence
– indicates that drug products, when given to the same
patient in the same dosage regimen, have the same
therapeutic and adverse effects.

45. Distribution
Distribution:
• The dispersion or dissemination of drugs throughout body fluids and
tissues after absorption.
– After a drug enters the systemic circulation, it is distributed to the body's
tissues.
• Distribution of drugs to tissues is determined by:
– Blood flow:
– well-perfused organs (eg, brain, heart, kidneys, and splanchnic organs) usually
achieve high tissue concentrations earlier than poorly perfused tissues (eg, fat,
bone).
– Binding to macromoclcules in blood (e.g albumin) or tissue compartment:
– highly plasma protein bound (e.g. warfarin) have restricted diffusion out of the
vascular compartment
– Solubility:
– The concentration of the drug in the extracellular fluid surrounding the blood
vessels is determined by the solubility of a drug in tissue
– Lipophillic (lipid soluble) drugs cross cell membranes easily, hence achieving a
wide distribution in tissues
– pH determines a molecule’s ionization state, hence its lipid solubility
– Size of organ:
– Large organs (e.g. skeletal muscle) take up a large amount of drug owing to a high
blood–tissue gradient

46. Distribution cont’
Binding:
• Plasma protein and tissue binding is an important
determinant of the extent of drug distribution into
tissues
• Transportation of drugs in blood:
– solution as free (unbound) drug and
– reversibly bound to blood components (e.g., plasma
proteins, blood cells).
• The most important proteins : albumin, α1-acid
glycoprotein, and lipoproteins.
– Acidic drugs: usually bind more extensively to albumin;
– Basic drugs: usually bind more extensively to α1-acid
glycoprotein, lipoproteins, or both.

47. • Note: Only the unbound drug can passively
diffuse to extravascular or tissue sites where
the pharmacologic effects of the drug occur;
– thus, a drug’s efficacy is typically dependent on the
unbound drug concentration in systemic circulation
• Apart from proteins, drugs also bind to other
substances-
– macromolecules in an aqueous environment or
binding in body fat
Distribution cont’

48. Distribution cont’
Blood-brain barrier:
• Entry of drugs to the CNS occurs via
• brain capillaries and CSF.
– blood-brain barrier; permeability to the brain is
restricted by presence of tight junctions between
endothelial cells in the brain capillaries;
– The junctions are reinforced by the astrocytic sheath
and a thick basement membrane

49. The Apparent Volume of distribution:
– the measure of the apparent space in the body available to contain a
drug
• It is the theoretical volume of fluid into which the total drug
administered would have to be diluted to produce the
concentration in plasma.
– Volume of distribution is a measure of the distribution of the drug
within the body; not the actual volume of the body or its fluid
compartments
Distribution cont’

50. – The apparent volume of distribution is represented by the
volume of compartments into which drugs diffuse after being
absorbed
• Volume of distribution (Vd):
– the ratio of the amount of drug in the body to the concentration
of drug (C) in blood or plasma
• Vd = amount of drug in body
C
• For example,
– if 1000 mg of a drug is given and the subsequent
plasma concentration is 10 mg/L,
• that 1000 mg seems to be distributed in 100 L;
– dose/volume = concentration; 1000 mg/x L = 10 mg/L;
» therefore, x = 1000 mg/10 mg/L = 100 L).
Distribution cont’

51. Metabolism
Metabolism
• The process through drugs/parent compounds are
biotransformed into daughter metabolites.
• Liver is the chief metabolic organ of the body; and by
extension also the principal site of drug metabolism
• Biotransformation of drugs usually results to
pharmacologically inactive metabolites, though can also lead
to active forms of the drug
• Roles of metabolism:
• As a mechanism of termination of drug action;
• many drugs are inactivated before excretion (e.g phenothiazines); in
this case, metabolism serves as a form of elimination.
• As a mechanism of drug activation:
• some drugs are activated through metabolism (Prodrugs)
• Other drugs are administered active, but also yield active metabolites
(eg, some benzodiazepines).

52. • Note: drug elimination and drug excretion are considered different
in context of the role each one of them plays
– Elimination (modification and termination of action) for some drugs
occurs before excretion
– Most of the excretion of drugs and their metabolites occurs in the
kidney
• Role of the liver:
– it contains a higher concentration of drug metabolizing enzymes
involved in metabolism than other tissues hence its the principal drug
metabolism site
• Other tissues where drug metabolism takes place:
– the gastrointestinal tract, the lungs, the skin, the kidneys, and the
brain
• Drug metabolism rates vary among patients
Metabolism cont’

53. • Determinants of drug metabolism rates
– Genetic individual factors:
• drug metabolism rates differ in families and populations, e.g. in metabolism of
isoniazid, there are slow acetylators who metabolize the drug slowly
– Non genetic individual factors:
• Age: an increased susceptibility to the pharmacologic or toxic activity of drugs
has been reported in very young and very old patients compared with young
adults
• Sex: some drugs exhibit sex dependent variations in metabolism
– Disease related:
• Coexisting acute or chronic diseases that affect liver architecture or function
markedly affect hepatic metabolism of some drugs; examples liver cirrhosis,
hepatitis.
• Cardiac disease may also impair drug metabolism by impairing disposition of
those drugs whose metabolism is flow-limited.
– Drug interactions
• Some drugs induce the microsomal enzymes, hence increasing rate of
metabolism of other drugs metabolized through the same pathway.
• Others inhibit the enzymes, hence resulting to slowed metabolism and
potential accumulation of drugs metabolized via the same system
Metabolism cont’

54. Metabolism cont’
• Nature of drugs:
• Many drugs are made relatively lipid soluble.
• A lipid soluble drug is readily reabsorbed from the urine in
the renal tubule, hence leading to slow excretion
• Role of metabolism:
• Metabolism facilitates excretion by conversion of drugs
from high to low lipid-solubility thus making them less
readily reabsorbed
• Metabolic reactions/processes are categorized into
two:
• Phase 1
• Phase 2

55. Metabolism cont’
Phase 1 metabolism:
• Phase I reactions usually convert the parent drug to a more polar metabolite
by introducing or unmasking a functional group (–OH, –NH2, –SH)
• Involve formation of a new or modified functional group or cleavage.
• They include: oxidation, reduction, deamination, and hydrolysis
• Note: these reactions are nonsynthetic.
• Phase I metabolism is mainly carried out by cytochrome P-450 (CYP450)
group of enzymes,
– a microsomal superfamily of isoenzymes that catalyze the oxidation of many
drugs
– These enzymes are highly concentrated in the liver
• CYP450 enzymes can be induced or inhibited by many drugs and substances,
– thus helping explain many drug interactions in which one drug enhances the
toxicity or reduces the therapeutic effect of another drug.
– See TABLE 4–1: Examples of phase I drug-metabolizing reactions
(Pharmacology: Examination & Board Review, 9e > Part I. Basic Principles >
Chapter 4. Drug Metabolism)

56. • Enzyme inhibition and induction:
– The synthesis of cytochrome P-450 (CYP450) can be
induced or their actions inhibited by some drugs:
• Such drugs can therefore alter their own metabolism and
the metabolism of other drugs either by inducing the
synthesis of larger amounts of the metabolizing enzymes
(usually P450 enzymes in the liver) or by inhibiting those
enzymes.
– See TABLES 4-3 and 4-4
(Pharmacology: Examination & Board Review, 9e > Part I. Basic
Principles > Chapter 4. Drug Metabolism)
Metabolism cont’

57. Phase 2:
• Involve conjugation with an endogenous substance e.g, glucuronic
acid, sulfate, glycine;
• Conjugation makes most drugs more water soluble and easily
excreted in urine or bile
• Phase 2 reactions are synthetic
• They include:
– Glucuronidation: addition of a glucoronide
– Acetylation: addition of an acetyl group
– Sulfation: addition of a sulfate group
– Methylation: addition of a methyl group
– Amino acid conjugation with glutamine or glycine
See TABLE 4–2: Examples of phase II drug-metabolizing reactions
(Pharmacology: Examination & Board Review, 9e > Part I. Basic Principles >
Chapter 4. Drug Metabolism)
Metabolism cont’

58. Metabolism cont’
• Note:
– Metabolites formed in synthetic reactions are
more polar and more readily excreted by the
kidneys (in urine) and the liver (in bile) than those
formed in nonsynthetic reactions
– Some drugs undergo only phase I or phase II
reactions;
• thus, phase numbers reflect functional rather than
sequential classification

59. Metabolism cont’
Rate of metabolism:
– First-order elimination (or kinetics),
– the rate of elimination is proportional to the concentration (i.e,
the higher the concentration, the greater the amount of drug
eliminated per unit time)
– That is, the metabolism rate of the drug is a constant fraction of the drug
remaining in the body (rather than a constant amount of drug per hour)
– In this case, usually only a small fraction of the metabolizing
enzyme's sites are occupied, and the metabolism rate increases
with drug concentration
– The drug has a specific/constant half life: The time required for
the amount of drug to fall to 50% of an earlier measurement
– For example, if 500 mg is present in the body at time zero, after
metabolism, 250 mg may be present at 1 h and 125 mg at 2 h (illustrating
a half-life of 1 h).
– The concentration of such a drug in the blood will decrease by 50% for
every half-life.
– Most drugs in clinical use demonstrate first-order kinetics.

61. Metabolism cont’
– Zero order kinetics
• the rate of elimination remains constant regardless of
concentration
– a fixed amount of drug is metabolized per unit time
• In zero order kinetics, most of the enzyme sites are occupied; and
– metabolism occurs at its maximal rate and does not change in proportion
to drug concentration
• Drugs metabolized through zero order kinetics have no specific
half-life; the half life changes with the concentration
– For example If 500 mg is present in the body at time zero, after
metabolism starts, 450 mg may be present at 1 h and 400 mg at 2 h
(illustrating a maximal clearance of 50 mg/h and no specific half-life).
• As drug concentration increases, metabolism usually shifts
from first-order to zero-order kinetics.

63. Excretion
Excretion
• Process of removal of the drug from the body
• Two key routes of excretion:
– Renal:
• The kidneys, which excrete water-soluble substances, are the principal organs
of drug excretion.
– Biliary:
• The biliary system contributes to excretion to the degree that drug is not
reabsorbed from the GI tract.
• Other routes (though not so significant):
– intestine, saliva, sweat, breast milk, and lungs
– Excretion via breast milk, although not important to the mother, may affect
the breastfeeding infant
• The role of hepatic metabolism is usually to make drugs more polar
and thus more water soluble;
– The resultant metabolites can then be more readily excreted since
they do not get reabsorbed back into circulation from the renal
tubules

64. Excretion cont’
Renal excretion: glomerular filtration and active tubular
secretion
• Renal filtration: most of the drugs are filtered through the
glomerulus
– Glomerular filtration- About 20% of the plasma reaching the
glomerulus gets filtered
– Renal tubular reabsorption:
• There is usually passive and active reabsorption of almost all water and
electrolytes filtered
• However for most drug metabolites (which are polar and
therefore lipid insoluble) reabsorption does not take place,
hence they can be excreted readily, unless a specific transport
mechanism exists for their reabsorption (e.g, as for glucose,
ascorbic acid, and B vitamins).
• Active tubular secretion:
• Several drugs are excreted in the proximal tubule via energy
dependent active tubular secretion mechanisms

65. Excretion cont’
• Renal handling of drugs is based on the principles of
transmembrane passage
• Factors affecting excretion:
– Plasma protein binding:
• only unbound drugs undergo filtration in the glomerulus
– Degree of ionization of the drug molecule:
– The ionization state of a drug and its metabolites determines its
lipid solubility and therefore the ease with which they get
reabsorbed
– Urine PH
– The degree to which a drug remains in un-ionized or ionized form
depends on pH
– Acidification of urine increases reabsorption and decreases
excretion of weak acids and decreases reabsorption of weak
bases.
– Alkalinization of urine has the opposite effect.

66. Excretion cont’
Biliary excretion
– Some drugs undergo active secretion into bile through
the biliary epithelium
– Properties of drugs excreted in bile:
– Larger molecules (molecular weight of > 300 g/mole)
– Drugs with both polar and lipophilic groups
– Biliary excretion is aided by conjugation
– Enterohepatic circulation:
– Some drugs secreted in bile may be reabsorbed back
into circulation from the intestines

67. Clearance
• A key parameter used in measuring the excretory capacity of the body
• The measure of the ability of the body to eliminate the drug
– Drug Clearance (CL): the ratio of the rate of elimination of a drug by all routes to the concentration of drug
in the plasma or blood:
• Drug Clearance (CL)= Rate of elimination
Plasma concentration of the drug (C)
• Major routes of elimination: renal, liver, others (lungs, muscle)
• Total/systemic clearance is a summation of clearance in all routes
• Drug clearance is governed by the same principles as in renal physiology;
– creatinine clearance is the rate of elimination of creatinine in the urine relative
to its serum concentration (UV/P)
– clearance is a constant for drugs that undergo first order kinetics
– that is, the ratio of rate of elimination to plasma concentration is the same regardless of
plasma concentration
– On the other hand, clearance is not constant for drugs eliminated with zero-
order kinetics
see Figure 3–2 (Pharmacology: Examination & Board Review, 9e > Part I. Basic Principles > Chapter 3.
Pharmacokinetics)
Excretion cont’

68. Excretion cont’
Half life (t1/2):
• The time required to change the amount of drug in the body by one-half
(50%) during elimination.
– t1/2 is dependent on Volume of distribution (Vd) and Drug clearance (CL)
t1/2= 0.7* Vd
CL
0.7- a constant
• t1/2:
• a useful indicator of the time required to attain 50% of steady state, or to decay
50% from steady-state conditions
• It may change in different disease states, due to the physiological
alterations occurring with the conditions e.g. reduced clearance in renal
disease
• For drugs eliminated by first-order kinetics, this number is a constant regardless of the
concentration

69. `
– The half-life of a drug determines the rate at
which blood concentration rises during a constant
infusion and falls after administration is stopped (
see Figure 3–3).
– In prediction of half life, both the volume of
distribution and clearance must be known
– In general about 3-4 half lives of a drug are
required for attainment of 87-90% of the final
steady state concentration;
• The effect of the drug at this concentration is clinically
the same as that at the final steady state concentration

70. Dosage Regimens and Related Concepts
• Dosage regimen:
• a plan for drug administration over a period of time.
– An optimal dosage regimen aims to achieve therapeutic
levels of the drug in the blood without exceeding the
minimum toxic concentration.
– A maintenance dose schedule is used to maintain the
plasma concentration within a specified range over long
periods of therapy
– In cases where it is necessary to achieve the target plasma
level rapidly, a loading dose is used to "load" the Vd with
the drug.
– An ideal dosing plan is arrived at basing on:
• knowledge of both the minimum therapeutic and minimum toxic
concentrations for the drug,
• as well as its clearance and
• Vd.

71. • Maintenance dose
• The dose required for regular administration to maintain a
target plasma level.
– The essence here is restore the amount of drug lost to
elimination , hence clearance is used in the calculation
as follows:
• Maintenance dose = Dosing rate/Bioavailability (F)
• Dosing rate= Target plasma concentration * CL (L/h/70Kg)
• For IV drugs, F=1 hence omitted in the calculation
• For other routes F should be included since bioavailability is
less than 100%
• This calculation is for drug given on continuous infusion
• The infusion rate is given as mg/h/70kg

72. • When the drug is being given on intervals:
– Size of each maintenance dose=
» Maintenance dose (dosing rate (Cp(target) x CL)/F) *dosing
interval (in hours);
» This is expressed as units of mg or any other measure of weight

73. • Loading dose:
– The dose required to achieve a specific plasma drug
concentration level (Cp) with a single administration.
– It is suitable for drugs with long half lives
• Because this requires filling the volume of distribution (Vd), the
calculation uses the volume of distribution (Vd) equation as:
– Loading dose = Cp(target) x Vd / F : expressed as unit (mg) or any other
measure of weight
• Steady state:
– The condition in which the average total amount of drug in
the body does not change over multiple dosing cycles i.e.,
• the condition in which the rate of drug elimination equals the rate
of administration
• The plasma concentration of a drug that consistently remains the
same, without rising or falling is referred to as: steady state
concentration
– Steady state concentration is usually achieved after
repeated doses or on continuous administration of a drug

74. • Peak and trough concentrations:
– The maximum and minimum drug concentrations
achieved during repeated dosing cycles
• Minimum effective concentration (MEC):
– The plasma drug concentration below which a
patient's response is too small for clinical benefit

75. • Therapeutic Window
• the safe range between the minimum therapeutic concentration and
the minimum toxic concentration of a drug.
– For every drug
– Effective Concentration: concentration which is just barely effective
– Toxic Concentration: dose which is just barely toxic
– therapeutic window is the range between these two; range
within which most safe and effective treatment will occur.
– Therapeutic window is useful in determining the acceptable
range of plasma levels when designing a dosing regimen.
– Thus,
• the minimum effective concentration usually determines the desired
trough levels of a drug given intermittently, whereas
– the minimum toxic concentration determines the permissible peak plasma
concentration
– See figure 3-6

76. • Adjustment of dosage when elimination is
altered by disease
– Some conditions warrant alteration of dosage of a
drug to prevent toxicity:
• Renal disease
• Heart failure resulting in reduced cardiac output
• Liver disease: severe cirrhosis and other forms of liver
failure

77. Bibliography
– Anthony J. Trevor, Bertram G. Katzung & Susan B.
Masters (2015) Pharmacology- Examination And
Board Review 11th ed., McGraw Hill, Lange
– Katzung B.G (2012) Basic & Clinical Pharmacology,
12th ed, McGraw Hill, Lange
– Merck Manual for Health Care Professionals.
Clinical Pharmacology.
http://www.merckmanuals.com/professional/clini
cal_pharmacology.html