"Discover the intricacies of drug science in 'Pharmacology and Chemotherapeutics.' Tailored for students and healthcare professionals, this comprehensive guide explores drug mechanisms, therapeutic applications, and cutting-edge research. Bridging theory and practice with real-world cases, it's an indispensable resource for understanding the dynamic world of pharmacology. Uncover the secrets of drug action and stay abreast of the latest advancements in this essential field."

1. BLT 2114
PHARMACOLOGY &
CHEMOTHERAPEUTICS
By John Kateregga

2. Module Learning outcomes
At end of this module, students are expected to be able to:
• Define the key concepts used in pharmacology
• Describe the processes drug absorption, distribution,
metabolism & excretion
• Describe major mechanisms of drug action
• Be well versed with drugs acting on key body systems
• Explain mode of action and spectrum of activity of major
chemotherapeutic agents
• Be familiar with key aspects of experimental pharmacology

3. Careers in pharmacology
• Universities – academia and research
• Large hospitals – clinical trials, drug monitoring
• Pharmaceutical industry – drug R&D and evaluation
• Government agencies – enforcing compliance
• Drug marketing – sales representative

4. Careers in pharmacology

5. Date Topic Lecturer
08/10 Introduction to Pharmacology and chemotherapeutics Kateregga
Pharmacokinetics Kateregga
Pharmacodynamics Kateregga
Autonomic nervous system pharmacology Olila
Cardiovascular system pharmacology Kateregga
Gastrointestinal and respiratory pharmacology Nakalembe
Antibiotics and other antibacterial agents Nakalembe
Antiviral, antiretroviral and antineoplastic agents Nakalembe
Antimalarials, antitrypanosomals, antamoebics, antifungals Olila
Anthelmintic pharmacology Kateregga
Renal pharmacology Olila
Endocrine Pharmacology Nakalembe
Experimental pharmacology: Quantifying drug action, animal
models
Olila
Practicals: Pharmacological agonism and antagonism Kateregga
28/10 Course Assessment Test Kateregga
Teaching schedule

6. PHARMACOLOGY: INTRODUCTION
• Pharmacology – science that deals with
properties of drugs, their interaction with and
effects on living systems
• Drug – is any chemical or substance used to
modify physiological processes or pathological
states for the benefit of the recipient

7. Drug names
• Chemical name - derived from chemical structure e.g.
[R-(R*, R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-
methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-
1Hpyrrole-1-heptanoic acid is the chemical name for
atorvastatin
• Generic name i.e. internationally recognized non-
proprietary name e.g. atorvastatin
• Brand (proprietary) name i.e. trade name as patented
e.g. Lipitor® (Pfizer, US), Filstat® (Fourts, India) have
atorvastatin as active ingredient
• Group name – indicates mode of action, effect or
clinical use e.g. atorvastatin is an antihyperlipidemic

8. Drug names
• Chemical name: (RS)-3-ethyl 5-methyl 4-(2,3-
dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate
• Generic name: felodipine
• Trade name: Felocard® (Cadila Pharmaceuticals,
India)
• Group name: Antihypertensive

9. Drug names
• Chemical name: N-acetyl-p-aminophenol
• Generic name: paracetamol, acetaminophen (US)
• Trade name: Panadol® (GSK), Maxadol® (Mac’s)
• Group name: analgesic-antipyretic

10. Drug names
• Chemical name: 2-(2,6-dichloranilino)
phenylacetic acid
• Generic name: diclofenac
• Trade names: D-Fenac®, Dicofen®, Clofenac®,
Ziclofen®
• Group name: non-steroidal anti-inflammatories

11. DEFINITIONS
Pharmacokinetics
• Mathematical description of changes in drug
concentrations with time and the processes
responsible for the changes
• Affect onset, duration and intensity of drug effect
• Pharmacokinetics is “what the body does to the
drug”.

12. DEFINITIONS
Pharmacodynamics
• Deals with drug mechanisms of action e.g.
interaction with receptors, enzymes etc and
the relationship between dose and response
• Pharmacodynamics is “what the drug does to
the body”

13. Definitions
Therapy -treatment of disease/disorder in general e.g.
• Pharmacotherapy
• Chemotherapy
• Physiotherapy
• Psychotherapy
• Radiotherapy
• Protontherapy etc.
Pharmacotherapy –with use of drugs in treatment of
disease including those of non-infectious causes e.g.
heart disease, renal disease, diabetes etc.

14. Definitions
Chemotherapy –deals with treatment of diseases
using drugs that kill causative organisms of
disease and cancer cells. Includes:
• Antibiotic drugs
• Antibacterial drugs
• Antimicrobial drugs
• Antiviral drugs,
• Antifungal drugs,
• Anthelmintic drugs,
• Antineoplastic drugs etc.

15. Definitions
Toxicology - study of adverse effects of drugs on
the body. It deals with mechanisms of toxicity,
detection and treatment of poisoning caused by
drugs or poisons
Pharmacognosy – branch of pharmacology dealing
with the study of sources of drugs or identification
of new drugs from natural sources

16. Drug dosage forms
• Physical forms by which drugs are conveniently
delivered to sites within the body
• Solid dosage forms e.g. tablets, capsules,
suppositories, powders, pellets, lozenges
• Semi-solid dosage forms e.g. creams, ointments,
liniments
• Liquid dosage forms e.g. injections, syrups, elixirs,
tinctures, aerosol sprays, lotions

17. Drug dosage forms
• Oral dosage forms - tablets, capsules, oral
solutions, oral suspensions (drenches), powders,
syrups, elixirs etc
• Parenteral dosage forms – Injections for
Intravenous (IV), Intramuscular (IM), Sub-cutaneous
(SC) injections etc
• Topical dosage forms – creams, ointments, dusting
powders, liniments, lotions
• Inhaled dosage forms – inhalers, nebulizers

18. The need for dosage forms
1- Accurate dose – e.g. tablet may have required dose
2- Protection from gastric juice – (e.g. enteric coated
tabs)
3- Masking taste and odour (e.g. sugar coated tabs)
4- Placement of drugs in tissue/cavity (e.g. inhalers)
5- Sustained release of medication (e.g. SC injection)
6- Vehicle may enhance drug absorption ()

19. Oral dosage forms
(I) Tablets
Tablets are hard, compressed medications in round,
oval or square shape.
A coating may be applied to tablets to:
1- hide the taste of the tablet's components
2- make the tablet smoother/easier to swallow
3- make it more resistant to acid environment
4- extending its shelf life

20. Oral dosage forms
Sugar-Coated Tablets (SCT)
Compressed tablets with a sugar coating which may be
colored
Useful in covering up drugs with objectionable tastes or
odors and in protecting drugs sensitive to oxidation
Film-Coated Tablets (FCT)
• Coated with a thin film of a water-soluble material
• Same effect as sugar coating with added advantage of
reduced time period required for the coating operation

21. Oral dosage forms
Enteric-Coated Tablets (ECT)
• Coated with substances that resist solution in
gastric fluid but disintegrate in the intestine
• Useful when tablets contain:
• drugs inactivated/destroyed in stomach
• those which irritate the mucosa
• Also for delayed release of the drug
(II) Boluses
A special tablet used to provide larger doses of
the drug especially in large animals

22. Oral dosage forms
Capsule is a medication in a gelatin container.
- Advantage: mask the unpleasant taste of its contents.
- The two main types of capsules are:
1- hard-shelled capsules - used for dry, powdered
ingredients
2- soft-shelled capsules - used for oils or active
ingredients that are dissolved or suspended in oil.
Soft gelatin capsule
Hard gelatin capsule
(III) Capsules

23. Oral dosage forms
-Solid preparation consisting of sugar and gum,
which gives strength and cohesiveness to the
lozenge and facilitates slow release of the drug
- It is used to medicate the mouth and throat for
slow administration of cough remedies
(IV) Lozenges

24. Oral dosage forms
(V) Oral powders
There are 2 kinds of powders for internal use
1-Bulk Powders are multi-dose preparations consisting dry
particles that contain one or more active ingredients e.g.
antacids. Usually dissolved in water before administration
2-Divided Powders are single-dose presentations of powder
(e.g. small sachet) usually added to water.

25. Oral dosage forms
(VI) Oral solutions
Clear liquid preparations for oral use containing one or more
active ingredients dissolved in a suitable solvent
(VII) Oral suspension
- Liquid preparations for oral use containing one or more
active ingredients suspended in a suitable solvent.
- May show a sediment which is readily dispersed on shaking
to give a uniform suspension

26. Oral dosage forms
(VIII) Syrups
- Conc. aqueous solutions of a sugar, usually sucrose
- Flavored syrups are a convenient form of masking bad
taste
(IX) Elixirs
- It is flavored clear liquid oral preparation e.g. for drugs
that may be nauseous
- May contain ethanol and sucrose, with antimicrobial
preservatives which confers stability to the preparation

27. Topical dosage forms:
(I) Ointments:
- Semi-solid, greasy preparations for application to
the skin, rectum or nasal mucosa
- Ointments may be used as emollients or to apply
suspended or dissolved medicaments to the skin
(contain lanolin or olive oil to enhance absorption)

28. Topical dosage forms
(II) Creams:
- Creams are semi-solid emulsions-mixtures of oil and water.
- They are divided into two types:
A- oil-in-water (O/W) creams: are composed of small
droplets of oil dispersed in an aqueous phase. Are less
greasy and more easily washed off using water.
B- water-in-oil (W/O) creams: are composed of small
droplets of water dispersed in an oily phase. Hydrophobic
drugs which are incorporated into such creams are released
more readily from these creams

29. Topical dosage forms
(III) Liniments:
- Liquid, semi-liquid or semi-solid preparations
intended for application to the skin
- They are applied by rubbing or massaging
- Contain counter-irritant for muscle/tendon
injuries
- Should not be applied to broken skin

30. Topical dosage forms
(IV) Lotions
- These are liquid preparations (aqueous) for
external application without friction
- They are applied directly on the skin or applied on
a suitable dressing to reduce evaporation

31. Parenteral dosage forms
An injection is a liquid infused into the body using a
hollow needle and a syringe. Parenteral dosage
form may be: (1) solution for injection
(2) suspension for injection
(I) An intravenous injection:
It is a liquid administered directly into the
bloodstream via a vein.
It is advantageous when a rapid
onset of action is needed.

32. Parenteral dosage forms
(II) Intramuscular injection:
-It is the injection of a substance directly into a muscle.
- Many vaccines are administered IM
-Depending on chemical properties of the drug, the drug
may either be absorbed fairly quickly or more gradually.
- IM injections are often given in neck or gluteal muscles
- Injection fibrosis may occur if the injections are delivered
with great frequency or with improper technique.

33. Parenteral dosage forms
(III) Subcutaneous injection
Subcutaneous (SC) injections are given by injecting a
fluid into the sub-cutis, the layer of skin directly below
the dermis and epidermis.
SC injections are used for administration of vaccines and
many other drugs e.g. some antibiotics etc
It enables slow release of the drug from the site of
injection

34. Inhaled dosage forms
1- Inhaler
- Solution/suspension of drugs held under pressure
in an aerosol dispenser & releases droplets of ∞50µm diameter.
The patient inhales the released drug through a mouthpiece
- Used to treat asthma and other respiratory problems
2- Nebulizer
- device used to administer drugs in form of a
liquid mist to the airways for treating
asthma, and other respiratory diseases
- It pumps air or oxygen through a liquid medicine to turn it into
a vapor, which is then inhaled by the patient.

35. Drug dosage forms
• Dosage forms

36. • Topical: Drugs are applied topically to the skin or
mucous membranes, mainly for local action.
• Oral: Drug is given via the digestive tract for local or
systemic (non-local) effect.
• Parenteral: The drug is injected via a hollow needle
into the body at various sites and to varying depth.
• Rectal: Drug is given through rectum by suppositories
or enema – e.g. to evacuate the lower intestine to
prepare for surgeries e.g. Caesarian Section
• Inhalation: The lungs provide an excellent surface for
absorption when the drug is delivered in gaseous,
aerosol or ultrafine solid particle form.
Routes of drug administration

37. Routes of drug administration
(A)Topical routes
(I) Skin/Dermal
e.g. creams, ointment (local action)
(II) Mucosal membranes
• eye drops (onto the conjunctiva)
• ear drops
(B) Oral route (Per Os or PO)
The drug is swallowed and produces systemic effects
after absorption through mucosa of GIT

38. 1- Convenient - portable, no pain, easy to take
2- Cheap - no need to sterilize, compact, multi-dose
bottles, automated machines produce tablets in
large quantities
3- Variety - tablets, capsules, suspensions, mixtures
Oral route disadvantages
1- Sometimes inefficient - low solubility drugs may
suffer poor availability e.g. Griseofulvin
Oral route - Advantages

39. 2- First-pass effect -Is hepatic metabolism of a drug
when it is absorbed from the gut and delivered to
the liver via the portal circulation. The greater the
first pass effect, the lower the bio-availability of
drug e.g. propranolol
3. Effect too slow for emergencies
Oral route - Disadvantages

40. 4- Food - Food can affect absorption e.g. Absorption
is slower for tetracyclines taken with milk. For
Griseofulvin absorption is higher after a fatty meal
5- Sometimes may have adverse reactions – e.g.
Antibiotics may kill normal gut flora and allow
overgrowth of fungi or pathogenic bacteria.
6- Not suitable for unconscious patient - Patient
must be able to swallow solid dosage forms.
7 May cause irritation gut mucosa, nausea & vomiting
Oral route - disadvantages

41. (C) Parenteral routes
The drug is injected via needle into the body at various
sites and to varying depth
Injectable forms are more expensive than e.g. oral forms

42. A- Intravascular (IV)
- placing a drug directly into blood stream.
-Drug is usually placed into a vein – Intravenous
Advantages
1- precise, accurate and immediate onset of action,
100% bioavailability.
Disadvantages
1- risk of embolism
2- high concentrations attained rapidly leading to
greater risk of adverse effects
3. Increased risk of infection if non-sterile
4. Drug not be easily removed after IV injection
Parenteral routes

43. Parenteral routes
B-Intramuscular: (into the skeletal muscle)
Advantages
Suitable for injection of drug in aqueous solution
(rapid action) and drug in suspension or emulsion
(sustained release)
Disadvantages
Pain at injection sites for certain drugs

44. C- Subcutaneous (under the skin), e.g. insulin
D- Intradermal (into the skin itself) is used for skin
testing some allergens e.g. tuberculin test.
E- Intrathecal (into the spinal canal) is most
commonly used for spinal anesthesia
F- Intraperitoneal (infusion or injection into the
peritoneum) e.g. peritoneal dialysis in case of
renal insufficiency
Parenteral routes

45. (D) Inhalation route
- For gaseous/volatile agents e.g.
volatile anesthetics, asthma drugs etc
Advantages
A- Large surface area, high blood flow
B- thin membranes separate alveoli from circulation
C-Rapid onset of action -rapid access to circulation
E- can be used to achieve a local effect on resp. tract

46. ROUTES OF DRUG ADMINISTRATION
ROUTE ONSET OF
ACTION
INDICATIONS EXAMPLES
oral (PO) 30 - 60 mins whenever possible, safest and most
convenient route
most medications e.g.
analgesics, sedatives,
antibiotics
Rectal
(PR)
15 - 30 mins for patients are unable to take oral
medications; where parenteral route is
not indicated, also for local effect
analgesics, laxatives
purgatives
SC several mins for drugs that are inactivated in GIT Insulin, antibiotics
IM several mins for drugs with poor oral absorption,
when high blood levels are required,
when rapid effect is desired
narcotic analgesics
antibiotics
IV within 1 min in emergency situations, when
immediate effect is desired, when large
volumes need to be admin, e.g. infusion
IV fluids, antibiotics
anesthetic drugs
inhalation within 1 min for local effects within respiratory tract Antiasthma drugs
bronchodilators
topical within 1 hr for local effects on skin and mucous
membrane of eye, ear, nose, mouth
creams, ointments,
sprays, tinctures

47. PHARMACOKINETICS
Math. description of drug conc. changes in body, the
processes responsible for the changes & how they affect
magnitude of drug’s pharmacological effects
PROCESSES INVOLVED IN PHARMACOKINETICS
1. Absorption
2. Distribution
• Drug conc. measured in plasma, saliva, urine, CSF etc.
• Assumption = drug conc. in fluids are in equilibrium
with drug conc. at the receptor
3. Metabolism
4. Excretion

48. Pharmacokinetics

49. Why study Pharmacokinetics?
• Essential during R&D - less efficacious drugs in
vitro can be more effective in vivo due to
favorable kinetics (better absorption, distribution)
• Correct use of drugs in therapy (choice of best
route of admin, best dose, dosage intervals etc)
• Prediction of drug toxicity basing on the levels
and duration of exposure of the body organs

50. Pharmacokinetics
• Drugs must cross several membranes to be
absorbed (i.e. enter the systemic circulation).
• Not all drugs need to enter circulation to act
• BUT, even drugs given orally to treat GI conditions
may cross membranes & enter circulation
• IV admin drugs also cross capillary membranes to
leave circulation and reach EC & IC sites of action

51. Pharmacokinetics
Rate at which drug reaches site of action depends on:
–Absorption - passage of drug from its site of
administration into the blood
–Distribution - delivery of the drug to the tissues
DRUG ABSORPTION
• Process by which drug enters systemic circulation
without being chemically altered or movement of
a drug from its site of administration into blood
• Often involves the drug traversing membranes

52. Drug absorption
• Membranes have a lipid layer (hydrophobic).
Drugs easily cross membranes if they are:
• Non-polar
• Have high lipid solubility
• Uncharged (non-ionized)
• Having low molecular weight
• Ionized/charged compounds are not compatible
with uncharged lipid environment in membranes

53. Drug absorption
• High lipid soluble drugs easily cross membranes
• High oil/water partition coefficient = high lipid
solubility & greater absorption e.g. absorption of
thiopental> secobarbital>barbital
• Aqueous pores (0.4nm) are NOT large enough –only
molecules of low mol. wt can pass through pores
• Most large mol. wt proteins because of charge and
size are not admin orally

54. Drug absorption
• The pH of a body compartment affects rate of drug
absorption into blood
• Acidic drugs well absorbed in acidic environment
e.g. stomach, because most of the drug remains
uncharged/non-ionized
• Basic drugs NOT well absorbed in acidic enviro’t
because most of the drug is in ionized/charged
form. This is called IONIC TRAPPING

55. Drug absorption: processes
• Simple passive diffusion – conc. gradient across
membrane determines absorption/distribution rate
• Active transport – ATP-driven, conc. gradient
independent –(renal tubule, bile duct, blood-brain
barrier, GIT)
• Facilitated diffusion - carrier molecules used, may
undergo saturation/competition and drug-drug
interactions –affect duration & intensity of action

56. Drug absorption
Summary of factors affecting drug absorption
• Lipid solubility of drug
• Molecular weight of drug
• Polarity and charge of drug molecules
• Presence of carrier molecules
• pH of compartment where absorption occurs

57. Drug distribution
• When the drug enters circulation it is distributed to
all parts of body. To be distributed to tissues the drug
has to cross the endothelial membrane or pores
• Therefore, many of the factors that affect absorption
also affect the extent of distribution i.e.
• Lipid solubility of drug
• Molecular weight of drug
• Polarity and charge of drug molecules
Other factors affecting distribution
• The degree of protein binding and;
• The extent of blood flow to the organs

58. Drug distribution
• Drug molecules are transported in plasma as free
molecules (unbound) or bound to plasma proteins,
mainly albumins (called protein binding of drugs)
• The bound drug is often in equilibrium with the
unbound drug
• Only the free drug is able to cross the endothelial
membranes (plasma proteins cannot cross pores)
• The degree of plasma binding therefore affects the
extent of distribution of the drug

60. Distribution to special organs
• Rate of blood flow determines maximum amount
of drug that can be delivered per minute to
specific organs at a given plasma conc.
• Well perfused tissues e.g. kidney receive a large
quantities of drugs
• Poorly perfused tissues e.g. fat receive drugs at a
slower rate – conc. in fat may be increasing long
after that in plasma has started to decrease

61. The blood brain barrier
• Many drugs do not readily enter brain tissue. Brain
capillaries have tight junctions between endothelial
cells i.e. there are no pores
• This barrier acts as a safety buffer, protecting brain
tissue from toxic effects of some xenobiotics
• Main mechanism of drug entry into the CNS is by
passive diffusion across membranes
• Only highly lipid soluble drugs cross the barrier

62. Blood-brain barrier

63. DRUG BIOTRANSFORMATION/METABOLISM
• Refers to enzymatically mediated chemical changes
that a drug undergoes before excretion from the body
• Usually result in inactivation or reduction in drug
activity; hence called drug detoxification
In a few cases metabolism leads to drug activation e.g.
• Lethal synthesis – yields metabolites of increased
activity e.g. parathion to paraoxon
• Pro-drug – drug is inactive but is metabolized into
active form in body e.g. cyclophosphamide converted
to 4-hydroxycyclophosphamide

64. DRUG BIOTRANSFORMATION
• Liver is the primary site of drug metabolism –
rich in drug metabolizing enzymes
• Detoxification can occur in lung, kidney, gut wall,
gut content, placenta
• Detoxification can also occur in plasma. Plasma
has esterases e.g. pseudocholinesterase acts on
procaine, Ach, atropine, meperidine

65. BIOTRANSFORMATION REACTIONS
• Occurs in hepatic microsomes – SER of hepatocytes
• Microsomal enzymes include oxidases, reductases,
hydroxylases, transferases
Biotransformation reactions usually occur in 2 phases
• Phase 1 reactions – introduce functional groups in drug
molecule where conjugants bind in phase 2
• Phase 2 reactions (conjugation reactions) - usually
result in polar metabolites of decreased activity

66. BIOTRANSFORMATION REACTIONS
Drug phase 1 reaction phase 1 phase 1 reaction conjugated
metabolite product
• Phase 1 reactions may be
• Oxidations – addition of O or removal of H
• Reductions - addition of H or removal of O
• Hydrolysis reactions - addition of OH
• Introduce or unmask reactive functional groups
such as –OH, -NH2 or –SH

67. PHASE I REACTIONS
Oxidation reactions require mixed-function oxidases,
O2, NADP or NADPH, Cytochrome P450, cytochrome
P450 reductase
• Cytochrome P450 - membrane proteins which when
oxidized have affinity for hydrophobic substrates
Example of an oxidation reaction
• Oxidative deamination of RNH2 groups to RHN-OH
e.g. amphetamine to hydroxyl-amphetamine

68. PHASE I REACTIONS
Reduction reactions – not frequent but can occur in
drugs which possess disulphide (S:S), azo (N:N) or
nitro (NO2) groups
• N:N and NO2 groups are reduced into NH2 e.g. in
biotransformation of chloramphenicol
Hydrolysis reactions – usually applicable to drugs that
contain ester or amide groups
• Reaction may involve conversion of RCOOH or
RCONH groups into ROH2. e.g. in breakdown of
acetylcholine by cholinesterase

69. PHASE 2 REACTIONS
• Convert phase 1 drug metabolite into more polar
metabolite which is not easily reabsorbed and is
readily excreted in urine
• These reactions require conjugants and transferase
enzymes. Common endogenous conjugants:
• glucuronic acid, sulfates
• amino acids -glycine, cysteine, glutamine,
methionine
• alky groups - acetyl and methyl groups
• Common transferases – Sulpho-transferase,
glucuronyl transferase, methyl transferase etc

70. PHASE 2 REACTIONS
• Phase 2 reactions are also called conjugation
reactions or synthetic reactions
• Phase 2 metabolites are called conjugates e.g.
glucuronides, ethereal sulfates etc. These
polar metabolites are mainly excreted in urine
• High MW metabolites are excreted via bile

71. Drug biotransformation: Summary

72. DRUG EXCRETION
Some pharmacologists make a distinction between the
terms “drug excretion” and “drug elimination”
• Drug elimination is removal of unaltered drug while drug
excretion is removal of drug after biotransformation
Drug excreting organs
• Kidney – eliminates mainly water soluble substances
• Liver (eliminates metabolites via bile)
• Lungs (excrete volatile agents)
• Saliva, milk – small quantity of drugs & metabolites

73. RENAL EXCRETION OF DRUGS
Renal excretion processes include: Glomerular
filtration; tubular secretion; tubular reabsorption

74. GLOMERULAR FILTRATION
Drug is filtered from blood into tubules in glomerulus
The efficiency of the process depends on:
1. Glomerular filtration rate – high GFR = high renal
excretion rate
2. Renal blood flow – high RBF = high GFR
3. Molecular weight of drug – only low mol wt filtered
4. Protein binding – high binding hinders filtration
5. Plasma drug concentration (bioavailability) – high
bioavailability = greater renal excretion of drug

75. TUBULAR SECRETION
Drug molecules are transported from renal tissues into
tubules across the tubular membrane
• ATP or carrier molecules in PCT transport ionized, non-
lipid soluble drug molecules into ultrafiltrate
• Non-specific process–transport endogenous substrates
(uric acid) and drugs (e.g. penicillin, ampicillin)
• Susceptible to competition -may lead to drug toxicity
i.e. rate of excretion for competing drugs reduced
• Susceptible to saturation - if drug conc. in interstitium
is high (number of carrier molecules not indefinite)

76. TUBULAR REABSORPTION
• Is not a drug excretion process but influences drug
excretion; is passive diffusion back into kidney tissue
• Occurs in DCT; extent of the process depends on:
• drug conc. in the ultrafiltrate
• degree of ionization in ultrafiltrate - non-ionised
forms can be reabsorbed
• Lipid solubility - only lipid soluble drugs reabsorbed
Effect of tubular reabsorption of drug excretion
• Low lipid soluble and ionized drugs in ultrafiltrate are
rapidly excreted (don’t undergo reabsorption)
• non ionized and lipid soluble slowly excreted

77. BILIARY EXCRETION
• Usually for high molecular weight drugs – since they
are not easily excreted via filtration into urine
• Drugs excreted via bile enter the small intestine and
are excreted via faeces.
• Only polar conjugated metabolites also excreted by
this route --- not readily reabsorbed in intestines

78. EXCRETION VIA MILK
• Antibiotics appear in milk after parenteral admin.
Milk is slightly acidic relative to plasma and tends to
accumulate basic lipid soluble drugs
• Milk withdrawal periods protect consumers from
toxic effects of drugs e.g. hypersensitivity
EXCRETION VIA LUNGS
• Alveolar surface and pulmonary capillaries in close
proximity enables rapid exhalation of drugs
• Examples are gaseous/volatile anesthetics

79. ENTEROHEPATIC CIRCULATION
• Drug metabolite excreted in bile may be reabsorbed
and the drug cycles between the liver and gut
• Bacterial β-glucuronidase (enzyme) in gut liberates
glucuronide group from conjugate – the re-formed
non-polar drug can be reabsorbed
• Extends drug’s duration of action but may induce
toxicity e.g. tetracyclines, ampicillin, erythromycin,
chloramphenicol etc

80. RATES OF PHARMACOKINETIC PROCESSES
• Drugs may obey zero-order kinetics or first-order kinetics
• Zero-order kinetics - reaction proceeds at constant rate
and is independent of drug conc. in the body
• Example: elimination of phenytoin, salicylates, alcohol – a
constant amount is eliminated in a certain time regardless
of the drug concentration
• This is because excretion mechanisms get saturated
= -k or = -k
k = zero-order rate constant

81. First-order kinetics
• The reaction proceeds at a rate that is dependent
on the drug conc. in the body
• amount of drug excreted increases at a rate
proportional to amount of drug remaining in body
• If amount of drug admin increases, body is able to
eliminate more accordingly = NO accumulation
= - kA
k = first-order rate constant

82. First-order kinetics
• Applies to most drugs used in clinical practice at
therapeutic dosages
• 50% of drug eliminated by its half-life e.g. if T½ of
drug = 30 mins and 2g are admin, 1g will be left in
the plasma after 30 min
• drugs that obey first-order kinetics at low doses
may obey zero-order kinetics with large doses (due to
saturation of elimination mechanisms)

83. Zero versus First order kinetics
Zero order kinetics First order kinetics
Definition – the process that
takes place at constant rate
independent of drug conc.
The process that is directly
proportional to the drug conc.
involved
Rate of progress cannot be
increased even if the drug
conc. is increased.
Rate of progress increases
linearly with increase in the
drug conc.
Half life depends on initial
drug concentration
Half life is a constant value
Examples: IV infusion, carrier
based systems after saturation
Drugs that undergo ADME and
not linked with carriers

84. Pharmacokinetic parameters
Determine the extent and rate of drug ADME. Include:
• Bioavailability (measures extent & rate of absorption)
• Bioequivalence (compares bioavailability of 2 drugs)
• Volume of distribution (measures extent of drug
distribution)
• Plasma half-life (measures rate of excretion)
• Plasma clearance (measures rate of excretion)

85. Bioavailability
• This is the percentage of admin. drug which arrives
in systemic circulation (central compartment)
• Bioavailability is evaluated by determining the:
• Peak plasma concentration (Cmax)
• Time at which Cmax occurs (Tmax)
• Area under the plasma concentration-time
curve (AUC) after a single dose

86. Bioavailability
• Bioavailability for other routes is measured by
comparing AUC for IV admin and AUC for that route
• After IV admin, the AUC obtained corresponds to
100% bioavailability
• Bioavailabilityoral =
• Bioavailability not 100% for oral route due to incomplete
GIT absorption, metabolism in enterocytes, or efflux
transport back into intestinal lumen etc.

87. Bioavailability

88. Bioequivalence
• Bioequivalence is the relative bioavailability of two drugs –
e.g. the innovator drug versus the generic drug.
• Measured by comparing ratio of pharmacokinetic variables
(Cmax, Tmax, AUC) for innovator versus generic drug.
• Bioequivalence studies evaluate if generic drug conforms to
high quality of innovator drug. 2 products are bioequivalent
there is no significant difference in their bioavailability.
• E.g. excipients used in generic formulation (preservatives, pH
adjusters etc.) could affect the absorption and metabolism
producing differences in pharmacokinetic parameters.

89. Bioequivalence
Innovator drugs = new patented drugs protected from market competition. Generic drug
manufacturers cannot replicate them while they remain under patent.
Generic drugs (generics) = "drug products comparable to innovator product in dosage form,
strength, quality, effectiveness and intended use."

90. Plasma half-life
• T½ = time taken to halve plasma conc. of drug e.g.
100 mg/L to 50 mg/L
• Pharmacological significance = Determines the
frequency of admin. of a drug
• Usually independent of the dose administered but if
drug obeys zero-order kinetics e.g. in overdose, T½
may change due to saturation of elimination processes,
catabolism, plasma proteins binding etc.

91. Plasma half-life
• Value affected by clearance and volume of
distribution (Vd)
• T½ can be read directly from conc. v time graph

92. Volume of distribution
• Hypothetical volume (litres) in which a drug would
be distributed, assuming its conc. is homogeneous,
i.e. if conc. in tissue is identical to that in plasma
Vd (liters) =
• e.g. 100 mg of drug is admin IV; initial plasma conc.
=10 mg/L, then Vd = 10 L
• Determines what dose to administer to achieve a given
conc. or the conc. achieved after admin a given dose
C0 = initial plasma conc.

93. Plasma clearance
• Volume of blood cleared of drug per unit time by
the kidney, liver; GIT etc
Total plasma clearance=sum of clearance by all routes
• constant for a particular drug in a specific patient
CLp (ml/min) =
• if 400µg of drug is eliminated each min. & plasma
conc. = 2µg/ml, total clearance is 200 ml/min

94. Plasma clearance
• Renal clearance = volume of plasma that needs
to be cleared per unit time by kidneys
CLr (ml/min) =
• Helps predict the state of renal function for
dosage adjustment to avoid toxicity

95. FACTORS AFFECTING PHARMACOKINETIC VALUES
1. Age –renal & hepatic clearance decrease with age
2. Renal impairment- alters clearance and half-life.
Total clearance is proportional to renal function
3. Hepatic disease- affects clearance, half-life of drugs
Reduced drug metabolism seen in hepatic cirrhosis
4. Drug Interactions – competition for carrier, active
transport mechanisms, metabolizing enzymes
5. Dose – Phenytoin shows dose dependency -enzymes
have limited capacity to metabolize them

96. FACTORS AFFECTING PHARMACOKINETIC VALUES
6. Plasma protein binding – affect distribution,
metabolism and clearance
7. First pass effect – low bioavailability for orally admin
drugs e.g. lidocaine, propranolol, felodipine, morphine
8. Enzyme induction -some drugs stimulate synthesis of
high levels of hepatic drug metabolizing enzymes
• The inducers are also substrates of enzymes they induce
but may result in metabolism of other drugs.
• Barbiturates, diazepam, alcohol are enzyme inducers
9. Enterohepatic circulation – affects drug half life