2. Module Learning objectives
At the end of this module, students are expected to be able to:
• Define the key concepts used in pharmacology
• Explain 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 well versed 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
5. Date Topic Lecturer
20/10 Introduction to Pharmacology and chemotherapeutics Kateregga
Pharmacokinetics Kateregga
Pharmacodynamics Kateregga
Autonomic nervous system pharmacology Vudriko
Cardiovascular system pharmacology Kateregga
Gastrointestinal and respiratory pharmacology Vudriko
Antibiotics and other antibacterial agents Nakalembe
Antiviral, antiretroviral and antineoplastic agents Nakalembe
Antimalarials, antitrypanosomals, antamoebics, antifungals Olila
Anthelmintic pharmacology Vudriko
Renal pharmacology Olila
Endocrine Pharmacology Nakalembe
Experimental pharmacology Vudriko
Practicals: Pharmacological agonism and antagonism Kateregga
13/11 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
concs with time and the processes responsible
• 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”
14. 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.
15. 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.
16. Definitions
Toxicology - study of adverse effects of drugs on
the body
• 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
17. 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/implants, lozenges
• Semi-solid dosage forms e.g. creams, ointments,
liniments
• Liquid dosage forms e.g. injections, syrups, elixirs,
tinctures, aerosol sprays, lotions
18. Drug dosage forms
• Oral dosage forms - tablets, capsules, oral
solutions, powders, syrups, elixirs etc
• Parenteral dosage forms – IV injections, IM
injections, SC injections
• Topical dosage forms – creams, ointments,
dusting powders, liniments, lotions,
transdermal patches
• Inhaled dosage forms – inhalers, nebulizers
19. The need for dosage forms
1- Accurate dose
2- Protection e.g. coated tablets
3- Protection from gastric juice
4- Masking taste and odour
5- Placement of drugs in body tissue/cavity
6- Sustained release medication
7- Use of desired vehicle for insoluble drugs
20. Oral dosage forms
(I) Tablets
Tablets are hard, compressed medications in round,
oval or square shape.
The excipients may include:
- Binders - ensure efficient tableting
- Disintegrants - ensure the tablet breaks up in GIT
- Sweeteners -mask bitter taste of active ingredients
- Pigments-make uncoated tablets visually attractive
21. Oral dosage forms
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
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
22. Oral dosage forms
Film-Coated Tablets (FCT)
• Compressed tablets covered 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
Enteric-Coated Tablets (ECT)
• Compressed tablets coated with substances that resist
solution in gastric fluid but disintegrate in the intestine
• Useful when tablets contain:
• drugs inactivated or destroyed in the stomach
• those which irritate the mucosa
• Also used as a means of delayed release of the drug
23. Oral dosage forms
Advantages of tablets
advantages afforded to the manufacturer
1- simplicity
2- economy of preparation
3-stability
4-convenience in packaging, shipping and dispensing
advantages to the patient
1-accuracy of dosage
2- compactness
3-portability
4 blandness of taste
5-ease of administration.
24. 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 - normally used for dry, powdered
ingredients
2- soft-shelled capsules - used for oils and for active
ingredients that are dissolved or suspended in oil.
Soft gelatin capsuleHard gelatin capsule
(II) Capsules
25. 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 indigestion or cough
remedies
(III) Lozenges
26. Oral dosage forms
(IV) Oral powders
There are 2 kinds of powder for internal use
1-Bulk Powders are multidose preparations consisting dry
particles that contain one or more active ingredients
- May contain drugs like antacids and are provided with a
5ml spoon to measure the dose. The powder is usually
dissolved in water before taking
2-Divided Powders are single-dose presentations of powder
(e.g. small sachet) usually to be taken with water.
27. Oral dosage forms
(V) Oral solutions
Clear liquid preparations for oral use containing one or
more active ingredients dissolved in a suitable solvent
(VI) 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
28. Oral dosage forms
(VII) Syrups
- Conc. aqueous solutions of a sugar, usually sucrose
- Flavored syrups are a convenient form of masking bad
taste
(VIII) 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
29. 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.
30. 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 a continuous 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 a continuous oily phase.
Hydrophobic drugs which are incorporated into such
creams are released more readily from a water-in-oil cream
31. Topical dosage forms
(III) Transdermal patch (skin patch)
-A medicated adhesive patch that is placed on the
skin to deliver a specific dose of drug
through skin and into the bloodstream
-Advantage over other types such as oral, topical, etc
is that it provides a controlled release of the
medicament into the patient.
- The first commercially available patch was
scopolamine for motion sickness.
32. Topical dosage forms
(IV) 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
33. Topical dosage forms
(V) 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
34. Parenteral dosage forms
An injection is a liquid infused into the body using a
hollow needle and a syringe. Parenteral dosage
form may be: solution for injection
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.
35. 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 the gluteal muscles.
- Injection fibrosis may occur if the injections are delivered
with great frequency or with improper technique.
36. Parenteral dosage forms
(III) Subcutaneous injection
Subcutaneous (SC) injections are given by injecting a
fluid into the subcutis, the layer of skin directly below
the dermis and epidermis.
SC injections are highly effective in administering
vaccines and such medications as insulin.
37. Inhaled dosage forms
1- Inhaler
- Solution/suspension of drugs held under pressure
in an aerosol dispenser & releases droplets of ∞50um diameter.
The patient inhales the released drug through a mouthpiece
- Used to treat asthma and other respiratory problems
2- Nebulizer
- device used to administer drug in form of
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.
39. • Topical: Drugs are applied topically to the skin or
mucous membranes, mainly for local action.
• Oral: used for systemic (non-local) effect, drug is given
via the digestive tract.
• 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 - to evacuate the lower intestine to prepare
for surgeries e.g. CS
• 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
40. Topical route
I. Skin
A-Dermal – cream, ointment (local action)
B- Transdermal- absorption of drug through skin (i.e.
systemic action)
I. stable blood levels (controlled drug delivery
II. No first pass metabolism
III. Drug must be potent or patch becomes too large
II. Mucosal membranes
• eye drops (onto the conjunctiva)
• ear drops
• intranasal route (into the nose)
41. Oral route
- Also called per os or PO
- The drug is swallowed
- It is intended for systemic effects resulting
from drug absorption through the various
epithelia and mucosa of GIT
42. 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 - Advantages
43. 1- Sometimes inefficient - low solubility drugs
may suffer poor availability e.g. Griseofulvin
2- First-pass effect - drugs absorbed orally are
transported to general circulation via the liver.
Drugs which are extensively metabolized will be
metabolized in the liver during absorption. e.g.
propranolol
Oral route - Disadvantages
44. First pass effect
- Is the 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
bioavailability of the drug (the rate and extent of
drug reaching systemic circulation).
45. 3- Food - Food and G-I motility can affect drug
absorption. Often patient instructions include a
direction to take with food or take on an empty
stomach.
- Absorption is slower with food (milk and milk
products) for tetracyclines and penicillins, etc.
However, for propranolol bioavailability is higher
after food and for griseofulvin absorption is
higher after a fatty meal
Oral route - disadvantages
46. 4- Sometimes may have adverse reactions – e.g.
Antibiotics may kill normal gut flora and allow
overgrowth of fungal varieties. Thus, antifungal agent
may be included with an antibiotic.
5- Not suitable for unconscious patient - Patient must
be able to swallow solid dosage forms. Liquids may be
given by tube.
6- May cause irritation to gastric mucosa, nausea and
vomiting.
7- Effect too slow for emergencies.
Oral route - disadvantages
47. Parenteral route
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
48. 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
49. 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
50. C- Subcutaneous (under the skin), e.g. insulin
D- Intradermal, (into the skin itself) is used for skin
testing some allergens.
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
51. Rectal route
Most commonly by suppository or enema
Advantages
1- By-pass liver - Some of the veins draining the
rectum lead directly to the general circulation, thus
by-passing the liver. Reduces first-pass effect
2- Useful
- For patients unable to take drugs orally
(unconscious patients) or with younger children
- For achieving a local effect in lower GIT
- If patient is nauseous or vomiting
53. Inhalation route
- Used for gaseous and volatile agents
and aerosols e.g. volatile anesthetics
Advantages
A- Large surface area
B- thin membranes separate alveoli
from circulation
C- high blood flow
D -Rapid onset of action due to rapid
access to circulation
E- can be used to achieve a local effect on resp. tract
54. 1- Most addictive route of administration because
it hits the brain so quickly.
2- Difficulties in regulating the exact amount of
dosage.
3- Sometimes patient having difficulties in giving
themselves a drug by inhaler.
Inhalation route - Disadvantages
55. 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
antiemetics,
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
hour
for local effects on skin and mucous
membrane of eye, ear, nose, mouth
creams, ointments,
sprays, tinctures
56. 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
• 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
58. 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
59. 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
60. Pharmacokinetics
The rate at which a drug reaches it site of action
depends on:
–Absorption - involves the passage of the
drug from its site of administration into the
blood
–Distribution - involves the delivery of the
drug to the tissues
61. Drug Absorption
• Absorption is the process by which a drug
enters the systemic circulation (bloodstream)
without being chemically altered or
• The movement of a drug from its site of
application into the blood
• Often involves the drug traversing membranes
62. 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
63. 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
64. 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
65. 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
66. 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
67. 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
• In addition - the degree of protein binding and;
• The extent of blood flow to the organs
68. Drug distribution
• Drug molecules are transported in plasma as free
molecules (unbound) or bound to plasma proteins
(this is 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
69.
70. 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
quantity of drug
• 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
71. The blood brain barrier
• Many drugs do not readily enter brain tissue
• Brain capillaries have tight junctions between the
endothelial cells i.e. there are no pores
• This barrier acts as a safety buffer
• Main mechanism of drug entry into the CNS is by
passive diffusion across membranes
• Only highly lipid soluble drugs cross the barrier
73. DRUG BIOTRANSFORMATION/METABOLISM
• 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
• 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
74. 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
• Plasma has esterases e.g. pseudocholinesterase
acts on procaine, Ach, atropine, meperidine
75. BIOTRANSFORMATION REACTIONS
• Take place in hepatic microsomes
• Microsomal enzymes include oxidases, reductases,
hydroxylases, transferases
• Phase 1 reactions - may result in metabolites of
increased or decreased activity
• Phase 2 reactions (conjugation reactions) - usually
result in decrease in activity
77. BIOTRANSFORMATION REACTIONS
Drug phase 1 reaction phase 1 phase 1 reaction conjugated
metabolite product
• Phase 1 reactions include oxidations, reductions
or hydrolysis reactions
• Introduce or unmask reactive functional groups
such as –OH, -NH2 or –SH
78. BIOTRANSFORMATION REACTIONS
• Oxidation requires 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 - oxidative deamination of RNH2 groups to
RHN-OH e.g amphetamine to hydroxyamphetamine
79. BIOTRANSFORMATION REACTIONS
• Microsomal reductions are less frequent
• can take place in drugs which possess disulphide
(S:S), azo (N:N) or nitro (NO2) groups
• N:N group is reduced into NH2 and NO2 into NH2
e.g. in biotransformation of chloramphenicol
80. BIOTRANSFORMATION REACTIONS
• Hydrolysis reactions – usually applicable to drugs
that contain ester or amide groups
• Reaction may involve conversion of RCOOH or
RCONH groups into ROH2
• Example is breakdown of acetylcholine by
cholinesterase
81. PHASE 2 REACTIONS
• Convert phase 1 drug metabolite into more polar
metabolite
• Phase 2 metabolite is not easily reabsorbed
• Phase 2 metabolite readily excreted in urine
• Phase 2 reactions require endogenous conjugants
and transferase enzymes
82. PHASE 2 REACTIONS
• Common endogenous conjugants:
• glucuronic acid, sulfates
• amino acids -glycine, cysteine, glutamine,
methionine
• alky groups - acetyl and methyl groups
• Common transferases
• Sulphotransferase
• glucuronyl transferase
• acetyl transferase etc
83. PHASE 2 REACTIONS
• Conjugates e.g. glucuronides are excreted in urine
• High MW metabolites are excreted via bile
• Phase 2 reactions – also called conjugation
reactions or synthetic reactions
84. DRUG EXCRETION
• Drug elimination = removal of unaltered drug
• Drug excretion = removal of drug after metabolism
• Kidney – eliminates mainly water soluble substances
• Liver (eliminates metabolites via bile)
• Lungs (excrete volatile agents)
• Saliva, milk – small quantity of drugs & metabolites
87. GLOMERULAR FILTRATION
• Glomerular filtration rate – high GFR =high renal
excretion rate
• Renal blood flow–high RBF = high GFR
• Molecular weight of drug – only low mol wt filtered
• Protein binding – high binding hinders filtration
• Plasma drug concentration (bioavailability) – high
bioavailability = greater renal excretion of drug
88. TUBULAR SECRETION
• ATP or carrier molecules in PCT transport ionized,
non-lipid soluble drug molecules into ultrafiltrate
• Non-specific –transport endogenous substrates
(uric acid) and drugs (e.g. penicillin, ampicillin)
• Competition -may lead to drug toxicity i.e. rate of
excretion for competing drugs reduced
• Saturation - if drug conc. in interstitium is high
89. TUBULAR REABSORPTION
• Occurs in DCT; is passive diffusion back into kidney
• drug conc. in the ultrafiltrate
• degree of ionization of drug in ultrafiltrate - non-
ionised forms can be reabsorbed
• Lipid solubility - only lipid soluble drugs reabsorbed
• Low lipid soluble and ionized drugs in ultrafiltrate
are rapidly excreted
• non ionized and lipid soluble slowly excreted
90. BILIARY EXCRETION
• Usually for high molecular weight drugs – not
easily excreted via filtration into urine
• Polar conjugated metabolites also excreted by
this route --- cannot be reabsorbed
• Drugs excreted via bile enter the small intestine
and are excreted via faeces.
91. 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
92. EXCRETION VIA LUNGS
• Alveolar surface and pulmonary capillaries in
close proximity enables rapid exhalation of drugs
• Examples are gaseous/volatile anesthetics but
this depends on:
• The conc. gradient across alveolar membrane
• The blood-gas partition coefficient of anesthetic
93. ENTEROHEPATIC CIRCULATION
• Drug metabolite excreted in bile may be reabsorbed
• Drug cycles between the liver and gut
• Bacterial β-glucuronidase in gut liberates the
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
94. 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
k = the zero-order rate constant
• Elimination of phenytoin, salicylates, alcohol – a constant
amount is eliminated in a certain time regardless of the
drug concentration
• excretion mechanisms get saturated
= -k or = -k
95. First-order kinetics
• The reaction proceeds at a rate that is dependent
on the drug conc. in the body
• 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
96. First-order kinetics
• amount of drug excreted increases at a rate
proportional to the amount of drug remaining in body
• If amount of drug admin increases, body is able to
eliminate it accordingly = NO accumulation
• drugs that obey first-order kinetics at low doses may
obey zero-order kinetics with large doses (due to saturation
of elimination mechanisms)
= -kA
97. 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
98. PHARMACOKINETIC MODELS
• Models in which hypothetical structures are used
to describe the fate of drug in a biological system
• Compartment indicates a fictitious volume in
which a drug would be distributed
• It can correspond or not to a real volume, e.g.
blood volume (first compartment), or the whole
body except blood (second compartment)
99. One-compartment model
• Depicts body as a kinetically homogeneous unit
• Assumes drug achieves instantaneous distribution
throughout body and equilibrates instantaneously
between tissues
• Drug conc.– time profile is monoexponential
• Changes in plasma conc. quantitatively reflect
changes in tissues
101. Two-compartment model
• Resolves body into central and peripheral
compartments
• Central compartment assumed to comprise
blood and highly perfused tissues e.g. heart,
lungs, kidneys, liver and brain
• Peripheral compartment comprises less well-
perfused tissues e.g. muscle, fat and skin
102. Two-compartment model
• Assumes that after drug administration into
the central compartment, it distributes
between central and peripheral compartment
• BUT, the drug does not achieve instantaneous
equilibration, between the 2 compartments
• Drug conc.–time profile on the logarithmic
scale shows a biphasic response
103. Two-compartment model
• In initial phase, drug conc. decline is due to
removal from central to peripheral compartment
• After some time, distribution equilibrium is
achieved between the two compartments
• The second phase of decline is due to elimination
of drug from the central compartment
105. Multi-compartment model
• Drug distributes from central compartment
into more than one compartment
• Conc.–time profile is multi-exponential
• Each exponential on the concentration–time
profile describes a compartment
• Gentamicin shows three-compartment model
after a single IV dose (concentrates in kidney)
107. Pharmacokinetic parameters
These are parameters used to determine the
extent and rate of drug ADME. Include:
• Bioavailability (measures extent and rate of
drug absorption)
• Volume of distribution (measures extent of
drug distribution)
• Plasma half-life (measures rate of excretion)
• Plasma clearance (measures rate of excretion)
108. 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
109. 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.
111. Plasma half-life
• T½ = time taken to halve plasma conc. of drug e.g.
100 mg/L to 50 mg/L
• Determines frequency of admin. of a drug
• Usually independent of the dose administered
• If drug obeys zero-order kinetics e.g. in overdose,
T½ may change due to saturation of elimination processes,
catabolism, plasma proteins binding etc.
112. Plasma half-life
• Value affected by clearance and volume of
distribution (Vd)
• T½ can be read directly from conc. v time graph
114. 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.
115. 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
116. 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
117. 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 for
drugs excreted unchanged
3. Hepatic disease- affects clearance, half-life of drugs
• Reduced drug metabolism seen in hepatic
cirrhosis
118. FACTORS AFFECTING PHARMACOKINETIC VALUES
4. Drug Interactions – competition for carrier, active
transport mechanisms, metabolizing enzymes
5. Dose – Phenytoin shows dose dependency -enzymes
have limited capacity to metabolize them
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
119. FACTORS AFFECTING PHARMACOKINETIC VALUES
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
