By

Dagim samuel
Dvm,Bpharm,Pharmacology Fellow

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 Chapter One
General Pharmacology

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 Learning objectives

Define the terms Pharmacology, Pharmacokinetics,

Pharmacodynamics, drug.
List the various routes of administration of drugs.
List factors affecting drug abs., dist., metabolism
Define terms against, antagonist, dependence, therapeutic index
and bioavailability.
Describe some factors that dedicate of the dose.

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 Definitions
Pharmacology: science that studies the effect of the drug on the
body.
Drug: chemical substance of known structure, which interacts
with living system & brings about a change in biologic
function through its chemical action especially by binding to
regulatory molecules and activating or inhibiting normal body
processes.
A medicine is a chemical preparation, which usually contain
other substances (excipients, stabilisers, solvents, etc.)
besides the active drug. 4
 Defns….
-Clinically used for
diagnosis, cure, treatment,
mitigation, or prevention
Receptor: Specific molecule which, plays a
regulatory role, drug may interact with
receptors

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 Source of drugs
1. Natural source
o Plants: Digitalis, vincristine , Morphine, atropine, castor oil...
o Animals: Hormone (Epinphrine, insulin, ACTH), enzyme(pepsin),

heparin...
o Micro-organisms: Antibiotics, vaccine ...

o Minirals: iron, iodine, MgSO4, kaolin...

2. Semisynthetic
o homatropine from atropine
3. Pure synthetic
o Aspirin, sulphonamides, paracetamol, zidovudine… 6
 Names of drug
Chemical name
– N-acetyl-para-aminophenol

Generic (non-proprietary ) name

– Acetaminophen

Brand(proprietary) name
– Tylenol
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 Properties of Ideal Drug
Effectiveness:
– A drug that elicits the response it was meant to. It is the most
important property. No effect=no justification of use .
Safety:
– Safe even at high concentrations and for long periods of
administration
No habit forming aspects
No side effects
– excessive dosage of opioid analgesics carries a risk of respiratory failure,
cancer drugs increase infections,aspirin causes gastric ulcer etc…
Selectivity:
– One that elicits only the response for which it is given
– Selective for specific reaction with no side effects:

Drowsiness can be caused by antihistamines

Morning sickness, cramps, and depression can be
caused by oral contraceptives
Constipation, urinary hesitance, and respiratory
depression can be caused by morphine
 Additional Properties of Ideal Drug (no drug is
ideal!)
1. Reversible action
– Effects be reversible, i.e., removal/subside w/i specific
time (1/2 life is short but potent during that time)
– Example: General Anesthetic; Contraceptives
2. Predictability
– Know how patient will respond
3. Ease of Administration
– Number of doses should be low and easy to administer
– 1. increase compliance & 2. decrease errors
Diabetic patient: Multiple daily injection of insulin
Intravenous infusion
4. Freedom from drug interactions
– Should not augment or decrease action of other drugs or have
adverse combined effects
Respiratory depression caused by diazepam (valium), which is
normally minimal, can greatly be intensified by alcohol.
Antibacterial effects of Tetracycline can be greatly reduced by
taking iron or calcium supplements
5. Low Cost
– Easy to afford (especially with chronic illness)

Growth hormone (somatrem) costs between $10,000 and

$20,000
6. Chemical Stability
– No lose of effectiveness with storage

7. Possession of a simple generic name

– Easy to remember and pronounce

Example: Viagra (sildenafil); Tylenol

(acetaminophen)
Because no drug is ideal…….
– No drug is safe
All drugs produce side effects

– Drug responses may be difficult to predict

– Drugs may be expensive
– Drugs may be hard to administer

All members of health care team must exercise care to

promote therapeutic effects and minimize drug induced
harm
 Subdivisions of Pharmacology

Pharmacokinetics: is about how the body deal with drug.

Pharmacodynamics: is effect of drug on the body.
Pharmacotherapeutics: is a clinical using of drug.
Toxicology: study of undesired effect of drug
Pharmacoeconomics
Pharmacoepidimplogy,
Pharmacogenetics/pharmacogenomics
etc
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 Pharmacokinetics(PKs)
o What the body does to drug
o ADME

o Life cycle of drug

o Dose/ plasma concentration r/sh

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Route of administration

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 Route of administration…
Reading assignment
o advantage and disadvantage of each
route of administration

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 PK: Absorption
o Absorption

The process of drug transfer from site (route) of

administration to general circulation.
oBioavailability(F)

fraction of unchanged drug reaching the systemic

circulation following administration by any route

F=AUCoral/AUCIV

F iv = 100% 19
 PK:
PK:Abs…
Abs..
Mechanisms by which a drug cross membrane

i) Simple (lipid)
diffusion
(a) Passive transport
ii) Filtration(aqs)
i) Facilitated diffusion
(b) Specialized
transport ii) Active transport
(Saturable, inhibitable)

iii) Endocytosis (vit B12) 20

 PK: Abs…
Difference among d/f transport mechanisms

X’cs SD FD AT
Incidence Commonest Less common Least common
Process Slow Quick Very quick
Movement Along concentration Along concentration Against
direction gradient gradient concentration
gradient

Carrier not needed Needed Needed

Energy Not required Not required Required

Example Lipid soluble drugs Tetracycline, Methyl dopa,

primidine levodopa, 5-FU, 5- 21
BU
 Factors affecting GI abs & F
o Physiological factor

o Gastric emptying(trasit) time

o Food: liquid ( ); solid and fat ( ).
o Pathological : gastroectomy ( ): DM ( )
o Pharmacological: cholinergics ( ); anticholinergics

o Intestine motility
o local blood flow and
o surface area
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 Factors affecting abs & F…
o Physico-chemical properties of the drug

o Solubility –dicumarol: ppt in gastric pH

o particle size-digoxin
o pKa / ionization

o Formulation factors
o Dosage form – soln, suspension, tablet, immediate
release, delayed release, entercoated tablet, etc.)
o Disintegration time solid dosage forms

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Rate of Drug Absorption varies by form

Liquids, elixirs, syrups Fastest

Suspension solutions ê
Powders ê
Capsules ê
Tablets ê
Coated tablets ê
Enteric-coated tablets Slowest
o Enterohepatic circulation (warfarin)
o Food (propernalol)
o Diet (fat reach meal, griseofulvin)
o Interactions with other drugs (anti-acid, vit C)
o Disease state(liver cirrhosis)
o Metabolism (firs pass effect) and efflux transport (p-
glycoprotine)

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 First pass effect
 The metabolism of a drug by liver (mainly) and GI wall

as it passes from the GIT into the circulation.

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 First-Pass
First Effect
pass effect…
 Routes that bypass the liver:
– Sublingual Transdermal
– Buccal Vaginal
– Rectal* Intramuscular
– Intravenous Subcutaneous
– Intranasal Inhalation

*Rectal route undergoes a higher degree of first-pass effects

than the other routes listed. 28
 PK: Distribution
 The transport of drug from systemic circulation to organs and
tissues.
 Rate & Extent depend upon
– Lipid solubility
– pH and pKa
Ionization & ion Trapping
– Rate of blood flow
o Areas of rapid distribution:
o heart, liver, kidneys, brain
o Areas of slow distribution:
o muscle, skin, fat
– Protein-binding
D + PP D-PP 29
 PK: volume of disn(vd)
 The volume of fluid required to contain the total amount, Q, of

drug in the body at the same concentration as that present in the

plasma, Cp.
Vd = Q/Cp = Dose/Co

Vd f xdose/c

– Vd is low when a high % of drug is bound to plasma protein

– Lipid-insoluble drugs are mainly confined to plasma; most do not enter

the brain following acute dosing.

– Lipid-soluble drugs reach all compartments and may accumulate in fat.

– For drugs that accumulate outside the plasma compartment (e.g. in fat or
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by being bound to tissues), V may exceed total body volume.
 Elimination
The irreversible removal of the parent drugs from the body

Elimination

Drug Metabolism
Excretion
(Biotransformation)
- Kidney/urine
-Phase –I (functionalization rxn)
- Liver- Bile/ faeces
- Lung/expired gas
-Phase-II (conjugation rxn)
- sweat gland/sweat
- mammary gland/milk
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 Elimination: parameteres
Elimination half life(t1/2) –time required to eliminate 50%
of a given amount of drug.
– Factors affecting half-life
age
renal disease
liver disease
protein binding & lipid solubility
Clearance(Cl) –volume of blood cleared of the drug in in unit
time. It represents the r/ship b/n the rate of drug elimination and
its plasma level.
Cl=kVd
Clt = ClR+ ClNR
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 PK: Metabolism/ Biotransformation
 The biologic transformation of a drug into
a more soluble (hydrophilic) compound
o Facilitate excretion
 Enzymatic in nature
 Major drug metabolizing organs:
o Liver (main organ) Kidneys
o Lungs Plasma(enzymes)
o Intestinal mucosa.
 Enzyme systems involved are localized in liver
 ER (microsomal) -CYP450 : CYP3A4/5, 2C9/19,2D6, 1A2, 2E1
 cytosolic –ADH, estrase, amidase, 33
 Phase I (fictionalization)
Converts the parent drug to a more polar metabolite by
introducing or unmasking a functional group (-OH, -NH2, -SH)
 Metabolite:
– Usually inactivite

– Sometimes may be equally or more active than parent

– may have toxic properties

 Prodrug(parent drug)
– Pharmacologically inactive
– Converted rapidly to active metabolite (usually hydrolysis of ester or
amide bond)
– Maximizes the amount of active species that reaches site of action
– eg., pivampicillin , valacyclovir, lisdexamfetamine, methyldopa 34
 Phase I…
Main function: is to prepare the compound for
phase II metabolism but not for excretion
types:
– oxidation,
– reduction,
– hydrolysis,
– ADH metabolism

o The phase I oxidative enzymes are almost exclusively localized

in the ER. 35
 Phase II (conjugation reactions)

covalent linkage is formed between a functional group on the

parent compound or Phase I metabolite and an endogenous
substrate
o glucuronic acid, sulfate, acetate, or an amino acid
o enzymes are located predominantly in the cytosol.

usually the true detoxification of drugs

type: sugar conjugation, sulfation, methylation, acetylation, amino
acid conjugation, glutathione conjugation
Highly polar – rapidly excreted in urine and feces
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 Factors affecting Drug Metabolism
1. Environmental Determinants
 Induction
 Inhibition
2. Disease Factors
3. Age and Sex
4. Genetic Variation

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 1. Environmental Determinants
Activity of most drug metabolizing enzymes can be
modulated by exposure to certain exogenous
compounds
o Drugs
o Dietary micronutrient (food additives, nutritional or
preservative)
o Environmental factors (pesticides, industrial
chemicals)
Modulation
– induction or
– inhibition
Contributes to interindividual variability in the metabolism38
 Induction of Drug Metabolism
Enzyme induction is the process by which exposure to certain s/bs (e.g.,

drugs, environmental pollutants) stimulates the synthesis of the enzyme and

the metabolic capacity is increased -drug gets metabolized faster

Some examples of drugs are the

 anticonvulsant

 phenobarbital and carbamazepine, and

 St. John’s Wort.

Cigarette smoking can cause increased elimination of theophylline and other

compounds.

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 Consequences of Induction

Increased rate of metabolism

Decrease in drug plasma concentration
Enhanced oral first pass metabolism
Reduced bioavailability
If metabolite is active or reactive, increased
drug effects or toxicity

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Therapeutic Implications of Induction

Most drugs can exhibit decreased efficacy due

to rapid metabolism
– but drugs with active metabolites can display
increased drug effect and/or toxicity due to
enzyme induction
Dosing rates may need to be increased to
maintain effective plasma concentrations

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 2. Inhibition of Drug Metabolism
Drug metabolism is an enzymatic process
can be subjected to inhibition.

Drugs and other substances can inhibit the

metabolism of other drugs.

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 Some types of inhibition

Competition between substrates for enzyme active

site
 Concentration of substrates
 Affinity for binding site (drug with high affinity for an
enzyme will slow the metabolism of any low affinity
drug)
Irreversible inactivation of enzyme
 Complex with heme iron of CYP450 (cimetidine,
ketoconazole)
 Destruction of heme group (secobarbital)
Depletion of cofactors such as NADH2 for phase II
enzymes
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 Consequences of Inhibition

Increase in the plasma concentration of parent

drug
Reduction in metabolite concentration
Exaggerated and prolonged pharmacological
effects
Increased likelihood of drug-induced toxicity

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 Therapeutic Implications of Inhibition

May occur rapidly with no warning

Affect patients on multidrug regimens
Knowledge of the CYP450 metabolic pathway
provides basis for predicting and understanding
inhibition especially drug-drug interaction

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 3. Disease Factors
 Liver Disease – Cirrhosis, Alcoholic liver disease,

jaundice, carcinoma
– Dysfunction can lead to impaired drug metabolism-
decreased enzyme activity
First pass metabolism effected – may inc 2-4 x F
Results in exaggerated pharmacological responses and
adverse effects

 Cardiac failure causes decreased blood flow to the

liver 46
 4. Age
Newborns and infants
– metabolize drugs relatively efficiently but at a rate
generally slower than adults

Full maturity appears in second decade of life

Slow decline in function associated with aging

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 4. Sex
Responsiveness to certain drugs is different for
men and women
Pregnancy
– induction of certain drug metabolizing enzymes
occurs in second and third trimester

Hormonal changes during development have a

profound effect on drug metabolism 48
 5. Genetic Variation

wide variability in the response to drugs

between individuals

consequences of such variation may be

therapeutic failure or an ADR

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inheritance leads to genetic polymorphisms with
different drug metabolizing abilities
 Extensive metabolizers (EMs) have functional enzyme
activity
 Intermediate metabolizers (IMs) have diminished
enzyme activity
 Poor metabolizers (PMs) have little or no activity

CYP2D6 is highly polymorphic gene

 5-10% of Caucasians and 1-2% of Asians exhibit the
PM phenotype
 Codeine is oxidized to morphine by CYP2D6
necessary for codeine’s analgesic effect 50
 Excretion
 The removal of drugs from the body
Kidneys (main organ)
1) glomerular filtration
- size constraints,
- protein binding
2) tubular reabsorption
- acidification/alkalinization,
3) secretion
- active transport, competitive/saturable,
- organic acids/bases
- protein binding
Liver & Bowel
– Biliary excretion
– Enterohepatic circulation
Lung = expired in the air 51
 DOSAGE REGIMEN
The objective of drug therapy is to bring plasma concentration
within the therapeutic window The decisions defining dosage
regimen are about:
– Route of administration
– Galenic formulation
– Unit dose
– Frequency
– Loading dose
– Length of treatmen

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Intravenous infusion and intermittent
intravenous bolus dosing

Continuous intravenous infusions and intermittent

intravenous boluses are common ways of
administering drugs such as gentamicin, lignocaine
and theophylline.
Given as a continuous infusion, the drug
accumulates to a steady state concentration (Css)
determined only by the dose rate and clearance (CL)
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Desired concentration (Css) = maintenance dose rate /
CL
The time to reach steady state is
1.determined by the half-life 3-5 half-lives
If intermittent bolus doses are given every half-life (8
hours in this case for theophylline), half the first dose
is eliminated over the first dosing interva

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Therefore, after the second dose there are 1.5 doses in
the body and half of this amount is eliminated before
the third dose.
The drug continues to accumulate with continued
dosing until there is double the dose in the body

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at which point the equivalent of one dose is
eliminated each dosing interval (half-life).
The plasma concentration is then at steady state (rate
of administration equals rate of elimination where
each is one dose per dosing interval).

At steady state with a dosing interval equal to the

half-life:
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 2. loading dose
The effect of a loading dose before an
intravenous infusion has been discussed
in Article 2 ('Volume of distribution' Aust
Prescr 1988;11:36-7).
The loading dose to achieve a desired
concentration is determined by the volume
of distribution (VD).

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equation 2
Loading dose = desired concentration x
VD

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Fig. 1
Intravenous infusion or intermittent dosing of a drug such as theophylline.

(a) Continuous intravenous infusion at a dose rate of 37.5mg/hour

(b) Intermittent bolus dosing 300 mg 8-hourly (dose rate (dose/dosing interval) is 37.5 mg/hour)
(c) As for (b) but with a loading dose of 600 mg, twice the maintenance dose

Parameters used in the simulations were: CL = 2.6 L/hour, VD = 30 L, t1/2 = 8 hours. At steady
state, the average plasma concentration over the dosing interval is the
same as that during a continuous infusion (14.4 mg/L in this case). The therapeutic range for
theophylline is 10-20 mg/L (55-110 mmol/L).

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If the loading dose achieves a plasma drug
concentration the same as the steady state
concentration for the maintenance infusion (see
equation 1), steady state will be immediately
achieved and maintained. If the loading dose
over- or under -shoots the steady state
concentration, it will still take 3-5 half -lives to
reach Css (see Article 2), but the initial
concentration will be closer to the eventual
steady state concentration.

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With intermittent bolus dosing, Fig. 1
shows that where the dosing interval is
equal to the half-life of the drug, a loading
dose of twice the maintenance dose
immediately achieves steady state. Half
the loading dose (one maintenance dose)
is eliminated in the first dosing interval
(one half-life) and is then replaced by the
first maintenance dose and so on.
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. Effects of varying the dose interval
So far we have considered a dosing interval equal to the half -life of the
drug. Fig. 2 shows the plasma concentration time profile for once daily
intravenous bolus dosing of drugs with half-lives of 6 hours, 24 hours and 96
hours (0.25, 1 and 4 times the dosing interval of 24 hours). For the drug with
a half-life of 6 hours (characteristic of theophylline), the concentration is
virtually at steady state shortly after the first dose, but there is a large
fluctuation (94%) over the dosing interval ((Cmax - Cmin) divided by Cmax
= 0.94). The drug with a half-life of 24 hours (characteristic of amitriptyline)
takes 3-5 half-lives to reach steady state and the fluctuation over the dosing
interval is 0.5. For the drug with a half-life
of 96 hours (characteristic of phenobarbitone), it takes 12-20 days (3-5 half-
lives) to reach steady state, and with once daily dosing (4 doses per half-
life), the extent of fluctuation over the dosing interval is small ((Cmax -
Cmin) divided by
Cmax = 0.16).
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A dosing interval of about a half-life is appropriate for drugs with
half-lives of approximately 8-24 hours allowing dosing once, twice or
three times daily. It is usually not practicable to administer drugs
with shorter half-lives more frequently. If such a drug has a large
therapeutic index, so that a large degree of fluctuation over the
dosing interval does not result in toxicity due to high peak
concentrations (e.g. many antibiotics and beta-blocking drugs), it
can be given at intervals longer than the half-life. For example, the
plasma concentration time profile shown in Fig. 2A is similar to that
for gentamicin when intravenous doses are given 8-hourly (half-life
is 1-2 hours).

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 4. Oral dosing
The principles applying to intermittent
intravenous dosing also apply to oral
dosing with two differences
the slower absorption of oral doses 'smooths' the plasma
concentration profile so that fluctuation over the dosing interval is
less than with intravenous bolus dosing. This smoothing effect is
exaggerated with sustained release formulations (see Article 3 and
Fig. 3), allowing less frequent administration for drugs with short
half- lives.
the dose reaching the systemic circulation is affected by the
bioavailability so that at steady state

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equation 3
Desired concentration (Css) = F x oral dose
rate / CL
where F is the bioavailability (compare with
equation 1 and see Article 5 'Bioavailability and
first pass clearance' Aust Prescr 1991;14:14-6).
The relationship between oral and intravenous
dose rates to achieve the same Css then
(combining equations 1 and 3) is

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equation 4
Oral dose rate = intravenous dose rate / F

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Summary
The intravenous loading dose is determined by the volume of distribution:

Loading dose = desired concentration x VD

The oral maintenance dose rate is determined by the clearance and bioavailability
and the desired steady state plasma concentration:

Maintenance dose rate = CL x Css / F

The time to reach steady state is determined by the elimination half-life:

Time to steady state = 3-5 half-lives

The degree of plasma concentration fluctuation over the dosing interval is determined
by:

the half-life
the absorption rate
the dosing interval
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68
69
Pharmacodynamics
(PDs)

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 PD:
– The study of the biochemical and physiologic effects of
drugs and the molecular mechanisms by which those
effects are produced.
– The study of what drugs do to the body and how they do
it.
– What the drug does to the body.
 Why be concerned about how drugs work?
– Aids in understandings of drug
interactions
adverse effects and
contraindications.
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 How do drugs act/ work
1. A few drugs act by simple mzms
– Related to their physicochemical ppties
– E.g., chelators, antacids, mannitol, adsorbents, etc
– Called “receptorless” drugs
2. Most drugs act by binding to cells
– To produce a biological response drug molecules must
exert some chemical influence on one or more
constituents of the cell
– Drug molecules must get very close to constituent
cellular molecules for their function to be altered.
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What are these binding sites?
1. Mainly proteins
a) Enzymes
b) Ion channels [voltage gated & ligand gated]

c) Receptors
d) Carrier molecules

e) Structural proteins

2. Nucleic acids- DNA

3. Lipids

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 Signal transduction pathways
Drug-receptor interactions
– The general equation for the interaction between drugs
and their receptors:
D+ R ⇌ D - R Complex→Response
Receptor families
– 4 fundamental mzms or types:
1. Cell membrane–embedded enzymes(KLR)
2. Ligand-gated ion channels
3. G protein–coupled receptor systems(GPCR)
4. Nuclear receptors(NR)
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 Functions of receptors
1. Determine the quantitative r/ship b/n drug dose &
pharmacologic effect
2. Responsible for the selectivity of drug action
3. Mediate the actions of both pharmacologic agonists and
antagonists
 Receptors and Selectivity of Drug Action
The more selective a drug is, the fewer side effects it will
produce

To bind with its receptor, a drug must have a appropriate shape,

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 Dose-Response Relationships

The r/ship between the size of an administered dose

and the intensity of the response produced
It determines:
1. The minimum amount of drug we can use
2. The maximum response a drug can elicit,
3. How much we need to increase the dosage in order to
produce the desired increase in response

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 Two types of responses
1. Graded (individual) responses
– As the dosage increases, the response becomes
progressively larger
– Responses are often described as a percentage of
maximal response
– Adjust the dosage until the desired response is achieved
– Essential for successful drug therapy

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1. Quantal/All-or-none/ responses
– Drugs produce only one intensity of response
– For too strong or too weak response
E.g., analgesia for headache, digitalis to stop heart, sleep or
lethal dose for anesthesia.
– Responses are represented as cumulative percentage of
subjects exhibiting a defined effect
– allows the calculation of therapeutic index
– The Therapeutic Index
A measure of a drug's safety.
Determined using laboratory animals
The ratio of a drug's LD50 to its ED50

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 Relatively safe drug

Not very safe drug

Therapeutic range (window)
– A range of plasma drug levels falling b/n MEC &
MTC
– The objective of drug dosing is to maintain
plasma drug levels within the therapeutic range
– Wide/narrow TR– safety
Two important terms of dose-response curve:
– Efficacy
– Potency

Potency
– The amount of drug we must give to elicit an effect
– A potent drug is one that produces its effects at low doses
– The potency of a drug implies nothing about its maximal
efficacy
Efficacy
– The largest effect that a drug can produce.
– Indicated by the height (plateau) of the dose-response
curve
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 Agonists, Antagonists, and Partial Agonists
Full agonists
– Produce maximal response
– Have both affinity & high intrinsic activity
Partial agonists
– Produce lower/submaximal/intermediate/ responses
– Have affinity but only moderate intrinsic activity
Antagonists
– Drugs that block the actions of endogenous & exogenous
agonists
– No response
– Have affinity but with no intrinsic activity
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 Types of antagonism
1. Chemical
– Interaction of two drugs in solution such that the effect
of active drug is lost
E.g. metal chelators and toxic metals
2. Physiological
– Interaction of two drugs with opposing physiological
actions
Histamine vs. epinephrine on BP
3. Pharmacological
– Blockage of the action of a drug-receptor interaction by
another cpd
Cimetidine vs. histamine
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 Two major types of pharmacological antagonists:
1. Competitive antagonists 2. Noncompetitive antagonists
• Reversible binding • Irreversible binding
• Reduce potency • Reduce maximal response
• Commonly used therapeutically • Rarely used clinically
• Effect is subside in a few days

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The End

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