IMPORTANT ASPECTS

OF PHARMACOLOGY

DR.DATTEN BANGUN,MSc,SpFK

Departemen Framakologi & Terapeutik

Fakultas Kedokteran
Universitas HKBP Nommensen
MEDAN
 Drug Dose

Amount (mass) of drug given at

ONE TIME (one administration)
100 mg
5 grams
4 mL from the 2 mg/mL bottle
 Drug Dosage

Amount of drug to be given to ANY ANIMAL

10 mg/kg IM q12h PRN

Duration
Amount of drug Dose
per body Route of Interval
weight or Administration
surface area
 Dose Interval

Identify these intervals:

s.i.d.
q12h
b.i.d.
qd
t.i.d.
q6h
 Loading Dose
versus
Maintenance Dose
Loading dose bigger than
normal dose
Establishes effective
concentrations immediately

Maintenance dose smaller

dose
Keeps concentrations
sufficiently high after
established by loading dose
 Drug Concentrations in the
Plasma
50 But whats
missing here
Drug 40 that is needed
Concentration
for this info to
in Plasma (Cp)
30 be of any use?
mcg/mL
20

10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time since administration of drug
(hours)
 Routes of administration
Enteral; oral, sub-lingual (buccal), rectal. Note
soluble, enteric coated or slow release
formulations
Parenteral; iv, im, sc, id, it, etc. Different rates of
absorption, different plasma peaks. Note iv
infusors
Skin; for local or systemic effect - note patches
Lungs; inhalation; local or systemic effect?
Vaginal; (usually local)
Eye; (usually local)
 Routes of Administration
Identify these routes:
IM ID
SQ topical
IV bolus aerosol
IV infusion perivascular
extravascular
PO
parenteral
IP

The route of administration (ROA) that is chosen may have

a profound effect upon the speed and efficiency with which
he drug acts
 Routes of Drug Delivery
Parenteral Inhaled
(IV)
Oral

Transdermal
Parenteral
Topical (SC, IM)

Rectal
 Route of administration
1. Enteral route
2. Parenteral route

Ad. 1. Enteral Routes

Drug placed directly in the GI tract:
sublingual - placed under the tongue
Buccal- placed in the buccal
oral - swallowing (p.o., per os)
rectum - Absorption through the
rectum
 Sublingual/Buccal
Some drugs are taken as smaller tablets
which are held in the mouth or under the
tongue.
= Advantages
rapid absorption
drug stability
avoid first-pass effect

= Disadvantages:= inconvenient
= small doses
= unpleasant taste of some
 Oral
Advantages
Convenient can be self- administered,
- pain free, easy to take
Absorption takes place along the
whole length of the GI tract
Cheap compared to most other
parenteral routes
 Oral
Disadvantages
Sometimes inefficient - only part of the
drug may be absorbed
First-pass effect - drugs absorbed orally
are initially transported to the liver via
the portal vein
irritation to gastric mucosa - nausea
and vomiting
-destruction of drugs by gastric acid and
digestive juices
-effect too slow for emergencies
-unpleasant taste of some drugs
-unable to use in unconscious patient
 First-pass Effect
The first-pass effect is the term
used for the hepatic metabolism of
a pharmacological agent when it is
absorbed from the gut and
delivered to the liver via the portal
circulation. The greater the first-
pass effect, the less the agent will
reach the systemic circulation when
the agent is administered orally
First-pass Effect
 Rectal
1. unconscious patients and children
2. if patient is nauseous or vomiting
3. easy to terminate exposure
4. absorption may be variable
5. good for drugs affecting the bowel such
as laxatives
6. irritating drugs contraindicated
 Parenteral Routes
Intravascular (IV, IA)- placing a drug
directly into the blood stream
Intramuscular (IM) - drug injected into
skeletal muscle
Subcutaneous - Absorption of drugs
from the subcutaneous tissues
Inhalation - Absorption through the lungs
Parenteral administration
 Intravascular
Absorption phase is bypassed
(100% bioavailability)
1.precise, accurate and almost immediate onset of
action,
2. large quantities can be given, fairly pain free

3. greater risk of adverse effects

a. high concentration attained rapidly
b. risk of embolism
c. OOPS factor or !@#$%
 Intramuscular
1. very rapid absorption of drugs in
aqueous solution
2.repository and slow release preparations
3.pain at injection sites for certain drugs

Subcutaneous
1. slow and constant absorption
2. absorption is limited by blood flow,
affected if circulatory problems exist
3. concurrent administration of
vasoconstrictor will slow absorption
 Inhalation
1.gaseous and volatile agents and aerosols
2.rapid onset of action due to rapid access to
circulation
a.large surface area
b.thin membranes separates alveoli from
circulation
c.high blood flow
Particles larger than 20 micron and the particles impact
in the mouth and throat. Smaller than 0.5 micron and
they aren't retained.
 Inhalation cont.
Respiratory system. Except for IN, risk hypoxia.
1. Intranasal (snorting) (Snuff),
= cocaine may be partly oral via post-nasal dripping.
=Fairly fast to brain, local damage to septum. =Some
of the volatile gases also appear to cross nasal membranes.
2.Smoke (Solids in air suspension, vapors):
= absorbed across lung alveoli: Nicotine, opium, THC,
freebase and crack cocaine, crystal meth.Particles or vapors
dissolve in lung fluids, then diffuse. Longer action than volatile
gases. Tissue damage from particles, tars, CO.
.
Volatile gases: Some anaesthetics (nitrous
oxide, ether) [precise control], petroleum
distillates. Diffusion and exhalation (alcohol).
Lung-based transfer may get drug to brain in
as little as five seconds.
 Topical
Mucosal membranes (eye drops, antiseptic,
sunscreen, callous removal, nasal, etc.)
Skin
a. Dermal - rubbing in of oil or ointment
(local action)
b. Transdermal - absorption of drug through
skin (systemic action)
i. stable blood levels
ii. no first pass metabolism
iii. drug must be potent or patch
becomes to large
 Route for administration
-Time until effect-

intravenous 30-60 seconds

intraosseous 30-60 seconds
endotracheal 2-3 minutes
inhalation 2-3 minutes
sublingual 3-5 minutes
intramuscular 10-20 minutes
subcutaneous 15-30 minutes
rectal 5-30 minutes
ingestion 30-90 minutes
transdermal (topical) variable (minutes to hours)
 Time-release preparations

Oral - controlled-release, timed-release,

sustained-release
designed to produce slow,uniform
absorption for 8 hours or longer
better compliance, maintain effect
over night, eliminate extreme peaks
and troughs
 Time-release preparations

Depot or reservoir preparations -

parental administration (except IV),
may be prolonged by using insoluble
salts or suspensions in non-aqueous
vehicles.
 Important
Info

The ROA is determined by the

physical characteristics of the
drug, the speed which the drug is
absorbed and/ or released, as well
as the need to bypass hepatic
metabolism and achieve high
conc. at particular sites
 r t a nt
I m p o
Very fo!
In

No single method of drug

administration is ideal for all
drugs in all circumstances
DRUG INTERACTIONS
 CONCEPT :

Drug interactions involve changes

in the duration or intensity of a
drugs action caused by the
presence of another drug.

It is the modification of the effect of one

drug (the object drug ) by the prior concomitant
administration of another (precipitant drug).
Drug interaction :
desirable
undesirable =adverse drug
interaction.
 Outcomes of drug interactions

1) Loss of therapeutic effect

2) Toxicity
3) Unexpected increase in pharmacological activity
4) Beneficial effects e.g additive & potentiation
(intended)
or antagonism (unintended).
5) Chemical or physical interaction
e.g I.V incompatibility in fluid or
syringes mixture
 Mechanisms of drug interactions
Pharmaceutical

Pharmacokinetics Pharmacodynamics

Pharmacokinitics involve the effect of a drug on another from

the point of view that includes absorption ,distribution , metabolism
and excretion.

Pharmacodynamics are related to the pharmacological activity

of the interacting drugs
e.g synergism.antagonism, altered cellular transport, effect
on the receptor site.
Pharmaceutical: Interaction that occur outside the body:
-in bottles,syrinx
 Pharmacokinetic interactions

1) Altered GIT absorption.

Altered pH, Altered bacterial flora, formation of drug
chelates or complexes, drug induced mucosal damage
and altered GIT motility.

a) Altered pH;
The non-ionized form of a drug is more lipid
soluble and more readily absorbed from GIT than the
ionized form does.
 Decrease the pH
Ex1., antiacids Decrease the tablet
dissolution
of Ketoconazole (acidic)

Ex2., H2 antagonists pH

Therefore, these drugs must be separated by at least 2h

in the time of administration of both .
b) Altered intestinal bacterial flora ;

EX., In 10% 0f patients receive digoxin..40% or more

of the administered dose is metabolized by the intestinal
flora
Antibiotics kill a large number of the normal
flora of the intestine

Increase digoxin conc.

and increase its toxicity
c) Complexation or chelation;

EX1., Tetracycline interacts with iron preparations

or
Milk (Ca2+ ) Unabsorpable complex

Ex2., Antacid (aluminum or magnesium) hydroxide

Decrease absorption of
ciprofloxacin by 85%
due to chelation
 d) Drug-induced mucosal damage.
Antineoplastic agents e.g., cyclophosphamide
vincristine
procarbazine

Inhibit absorption
of several drugs
eg., digoxin

e) Altered motility
Metoclopramide (antiemitic)

Increase the toxicity Increase absorption of cyclosporine due

of cyclosporine to the increase of stomach empting time
f) Displaced protein binding
It depends on the affinity of the drug to plasma protein.
The most likely bound drugs is capable to displace others.
The free drug is increased by displacement by another drug
with higher affinity.

Phenytoin is a highly bound to plasma protein (90%),

Tolbutamide (96%), and warfarin (99%)

Drugs that displace these agents are Aspirin

Sulfonamides
phenylbutazone
g) Altered metabolism

The effect of one drug on the metabolism of the

other is well documented. The liver is the major site of drug
metabolism but other organs can also do e.g., WBC,skin,lung,
and GIT.

CYP450 family is the major metabolizing enzyme

in phase I (oxidation process).

Therefore, the effect of drugs on the rate of metabolism

of others can involve the following examples.
EX1., Enzyme induction

A drug may induce the enzyme that is responsible

for the metabolism of another drug or even itself e.g.,
Carbamazepine (antiepileptic drug ) increases its own
metabolism

Phenytoin increases hepatic metabolism of theophylline

Leading to decrease its level Reduces its action
and
Vice versa

N.B enzyme induction involves protein synthesis .Therefore,

it needs time up to 3 weeks to reach a maximal effect
 EX2., Enzyme inhibition;

It is the decrease of the rate of metabolism of a drug by

another one.This will lead to the increase of the concentration
of the target drug and leading to the increase of its toxicity .

Inhibition of the enzyme may be due to the competition

on its binding sites , so the onset of action is short
may be within 24h.

N.B; When an enzyme inducer (e.g.carbamazepine) is

administered with an inhibitor (verapamil)
The effect of the
inhibitor will be
predominant
Ex.,Erythromycin inhibit metabolism of astemazole and terfenadine

Increase the serum conc.

of the antihistaminic leading to
increasing the life threatening
cardiotoxicity

Inhibits oxidative of diazepam

EX., Omeprazole
metabolism
First-pass metabolism:

Oral administration increases the chance for liver

and GIT metabolism of drugs leading to the loss of a
part of the drug dose decreasing its action. This is
more clear when such drug is an enzyme inducer
or inhibitor.

EX., Rifampin lowers serum con. of verapamil level by

increase its first pass . Also, Rifampin induces the
hepatic metabolism of verapamil
 Renal excretion:
Active tubular secretion;
It occurs in the proximal tubules (a portion of renal tubules).
The drug combines with a specific protein to pass through
the proximal tubules.

When a drug has a competitive reactivity to the protein that is

responsible for active transport of another drug .This will reduce
such a drug excretion increasing its con. and hence its toxicity.

EX., Probenecid .. Decreases tubular secretion of

methotrexate.
* Passive tubular reabsorption;
Excretion and reabsorption of drugs occur in the tubules
By passive diffusion which is regulated by concentration
and lipid solubility.

N.B., Ionized drugs are reabsorbed lower than non-ionized ones

Ex1., Sod.bicarb. Increases lithium clearance

and decreases its action

Ex2., Antacids Increases salicylates

clearance and decreases its
action
Pharmacodynamic interactions;
It means alteration of the dug action without change in its
serum concentration by pharmacokinetic factors.

Synergistic or additive
EX., Propranolol + verapamil effect
Synergism means =1+1=3 On the other hand
Additive means= 1+1=2
Effect at the receptor site
Potentiation means= 1+0=2 Antiadrenegic
anticholinergic
Antagonism means 1+1=0 or 05.
 * Risk factors:
1) High risk drugs; these are the drugs that show a narrow
therapeutic index e.g., corticosteroids, rifampin,
oral contraceptives, quindine, lidoquine

2) High risk patients; these are the groups of patients

that should be treated with caution due to a specific
heath condition e.g., pregnant women, malignant cases,
diabetic patients, patients with liver or kidney disorders
asthmatic patients and cardiac disorders.
Onset of drug interaction
It may be seconds up to weeks for example in
case of enzyme induction, it needs weeks for protein synthesis
, while enzyme inhibition occurs rapidly.

The onset of action of a drug may be affected by the half

lives
of the drugs e.g., cimitidine inhibits metabolism of
theophylline.

Cimitidine has a long half life, while, theophylline has a short

one.

When cimitidine is administered to a patient regimen for

Theophylline, interaction takes place in one day.
* Prevention of drug interaction

1) Monitoring therapy and making adjustments

2) Monitoring blood level of some drugs with narrow

therapeutic index e.g., digoxin, anticancer agents
etc

3) Monitoring some parameters that may help to

characterize the the early events of interaction
or toxicity e.g., with warfarin administration, it
is recommended to monitor the prothrombin time
to detect any change in the drug activity.

4) Increase the interest of case report studies to

report different possibilities of drug interaction
Causes of Variability in Drug
Response
Those related to the biological system
1. Body weight and size
2. Age and Sex
3. Genetics - pharmacogenetics
4. Condition of health
5. Placebo effect
 Causes of Variability in Drug
Response
II.Those related to the conditions of administration
1. Dose, formulation, route of administration.
2. Resulting from repeated administration of drug:
drug resistance; drug tolerance-tachyphylaxis; drug
allergy
3. Drug interactions:
chemical or physical;
GI absorption;
protein binding/distribution;
metabolism (stimulation/inhibition);
excretion (ph/transport processes);
receptor (potentiation/antagonism);
changes in pH or electrolytes.