DRUGS AND BEHAVIOR

Chapter 1
Basic Pharmacology
SMALL GROUP DISCUSSION
 What is a drug?

 Is Vitamin C a drug?

 Why would you categorize coffee (caffeine) as a

drug?
DRUG:
 Drug is any substance that alters the physiology
of the body, but is not a food or nutrient

 Definition sometimes excludes toxins

 Definition often accounts for the intention of the

user
 High, treat illnesses
Examples:
Vitamin C - in pills
- in fruits and
vegetables

Caffeine - taste or CNS effect

Nicotine – taste or CNS effect

DRUG NAMES:

 Chemical Name:
7-cloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4 benzodiazepin-2-one

 Generic Name (Nonproprietary Name):

diazepam
SKF 10047

 Trade name (Proprietary name):

Valium
Diapam
FORMULATION:
 Trade name refers to the formulation, i.e. the way a
medicine is made

 Includes both the active ingredient and the

excipients, i.e., the non-active ingredients such as
coloring and binding agents and fillers
 May differ in effectiveness
COMPENDIUM OF PHARMACEUTICALS AND
SPECIALITIES (CPS)
DESCRIBING DRUG DOSES

 Doses: mg/kg (body weight)

 Concentration at the site of action

 Not the amount given

Which one rat/tiger would

you give a higher dose?

Why?
DOSE RESPONSE CURVE (DRC)

Vertical axis:
 Frequency of
effect
 Extent of effect

Horizontal axis:
dose
Dose Response Curve (DRC)
LD50 AND ED50

 LD50 – medial lethal dose

 Dose that kills half of the subjects.

 ED50 – median effective dose

 Dose that causes half the maximum effect.
ED50 AND LD50 ??

Experimental drug
“Endital”

ED50 –Dose that causes half

the maximum effect.

LD50 – Dose that kills

half of the subjects.
DRUG SAFETY
 Therapeutic Index

 TI= LD50/ED50

 What is TI for “Endital”?

 84/35=2.4

 fentanyl has a higher therapeutic index than morphine

(400 vs 70), and remifentanil has the highest therapeutic
index of any opioid or anesthetic (33,000) thus which of
these anesthetics is the safest?
 The higher the number, the safer the drug
POTENCY VS EFFECTIVENESS
 When describing drugs with similar effect, the more
potent drug is the one which produces the effect at
the lowest dose (amount of drug).

 Is the ED50 of the more potent drug higher or lower

compared to a less potent drug?

 The lower the ED50 the more potent the drug

EFFECTIVENESS (EFFICACY)
 The maximum effect a drug will produce, i.e., The
drug that causes the greatest maximum effect has
the greatest effectiveness.
PRIMARY EFFECTS AND SIDE EFFECTS

 Primary or main effect

 The effect you want
PRIMARY EFFECTS AND SIDE EFFECTS

 Side effect
 All other effects
 May be useful or
harmful

 E.g. Aspirin
 Cox-2 and Cox-1 enzyme
inhibitor
DRUG INTERACTIONS

 Antagonism
 Where one drug shifts the DRC of another drug to the
right
 ED50 ???
 Potency or effectiveness?
DRUG INTERACTIONS
 Additive effect
 Where one drug shifts the DRC of another drug to the
left as much as could be expected if the effect of both
drugs were being added together.
DRUG INTERACTIONS
 Superadditive effect (potentiation)
 Where the effect of one drug shifts the DRC of another
drug to the left further than would be expected if the
effects of the drugs were being added together.
 DRUG INTERACTIONS
When mixing two drugs… effectiveness can change as well

Antagonism Additive Potentiation or

Effects “superadditive”
One drug
diminished the Each drug effect is The whole effect is
effects of the other added greater than the sum
of the effects
SOME BASIC PHARMACOLOGY
Chapter Outline

 What is a Drug?
 Names of Drugs
 Describing Dosages
 Potency and Effectiveness
 Primary and Side Effects
 Drug Interactions
 Pharmacokinetics (pg. 6)
 Routes of Administration
 Absorption from Parenteral Sites
 Inhalation of Gases
 Inhalation of Smoke and Solids
 PHARMACOKINETICS
How drugs get to and from their
site of action

 Absorption: How drugs get into

the blood-GI tract, skin,
respiratory surface
 Distribution: Where drugs go in
the body
 Excretion or Elimination: How
drugs leave the body-kidney, GI
tract, skin, lungs, liver
 Site of action: not all areas of
body affected
ABSORPTION
 Routes of administration
1. Parenteral
2. Inhalation
3. Oral
4. Transdermal
1. PARENTERAL ADMINISTRATION
 Drugs are dissolved in a
vehicle (saline).

 Injected through a hollow

needle and left in a bolus.

 Catheter: chronically implanted

tube through which drugs are
administered
 Usually into a vein.

 Cannula: rigid catheter, usually

into the brain, or i.v.
1. Parenteral:

Subcutaneous, s.c.
Intramuscular, i.m.
Intraperitoneal, i.p
Intravenous, i.v.
SUBCUTANEOUS, S.C.
Skin popping
INTRAMUSCULAR, I.M.

Deltoid muscle

Depot injection
The drug that has to be administered continuously
can be dissolved in oil which is then injected into a
muscle, e.g. antipsychotic drugs
INTRAPERITONEAL, I.P.

Into the peritoneum, cavity filled with visceral organs

INTRAVENOUS, I.V.

Mainlining

Fastest of parenteral routes in

drug absorption
Permanent catheters used in
behavioral pharmacology
1. OTHER PARENTERAL ROUTES

Intracerebroventricular
(i.c.v.) Injections

- Brain and spinal cord are

surrounded with cerebrospinal
fluid
- Ventricles are spaces in the
brain filled with cerebrospinal
fluid
- i.c.v. injections are directly into
ventricles of brain via cannula
INTRATHECAL

 Injection
into the
cerebrospinal fluid in
the spinal cord
1. PARENTERAL ABSORPTION RATES
blood stream
 The movement of a drug from the
site of administration to the blood
stream.
 Pores in capillary walls

 Factors that influence absorption

from parenteral sites:

Tissue cells
 1. Temperature

 2. Blood flow to the area

blood>peritoneum>muscles>skin
 ABSORPTION RATES: DIFFUSION
 A substance will move from an area of high concentration
to an area of low concentration until concentration is
even everywhere, i.e., drugs will move down their
concentration gradient

 Drugs diffuse from the bolus (high concentration) into

blood in capillaries through pores.
1 min after
i.v
injection
SMALL GROUP DISCUSSION
 Come up with 1 and 2 and think of an example
why/when that would be used?

 1. the slowest possible absorption via parenteral

route

 2. the quickest way to manipulate CNS activity

2. INHALATION OF GASES

 Lungsare an efficient
gas exchange system

 Absorb oxygen and

release carbon
dioxide

 Works by diffusion
2. INHALATION OF GASES

 Very rapid absorption

 Very rapid delivery to

the brain

 Gases can move in

and out of the body
Explain how drugs can enter the body from smoke?
Why smoking is more detrimental to lung tissue
compared to gas inhalation?
2. INHALATION OF SMOKE AND SOLIDS
 Smoke
 Burning dried plant material
 Tobacco, marijuana, opium
 Drug is vaporized or remains in ash and dissolves in the
moist surface of the lung
 Diffuses into capillaries
 Cannot revaporize so cannot be exhaled like gases
2. INHALATION OF SOLIDS
 Drugs in the form of fine powders or droplets
 Cocaine, aerosols (inhalers), tobacco snuff, heroin
 May be inhaled into lungs (aerosols) or snorted into
nose (intranasal administration)
2. INTRANASAL ADMINISTRATION
 Enters nasal cavity
and dissolves in
mucous membrane.
Then diffuses into
blood.
 Some enters lungs

 Some runs down

throat to stomach
SOME BASIC PHARMACOLOGY
Chapter Outline

 3.Oral Administration (pgs. 11-12)

 The Digestive System

 4. Transdermal Administration

 Distribution of Drugs

 Excretion and Metabolism

 First-Pass Metabolism

 Factors That Alter Drug Metabolism

 Combining Absorption and Excretion Functions

 The Therapeutic Window

3. ORAL (PERORAL, P.O.)
ADMINISTRATION
 Drugs administered to the
digestive system are
usually administered by
mouth, but the nose and
rectum may also be used

 Some drugs are absorbed

by the buccal membranes
in the mouth (eg.
nitroglycerine for angina)
3. ORAL ADMINISTRATION
 Some absorption from
the stomach, but it is
designed to digest
food. It is acidic with a
pH of about 3.5

 Most absorption is from

the small intestine
which is designed to
absorb nutrients from
food
3. ORAL ADMINISTRATION
 In the small intestine drug molecules must pass through a tissue
barrier to enter the capillaries.
 Tissue is made of cells and cells are surrounded by a membrane
made of lipid (fat) molecules.
 Rate of absorption is therefore controlled by the ability of drug
molecules to dissolve in lipids, i.e. lipid solubility
LIPID BILAYER OF MEMBRANES
3. ORAL ADMIN: LIPID SOLUBILITY
 Oliveoil partition
coefficient

 When a drug is dissolved in

a mixture of oil and water,
different proportions of the
drug will end up dissolved in
the oil and the water

 A high partition coefficient

means that most of the drug
ended up in the oil
 Becomes inactive in body since
gets trapped in fat tissue

 A low coefficient means that

most ended up in the water
 Highly lipid soluble drugs can diffuse through a
membrane and be absorbed from the small
intestine.
 Drugs with low lipid solubility diffuse slowly into
the blood from the small intestine.
 When molecules of a drug have an electric
charge, i.e., they are ionized, they are not lipid
soluble at all.
3. ORAL ADMIN: IONIZATION
 When few molecules of a
drug are ionized,
absorption is as fast as
the natural lipid solubility
of the drug will allow.

 When many molecules

of a drug are ionized,
absorption will be very
slow no matter what the
natural lipid solubility of
the drug is.
 % of ionization is constant
WANT DETERMINES THE PERCENT OF
IONIZED MOLECULES?
 THE DRUG – whether
it is a weak acid or a
base (alkaloid).

 THE SOLUTION –
whether it is an acid or
a base, i.e., its pH

 pKa of the drug – the

pH at which half the
molecules of the drug
are ionized
 PKA
 pH of solute at which the molecules of the drug are 50%
ionized.
 Drugs that are bases have few ionized molecules when
dissolved in bases.
 Drugs that are acids have many ionized molecules when
dissolved in bases
 PKA

e.g., damital
(acid)

pH of solution:
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

0 0 0 1 8 50 90 95 100 100 100 100 100 100 100

Percentage of nonionized molecules determines the rate of absorption

USING PKA TO PREDICT ABSORPTION
Morphine is a base
with a pKa of 8
Lining of intestine has
a pH of about 3.5
Nearly all molecules of Morphine
morphine will be
ionized in the
intestine
Morphine is slowly
absorbed when
given orally
WHAT HAPPENS TO THE IONIZED MOLECULES?

 Once non-ionized molecules are absorbed, ionized

molecules can become non-ionized, and become
absorbed

Morphine
ABSORPTION OF ACIDS ASPIRIN??
 pKa? Is this quickly or
slowly absorbed when
taken orally?
 Aspirin has a pKa of
3.5.
 Aspirin is an acid
(acetylsalicylic acid,
ASA).
 50% of molecules are
not ionized in digestive
system
 Aspirin is quickly
absorbed when taken
orally
4. TRANSDERMAL ADMINISTRATION
 Salves, lotions and patches
 Epidermis cells are packed with keratin which
blocks water soluble drugs and slows down
absorption of lipid soluble drugs
 Antipsychotics
 Motion sickness
SOME BASIC PHARMACOLOGY
Chapter Outline

 3. Oral Administration (pgs. 11-12)

 The Digestive System

 4. Transdermal Administration

 Distribution of Drugs

 Excretion and Metabolism

 First-Pass Metabolism

 Factors That Alter Drug Metabolism

 Combining Absorption and Excretion Functions

 The Therapeutic Window

DISTRIBUTION
 Where drugs go in the body

 Lipid solubility
 Barriers
 Blood-brain
 Placental
BLOOD-BRAIN BARRIER
PLACENTAL BARRIER
Maternal and fetal blood are separated however lipid
soluble molecules can diffuse to fetal blood.
TRANSPORT MECHANISMS
 Active
 Pumps non-lipid soluble molecules across membrane
 Uses energy
 Can work against diffusion

 Passive
 Attaches to a “carrier” in the membrane which is lipid
soluble
 Passes through the membrane by diffusion along the
concentration gradient.
PROTEIN BINDING
 Blood contains large
protein molecules that
can bind to a drug
molecule
 These protein
molecules cannot
leave the blood
 Drug is trapped in the
blood until it is
metabolized
 albumin
EXCRETION AND METABOLISM
 Liver and kidneys, the “dynamic duo” of drug
elimination.
THE KIDNEYS
MAINTAIN CORRECT BALANCE OF
ELECTROLYTES IN BODY FLUIDS

Na+, K+, Mg2+,

Ca2+, HCO- etc
THE NEPHRON
 The nephron is the functional unit of the kidney. There are
millions of nephrons.
 Explain how nephron works?
 KIDNEYS
 The kidneys filter everything out of the blood and then
reabsorb molecules the body needs.
 Uses transport mechanisms

 Lipid soluble molecules are reabsorbed

 Non lipid soluble molecules are eliminated in the urine

KIDNEYS

 If the urine is acidic, bases will ionize and be

excreted, if the urine is basic, acidic drugs will be
excreted
 Barbiturate overdose: give sodium bicarbonate to
increase urine pH, thus more acidic barbiturates will
remain in urine
THE LIVER
 Chemical factory that
controls chemical
reactions
 Chemical reactions are
controlled by enzymes
 Makes molecules useful to
the body
 Modifies chemicals
harmful to the body
 Metabolism: the
restructuring of molecules
 Metabolite: restructured
molecules - ionized
ENZYMES

 An enzyme is a catalyst that controls a chemical

reaction
 Name usually ends in “ase”, eg, alcohol
dehydrogenase.
DETOXIFICATION

 Restructured molecules are usually less

physiologically active, but not always
 Restructured molecules are usually more likely to
ionize and have less lipid solubility so the liver can
eliminate them
FIRST PASS METABOLISM
 Some drugs are degraded by enzymes in the
stomach, intestines, and liver before they
circulate to the rest of the body.
HALF-LIFE
 Time taken to reduce
blood level by ½
 Kidneys are more
efficient when blood
levels are high
 Causes an excretion
curve that is not a
straight line
 How much is left of 100
mg after four hours if
half-life is 1 hr?
HALF-LIVES OF SOME DRUGS
 Cocaine 0.5-1.5 hr
 Nicotine 2 hr
 THC 20-30 hr
 Aspirin 3-4 hr
 Prozac (fluoxetine) 7-9 days
 Morphine 1.5-2 hr
ZERO ORDER KINETICS
 Some drugs like alcohol do not have a half life
because they are eliminated at the same rate no
matter what their concentration
 This is because the enzyme that destroys alcohol
works at the same rate no matter what the
concentration
ZERO ORDER KINETICS

 Alcohol has zero

order kinetics
nicotine

 Alcohol
dehydrogenase
works at a constant
rate, 15 mg/ 100ml
blood/hr
alcohol
FACTORS THAT ALTER METABOLISM
 1. Stimulation of enzymes
 2. Depression of enzymes

 3. Species

 4. Age
1.STIMULATION OF ENZYMES

 Metabolism of alcohol
 Heavy drinkers have
higher levels of alcohol
dehydrogenase
 Causes metabolic
tolerance
 Also against barbiturates
1. STIMULATION OF ENZYMES
 St. John’s Wort – used as a natural antidepressant
 Stimulates cytochrome P4503A4 (intestines)

 Causes reduced blood levels of many drugs

including cyclosporine, alprazolam (tranquilizer)
and oral contraceptives
2. DEPRESSION OF ENZYME ACTIVITY

 Enzyme activity can be

suppressed by blocking
their activity or giving
another drug for them
to metabolize
 Disulfiram blocks disulfiram
aldehyde
dehydrogenase
 Alcoholism treatment
2. DEPRESSION OF ENZYME ACTIVITY
 Grapefruit juice can block cytochrome P4503A4
which destroys many drugs in the intestine (first
pass metabolism)
 Grapefruit juice will increase levels of busparone
(antidep), lovostatin (cholest) and sildenafil (Viagra)
3. SPECIES DIFFERENCES
 Many species have different enzymes and different
levels of enzymes.
 The same drug at the same dose may have
different effect in different species

 Alcohol dehydrogenase
 Rat 60%
 Guinea pig 160%
4. AGE
 As organisms grow and as they age enzyme levels
change and different enzymes are used causing
different concentrations of the drug and different
metabolites (theophylline into caffeine in infants)
 Elderly people are often more sensitive to drugs
because of reduced liver function
 Newborns have immature liver
TIME COURSE FOR BLOOD LEVEL OF
DRUGS
 A graph that plats the effect of a
drug over time after
administration

 This is the time course for

absorption (assuming no
excretion) and the time course
for excretion assuming
instantaneous absorption

 The resultant is the combination

of absorption and excretion
functions.
 Absorption rate varies depending
on the administration route
TIME COURSE FOR BLOOD LEVEL OF
DRUGS

 Different rates of
absorption can cause
quite different curves.
 Fast absorption causes
high peak levels and
short duration
 Slow absorption
causes low peak levels
and long effect
 Antibiotics p.o.
THERAPEUTIC WINDOW
 Therapeutic drugs
require that a blood
level be maintained
that is high enough to
have a therapeutic
effect (main effect),
but not so high that
there are toxic (side)
effects.
THERAPEUTIC WINDOW
 This is difficult to do with
drugs that are rapidly
absorbed

 Rapidly absorbed drugs

require small doses many
times a day

 For this reason many drugs

have formulations that are
released and absorbed
slowly
 Bid
 Tid
 Qid
Lithium: sustained-release matrix tablets