Download Elicited Behavior and Classical Conditioning

Principals of Pharmacology for the Health
Sciences
Lecture 1
Dr. Steven I. Dworkin
What is a Drug?
•
•
A substance used in the treatment of disease: medicament,
medication, medicine, pharmaceutical.
A substance that affects the central nervous system and is
often addictive: hallucinogen, narcotic, opiate.
Dr. Steven I. Dworkin
What is a Drug?
• Definition can depend on culture and can change within a
culture
• Examples
– Herbal antidotes
– Vitamines
– Food additives
– Prescription Medications
– Illicit Substances
• Recreation
• Augment natural abilities
Dr. Steven I. Dworkin
Pharmacology
– Scientific study of the actions of drugs and their effects on a living
organism.
• Neuropharmacology
– How drugs effect the central nervous system.
• Psychopharmacology
– Drug-induced changes in mood, thinking, and behaviors.
• Behavioral Pharmacology
– Evaluate specific behavioral effects of drugs
• Change on-going patterns of behavior
• Produce reinforcement
• Produce specific internal states.
Dr. Steven I. Dworkin
Human Nervous System
The nervous system has two major divisions: the central nervous
system and the peripheral nervous system. Each of these has major
subdivisions, as shown.
Dr. Steven I. Dworkin
Drug Action
• Specific molecular changes produced by a drug
when it binds to a particular target site or receptor.
• Drug effects – alterations in physiologic or psychological
functions.
– Specific Effects
• Therapeutic effect
• Side effect
– Nonspecific Effects
• Unique characteristics of the individual
– Context dependent tolerance
– Placebo effects
Dr. Steven I. Dworkin
Herbal Medicine
• Opium poppy – morphine
• Madagascar rosy periwinkle – chemotherapy
• Foxglove plant – digitalis
• Coca Plant
• Ephedra plant
Concerns
variations in potency
contain toxons
augment or attenuate effects of therapeutics
adverse side effects
Dr. Steven I. Dworkin
Pharmacokinetic Factors
Determine Drug Action
• Bioavailability
• amount of drug in the blood free to bind at specific
target site to elicit a drug effect
– 1) Route of Administration
– 2) Absorption and distribution
– 3) Binding
– 4) Inactivation or biotransformation
– 5) Excretion
Dr. Steven I. Dworkin
Methods of Drug Administration
– Determines amount of drug reaching site of action and
how quickly drug effect occurs.
• Oral administration (PO)
– Safe and economical
– Drug must dissolve in stomach fluids and pass through
stomach wall.
– Absorption by small intestine
– Influenced by stomach load
– First pass effect
• Metabolism by liver
Dr. Steven I. Dworkin
Methods of Drug Administration
• Intravenous (IV)
– Rapid and accurate method of drug administration
– Large potential for adverse effects
• Overdose
• Allergic reaction
• Hepatitis, HIV……
• Intramuscular (IM)
– Slower more even distribution
• 10- 30 minutes – longer with a drug constricts blood
vessels
– Muscle irritation
Dr. Steven I. Dworkin
Methods of Drug Administration
• Intraperitoneal (IP)
– Injection through abdominal wall into the peritoneal
cavity
• Rapid
• Somewhat variable effects
• Subcutaneous (SC)
– Injection just below skin
– Absorption dependent on blood flow to site
• Fairly slow and steady
• Slow release metods
Dr. Steven I. Dworkin
Methods of Drug Administration
• Inhalation
– Rapid delivery
– Absence of first-pass effects
– Irritation of nasal mucosa and lungs
• Topical
• Transdermal
• Epidural
• Intracranial
• Intracerebralventricle
Dr. Steven I. Dworkin
Pharmacokinetic factors that determine bioavailability or drugs From the site of administration
(1),the dose moves through cell membranes to be absorbed into the blood (2), where it circulates to all
cells in the body. Some of the dose molecules may bind to inactive sites such as plasma proteins or
storage depots (3) and some to receptors in target tissue. Blood-borne dose molecules also enter the liver
(4), where they may be transformed into metabolites and travel to the kidneys and other discharge sites
for ultimate excretion (5) from the body.
Dr. Steven I. Dworkin
Dr. Steven I. Dworkin
The time course of drug blood level depends on route of administration The blood level of the same amount of dose
administered by different procedures to the same individual varies significantly. Intravenous (IV) produces an instantaneous
peak when the dose is placed into the blood and rapid decline. Intramuscular (IM) administration produces rapid absorption
and rapid decline, although IM administration in oil (IM-oil) shows slower absorption and gradual decline. Slow absorption
following subcutaneous (SC) administration means some of the dose is metabolized before absorption is complete. For that
reason, no sharp peak occurs and overall blood levels are Iower. Oral (PO) administration produces the lowest blood levels
and a relatively short time over threshold for effectiveness in this instance. (After Levine,1973.)
Dr. Steven I. Dworkin
TABLE 1.1 Advantages and Disadvantages of Selected Routes of Drug Administration
Route of
administration
Advantages
Disadvantages
Oral (PO)
Safe; self-administered; economical;
Slow and highly variable absorption;
Intravenous (IV)
no needle-related complications
Most rapid; most accurate blood concentration
subject to first-pass metabolism;
less predictable blood levels
Overdose danger; cannot be readily reversed;
Intramuscular (IM)
Slow and even absorption
requires sterile needles and medical technique
Localized irritation at site of injection;
Subcutaneous (SC)
Slow and prolonged absorption
needs sterile equipment
Variable absorption depending on blood flow
Inhalation
Large absorption surface; very rapid onset;
Irritation of nasal passages; small particles
inhaled
Topical
no injection equipment needed
Localized action and effects; easy to selfadminister
may damage lungs
May be absorbed into general circulation
Transdermal
Controlled and prolonged absorption
Local irritation; useful only for lipid soluble
drugs
Epidural
Bypasses blood—brain barrier;
Not reversible; needs trained anesthesiologist;
very rapid effect on CNS
possible nerve damage
Dr. Steven I. Dworkin
Transport Across Membranes
• Phospholipid
– Complex lipid molecules form cell membranes
– Negative charge at one end two uncharged lipid tails
Dr. Steven I. Dworkin
Transport Across Membranes
• Lipid-soluble drugs
– Enter cells by passive diffusion across concentration
gradient.
• Ionized drugs
– PH of the solution
– pKa (PH at which drug is 50% ionized
TABLE pH of Body Fluids
Fluid
pH
Stomach fluid
1.0—3.0
Small intestine
5.0–6.6
Blood
7.35–7.45
Kidney urine
4.5–7.5
Saliva
6.2–7.2
CSF
7.3–7.4
Dr. Steven I. Dworkin
Transport Across Membranes
Effect of ionization on drug
Fabsorption On the right side of the cell
i barrier in stomach acid (pH 2.0),the
molecules tend to remain in the
gaspirin
non-ionized form (1), which promotes the
upassage of the dose through the cell
r walls (2) to the blood. Once the intact
easpirin molecules reach the blood (pH
7.4), they ionize (3) and are"trapped"in
1the blood to be circulated throughout the
. body. In the lower portion of the figure,
5when the aspirin has reached the intesit tends to dissociate to a greater
Etine,
extent (4) in the more basic pH. Its more
f ionized form reduces passage (5)
f through the cells to the blood, so
eabsorption from intestine is slower than
from the stomach.
c
t
o
f
i
o
Dr. Steven I. Dworkin
Drug Distribution
• Once in blood carried throughout body in 1-2 min
• Areas with most blood flow highest concentration of drug
• Greatest concentration in heart, brain, kidneys and liver
Dr. Steven I. Dworkin
Blood-Brain Barrier
Distribution of cerebrospinal fluid
(A) The CSF (blue) is manufactured by the
choroid plexus within the cerebral ventricles. In
addition to filling the ventricles and their
connecting aqueducts, CSF fills the space
between the arachnoid membrane and the pia
mater (subarachnoid space) to cushion the brain
against trauma. (B) Enlarged diagram to show
detail of CSF-filled subarachnoid space and the
relationship to cerebral blood vessels. Notice how
blood vessels penetrate the brain tissue.
Dr. Steven I. Dworkin
Blood-Brain Barrier
Cross section of typical capillaries and brain capillaries (A) I he capillaries
found throughout the body have characteristics that encourage the movement of
materials between the blood and surrounding cells. (B) Brain capillaries minimize
movement of water-soluble molecules through the blood vessel wall because
there are essentially no large or small clefts or pinocytotic sites. (After Oldendorf,
1975.)
Dr. Steven I. Dworkin
Biotransformation and Elimination
• Drug Clearance
– First-order kinetics
• Constant fraction (50%) free drug in blood removed
in each time interval.
– Half-life or T1/2
– Zero-order kinetics
• Drug cleared at constant rate regardless of
concentration
– Ethanol
» 10-15 ml/hour or 1.0 ounce of 50%
alcohol/hour
Dr. Steven I. Dworkin
Drug Elimination
First-order kinetics of drug clearance
Exponential elimination of dose from the
blood occurs when clearance during a fixed
time interval is always 50% of the dose
remaining in blood. For example,the half-life
of orally administered dextroamphetamine
(Dexedrine) is approximately 10
hours.Therefore,10 hours (1 half-life) after the
peak plasma concentration has been
reached, the dose concentration is reduced to
about 50% of its initial value. After 20 and 30
hours (i.e.,2 and 3 half-lives) have elapsed,
the concentration is reduced to 25% and
12.5%, respectively. After 6 half-lives,the dose
is essentially eliminated, with 1.6%
remaining.The curve representing the rate of
clearance is steeper early on when the rate is
more rapid and becomes more shallow as the
rate of clearance decreases.
Dr. Steven I. Dworkin
Half-Life of Some Common Drugs
Drug
Trade/Street Name
Half-life
Cocaine
Coke, snow
0.5-1.5 hours
Nicotine
Tobacco
2 hours
THC
Marijuana
20-30 hours
Acetylsalicylic Acid
Asprin
3-4 hours
Ibuprofen
Advil
3-4 hours
Naproxen
Aleve
12 hours
Ultram
Tramidol
6-7 hours
ketoprofen
Orudis
5 hours
Morphine
Morphine
1.5-2 hours
Dr. Steven I. Dworkin
Biotransformation
• Liver microsomal enzymes
– Phase 1 nonsynthetic modification
• Oxidation, reduction, hydrolysis
• Active metabolites
– Phase II synthetic
• Conjugation of drug with small molecule
• Inactive
• Cytochrome P450 enzyme family
– Enzyme induction
Dr. Steven I. Dworkin
Factors Influencing Drug Metabolism
• Enzyme induction
– drug produced increase in liver enzymes
– Carbamazepine and oral contraceptives
– Cigarette smoke and antidepressants and caffeine
• Enzyme inhibition
– MAOIs and tyramine
• Drug competition
– Ethanol, barbiturates, benzodiazepines
• Age, sex, genetics
– Genetic polymorphisms
Dr. Steven I. Dworkin
1.
2.
What do all drugs share in common?
Name one route of drug administration and list advantages and disadvantages of its
use.
3.
What are the two major divisions of the central nervous system?
4.
What are the two major divisions of the peripheral nervous system?
5.
Name two potential problems associated with herbal compounds.
6.
List two of the major differences between lipid soluble and ionized drugs.
7.
Describe the blood-brain barrier. What purpose does it serve?
8.
I have just taken 2 Aleve tablets (50 mg/each), how long will the drug remain in my
body.
9.
During the past 3 hours I have consumed 3 glasses of wine (12% ethanol) and one
large cigar. How long should I wait before trying to drive home safely?
10. What factors are important in estimating the latency from drug administration to drug
effect (latency of drug action)?
Dr. Steven I. Dworkin