·Definition of a Drug:

· Any chemical substance, natural or man-made (usually excluding nutrients, water, or oxygen), that - by its chemical nature - alters biological functioning when administered and absorbed.

·Recognizing something as a drug is usually
pretty straightforward,  but how about:

· Wine cooler?

· Coffee?

· Cigarettes?

· Airplane glue?

· Ice Cream?

· Cough drops?

· Soft drinks?

· Water?

· Candy?

· Salt?

· Vitamins?

· Dietary supplements

· Herbal or natural remedies?

·How about when we see a physiological or behavioral effect even though what the person took contained no active chemicals?

·Placebo & Placebo Effects

· Placebo - typically an inert (chemically inactive) substance administered like a drug

· Placebo effect - any psychological or physiological effect that is due to expectancy  rather than chemical action

·Psychoactive Drug:

· Any drug that affects feelings, perceptions, thought processes, and/or behavior.

· All psychoactive drugs exert their effects by altering the functioning of the nervous system.

·Classifying Drugs

· By their availability/commercial status

· (prescription vs nonprescription drugs; licit vs illicit drugs)

· By their potential for abuse

· (Schedules of Controlled Substances)

· By their typical effects/actions

·Categories We’ll Use Most

· Depressants

· Stimulants

· Narcotic Analgesics

· Psychotherapeutics

· Psychedelics/Hallucinogens

· Cannabis

· Inhalants

·Some current statistics:

· ~51% of American adults consume alcohol

· ~29% smoke (60 million)

· ~6% use illegal drugs (14 million)

·Drug Use is Related to:

· Over 500,000 emergency room visits/yr

· 193,000 attempted suicides

· 208,000 related to recreational use or dependence

· 66,000 unexpected drug reactions

· 52,000 related to withdrawal/detoxification

· Over 1 million arrests/yr

·Spending Estimates:

· 49 billion/yr purchasing illegal drugs

· 50 billion/yr on prescription & nonprescription drugs

· 30 billion on drug enforcement

·Deaths Attributed to Drugs

· ~25,000/yr due to illegal drugs or drug related activities

· ~100,000/yr related to alcohol

· ~400,000/yr related to tobacco use

·Following a Drug
Through the Body

· Administration – Get drug into person.

· Absorption - Drug gets into bloodstream

· Distribution - Blood carries drug to tissues

· Drug Action - Drug interacts with cells

· Termination of Effect, Metabolism and/or Elimination

· Study of 1,2,3, & 5= pharmacokinetics

· Study of action = pharmacodynamics

Routes of Administration

·Oral Route

· Easy, convenient, accepted

· Gradual onset (5-30 min) with 75% absorbed within 2-3 hrs; provides a longer lasting effect .

· Reversible for a while

· But:  Not all drugs can withstand          stomach acids, some upset stomach

· Absorption variable depending on stomach contents; dosing not precise

·Inhalation

· Rapid absorption & fastest route to brain

· Fairly easy

· But:  Many drugs cannot be inhaled

·          Dose can be difficult to control

·          There is no drug depot.

· Inhalation via smoking can present special risks.

·Injection (aka Parenteral)
(drug prepared in a liquid vehicle)

· Intravenous (IV)

· Fast, bypasses absorption obstacles

· Most difficult & risky route

·  Intramuscular (IM)

· Intermediate speed depending on muscle selected (arm faster than butt)

· Subcutaneous (SC)

· Fairly rapid injection route; can irritate skin

· All give good control of dose

Injection Problems

l Intravenous route most dangerous because of risk of possible life-threatening reactions or allergic responses

l Risk of clots or emboli due to particles, air bubbles

l Must use sterile procedures or risk infection.

l Site of injections deteriorates.

·Miscellaneous 

· Intranasal ; nasal sprays

· Sublingual    

· Topical or Transdermal

· Rectal

· Implantable

·Routes Vary in:

· Form of drug

· Dose necessary due to absorption diffs

· Time course (latency period, length       of effect)

· Risks & benefits

· Intensity of drug effects

·Some Absorption-Related Food/Drug Interactions

· Grapefruit juice increases absorption of antihistamines, codeine, tranquilizers, cardiovascular & AIDs drugs

· Pop, fruit or veggie juice or vitamins with iron can decrease absorption of erythromycin

· Dairy foods or other calcium rich items decrease absorption of tetracycline

· Excess salt alters lithium absorption

·Distribution

· Bloodstream distributes drug widely (not just to the problem area)

· Speed with which a drug leaves the blood and enters other tissues depends on concentration, binding to proteins in blood, and degree to which the drug is fat-soluble

· Speed altered by other drugs present

·Distribution (continued)

· Limitations to the distribution of some drugs:

· the “blood-brain barrier” restricts the entry of some substances into the brain. Psychoactive drugs are the ones that do make it into brain.

· the “placental barrier” excludes some large molecule chemicals but does NOT exclude psychoactive drugs.

·Why Drug Effects End

· *Drug may be metabolized by liver, then removed by kidney

· Drug may be removed by kidney

· Drug may be redistributed to body fat

· Some drugs may leave in feces or other bodily fluids (milk, sweat, breath)

· Some molecules may be broken down at site of action  (receptor sites in CNS) or before they are even absorbed

·Some Food-Drug Interactions Where Food Affects Drug Elimination

· Grapefruit juice interferes with metabolism of a wide range of drugs by affecting CYP enzymes

· Broccoli and similar veggies counteract blood thinner coumadin

· Licorice is dangerous when using heart med Lanoxin (hyperadditive effect)

·The “Half-Life” of a Drug

· The half-life of a drug is the time it takes for half the dose to be eliminated from the body.

· A drug’s effects may be longer and more intense if liver and/or kidney are not functioning up to par.

· Knowing half life  is important for understanding time course of drug and how often to administer it to achieve steady-state levels.

·Sample Half-Lives

· Aspirin                  1+/- .5 hrs

· Morphine         2 +/- .5 hrs

· Tetracycline         4 +/- 1.5 hrs

· Haldol                   12 +/- 6 hrs

· Lithium                 24 +/- 6 hrs

· Phenobarbital >30 hrs

· Valium                  several days

Meet the Families

Cytochrome P450 Families

l Enzymes found in liver & a little in GI tract

l Break down or detoxify lots of chemicals

l Different subfamilies handle different drugs

The Subfamilies

l CYP 3  - metabolizes about 50-55% of all known drugs; CYP 2 – 45-50%; CYP 1 - 5%

l Anything that affects these enzymes will alter drug metabolism (e.g. grapefruit juice)

l Some drugs alter these enzymes (Tegretol increases them, Prozac decreases them)

l Our genes determine our individual levels

·Dose

· Most drugs we discuss have doses expressed in milligrams (mg.) (thousandths of a gram)

· Exceptions: LSD  (50-150 micrograms (millionths)); fentanyl (.05 mg-.10mg)

·Dose

· That many drugs are sold in just a few dosages belies the fact that there is wide individual variability in drug response. We do not all have the same absorption, distribution, drug action, or elimination and shouldn’t be surprised that we respond differently !

·The Dose-Effect or Dose-Response Curve

· Graphic representation relating the amount of drug administered to the response produced

· Response may be represented as intensity of response OR as % of population responding

·Potency vs Effectiveness

· Potency – the amount of drug required to produce a particular effect

· Effectiveness – the maximum effect obtainable from a particular drug

·Comparing Curves - Be Sure You  Understand Dose-Response Graphs

·Sample Contents of a Coated Tablet:

· 5 mg active drug

· 30 mg sugars

· 6 mg cornstarch

· 9 mg miscellaneous

· 10 mg coating

With such a composition, would it be very useful to come up with a more potent drug (say one that only required 2 mg active drug)?

·Drug Interactions

· Additive/potentiating/synergistic interactions

· Antagonistic interactions

· Altered side effects, time course

· The presence of another drug may alter absorption, distribution, metabolism, elimination, or receptor interactions.

·Some examples:

· Tagamet, Zantac, birth control pills, or erythromycin  can increase effects of benzodiazepines like Xanax

· Smoking can decrease the effectiveness of a wide range of medications

· Taking antacids can affect the absorption of lots of drugs

· Taking alcohol and aspirin increases stomach upset

·Tolerance:

· Tolerance:  progressively decreasing drug effects due to regular, repeated administration.  In order to experience the original degree of drug response the individual must increase their dose.

·Time-Related Tolerance Terms

· Acute tolerance or tachyphylaxis – rapid tolerance which develops during a single drug use period (e.g. during an evening)

· Protracted tolerance - tolerance which occurs over the course of 2 or more drug use occasions

· Reverse tolerance or sensitization - increased response with repeated use

·Mechanisms by Which Tolerance Occurs:

· Metabolic or dispositional tolerance (increased liver metabolism of drug)

· Cellular adaptation or tissue tolerance or pharmacodynamic tolerance (cells at drug’s site of action adapt to the presence of drug)

· Behavioral conditioning/tolerance (learning and conditioning lead to decreased drug effects)

Example of Behavioral Conditioning

· Measure tolerance of Group A getting drug 10 times in same situation vs tolerance of Group B getting same drug  in 10 diff. situations. Group A  shows more tolerance due to learned counter-reaction or compensatory mechanisms.

·Physical or Physiological Dependency:

· Body has physiologically adapted to, and (to a certain extent) compensated for the regular presence of the drug. 

· Adaptation/compensation processes result in tolerance (having to increase your dose to achieve the same degree of effect) and may produce withdrawal symptoms when drug levels drop.

·Cross-Tolerance &
Cross-Dependence

· When tolerance to a drug develops         it often extends to other (usually chemically related) drugs although     they have not been used.

· When physical dependence occurs, other chemically-related drugs can “satisfy” that dependency & prevent withdrawal

·Psychological Dependency:

· Emotional or psychological reliance on the reinforcing effects of the drug.

· Drug-taking behavior is reinforced by the positive feelings or escape the drug provides, leading to a well-learned behavioral habit difficult to extinguish. 

· Trying to break this habit leads to craving the missing reinforcement and desire to return to the more comfortable drug-taking behavior pattern.

.

·Drug Names

· Chemical name

· Generic name – official, nonproprietary

· Brand name(s) – owned by a company

· Street names

·Examples:

· sodium 5-ethyl-5-(1-methyl butyl)barbiturate

· sodium pentobarbital

· Nembutal

· bluebirds

·Which name is which?

· Benedryl

· 2-(diphenyl methoxy)-N,N-dimethylamine HCl

· allergy pills*

· diphenhydramine

·Generic vs Brand Name Drugs

· Are they equivalent?

· Are generic substitutions fair to brand-name companies?

· Will generic availability decrease drug development research?

·Side-Effects of Drugs

· All drugs produce multiple effects. 

· “Side-effects” are effects not sought by the user.

· One person’s desired effect may be another person’s “side effect”. 

· Side effects may be mild or disturbing or even dangerous.

· Serious side-effects are often called “adverse reactions”.

· Every drug has some side-effects that are quite common & others that occur more rarely.

·Some Adverse Reactions:  Hypersensitivity

· An allergic response to a drug after it has been given more than once. May cause rash, swelling, fever, or, in the worst cases, anaphylactic shock. Anaphylaxis is a life-threatening medical emergency.

·Signs of anaphylaxis:

· tingling lips and mouth 

· flushing of face, body 

· itchy eyes, nose, face 

· eyes and face swelling  

· hives

· wheezing

· diarrhea, nausea    

· Symptoms rapidly progress to: 

· weakness,dizziness

· throat swelling closed

· low blood pressure

· loss of consciousness

· possible death 

·Some Adverse Reactions:  Idiosyncratic Response

· Rare, unpredictable, highly individual response to a drug. The user may be at the extremes of the dose-response curve or may exhibit unusual physiological or behavioral  responses to the drug.

·Risks With Street Drugs

· Actual drug composition unknown

· Dose variable and unknown

· Possibly harmful diluents/contaminants

· Abuse liability 

·Signs of Drug Distress

· slowed respiration (16-20 inhalations/min is normal)

· cyanosis

· fast (>140), slow (<50), or irregular pulse

· high temperature

· loss of consciousness

· extreme behavioral change (agitated, aggressive, suicidal)

·Factors Influencing Drug Response

· Route

· Dose

· Tolerance

· Other Drugs

· Genetics

· Gender

· Age

· Health

· Weight

· Biorhythms

· Mood

· Setting

· Baseline behavior

· Expectancy

· Learning

·A Few Examples:

· Genetic diffs in initial sensitivity.

· Women respond more strongly than men to equivalent doses of alcohol

· Asians require lower doses of tranquilizers and antipsychotics. Also handle caffeine and alcohol differently.

· Blacks require higher doses of BP meds

· The elderly often require lower doses.

·Basic Nervous System

· All psychoactive drugs change nervous system functioning. Even non-psychoactive drugs often produce their “side-effects” by affecting the peripheral parts of the nervous system.

·Best Known Neurotransmitters

· Acetylcholine (ACh)

· Norepinephrine (NE)

· Dopamine DA)

· Serotonin or 5-Hydroxytryptamine (5HT)

· GABA

· Endorphin

    Glutamate

Receptor Specificity

l Each transmitter binds only to its receptors, but there are multiple types of receptors for each.

Eliminating Neurotransmitter

l Transmitter must be removed from synapse after its release

l Most neurotransmitters are recycled thru a process called “reuptake”.

l Less often an enzyme breaks down transmitter into inactive components.

·Acetylcholine (ACh)

· neurons using ACh are known as “cholinergic neurons”.  Examples:

· Carries messages to skeletal muscle

· parasympathetic effects(e.g. slowing HR)

· Learning and memory

· some drugs (Cognex (tacrine)increase ACh; others (“anticholinergics”) block it

·Norepinephrine (NE)

· Neurotransmitter of the sympathetic  (fight or flight)  nervous system

· Brain areas involved in appetite, arousal, mood

· closely related to DA (“catecholamines”) and both NE and DA are related to 5HT (“monoamines”)

· some drugs activate NE receptors (sympathomimetics); others block NE receptors (“beta-blockers”)

·Dopamine(DA)

· transmitter in basal ganglia (voluntary movement), limbic system (emotion & mood) & frontal cortex (judgement & reasoning) & parts of hypothalamus that control pituitary

· some drugs increase DA (l-dopa); others block DA (antipsychotics) 

·Serotonin (5HT)

· found in neurons of brainstem associated with sleep & pain suppression, & in limbic system (mood) and in sensory processing areas

· several drugs increase 5HT (antidepressants)

·GABA

· best known inhibitory transmitter

· widely distributed in CNS

· seems necessary to keep neuron activity “in check” - without enough of it you might suffer from anxiety or epilepsy

· several drugs increase the effects of GABA (benzodiazepines, alcohol)- too much can be dangerous

Glutamate

l Amino acid which acts ax as excitatory transmitter almost everywhere in the CNS

·Endorphin

· Peptide transmitter  which decreases pain perception and elevates mood

· narcotic drugs act on endorphin receptors

·Ways Drugs Affect Neurons

· Drugs may affect

· Synthesis of transmitter

· Storage of transmitter in vesicles

· Release of transmitter

· Binding of transmitter to receptor sites

· Elimination of transmitter by reuptake or enzymatic breakdown

·Drugs & Receptor Sites

· AGONIST: A drug that produces the effects or increases the effects of a transmitter

· E.g. A drug which fits receptor site and MIMICS action of transmitter

· ANTAGONIST:  A drug decreases or prevents the usual effects of a transmitter

· E.g. A drug which fits receptor site but does not trigger a response. This drug is a BLOCKER.

·Drugs Affecting Receptor Sites

· AGONIST example:

· Narcotic pain relievers fit and activate opiate receptors mimicking the action of normal endorphin.

· Nicotine stimulates ACh receptor sites

· ANTAGONIST example:

· Thorazine blocks DA receptors in schizos

· Atropine blocks ACh receptors in parasympathetic NS

· Naloxone blocks opiate receptors