“How strange would appear to be this thing that men call pleasure! And how curiously it is related to what is thought to be its opposite, Pain! Wherever the one is found, the other follows up behind.”

Plato, Phaedo, fourth century B.C.

http://www.youtube.com/watch?v=uMBozVgO77A

Necro - I Need Drugs

Terminology

• Pharmacology – science of how drugs affect the body

• Psychopharmacology – how drugs affect the brain and behavior

• Pharmacokinetics – basic principles of drug absorption,distribution,metabolism and excretion.

• Pharmacodynamics – interaction of the drug with its receptor or other cell functions

Names of drugs

• Chemical name – using the chemical jargon, i.e. 7-chloro-1,3-dihydro-1-methyl1-5phenyl1-2H-1,4-benzodiazepin-2-one.

• Generic name – diazepam. Textbooks use the generic name.

• Trade name – property of the company that sells the drug. In this case, the trade name is Valium

PHARMACOKINETICS• DOSAGE

use metric system

• ROUTES OF ADMINISTRATIONInjection (intravenous, intramuscular, or subcutaneous injection)Inhalation (smoking)Oral administration (by mouth)Absorption through the skin or membranes (intranasal sniffing, sublingual absorption, rectal suppository, transdermal patch)

Dosage Use the metric system: a milligram is 1/1,000of

a gram. ( a little over 28 grams in 1 ounce)

Dosage continued

• Doses are therefore reported in terms if milligrams per kilogram (kg) of body weight. A kg is 2.2 pounds)

• LSD is the exception. Reported in micro grams

• 1 gr of LSD = 4,000 hits (McKim,1987)

Dose Response CurvesDRC

• Necessary to give a range of doses

• Range needs to cover a dose so low that there is no detectable effect and a dose so high that increases in dose have no further effects (McKim,1987)

DRC continued

• Plot the effects on a plot

• Dose is reflected on the horizontal axis

• Effect is plotted on the vertical axis

The majority of clinical benefit is achieved at low doses, after which the efficacy curve begins to flatten out.

DRC characteristics

• Potency – how much is required to get a response

• Efficacy - maximum effect obtained

• Variability – individual differences in drug response

Effectiveness of drugs

• Use ED (effective dose) and LD (lethal dose)

• Drugs’ toxicity is measured by looking at the ratio of lethal and effective dose

EFFECTIVE DOSE (ED)LETHAL DOSE (LD)

• The effective dose (ED) is the minimal dose necessary to produce the intended drug effect in a given percentage of the population under study

• The lethal dose (LD) is the minimal dose necessary to produce death in a given percentage of the population under study

Effectiveness of drugs continued

• The ratio of LD50/ED50 is called the therapeutic index

• Margin of safety – another ratio which uses 1% and 99% - the higher the ratio, the safer the drug

AN EXAMPLE OF ED-RESPONSE AND LD-RESPONSE CURVES THAT WOULD PRESENT SERIOUS TOXICITY

PROBLEMS

Allyn and Bacon

Examples of LD

• Nicotine - LD50 (in mice) orally is 0.23g/kg

• Caffeine – 250mg/kg in mice; 70 to 100 cups of brewed coffee (Barnes,1973)

EXAMPLES continued

• Cocaine – depends on route of administration• The LD50 in a 150 pound man is about 500 mg

• When it is taken intranasally,however,the LD50

may be as low as 30 mg.(Crowley, 1987)(Related to sudden increase in drug levels in the brain)

More examples

• Amphetamine deaths – the lethal dose ranged from 5 mg to 630 mg (O.J. Kalant,1973)

• Barbiturates – 4,000 to 6,000 mg is the estimated lethal dose. (Moeschlin,1971)

EXAMPLES continued

• Alcohol – blood alcohol level of about 500 mg per 100 ml – probably a lethal dose for most people ( 25 ounces of liquor)

• LSD – 0.3 mg/kg I.V. for mice,rats, and rabbits. It is, in the toxic sense, one of the safest drugs known

Poisons

• Botulinum toxin A5g – about a teaspoonful could kill a

quarter of the world’s entire current population.

1 out of 4 persons alive today

Poisons continued

• Tetanus toxin

1 teaspoon could kill about 7 million people

• Sarin (nerve gas) – 0.01mg/kg

Remember

• Drugs do not create any unique effects- they merely modulate normal neuronal functioning – they mimic or antagonize the actions of a specific neurotransmitter.

(Julien,R.2001)

Factors influencing Drug Responsessome of these you listed this morning in class!

Route of administration DoseOther drugs Genetics Gender AgeHealth WeightBiorhythms MoodSetting ToleranceExpectancy Learning

Many Factors Affect Drug Response

MERCK MANUAL

Tolerance(McKim,1987)

• Cross Tolerance- tolerance to one drug may diminish the effect of another drug (i.e. opiates)

• Behavioral tolerance/conditioned tolerance

Tolerance

• Metabolic tolerance – metabolism increase (i.e. enzyme induction to destroy the drug)

• Cellular or pharmacodynamic tolerance ( body makes adjustments to maintain homeostasis)

Tolerance

• Acute tolerance – i.e. alcohol- effects of alcohol are more pronounced while the BAL is rising( Vogel-Sprott,1992)

Half-life of a drug

• Time it takes for half the dose to be eliminated from the body

• need to maintain steady-state level (i.e. prescription medication)

Half-life calculations

Amount of drug in the body

Number of half lives % eliminated % remaining

0 0 1001 50 502 75 253 87.5

12.54 93.8

6.25 96.9 3.16 98.5 1.6

Examples

• Aspirin ca. 1 hr• Morphine ca 2 hours• Lithium 24 hours• Valium several days

• Assuming liver and kidneys are up to par!

http://www.youtube.com/watch?v=mp93nPUzHqM

A good video on pharmacokinetics