A drug is a chemical compound that may produce psychological, behavioural and
Psychoactive effects refer to alteration in cognitive, behavioural and motor processes eg
euphoria, distortions of time perception, hallucinations or increased libido.
Drugs are distributed throughout the body via the circulatory system
PROCESS: Administration, absorption, distribution, metabolism ad elimination are known
collectively as pharmacokinetics.
Processes involved in the interaction of the drug with receptors at the site of action are
known as pharmacodynamics.
Cytochrome P-450 is a term used for a very large group of enzymes, found primarily in the
endoplasmic reticulum of liver cells, that are involved in the metabolism of most drugs.
Injection: Absorption is more rapid following intraperitoneal(stomach) administration than
following intramuscular (muscle), which is more rapid than following subcutaneous (just
below skin/ into fatty layer).
Mainling in s the term used for intravenous injections in the drug subculture.
Skin popping is the term often used to refer to subcutaneous injections of illicit drugs
Drugs that are guven by injection or via pulmonary route enter the circulation diffusinf
through pores in capillary walls.
Drugs taken orally must be lipid soluble to be absorbed from the digestive system since
there are no pores in the lining of the stomach or intestines.
Factors which affect entry of a drug into circulation:
1) Ionization – most drugs are either weak acids or weak bases. Drugs that are weak acids
readily ionize in alkaline environments and become less ionized in acidic environments.
Reverse is true for week bases. Ionized molecules are not readily absorbed, therefore
percentage of nonionized molecules determines the rate of absorption. Ionized particles
penetrate cell membranes poorly compared to unionized particles.
2) Lipid solubility – lipid soluble compounds penetrate cell membranes more readily than non
lipid soluble compounds more compounds than non-lipid soluble compounds. Compounds
that are lipid soluble are also usually unionized.
The brain is protected by the blood brain barrier. It restricts the permeability characteristics
of brain capillaries, by reducing the diffusion of water soluable or ionized molecules, but
does not impede lipid soluable or un-ionized molecules. The concept arose from the work of
Paul Ehrlich in 1882.
3) Receptor Binding – Drigs exert their effects by binding with receptors at relevant target
tissue. A bind forms between charged groups in the receptor molecule and oppositely
charged groups on the drug.
An agonist is a drug that mimics the effect of a neurotransmitter. This may occur because
the agonist bonds to receptors, blocks reuptake or inhibits metabolic breakdown. Antagonists are compounds which reduce the effects of a receptor agonist by biding to
active receptors but producing no pharmacological action.
Drug Response Curve:
Drug dosages are usually expressed as milligrams (mg), or if given on weight basis, mg/kg.
The dose-response curve (DRC) I the most commonly used graphical presentation mode of
The ED50 is the dose of a drug that is effective in producing a response in 50% of the
experimental subjects. (allows you to compare potency)
LD50 refers to the dose which kills 50% of the subjects.
Therapeutic index for a given drug effect is given by the ratio LD50/ ED50. The higher the
ratio, the greater the difference btw the LD50 and ED50 and the less likelt chance that a
lethal or other non- lethal effect will occure.
Margin of safety is a more conservative measure of a drugs safety and is the ratio of the
Phenomena associated with chronic drug administration, can be depicted by the DRC.
Tolerance is represented by a shift to the right in the DRC. Sensitisation is depicted by a shift
to the left in the DRC.
Termination of Drug Action:
Drugs are eliminated by skin, lungs and kidneys.
The liver is important organ in this process because it is the major site of enzymatic
breakdown of drugs.
Cytochromme P450 enzyme family is the primary agent involved in drug metabolism.
Individuals differ in the level of CYP enzyme activity, which in turn affects how rapidly drugs
Many drugs (eg: alcohol) induce the activity of CYP enzymes, and this results in a more rapid
metabolism of not only the original drug, but other drugs. Most often, enzymatic breakdown results in inactive molecules that are subsequently
excreted via urine.
Enzymatic breakdown most often results in metabolites thate are less soluble, are lagrer,
carry a greater charge, and are inactive or less active than the original compound. This is
important because these molecules are less rapidly reabsorbed from the kidney to the
Weak acids are excreted more readily when tubular urine is alkaline because the weak acids
become ore ionized and are “trapped” in tubular urine. Conversely weak acids are excreted
more if urine is acidic.
The relation between reabsorption and pH is frequently used in treatment of drug toxicity.
Elimination half-life – time needed for half of a drug dose to be eliminated from the body –
helps understand drug effects and is important when considering which drug to use for
certain medical conditions.
It takes about 6 half-lives for most of a drug to be eliminated and for a person to be
considered drug free.
Pot had a long half life hence naturally weens the body as it take a long time to leave.
“Steady State Concentration”- relatively steady blood concentration is required to maintain
effects of the drug.
Neuron and Neurotransmission
Drugs exert their actions by affecting neurotransmission.
The Neuron is the functional unit of the nervous system.
An action potential arriving at an axon terminal can cause the release from the
presynaptic element of substance known as neurotransmitters.
Neurotransmitter release: neurotransmitter substances are stored in synaptic vesicles in
the axon terminal the presynaptic element. The arriving action potential causes these
vesicles to attach to the presynaptic membrane and open exuding the stored
neurotransmitter. The exuded neurotransmitter crosses the synaptic cleft where it binds
to receptor elements (transmembrane proteins) on the postsynaptic membrane.
Neurotransmitters are basic components of CNS functioning. Most drugs exert their
action by affecting the synthesis, release or reuptake of neurotransmitters.
General model of the synthesis and breakdown of neurotransmitter substance:
1) Precursor substances (amino acids from diet), are the basic building blocks of
2) Synthesizing agents are needed to build neurotransmitters from the precursor
3) Once synthesized the neurotransmitter must be transported to the presynaptic
terminal and stored
4) The stored, or newly synthesized neurotransmitter is released.
5) Released neurotransmitters bind to postsynaptic receptors
6) The neurotransmitter becomes unbound, at which point it can bind again to the
receptor to produce additional action, attach to transporter proteins and be taken
back up (reuptake) into the presynaptic element to be used again, or attach to
proteins that breakdown the neurotransmitter. UP TO PAGE 9 Classical Conditioning and Tolerance:
The occurrence of tolerance may present problems in achieving effective medication since,
as tolerance develops to some desired medical effect of a drug, the dose must be increased
to reproduce the desired effect.
Many of the mechanisms underlying the development of tolerance to a drug also underlie
physical dependence to the drug.
Withdrawal symptoms, the benchmark of physical dependence, to a drug are directly
opposite to the actual drug effects.
Pavlovian or Classical conditioning was identified by Russian physiologist Ivan Pavlov. (Dog
“Psychic secretion” or Conditional Response – salivation (reponse) in advance or anticipation
to the food (stimuli)
In Pavlovian conditions, a stimulus which does not elicit the response of interest at the
beginning (conditioned stimulus CS) is paired with another stimulus that does elicit the
response from the outset (unconditional stimulus UCS) and the response it elicits is the
unconditional response (UCR).
If the CS is paired enough times with the UCS, the CS comes to elicit a response which Pavlov
called the conditioned response (CR).
Since CRs strengthen, grow bigger and occur sooner, as the number of CS-UCS pairings
increase, the degree to which the drug effect is reduced by the opposing CR should increase
over the course of the drug administrations – characteristic of tolerance.
Shepard Siegel proposed that pav. Conditioning of drug-opposite CRs may play a role in
1) Situational Specificity of Drug tolerance: morphine with cues A and saline with cues B.
Tolerance is always greater when the drug is given in the context of the usual CS predrug
cues, hence showing situational specificity.
2) Placebo CR test – giving a drug in the context of consistent set of CS predrug cues results
in the development of a drug compensatory CR, and that the drug compensatory CR,
elicited by the predrug cues, reduces the effect produced by the drug. Results show that
usual CS predrug cues elicit the drug opposite CR predicted by pav conditioning model.
3) How might a drug opposite CRs be involved in withdrawal and relapse? Research has
shown that these subclinical withdrawal symptoms are most likely drug compensatory
CRs being elicited by the usual predrug cues. Hence people crave drug more (CR) when
they experience the CS. Pav. Conditioning model provides explanation of why treated
addicts may experience withdrawal symptoms that may lead to relapse, and also
provides a connection btw the processes involved in the development of tolerance and
the occurrence of withdrawal.
4) How is tolerance lost and what are the implications for treatment? Pavlov found that in
order to get rid of a CR he had to present the CS and not follow it with the expected UCS,
a procedure that he called extinction. If drug compensatory CRs are the basis of
subclinical withdrawal symptoms and subsequent relapse in treated addicts, extinction
procedures could be useful in reducing the likelihood of any such withdrawal and
perhaps reduce the likelihood of relapse. PARADIGMS TO STUDY DRUG REINFORCEMENT:
Behaviour, such as drug self administration, in maintained by one of two processes, either
positive or negative reinforcement
Positine reinforcement- situation in which the performance of some behaviour results in the
experiencing of some desirable or rewarding outcome.
Negative reinforcement involves situations in which the performance of some behaviour
results in the termination or avoidance of some undesirable or aversive outcome.
The most common procedure used to study positive reinforcement is call the operant self-
administration paradigm. (Animals required to press lever to get reward)
Research of this type (investigation what brain regions or neurotransmitters are involved)
has led to the general conclusion that an increase in dopaminergic activity in the ventral
tegmental area and nucleus accumbens is very importantly involved in the positively
reinforcing properties of the vast majority of drugs.
The progressive ratio procedure is a self-administration paradigm that provides info in the
relative reinforcing properties of drug (ie; how far someone is willing to go/ pay for the
drug). The largest number of responses that the animal will make to obtain the drug is called
the break point.
Studies of the reinforcing effects of drugs comparison
Self-Administration Paradigm Conditioned Place Preference (CPP)
Animals surgically prepared, put in Based on classical conditioning
skinner boxes and press lever to be Rectangle tube with 2 boxes at either
administered drug. end. Mice given drug placed in one box.
Allows for more obvious comparison of Mice then given saline, placed in other
differential reinforcement effects of box. Test by placing animal in middle of
drugs (progressive ratio procedure) box and allowed to move around freely,
Allows researches to examine the dependant measure is amount of time
pattern of drug admin. spends in the boxes (if drug has positive
Difficult to determine adverse properties reinforced properties, it will stay in box
associated with drug).
Shows adverse effects – animal will
spend less time in box associated with
Alcohol is ethanol or ethyl alcohol
C6H 12 6 C2H 5H + 2CO 2
One molecule glucose acted upon yeast in the presence of heat and absence of oxygen
produces cellular energy and 2 molecules of ethanol and 2 molecules of carbon dioxide as
waste. This process is called fermentation and occurs naturally in any item that has sugars or
starches (which can be converted to sugars).
Consumption in modern times: Alcohol is the second most widely used psychoactive substance in the world. It is
estimates that 90% of the people in westernized societies have consumed alcohol at some
point in their lives.
In Canada and the US the average age of first drink is 12, with the average age of regular
Binge drinking is define as having 5+ drinks on one occasion.
When taken orally, 20% of alcohol is absorbed from the stomach and 80% from the small
Absorption from the gastrointestinal tract is influenced by:
o Greater concentration of alcohol the more rapid it is absorbed – because higher
concentration alcohol beverages tend to be more radpidly moved from the stomach
to the small intestine
o Other chemical in alcohol (ie: vodka and gin more pure so more rapidly absorbed)
o Food in stomach slows absorption
o Alcohol in carbonated beverages is more rapidly absorbed – carbonation speeds
gastric emptying into small intestine
o Ingested alcohol goes to liver then brain. If absorption is slow BAC will be lower
since liver can metabolize more alcohol. Liver metabolises alcohol at constant rate,
and if alcohol is consumed rapidly (leading to absorption) then alcohol will enter
bloodstream since liver cannot keep up.
o Lean bodies have more water. Alcohol is more widely distributed the higher the
water content. Hence leaner person has lower BAC.
o Women have about 50% less alcohol dehydrogenase than men, meaning more
alcohol enters the blood stream of a female.
Alcohol is metabolised primarily in the liver by alcohol dehydrogenase
Alcohol acetaldehyde acetic acid (by acetaldehyde dehydrogenase)
carbon dioxide and water.
Typical measure of alcohol is the blood alcohol curve (BAC) – shows amount of alcohol in
blood as a function of time since ingest