Routes of Administration --

Inhaled -- the onset of action (OOA) for inhaled drugs may range from 7 to 10 seconds
Injected -- OOA for intravenous use, 15-30 sec -- OOA for intramuscular 3-5 minutes
Mucosal administration -- snorting, dipping, place in the eye, OOA 3-5 min
Oral/Rectal -- OOA, 10-30 min
Cutaneous -- OOA, up to one day

Once absorbed, the drugs are distributed throughout the body (not just in the brain).  Recall that drugs may be metabolised by the liver before ever reaching the brain, thus decreasing their potential action (when this occurs immediately after oral ingestion it is called the first pass effect).  It may also be absorbed in various sites in the body, making it appear to be very widespread throughout the body with corresponding lower blood levels (recall that the Volume of distribution is an indirect measurement of the distribution of a drug).  Finally recall that drugs are often not selective in their site of action -- while a drug of abuse may be producing euphoria in the CNS, it may also be causing potentially severe damage to other organs.

Before the drug can achieve its desired effect, it obviously must be distributed to the brain.  In order to be absorbed into the CNS a drug must cross the blood brain barrier.  Recall that this refers to an anatomical arrangement of tightly joined endothelial cells that comprise the blood vessels to the CNS.  This decreases the passage of substances from the blood to the brain.  In order to cross the endothelial wall, a drug must be very lipophilic and cross the cells lining the vessels by passive diffusion.

NERVOUS SYSTEM -- Site of action for Drugs of Abuse
Recall that the nervous system is composed of both central and peripheral components that perform specific functions.

Within the CNS, the brain is divided into two portions (actually, there are many classifications of brain parts -- for the purposes of this class, the following discussion is particularly useful) -- an evolutionary older brain (lower brain) and a more advanced newer (higher) brain.

The lower brain is composed of the stem, cerebellum, and midbrain and is responsible for basic physiology and those emotions that are important in basic survival -- anger, fear, hunger, thirst, pleasure.

The higher brain (cerebrum, cerebral cortex) is the portion that permits and controls speech, reason, and the ability to create -- higher level functions.

NOTE that often the lower brain may predominate -- the need to survive is often more powerful than the need to write poetry!

RECALL that nerves within and without the CNS synthesise, store and release specific neurotransmitters (NT).  When a nerve is activated, a process involving the exocytosis of storage granules containing the NT begins and the NT is released from this presynaptic nerve into a small area called the synapse.  This synapse is between the releasing nerve and either an organ or a second nerve (the post synaptic site of action).  Once released the NT will bind to a receptor on the post synaptic site and elicit some action.  Once this has been accomplished the NT will either 1) be metabolised or
2) be taken back up into the pre-synapse where it is either metabolised or re-stored for future use.

RECALL that the receptors on the post-synaptic site in part determine the effect of the NT.  The number or nature of these receptors may be altered (up or down regulated) in response to how much NT is available and acting at the receptor.

ALSO RECALL that there exists drugs that either mimic the actions of the NT at the receptor (agonists) or block the effect of the NT (antagonists).  Additionally, some drugs may specifically block the re-uptake (re-storage) of the NT.

When a drug is taken for an extended period, it may become less effective over time.  This phenomenon is called tolerance and may exist in several forms.

Dispositional Tolerance -- the more a drug is used the more it is eliminated (the body gets rid of it faster -- NOTE that this may often be induced by the drug itself as with alcohol or barbiturates inducing the liver metabolism.

Pharmacodynamic Tolerance -- this refers most often to the change in receptors described above, when an agonist activates receptors more than normal and the body thinks it must have too many receptors -- so the receptors are "down regulated" or reduced in number, lessening the effect of the drug.

Acute Tolerance -- Tachyphylaxis -- this type of tolerance occurs very rapidly (often with one dose of a drug -- the second dose is not as effective) and is most often associated with depletion of the NT that mediates the effect of the drug.

Behavioural Tolerance -- this type, as defined by the text, is when a person may appear tolerant for a brief period before the effects of the drug re-exert themselves.  This is more likely to due to a sudden release of adrenaline, which may temporarily override the effects of the drug.  This is not a true tolerance.

Reverse Tolerance -- the situation, as described by the text, when once tolerance has developed a physiologic change occurs that obliterates the tolerance and the effects of the drug may re-exert themselves.  NOTE that this is not true tolerance, either in effect or mechanism.

Inverse Tolerance --also not a true tolerance -- is described by the book as a situation where the drug may not exert an effect for a long period and then the effect will suddenly appear.  The example used by the book is the ability of cocaine to "kindle" seizures after a long period of seizure-free use.  Pharmacologically this ability is more appropriately described as a process of sensitisation (becoming more sensitive to the effects of a drug) rather than desensitisation that more accurately describes tolerance.

NOTE that tolerance may be selective -- a good example of this is the fact that tolerance develops relatively rapidly to the euphoria produced by opiates -- however it does not develop as quickly to the respiratory depressant actions and as the abuser uses more drug to achieve the same level of  euphoria he depresses the respiration even further.

Psychic Dependence -- The person THINKS they need the drug -- this is a major component of continued use -- the "reward" aspect of drug abuse discussed later.

Withdrawal -- This usually describes the physical effects of stopping a drug.  As noted above with physical dependence, the body must adjust to the absence of a drug that has been taken over time.  Often, the effects of withdrawing a drug are the opposite of the drug itself. (That is if a drug caused constipation -- the withdrawal effect would be diarrhoea.)  The text classifies three types of withdrawal

Non-purposive withdrawal -- those signs and symptoms that are directly observable -- seizures, sweating, diarrhoea, et c.  Note that these signs a symptoms may occur even with placebo -- stressing the impact of psychic dependence.

Purposive withdrawal -- this is not true withdrawal.  Although it may intentional (conscious) or unintentional (unconscious) on the part of the patient, it is a "faking" of withdrawal in order to get sympathy, support, or more drug.  Often this "withdrawal" will present with signs and symptoms that would not be present with true physical withdrawal.

Protracted withdrawal -- This is often referred to as "flashbacks".  Again, this is not a true withdrawal.  However, as discussed in the text it is the situation where, after a long period of abstinence, the former user experience and unpleasant sensation upon some stimulus that is associated with the drug use.  An appropriate analogy would be "post-traumatic stress" for addicts.  NOTE:  This may represent a component of the psychological withdrawal that a user may experience.

RECALL that these drugs as acting in places other that the CNS.  They often produce a wide range of side effects that, in non-abusing individuals, would be considered bothersome, but that the abuser will tolerate to achieve the desired effect.  Also recall that many additional actions of the drug may be detrimental to the health of the abuser.

In the drug abuse arena, there are many levels of use.  These may range from

experimentation (one time use to see what the experience is like),
social or recreation (occasional use in a specific setting),
habituation (where the use becomes a part of the daily life).

The text defines drug ABUSE as the "continued use of a drug despite negative consequences".  NOTE that this definition could include the social user or experimentor as easily as it does the habitual user.

The compulsion component of drug addiction may include, but is not limited, to the following
1) spend the majority of time using/getting/thinking of the drug
2) continue use in presence of adverse life, health, mental, or physical consequences
3) deny the existence of a problem or "can stop at anytime"
4) after physical withdrawal, still have tendency/desire to use again

There are three primary theories of addiction:

Addictive Disease Model -- this model purports that there is a genetic predisposition to abuse.  This predisposition is mediated by innate differences in neurotransmitter systems, enzymes, and/or brain function.  The extreme view supporting this model is that the abuser has no choice.  Once exposed to a drug they are automatically addicted.  Moderate supporters of this theory state that a predilection exists but may be overcome by conscious decisions on the part of the potential abuser.  Regardless of the stance taken, the theory supports the view that once a person with the predilection for abuse is exposed to a drug, they react differently than one who is not predisposed.  This theory is partially supported by studies comparing drug abuse in twins (however, there are contradictory studies as well).

Behavioural/Environmental Model (including the Developmental Model) -- this model supports the view that actions taken by family during early childhood development, the home/living environment, and/or the behaviours of family or self will result in addiction.  The addiction is a result of emotional or physical stress (such as abuse as a child, living conditions, work) causing the person to seek an escape from that environment (also included in this model are inadequacies in self-worth, where the drug makes them more important or to feel better about themselves -- a result of subconscious memories of emotional abuse as a child) or peer pressure to join in the abuse of drugs (a choice on the part of the abuse to persist in that environment).  The addiction will usually follow the sequence of events that begins with abstinence or non-use and progress through experimentation, social/occasional use, habituation, abuse, and finally addiction.  There are studies that support this theory and those that refute it.

Academic Model -- This is the older and more pharmacologically based theory of addiction.  The theory states that the drug, through its actions on the reward/pleasure centres of the brain, will alter the neurochemistry such that the desire to use again is stronger either for the euphoria produced or the perception of reward, leading to abuse through re-inforcement, physical dependence, and psychological dependence.  Again, there is a strong record of animal research to support this theory at least in part (where upon repeated exposure, animals will choose a drug over food or water, even in the presence of aversive stimuli such as pain) and studies that fail to correlate the abuse with the drug.

These theories supported in part a study in which two different strains of mice were tested for alcohol preference.  Normal mice (who do not prefer alcohol or N) and mice genetically predisposed to prefer alcohol (A) were used in the study.  When given a choice between water and alcohol, the N mice consistently chose the water while the A mice consistently chose the alcohol.  However, N mice who were
1) force feed large amount of alcohol (drug induced-CNS changes),
2) submitted to a stressful environment, or
3) deprived of proper nutrition
all preferred alcohol when given the choice.  NOTE that the study, by necessity, omitted the one factor that is present in human abusers -- that is the order of higher level thinking and the ability to make reasoned decisions that is often a component of the choice of whether to abuse or not.

In all probability, it is a combination of all three models that results in drug abuse and addiction. Namely

1) Heredity -- where the potential for abuse is there
2) Drug action -- when exposed to the compound, the reinforcement encourages additional use and
3) Environment -- when the person may choose to abuse as a route of escape or to increase feelings of
    self-worth, or even because their friends are also using the drug -- the catalyst for continued use.

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