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The Alcohols


Ethanol: Metabolic Pathways

The Alcohols (Ethanol, Methanol, Ethylene Glycol)


Very common abused substance

Clinical Pharmacology
Pharmacokinetics: Ethanol- Absorption and Distribution
Small water soluble easily absorbed
Rapid GIT absorption (esp. empty stomach)
Food: Absorption retardant (slow gastric empting

Alcohol DH is the one the oxidizes ethanol into

acetaldehyde normally

Rapid distribution- tissue levels approx. blood

concentration (gender difference)

But with higher amounts of alcohol, the normal

pathway is overwhelmed so the liver will activate the
hepato-oxidizing system

Alcohol is more readily distributed among

females due to small body proportion

In chronic alcoholism, the CYP450 takes its action

which produces several effects

The smaller you are the more readily

alcohol can be absorbed

Once ethanol is converted into acetaldehyde, 2nd

enzyme will be activated which is the aldehyde DH
which control the production of acetate that cause
many adverse effects utilizing body processes and
biosynthesis. Disulfiram inhibits the activity of
aldehyde DH.

Acetaldehyde can be very toxic to body tissues

thats why it has to be broken down further and is
also responsible for adverse reaction

Levels rise fast in the brain (crosses biologic barriers)


The smaller the molecule, the more readily

it can passed thru the BBB

Pharmacokinetics: Ethanol- Metabolism and Excretion

90% liver oxidation, lungs, urine

Liver is responsible for most of the

metabolism of alcohol

At higer doses, recruited by the lungs

Alcohol Dehydrogenase Pathway

The primary metabolic pathway

Zero order kinetics (150-220 mmHg/hour)


This causes accumulation of alcohol in our


Enzyme in the Liver, brain, stomach


Mostly concentrated in liver

A little in brain

Reduced activity (some Asians)

increased risk of alcoholism
NADH accumulation*
Gender differences (stomach ADH)



as of 1/11/12

In men, ADH has more activity because they

have more concentration in their stomach
thats why the ladies has more tendency to
absorb the parent compound of alcohol

Smaller distribution of women probably

explain why women has to be symptomatic
in terms of alcohol

In men, they are able to metabolized

alcohol in their stomach due to presence of

In some Asian populations, there are those with ADH

that have reduced activityincreased risk of

Chronic alcoholism-MEOS is activated so many other drugs

have faster clearanceincrease toxic products of
metabolism(toxins, free radicals, hydrogen peroxide)
Acetaldehyde Metabolism by Acetaldehyde Dehydrogenase
Mitochondrial NAD-dependent ALDH
Oxidation is inhibited by disulfiram * acetaldehyde
elevation (untoward reactions):
protective against alcoholism?
greater risk of liver disease

Due to gender and genetic make up

NADH metabolic




For example, elevated levels of NADH cause the

formation of abnormally high levels of lactic acid, which
in turn reduce the capacity of the kidney to excrete uric
Excessive uric acid in the body can exacerbate gout, a
disorder characterized by extremely painful swelling of
certain joints.
Therefore, alcohol-induced increases in NADH levels and,
subsequently, uric acid levels, which can be worsened by
other alcohol-induced metabolic effects, may at least
partly explain the common clinical observation that
excessive alcohol consumption causes or aggravates
attacks of gout.
In addition, increased NADH promotes the generation of
the building blocks of fat molecules and reduces the
breakdown of fats in the liver, thereby contributing to fat
accumulation in that organ.
Microsomal Ethanol Oxidizing System (MEOS)

Disulfiram is a drug to address addiction

and to induce the relapse state but the
problem is that it is able to inhibit very well
the aldehyde DH

* exhibited by other drugs

* Asians-lower activity of ALDH

Alcohol can reduce the clinical efficacy of

other drugs taken

Ex. An antibiotic that is metabolized by

CYP450, it clinical effect would be reduced
because it was metabolized earlier

Due to action of CYP450, metabolites

produced rapidly can be toxic to liver
especially during continuous utilization of

Asian has lower concentration of ADH

compare to Caucasian and Africans

If acetaldehyde is increased, it can produce

untoward reactions such as generalized
pain, flushing, nausea and vomiting as well
as autonomics fluctuation

Metronidazole not taken with alcohol

Activated when alcohol levels are high (ADH system

saturation >100mg/dl)

Accumulation of acetaldehyde flushi, has disulfiram

reactionng, nausea, vomiting, dizziness, headache

Involves CYP P450s

Other drugs with disulfiram effect when taken with alcohol:

metronidazole, cefotetan, trimethoprim

Activated in chronic alcoholism*

faster metabolism of other drugs
generation of more toxic metabolites



Some Asians have lower ALDH activity reduced likelihood of

alcoholism due to earlier appearance of untoward reactions
from accumulation of acetaldehyde but this increases risk of
severe liver disease

as of 1/11/12

Pharmacodynamics: CNS

The no.1 effect of alcohol is neural: to the

nervous tissue

It affects more areas of the brain

Starts with sedation


experience this clinical effect. So chronic alcoholics

are not exempted to the damage, they also
experience cellular damage due to exposure to
higher level of alcohol

Resistance and tolerance was only up to some

extent. Once tolerance stop, manifestation can be

Ethanol and Neurotransmission


Glutamate and the NMDA receptor

Slurred speech

GABA mostly affected arising to depressant effect


Has the dominant effect

Impaired judgement which can lead to accident

especially when driving
Disinihibited behavior
Impairment of attention and information processing
cognitive performance are also affected
Impairment of motor skills
CNS depression, coma, death

Alcohol can also lead to death especially in


Remember! Alcohol is a sedative as well as

depressant it can alter the function of the
brainstem and also the autonomic function
(Tolerance in Chronic Alcoholics)
Ethanol affects large number of proteins trhat are involved
insignalling e.g. nts receptors for amines, amino acids,
opioids; enzymes such as Na/K ATPase, adenyl cyclase,
phospholipase C, ion channels
Acute alcohol exposure enhances GABA (main inhibitory nts in
the CNS) and inhibits glutamate in opening NMDA glutamate
receptors (main excitatory nts in the CNS)
Pharmacodynamics: Heart
Depression of myocardial contractility thats why it
is not possible to see alcoholics who has a congestive
heart failure
Pharmacodynamics: Smooth Muscles
Vasodilators (central and direct effects):

Asian has lower threshold for respiratory depression

Chronic alcoholics can develop tolerance. But at

some point tolerance STOP and the individual may



Hypothermia esp. in cold environments (severe


as of 1/11/12

Commonly mistaken by laymans that taking alcohol

may increase temperature but in fact it does not

Uterine relaxant not use for practical value

*By direct effects of ethanol or its metabolites or by bacterial

endotoxins gaining access from the GIT due to alcohol
induced changes in the intestinal mucosa

Chronic Alcohol Consumption: Effects and Consequences

- mucosa lining are destroyed and become corrosive leading

to malnutrition and eventually malabsorption of folic acid

Mechanism of Tissue Damage

Liver and GIT

Direct effects of ethanol + Active metabolites

Chronic pancreatitis

increased oxidative stress producing free radicals


decreased glutathione decrease antioxidant

Protein malnutrition

mitochondrial damage- begin from cell to cell

Small intestinal injury*

growth factor dysregulation

*diarrhea, weight loss, vitamin deficiencies (malabsorption)

cytokine-induced injuries
Chronic Alcohol Consumption in large amounts
liver disease
Liver and the GIT
Most common medical complication
Alcoholic fatty liver, alcoholic hepatitis, cirrhosis,
liver failure
Risk is related to amount and duration of use
Susceptibility to hepatotoxicity : Female >Male

Spectrum of Fatty liver alcoholic hepatitis liver


In ethanol toxicity, the individual phagocytes

become less efficient in function and was not able to
convert glycogen glycogen will be deposited in
the liver causing the liver to enlarged (fatty liver)

Activation of cytokine and TNF- alpha causing

liver cirrhosis

Asian women has less defenses against alcoholism

due to gender and genetic make up

Risk of severe disease greater with preexisting

hepatitis B or C

Metabolic effects of ethanol oxidation in the liver


Dysregulation of fatty acid oxidation and synthesis


Activation of innate immune system

e.g. TNF -

Nervous System


Tolerance (there is a limit to this!)



as of 1/11/12

Physical dependence Alcoholic Withdrawal

Syndrome * untoward effects
hyperexcitability, seizures, toxic psychosis,
delirium tremens
*severity depends on dose, rate and duration of
Psychological dependence (cravings)

Urge or compulsion to take substances

Recalcitrant disease keep on coming back

Molecular basis of tolerance and dependence

Tolerance: ethanol upregulation of a pathway
Dependence: overactivity of same pathway after
dissipation of ethanol effects
Changes in GABA neurotransmission according to
most studies
Changes in levels of neurotransmitters involved in
brain reward circuits (e.g. serotonin, opioids,

Nowadays! They try to develop drug to address

addiction but no successful drug was produced

Coronary Heart Disease
#1 dilated cardiomyopathy, ventricular hypertrophy, fibrosis.
Alcohol induced changes in heart cells- membrane disruption,
depressed function of mitochondria and sarcoplastic
reticulum, intracellular accumulation of phospholipids and
fatty acids, upregulation of voltage dependent calcium
#2 atrial and ventricular arr., reflects abnormalities of
potassium and magnesium metabolism and enhanced release
of catecholamines
#3 independent of obesity, salt intake, coffee intake, cigarette
#4 cardioprotective effects of moderate drinking is still
unestablished-based on ROH ability to raise HDL
Mild anemia (folic acid deficiency)
IDA from gastrointestinal bleeding
Hemolytic syndrome

G6PD and thalassemia bad reaction to


Endocrine System and Electrolyte Balance

Gynecomastia, testicular atrophy

Nervous System
generalized symmetric peripheral nerve injury
(distal paresthesias of hands and feet)
gait disturbances and ataxia motor and gait

Alcohol is toxic to testis

Induces testicular atrophy testosterone

production decreases

Unopposed action of estrogen


Fluid and electrolyte imbalances (ascites, edema,



Potassium depletion

demyelinating disease


impairment of visual acuity and optic nerve


Ketosis due to damage kidney

Wernicke-Korsakoff syndrome thiamine deficiency

Cardiovascular System
Cardiomyopathy and heart failure



as of 1/11/12

Fetal Alcohol Syndrome

Immune System

Immunodepressant chronic alcoholics prone to


Immune function in some areas (lung) are inhibited

while hyperactivity is triggered in other tissues (liver,
Chronic use leads to inflammatory damages in liver
and pancreas, increased susceptibility to lung
Increased cancer risk

Carcinogenic because of toxic metabolites prone

to asian due to acetaldehyde concentration
especially female

Mouth, pharynx, larnyx, esophagus, liver, breast

Cause cognitive impairment

fetal alcohol effect

Pregnant, NO TO ALCOHOL even a small amount.

there is no threshold for alcohol. Since alcohol is a
small molecule it can cross the placenta and produce
untoward effects to the fetus

Threshold of consumption for carcinogenic effects?

Metabolites e.g. acetaldehyde
Changes in folate metabolism
Effects of chronic inflammation
Alcohol and Drug Interactions: Pkinetic


Alcohol (+) CYP450 enhance the clinical effect

Poor coordination

Always additive and synergistic effect with other

drugs sedative hypnotics

Underdeveloped midfacial area (flat face)

Minor joint anomalies
Congenital heart anomalies

Alcohol induced changes in drug-metabolizing

enzymes: MOST common (chronic alcohol use)
ex. Acetaminophen and chronic use of alcohol
Alcohol may also inhibit metabolism of other drugs
(acute alcohol intake)

Mental retardation
FAS Mechanism

ex. Phenothiazines, TCAs, sedative hypnotics

Chronic alcohol: This enhances metabolic biotransformation
of other drugs. Ethanol-mediated induction of hepatic CYP
450 especially with regards acetaminophen.Chronic alcohol
use (3 or more drinks daily) increases risk of hepatotoxicity
due to toxic or high toxic levels of acetaminophen
converted to hepatotoxic active metabolites
Acute alcohol: may induce decreased enzyme activity or liver
blood flow



as of 1/11/12

Alcohol and Drug Interactions: Pdynamics

Additive CNS depression with sedative-hypnotics,
other depressants
Potentiation of effects of vasodilators and oral
Clinical Pharmacology
Acute Intoxication: Management
Goal: Prevention of severe respiratory depression
and aspiration
Average fatal blood levels (>400mg/dL)- maybe
variable due to differences in tolerance
Address hypoglycemia and ketosis: Glucose
Wernicke-Korsakoff syndrome: Thiamine
Vomiting and dehydration: Fluid and electrolyte
Alcohol Withdrawal Syndrome: management

withdrawal syndrome


Abrupt drop

Opioid withdrawal worst effect!

Oral in mild to moderate; parenteral for severe cases

Tapering of sedative- hypnotics takes place over
several weeks
*chlordiazepoxide, ,chlorazepate, diazepam-less frequent
pharmacologically active metabolites that are eliminated
slowly: Built-in tapering effect.
However, these agents and their metabolites tend to
accumulate esp in liver disease. Short acting agents (e.g.
lorazepam, oxazepam) are rapidly converted to inactive
metabolites that are water soluble and do not
accumulate. Hence, these are preferred for alcoholic
patients with liver disease.
Alcoholism: Treatment
Primary treatment after detoxification: intensive
psychosocial therapy
Treatment of associated disorders such
depression or anxiety with drugs and counseling

Goal: prevention of seizures, delirium, arrhythmias


lead to withdrawal



Prompt resoration of potassium, magnesium and

phosphate balance

People who continue to drink ROH despite medical or societal

consequences related to consumption suffer from alcoholism.
It is a complex disorder with genetic and environmental


Drugs for adjunctive treatment: NALTREXONE


Mild cases need no other pharmacologic assistance


Gradually taper the substances to protect the

patient from withdrawal syndrome (esp. opiods)

AWS: motor agitation, anxiety, insomnia, reduction of seizure

threshold, visual hallucinations, total disorientation, marked
abnormalities of vital signs
Severity is proportional to degree and duration of alcohol
Alcohol Detoxification:
Basic Principles
Substitution with long-acting sedative hypnotic then
gradual tapering of dose of the drug
(benzodiazepines esp. long-acting ones)* thru for
chronic alcoholics

moderate reduction in relapse state

opioid receptor antagonist (p.o.50 mg /day) at the

(link between alcohol consumption

long acting agent that reduces craving and rate



not given for alcoholics who are also dependent on



for alcoholics with hepatic enzyme

elevation; not given with disulfiram

Drugs for adjunctive treatment: ACAMPROSATE

Weak NMDA-receptor antagonist and GABA A
receptor activator*

Dosage interval should be far apart



as of 1/11/12

Reduces short-term and long term (>6 mos) relapse

rates when used with psychotherapy
Enteric coated tablets (poor absorption esp.with
Wide distribution, renal elimination*
GIT, rash
Also with GABA, glutamate, serotonergic,
noradrenergic, and dopaminergic effects
CI: renal impairment

Cause serious morbidity and prolong

hospital stay

Extreme discomfort in alcoholic usersflushing, headache, nausea and vomiting, sweating,

hypotension, confusion

Rapid and complete GIT absorption

12 hours for complete action but persistent

Slow elimination

Inhibits metabolism of drugs such as phenytoin,

warfarin, INH

Not very effective

Other Drugs
Ondansetron anti-emetic



as of 1/11/12

Drug of Abuse

Basic Neurobiology (Dependence vs Addiction)


Physical dependence

Addictive: euphoria, rewards, adaptive changes

(tolerance effects)

Withdrawal manifestations upon drug


Not very common (1 in 6)

o But it is quiet common

Psychological dependence

Compulsive, relapsing drug use even with bad


Triggers: cravings

Common in addicts after successful withdrawal

Drug abuse doesnt necessarily mean addiction

Example of drug abuse
o A person is using amphetamine (anaesthetic
drug) for its hallucinogenic effect
A drug abused is said to be addictive if the primary effect is
at the dopamine system
Not all drugs that are abused are addictive
o Ex. Amphetamines, LSDs, Mescaline, Psilocybin

They are hallucinogenic but their

addictive potential is very low

They are abused because of their

hallucinogenic effect

They affect the serotonin pathway

They are not addicting but they can

cause psychosis

These dopaminergic neurons in the midbrain region of the

central nervous system project an extensive network of connections
throughout the forebrain, including the neocortex. The midbrainforebrain dopaminergic circuits are thought to regulate a diverse set
of behaviors, from the control of movement to modulation of
cognition and desirebecause they relate to mood, attention,
reward, and addiction.
Defects in these pathways, including neurodegeneration,
are implicated in a variety of psychiatric and neurological diseases,
such as schizophrenia, attention-deficit/hyperactivity disorder, drug
addiction, and Parkinson disease.
Based on the importance of the midbrain dopaminergic neurons to
normal and pathological brain function, there is considerable interest
in the molecular mechanisms that regulate their development.
It has been elucidated that DOA increase dopamine in the
mesolimbic system (except Bzp). It is widely accepted that increased
dopamine levels in the nucleus accumbens are key in mediating the
rewarding effects or positive reinforcement of drugs of abuse.

Addiction and Dopamine Levels

Addiction results when an individual abusing the drug

develops compulsion or uncontrollable urge to keep on
using the drug at higher and higher doses
Such that they go into maladaptive behaviour just to
obtain the drug
This is coupled with permanent adaptive change in brain
All addictive drugs activate the mesolimbic dopamine
o Especially the Ventral Tegmental Area (VTA) in
the brain

Dopaminergic Pathway:
The mesolimbic dopamine sysytem consists of
dopaminergic neurons that originate in the VTA (ventral tegmental
area) and terminate in the nucleus accumbens.



as of 1/11/12


Dopamine mediates motivation and reward

If you are motivated to obtain a reward dopamine is
expected to increase
If the reward is obtained the dopamine level will stabilize
So you feel satisfied
If the dopamine system is deranged because of substance
o The dopamine level increases
o Eventually it becomes higher and higher to
satisfy because it takes lower and lower time for
dopamine to stop increasing
o Dopamine increases, and plateau is not reached,
thus, the feeling of satisfaction is not met
o Dopamine becomes hyperactive as well, it is then
easily triggered in addicts

Specific Molecular Targets: Three Classes of Drugs

Note the RR
o It represents the potential for addiction
o 5 highest, 1-lowest addictive drug
The vulnerability for addiction can be inherited
o the higher the RR of the drug, the more likely you
are to transmit this vulnerability to your children
LSDs, Mescaline, Psilocybin
o They have RR of 1
o Because they are anaesthetics that are usually
There potential is low because they affect the
serotonin system
Phencyclidine, Ketamine
o They are anaesthetic




They affect the serotonin more than

dopaminergic system
Main problem is psychosis and not addiction

Dependence: Tolerance and Withdrawal


Results as the brain adapts to repeated exposure to an

addictive agent such that the dose has to be increased
progressively in order to achieve a particular effect
Tolerance to Opiods

Reduction of concentration of a drug

Shorter duration of action in the target tissue

Changes in receptor function e.g. internalization

Yet undefined mechanisms (morphine)


With prolong exposure to substance there are some

receptors that collapse into the cytoplasm
They get covered into the cytoplasm, decreasing the
Clinical translation:
o It will take some time to elicit the same effect
But tolerance cant be explained in all substances
Route of drug is through IV hardcore addiction
o Fast onset of action


Drug withdrawal occurs because the body is physically

dependent on the effects of a drug. When the drug is
stopped, the body must adjust to the absence of the drug.
Nerves throughout the body become excessively
stimulated without the drug, which causes the symptoms
of drug withdrawal.

o MILD- anxiousness, abdominal pain, diarrhea,
insomnia, headache, nausea, vomiting, tremors
o SERIOUS- rapid pulse, fever, palpitations,
excessive sweating, difficulty in walking, rapid
breathing, hallucinations, confusion, seizures
Dependence: Mechanism (e.g. Opiods)

as of 1/11/12

Initial activation of the opioid receptor strongly inhibits

adenylyl cyclase but this inhibition becomes weaker with
repeated exposure
Weakening of inhibition of adenyl cyclase is a counter
adaptation of the enzyme with exposure to the drug
results to cAMP overproduction
Increased cAMP strongly activates transcription factor
CREB which leads to regulation of downstream genes
including the gene for endogenous opioid ligand
Withdrawal: nucleus accumbens releases high levels of
dynorphins with GABA into the VTA dopamine neurons.
These neurons have opioid receptors and as a result, they
are inhibited and dopamine release is reduced (hence
dysphoria during withdrawal)

Addiction Maladaptive Learning

High motivation to use a drug despite the negative


Recalcitrant, relapsing, chronic disease

HIGH RISK of relapse after successful withdrawal

Triggered by:
o Stress
o Drug re-exposure
o Condition/context that recalls prior drug use
Mechanism of Relapse

Drug + neutral stimulus (contextual cues) switch

triggers addiction-related behavior

Involves learning and memory system

DOA continue to raise dopamine even when reward is

already expected (in contrast to natural rewards):
overriding of the prediction error signal
Vulnerability to Addiction


Environment + genetics

Potential for addiction to certain drugs maybe strongly

inherited (e.g. cocaine)

The RR for addiction correlates with its hereditability

Nonaddictive Drug Abuse

Alter perception without sensation of reward and

euphoria (hallucinogens, dissociative anesthesia)

Target: cortical and thalamic areas*

LSD, Phencyclidine

May have long-term effects**


Basic Pharmacology: Drug of Abuse




Basic of Classification of DOAs:

Molecular Targets and Underlying Mechanism

1st- action on Gio protein-coupled receptors

2nd- interact with ionotropic receptors and ion channels

3rd-bind to monoamine transporters

*nonaddictive drugs are also classified the same way


Drugs that activate Gio-coupled receptors

(Pharmacology and Clinical Aspects/Treatment)


Agonists at

When activated, these receptors have distinct

and sometimes opposing effects*

Commonly abused opioids are morphine, heroin,

codeine, oxycodone
o Heroin street drug, administered
through IV

Meperidine - among health professionals

o Strong u agonist
o Euphoriant
o Relaxation
o Only opiod that can cause tachycardia

Strong tolerance and dependence

Opioids Withdrawal


Nausea and vomiting

Muscle aches




Piloerection goosebumps





Naloxone- life saving, may precipitate acute

o Rapidly saving opioid antagonist
o It can also precipitate severe
withdrawal syndrome in patients that
are not in opioid but with previous

Methadone- treatment of opioid addiction

o Synthetic opioid
o Strong acting
o Longer plasma half life
o Plasma decrease in gradual, so the
withdrawal symptoms are much

as of 1/11/12



e.g. marijuana: THC (strong psychoactive drug)

Disinhibition of dopamine neurons by

presynaptic inhibition of GABA neurons in the

Half-life- 4 hours


Maximum effect-2 hours

Cannabinoid THC Effects

Euphoria, relaxation, visual hallucinations,

depersonalization, psychotic episodes, increased
appetite, attenuation of nausea, decreased IOP,
relief of chronic pain
o Can also affect the serotonin system

Chronic use-dependence and withdrawal



Hallucinogens, Psychotomimetics
Somatic symptoms, Flashbacks (hallucination)
Not usually addictive but repetitive exposure
may lead to tolerance (tachyphylaxis)
Non-rewarding: does not stimulate dopamine
release, increase cortical glutamate release

LSD, Mescaline, Psilocybin: Target

5-HT2A receptors which couple to G proteins

increase release of intracellular calcium

Drugs that mediate their effects via ionotropic receptors

Cannabinoid Withdrawal

Usually mild and short

Restlessness, irritability, mild agitation,

insomnia, nausea, cramping
THC Analogs

They are drugs that address relapse

But they are not 100% effective

o Synthetic THC analog cannabinoid
o the only FDA approved one surrently
marketed in the USA



Synthetic GHB first used as GA*

Euphoria, enhanced sensory perception, feelings

of social closeness, amnesia, sedation, coma

club drug, liquid ecstasy

Used in date rapes (odorless, readily soluble)

Rapid absorption

Max plasma levels-20 to 30 minutes

Elimination half-life-30 minutes

GHB: Target

GABA neurons more sensitive to GHB than

dopamine neurons so at recreational uses only



GABA neurons are inhibited basis for

Higher doses eventually hyperpolarizes
dopamine neurons to inhibit dopamine release
(anti-craving effect)


Drugs of abuse are usually receptor agonists,

such as endogenous neurotransmitters, that act
on two different types of membrane receptors:
ionotropic (shown in this figure) and
metabotropic (shown in Fig. 2). Ionotropic
receptors (ligand-gated ion channels) mediate
fast synaptic transmission.
The neurotransmitter or the drug binds to the
receptor, which undergoes a conformational
change, opening the gate and allowing ions to
enter the cytoplasm and causing depolarization
or polarization of the membrane and activation
of various proteins.
Nicotine binds to nicotinic cholinergic receptors,
Benzodiazepines, barbiturates, and ethanol bind
to g -aminobutyric acid (GABA) type A receptors,
facilitating the entry of
Ethanol and phencyclidine inhibit N-methyl-d aspartatesensitive glutamate receptors, which
contain calcium and sodium channels.
Phencyclidine also acts as an antagonist.
Exceeds all other forms of addiction
Smoking, chewing, snuff

LSD, Mescaline, Psilocybin



as of 1/11/12

Selective agonist of the nicotine acetylcholine

receptor (nAChR)* which is normally activated
by acetylcholine
o Tachycardia, hypertension
Rewarding effect: increase in dopamine release
in VTA (nAChR are present on dopamine

Nicotine Withdrawal

Milder than in opioids

Irritability, sleeplessness

Relapse is very common

o More addictive than alcohol and

K and PCP: Effects

unpleasant dreams and hallucinations upon

recovery from surgery

Psychedelic effects lasts for 1 hour

Increased BP, impaired memory, visual


Higher doses: unpleasant out-of-body

experience, near-death experiences


Long-lasting psychosis (esp. PCP) with chronic



Substitute smoking with nicotine gum (longer

acting at lower doses of nicotine), inhalational
nicotine, or nicotine patches


Behavior therapy

Not successful


Commonly used as anxiolytic and sleep agent
Moderate risk of addiction (euphoric effects)
RR 3
Usually abused with other drugs (increase RR)
Barbiturates were the most commonly abused
prescribed sedative before the benzodiazepines
but they are now rarely prescribed and therefore
is less of a problem today in terms of prescribed
abused drugs. Street versions however continue.
Withdrawal and addiction is similar to the BZs.

Benzodiazepine: Mechanism

Positive modulators of GABAA receptors

(pentameres with subunits)

Disinhibition of mesolimbic dopamine system:

rewarding effect

Receptors with 5-mediates tolerance to Bzs

club drug, angel dust etc.

Use-dependent noncompetitive antagonism of
the NMDA channel effect
White crystalline powder (pure), liquids,
capsules, pills
Snorted, ingested, injected, smoked
o Injected hardcore addiction

Abuse: recreational exposure to chemical
vapors*which are present in many common
household and industrial products
Hydrocarbons sweet smelling
sniffing, huffing, bagging
Inhalant abuse common in children and young

Inhalants: Mechanism

Largely unknown

Altered function of ionotropic receptors and ion

channels demonstrated in some
o e.g. nitrous oxide NMDA receptors


o fuel additives GABAA receptors

Most produce euphoria e.g. toluene increases
VTA excitability addiction risk
Management of overdose: supportive

Drugs that bind to transporters of biogenic amines

Benzodiazepine: Withdrawal

Occurs within days of discontinuation

Varies as a function of the elimination half-life

Irritability, insomnia, phono- and photophobia,

depression, muscle cramps, seizures

Gradually subside in 1-2 weeks



Ketamine and Phencyclidine (PCP)

Were used as general anesthetics
o hallucinogenics



as of 1/11/12


Alkaloid from Erythroxylon coca
Initially used as local anesthetic and mydriatic
Highly addictive at RR=5
Water soluble, can be absorbed through mucosal
surfaces (nasal snorting) or injected
heated in alkaline solution smoked (crack cocaine)
swift distribution to brain rush

Cocaine Mechanism

NT - from cytosol back into the synapse

Increased dopamine levels in the nucleus accumbens

of the mesolimbic area: rewarding effect
Cocaine: Effects

Activation of sympathetics (blocks NET) increase in

autonomic signals: BP, tachycardia, ventricular
o Note that this drugs effect on DAT is the
same with NET
o Thus, if you are using cocaine, dopamine
and NE released in the synapse are both

Loss of appetite and, hyperactivity

Increased risk of intracranial hemorrhage, ischemic

stroke, MI, seizures

Hyperthermia, coma, death

Cocaine Addiction and Dependence

Develops after only a few exposures in susceptible


Withdrawal is not as strong as in opioids

Tolerance, reverse tolerance*

o *Sensitization to small doses

Very strong cravings

No specific antagonists

Supportive management of intoxication



Synthetic, indirect-acting sympathomimetics
Substrates of DAT and competes with dopamine



As a consequence, dopamine levels or other

neurotransmitter amines in the cytoplasm increase
which causes a reversal of DAT directionincreased
nonvesicular release of DA, increase in extracellular
DA concentrations( and other biogenic amine

Note that this drug affect DAT, NET and SERT

o Thus they are more hallucinogenic
Amphetamine Use

IV use and hard core addiction is more common than

with ecstasy, club drugs

Pills, smokes, injectables

Amphetamine Effects

Elevates catecholamine levels increases arousal

and reduces sleep

Elevates dopamine euphoria, abnormal

movements, psychotic episodes

Effects on serotonin hallucinations, anorexia,


NEUROTOXIC* - more, bec of serotonin

Affects Serotonin and Dopamine Neurons

Increased alertness, euphoria, agitation, confusion

Tooth grinding, skin flushing

Tachycardia, dysrhythmias

Hypertensive crisis, vasoconstriction, strokes

HIV and hepatitis infection (needle sharing)

Tolerance with chronic use

Amphetamine Withdrawal





Ecstasy (MDMA)
Derivatives of methylmedioxymethamphetamine
Same mechanism as amphetamines
Designer drug

Ecstasy: Effects

Fosters feelings of intimacy and empathy

Has preferential affinity for SERT (serotonin

transporter ) increases extracellular serotonin*


as of 1/11/12

Serotonin syndrome**
o All serotonin gets thrown in the synapse,
nothing is left on the cell
*Profound effect leading to depletion of intracellular
serotonin for 24 h after a single dose and repeated
exposure may lead to permanent serotonin depletion:
Neurotoxic- long term cognitive impairment
**autonomic hyperactivity, mental status changes,
neuromuscular abnormalities
Severe acute toxic effects (hyperthermia,

Ecstasy Withdrawal

Depression for several weeks

Increased aggression




as of 1/11/12