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The Alcohols

J. ONA CRUZ, MD, MHPED, FPOGS

Ethanol: Metabolic Pathways

The Alcohols (Ethanol, Methanol, Ethylene Glycol)


-

Very common abused substance

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

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


body

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)

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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
ADH

In some Asian populations, there are those with ADH


that have reduced activityincreased risk of
alcoholism
-

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
alcoholism-

abnormalities

in

chronic

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
acid.
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
alcohol

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

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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

Sedative

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
seen

Ethanol and Neurotransmission

Anxiolytic

Glutamate and the NMDA receptor

Slurred speech

GABA mostly affected arising to depressant effect

Ataxia

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


women

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

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Hypothermia esp. in cold environments (severe


overdoses)

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
Gastritis

increased oxidative stress producing free radicals

Anemia

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
INCREASED RISK OF DEATH
liver disease
cancer
accidents
suicides
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


cirrhosis

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
PATHOGENESIS OF ALCOHOLIC LIVER DISEASEMULTIFACTORIAL:
1.

Metabolic effects of ethanol oxidation in the liver

2.

Dysregulation of fatty acid oxidation and synthesis

3.

Activation of innate immune system


e.g. TNF -

Nervous System
-

neurotoxic

Tolerance (there is a limit to this!)

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Physical dependence Alcoholic Withdrawal


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

Urge or compulsion to take substances

Recalcitrant disease keep on coming back

Molecular basis of tolerance and dependence


LARGELY UNCLEAR
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,
dopamine)
-

Nowadays! They try to develop drug to address


addiction but no successful drug was produced

Hypertension
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
channels
#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
smoking
#4 cardioprotective effects of moderate drinking is still
unestablished-based on ROH ability to raise HDL
Blood
Mild anemia (folic acid deficiency)
IDA from gastrointestinal bleeding
Hemolytic syndrome
-

G6PD and thalassemia bad reaction to


alcohol

Endocrine System and Electrolyte Balance


Gynecomastia, testicular atrophy

Nervous System
Neurotoxicity
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

abnormality

Fluid and electrolyte imbalances (ascites, edema,


effusions)

dementia

Potassium depletion

demyelinating disease

Hypoglycemia

impairment of visual acuity and optic nerve


degeneration

Ketosis due to damage kidney

Wernicke-Korsakoff syndrome thiamine deficiency


Cardiovascular System
Cardiomyopathy and heart failure
Arrhythmias

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Fetal Alcohol Syndrome

Immune System
-

Immunodepressant chronic alcoholics prone to


pneumonia

Immune function in some areas (lung) are inhibited


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

Carcinogenic because of toxic metabolites prone


to asian due to acetaldehyde concentration
especially female

FAS
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

IUGR
Microcephaly

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

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Alcohol and Drug Interactions: Pdynamics


Additive CNS depression with sedative-hypnotics,
other depressants
Potentiation of effects of vasodilators and oral
hypoglycemics
Clinical Pharmacology
ETHANOL
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
replacement
Alcohol Withdrawal Syndrome: management

Seizure:
common
withdrawal syndrome

manifestation

Abrupt drop
syndrome

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
dosagingthese
long
acting
agents
have
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

of

as

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
determinants

Thiamine

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
abuse
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
and
opioids)

long acting agent that reduces craving and rate


relapse

caution

not given for alcoholics who are also dependent on


opioids

of

for alcoholics with hepatic enzyme


elevation; not given with disulfiram
(hepatotoxic)

Drugs for adjunctive treatment: ACAMPROSATE


Weak NMDA-receptor antagonist and GABA A
receptor activator*

Dosage interval should be far apart

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


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

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
Topiramate
Ondansetron anti-emetic

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Drug of Abuse
J. Ona Cruz, MD, MHPED, FPOGS
A.

Basic Neurobiology (Dependence vs Addiction)


Dependence

Physical dependence

Addictive: euphoria, rewards, adaptive changes


(tolerance effects)

Withdrawal manifestations upon drug


discontinuation

Not very common (1 in 6)


o But it is quiet common
Addiction

Psychological dependence

Compulsive, relapsing drug use even with bad


consequences

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
function
All addictive drugs activate the mesolimbic dopamine
system
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.

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o
o
B.

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
abuse
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
abused
o
There potential is low because they affect the
serotonin system
Phencyclidine, Ketamine
o They are anaesthetic

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They affect the serotonin more than


dopaminergic system
Main problem is psychosis and not addiction

Dependence: Tolerance and Withdrawal

Tolerance

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
receptor
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

Withdrawal

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.

Symptoms:
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
dynorphin.
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


consequences

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

LARGE INDIVIDUAL DIFFERENCES

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**


C.

Basic Pharmacology: Drug of Abuse

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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


1.

Drugs that activate Gio-coupled receptors


(Pharmacology and Clinical Aspects/Treatment)
a.

Opioids

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

Dysphoria

Nausea and vomiting

Muscle aches

Lacrimation

Rhinorrhea

Mydriasis

Piloerection goosebumps

Sweating

Diarrhea

Yawning

Fever
Treatment

Naloxone- life saving, may precipitate acute


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

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
tolerable

as of 1/11/12

b.

Cannabinoids

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

Disinhibition of dopamine neurons by


presynaptic inhibition of GABA neurons in the
VTA

Half-life- 4 hours

Onset-minutes

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


symptoms

RR=2

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
2.

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


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

c.

GHB

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

d.

12

GABA neurons are inhibited basis for


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

a.

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,
which
contain
a
sodium
channel.
Benzodiazepines, barbiturates, and ethanol bind
to g -aminobutyric acid (GABA) type A receptors,
facilitating the entry of
chloride.
Ethanol and phencyclidine inhibit N-methyl-d aspartatesensitive glutamate receptors, which
contain calcium and sodium channels.
Phencyclidine also acts as an antagonist.
Nicotine
Exceeds all other forms of addiction
Smoking, chewing, snuff

LSD, Mescaline, Psilocybin

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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
neurons)

Nicotine Withdrawal

Milder than in opioids

Irritability, sleeplessness

Relapse is very common

RR=4
o More addictive than alcohol and
marijuana

K and PCP: Effects

unpleasant dreams and hallucinations upon


recovery from surgery

Psychedelic effects lasts for 1 hour

Increased BP, impaired memory, visual


alterations

Higher doses: unpleasant out-of-body


experience, near-death experiences

RR=1

Long-lasting psychosis (esp. PCP) with chronic


exposure

Treatment

Substitute smoking with nicotine gum (longer


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

Bupropion

Behavior therapy

Not successful
b.

d.

Benzodiazepine
Commonly used as anxiolytic and sleep agent
Moderate risk of addiction (euphoric effects)
RR 3
Usually abused with other drugs (increase RR)
Note:
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

Inhalants
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
adults

Inhalants: Mechanism

Largely unknown

Altered function of ionotropic receptors and ion


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

3.

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


c.

13

Ketamine and Phencyclidine (PCP)


Were used as general anesthetics
o hallucinogenics

Jcelimpin

Jmmission

as of 1/11/12

a.

Cocaine
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
arrhythmias
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
increased

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


individuals

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


b.

14

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

Jcelimpin

Jmmission

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
neurotransmitters)

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,


hyperthermia?

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

Dysphoria

Drowsiness

Insomnia

Irritability
c.

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

Ecstasy: Effects

Fosters feelings of intimacy and empathy

Has preferential affinity for SERT (serotonin


transporter ) increases extracellular serotonin*

NEUROTOXIC - most

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,
dehydration)
Seizures

Ecstasy Withdrawal

Depression for several weeks

Increased aggression

15

Jcelimpin

Jmmission

as of 1/11/12