Abuse and Alcohol

1 Jcelimpin ♥ Jmmission as of 1/11/12

The Alcohols

J. ONA CRUZ, MD, MHPED, FPOGS

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)

Rapid distribution- tissue levels approx. blood concentration (gender difference)

- Alcohol is more readily distributed among females due to small body proportion

- The smaller you are the more readily alcohol can be absorbed

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

Zero order kinetics (150-220 mmHg/hour)

- This causes accumulation of alcohol in our body

Ethanol: Metabolic Pathways

- Alcohol DH is the one the oxidizes ethanol into acetaldehyde normally

- But with higher amounts of alcohol, the normal pathway is overwhelmed so the liver will activate the hepato-oxidizing system

- In chronic alcoholism, the CYP450 takes its action which produces several effects

- 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 that’s why it has to be broken down further and is also responsible for adverse reaction

Alcohol Dehydrogenase Pathway

The primary metabolic pathway

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)


- In men, ADH has more activity because they have more concentration in their stomach that’s 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

- Due to gender and genetic make up

NADH metabolic abnormalities in chronic alcoholism-

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)

Activated when alcohol levels are high (ADH system saturation >100mg/dl)

Involves CYP P450s

Activated in chronic alcoholism*

faster metabolism of other drugs

generation of more toxic metabolites

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 *è acetaldehyde elevation (untoward reactions):

protective against alcoholism?

greater risk of liver disease

- 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

Accumulation of acetaldehyde flushi, has disulfiram reactionng, nausea, vomiting, dizziness, headache

Other drugs with disulfiram effect when taken with alcohol: metronidazole, cefotetan, trimethoprim

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


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

Anxiolytic

Slurred speech

Ataxia

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)

- Asian has lower threshold for respiratory depression

- Chronic alcoholics can develop tolerance. But at some point tolerance STOP and the individual may

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

Glutamate and the NMDA receptor

GABA – mostly affected arising to depressant effect

- Has the dominant effect

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 – that’s why it is not possible to see alcoholics who has a congestive heart failure

Pharmacodynamics: Smooth Muscles

Vasodilators (central and direct effects):

Hypothermia esp. in cold environments (severe overdoses)


- Commonly mistaken by layman’s that taking alcohol may increase temperature but in fact it does not

Uterine relaxant – not use for practical value

Chronic Alcohol Consumption: Effects and Consequences

Mechanism of Tissue Damage

Direct effects of ethanol + Active metabolites

increased oxidative stress – producing free radicals

decreased glutathione – decrease antioxidant

mitochondrial damage- begin from cell to cell

growth factor dysregulation

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

Risk of severe disease greater with preexisting hepatitis B or C

PATHOGENESIS OF ALCOHOLIC LIVER DISEASE-

MULTIFACTORIAL:

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 - α

*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

- mucosa lining are destroyed and become corrosive leading to malnutrition and eventually malabsorption of folic acid

Liver and GIT

Chronic pancreatitis

Gastritis

Anemia

Protein malnutrition

Small intestinal injury*

*diarrhea, weight loss, vitamin deficiencies (malabsorption)

- 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

Nervous System

- neurotoxic

Tolerance (there is a limit to this!)


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

Nervous System

Neurotoxicity

generalized symmetric peripheral nerve injury (distal paresthesias of hands and feet)

gait disturbances and ataxia – motor and gait

abnormality

dementia

demyelinating disease

impairment of visual acuity and optic nerve degeneration

Wernicke-Korsakoff syndrome – thiamine deficiency

Cardiovascular System

Cardiomyopathy and heart failure

Arrhythmias

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

- Alcohol is toxic to testis

- Induces testicular atrophy testosterone production decreases

- Unopposed action of estrogen

Fluid and electrolyte imbalances (ascites, edema, effusions)

Potassium depletion

Hypoglycemia

Ketosis – due to damage kidney


Fetal Alcohol Syndrome

FAS

- 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

IUGR

Microcephaly

Poor coordination

Underdeveloped midfacial area (flat face)

Minor joint anomalies

Congenital heart anomalies

Mental retardation

FAS Mechanism

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

Mouth, pharynx, larnyx, esophagus, liver, breast

Threshold of consumption for carcinogenic effects?

Metabolites e.g. acetaldehyde

Changes in folate metabolism

Effects of chronic inflammation

Alcohol and Drug Interactions: P’kinetic

- Alcohol (+) CYP450 enhance the clinical effect

- Always additive and synergistic effect with other drugs sedative hypnotics

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)

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


Alcohol and Drug Interactions: P’dynamics

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

Goal: prevention of seizures, delirium, arrhythmias

- Seizure: common manifestation of withdrawal syndrome

Prompt resoration of potassium, magnesium and phosphate balance

Thiamine

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

- Dosage interval should be far apart

- Abrupt drop lead to withdrawal 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 dosaging- these 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 as depression or anxiety with drugs and counseling

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

Drugs for adjunctive treatment: NALTREXONE

- moderate reduction in relapse state

opioid receptor antagonist (p.o.50 mg /day) at the μ(link between alcohol consumption and opioids)

long acting agent that reduces craving and rate of relapse

caution for alcoholics with hepatic enzyme elevation; not given with disulfiram (hepatotoxic)

not given for alcoholics who are also dependent on opioids

Drugs for adjunctive treatment: ACAMPROSATE

Weak NMDA-receptor antagonist and GABA A receptor activator*


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 users-

flushing, 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


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 doesn’t 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

Addiction and Dopamine Levels

Dopaminergic Pathway:

The mesolimbic dopamine sysytem consists of

dopaminergic neurons that originate in the VTA (ventral tegmental

area) and terminate in the nucleus accumbens.

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 midbrain-

forebrain dopaminergic circuits are thought to regulate a diverse set

of behaviors, from the control of movement to modulation of

cognition and desire—because 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 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


- 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

o They affect the serotonin more than

dopaminergic system

o Main problem is psychosis and not addiction

B. 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 μreceptor 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 can’t 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)


Initial activation of the υ 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 κ opioid ligand

dynorphin.

Withdrawal: nucleus accumbens releases high levels of

dynorphins with GABA into the VTA dopamine neurons.

These neurons have κ 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

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 μκδ

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


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

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

GABA neurons are inhibited basis for

addiction

Higher doses eventually hyperpolarizes

dopamine neurons to inhibit dopamine release

(anti-craving effect)

d. LSD, Mescaline, Psilocybin

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

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 -

aspartate–sensitive glutamate receptors, which

contain calcium and sodium channels.

Phencyclidine also acts as an antagonist.

a. Nicotine

Exceeds all other forms of addiction

Smoking, chewing, snuff


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

Treatment

Substitute smoking with nicotine gum (longer

acting at lower doses of nicotine), inhalational

nicotine, or nicotine patches

Bupropion

Behavior therapy

Not successful

b. 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 αβγsubunits)

Disinhibition of mesolimbic dopamine system:

rewarding effect

Receptors with α5-mediates tolerance to Bzs

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. Ketamine and Phencyclidine (PCP)

Were used as general anesthetics

o hallucinogenics

“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

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

d. 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

o fuel additives GABAA receptors

Most produce euphoria e.g. toluene increases

VTA excitability addiction risk

Management of overdose: supportive

3. Drugs that bind to transporters of biogenic amines


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 drug’s 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. Amphetamines

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

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


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

Documents

Abuse and Alcohol