Pharmacological Targets for the Action of Drugs of Dependence

Question 1

physical dependence

Answer 1

which occurs when pharmacological adaptation

leads to tolerance – thus more drug is needed to reach the same effect.

Question 2

Withdrawal symptoms definition

Answer 2

If the drug is stopped, withdrawal symptoms may emerge; if there are
withdrawal symptoms, there is physical dependence.

Question 3

psychological dependence

Answer 3

psychological dependence may lead to emotional- motivational withdrawal symptoms – many daily drug users show both dependences.

Question 4

Addiction

Answer 4

addiction, which occurs in a small minority of people who initiate drug use – addiction leads to compulsive and out-of-control drug use as a component of physical dependence.

Question 5

Some drugs may produce changes in the CNS which lead to abnormal states. Name the three:

Answer 5

• Physical dependence –> leads to withdrawal
• psychological dependence
• addiction

Question 6

variables that influence the probability and likelihood that a beginning user will develop physical/psychological dependences and/or an addiction.

Answer 6

• agent (drug)
• host (user)
• environment in which use occurs

Question 7

Reinforcement

Answer 7

Reinforcement is the ability of drugs to produce effects in the user which make reuse more likely and desirable.

The more reinforcing the drug is, the more likely the user will seek to re-use, possibly leading to abuse.

Reinforcement is due to effects within the CNS.

Question 8

Natural brain reward systems

Answer 8

These natural systems reward actions as basic as the intake of nutrients and procreation, leading to the propagation of the species.

Activation of brain “reward systems” produces slight mood elevation to intense pleasure and euphoria, and these psychological states normally help to direct behaviour toward “natural” rewards

Question 9

Physical reward pathways

Answer 9

• the ventral tegmental area (VTA), the nucleus accumbens, and the frontal cortex.
• Collateral communication also occurs to the amydala and hippocampus such that affective and memory systems are impacted, and 5-HT, glutamate, NA, GABA and endogenous opioids may play roles as well.

Question 10

abused substances share one physiological effect:

Answer 10

an increase DA release in the nucleus accumbens.

Drugs which block DA receptors in this region
can generally produce bad feelings – dysphoria.

Question 11

The dopamine D2 receptor in the nucleus accumbens

Answer 11

Transgenic mice without D2 receptors do not demonstrate reward properties of morphine administration;

Interestingly, these animals still went through physical withdrawal syndrome…

This suggests that the D2 receptors are involved in the reward dimension of addiction, but not the withdrawal aspects.

Question 12

What affects drug (agent) likelihood for abuse?

Answer 12

Availability
Cost
Purity and Potency
Mode of administration

Rapidity of onset: when coca leaves are chewed, cocaine is absorbed slowly, and this results in low cocaine levels within the blood and CNS. Crack cocaine is alkaloid cocaine which can be readily vaporised by heating, which when inhaled, produce blood levels comparable to iv administration of drug.

Inhalation of crack cocaine is much more addictive than chewing, drinking or sniffing cocaine.

Question 13

What about variables about the host (user)?

Answer 13

Effects of all drugs vary from person to person.

• Genetic differences (absorption, metabolism and excretion)
• Tolerance
• Heredity: Innate tolerance, speed of developing tolerance
• Metabolism of the drug
• Psychiatric symptoms
• Prior experiences/expectations
• Propensity for risk-taking behaviour

Genetic differences affect aspects of absorption, metabolism, and excretion, as well as the receptors expressed (subunits) may combine to determine the overall degree of reinforcement or euphoria experienced.

Tolerance to some drug effects develops much more rapidly than to other effects of the same drug, e.g. tolerance to opioid euphoria occurs quickly, so more drug is taken for the “high”. Tolerance to constipation effects, however, is much slower, as is that of decreased respiration, meaning that fatal overdose is possible.

Tolerance is the most common response to repetitive use of the same drug, defined as the reduced response to a drug with repeated use. As the dose of the drug increases, the curve shifts to the right, with less effect.

Question 14

environment in which use occurs…?

Answer 14

• Social setting
• Conditioned stimuli : environmental cues become associated with drugs after repeated use in the same environment
• Community attitudes
  • Peer influence, role models

Associating drug use with a certain place or group of people, sounds and smells can initiate the euphoria of expectation, and such conditioning responses need to be minimised should an addict seek to stop the habit.

Environmental changes are key for rehabilitation success.

Question 15

“Narcotics”

Answer 15

“Narcotics” refers to the pain-relieving and sleep-inducing properties of these addictive alkaloids, including morphine and codeine.

Question 16

MOA of heroin/morphine

Answer 16

Heroin/morphine modifies the action of DA in the nucleus accumbens and the VTA. The binding of morphine to the μ opioid receptors inhibits the release of GABA from the nerve terminal, reducing the inhibitory effect of GABA on DA neurones.

The increased activation of DA neurones and the release of DA into the synaptic gap results in sustained activation of the post-synaptic membrane.

Effects wear off after 3-5 hours

Question 17

Opioid dependence

Answer 17

• Tolerance occurs involving a decrease in adenylyl cyclase activity, with a progressive uncoupling of receptor with second messenger systems as well (desensitization).
• Tolerance to the euphoric effects occurs before tolerance to respiratory depression.
• Purity ranges from 25%- 90% pure. Users can never be sure which concentration they are receiving, and overdose can occur very easily.

Question 18

How heroin affects the brain and body

Answer 18

1. Heroin enters the bloodstream through a vein, muscle or nose. It reaches the brain in 10 seconds
2. In the brain, heroin is converted into morphine, which binds to opiate receptors in the limbic system, brain stem and spinal cord.
3. In the limbic system of the brain, morphine causes the release of dopamine which produces feelings of intense pleasure.
4. As morphine diffuses through the brain, users feel a comfortable high that lasts 4-5hrs.
5. In the brainstem, morphine slows down breathing and heart rate - sometimes to the point of death
6. In the spinal cord, it blocks transmission of pain messages from body to brain.
7. Over time, neurons in the brain adapt to the presence of morphine - when the drug is stopped, users experience withdrawal symptoms (nausea, diarrhoea, vomiting, cramping, severe shaking)

Question 19

Cocaine

Answer 19

• Cocaine can be snorted in power form and absorbed across the nasal mucosa (septum issues and runny nose); or dissolved in water and injected into the bloodstream.
• Crack cocaine is processed to crystalline form, and this can be smoked. Heating it produces vapours which are breathed in, and absorption occurs through the lung mucosa.

Question 20

Cocaine MOA

Answer 20

• Cocaine binds and blocks DA re-uptake transporters (DAT) on the pre- synaptic membranes of DA neurones, inhibiting the clearance of DA from the synaptic cleft and its degradation by MAO in the nerve terminal.
• DA remains in the synaptic cleft and is free to bind to its receptors on the post-synaptic membrane, producing feelings of euphoria and the ‘high’ associated with cocaine use in the nucleus accumbens.

Question 21

Heroin/morphine + cocaine = speed-ball

Answer 21

Because heroin and cocaine work via different mechanisms on DA neurons of the reward pathway, they can be combined to produce even more intense dopamine activation. The IV combination of heroin/morphine and cocaine is known by users as a “speed-ball” and is extremely dangerous. Users show very rapid psychological and physiological deterioration, and there is a very high fatality rate.

Cocaine (20 mg/kg, i.p.) elevates DA in nucleus accumbens by ~ 380% above baseline in mice, while heroin elevates DA by ~ 70%.

Coadministration of these two drugs, however, produces a synergistic DA elevation of 1000%.

Question 22

Amphetamine and methamphetamine

Answer 22

Amphetamine use results in a variety of effects, including euphoria, insomnia, psychomotor stimulation, anxiety, loss of appetite, decreased fatigue, increased concentration, respiratory stimulation.

It also produces sympathomimetic effects: mydriasis, tachycardia, and hypertension.

The euphoria is largely due to DA effects, whereas the jittery and anxious feelings are largely due to the NA effects.

Medical uses may include for ADHD, narcolepsy, and obesity.

Crystal meth (ice) is preferred by abusers as it has fewer NA effects.

Question 23

methamphetamine: short term effects

Answer 23

Short term effects: increased energy, attention, alertness, talkativeness, decreased appetite, increased heart rate, breathing and body temperature, nausea, vomiting, anxiety and paranoia - “psychosis”. High doses may lead to aggressiveness and violent behaviour.

Question 24

methamphetamine: long term effects

Answer 24

Long term effects: agitation or aggression, depression and anxiety, poor concentration and memory, weight loss, chest pains.

Heavy users may also experience blurred vision, tremors, irregular breathing, loss of coordination or collapse.

Question 25

Nicotine

Answer 25

• Nicotine provides the reinforcement for cigarette smoking, which has been identified as the number one cause of preventable death and disease in Australia (total costs $31.5B)
• This makes nicotine, perhaps, the most dangerous dependence- producing drug in current society.
• In low doses, nicotine has stimulatory effects, while in high doses, it is reported by users to be “relaxing”.
• Cardiovascular vessels are seen to constrict initially, followed by dilation, with decrease in bp.
• Antidiuretic actions as well as a decrease in GI motility.
• Steady use of nicotine leads to tolerance of nausea and anxiety initially experienced with use.

Question 26

Nicotine activates nAChRs

Answer 26

• Systemically, nicotine temporarily stimulates all sympathetic and parasympathetic ganglia, skeletal muscle and CNS followed by depression.
• These receptors are located pre- and post-synaptically, and activation leads to enhanced NT release and increased excitation.
• Nicotine also causes receptor desensitization, with reduced effects resulting from the same dose.
• Long-term use, interestingly, up- regulation of nicotine receptor numbers occurs as well.
• Increased DA in nucleus accumbens results.

Question 27

Pharmacokinetics of ethanol

Answer 27

• rapidly absorbed in GI tract

• first-pass metabolism in most cases, although
saturation of enzymes occurs quickly

• can lead to quick distribution of ethanol into blood stream if taken on an empty stomach.

Ethanol can also undergo oxidation by cytochrome P450 enzymes, with CYP2E1 being the key, which is induced by long- term alcohol use, contributing to tolerance

Question 28

Metabolism of methanol

Answer 28

Methylated spirit is ethanol purposefully contaminated with methanol to prevent (or at least discourage) consumption. Methanol, or methyl alcohol, is highly toxic. Mouth “pipetting” fuel or organic solvent? Methanol is converted to formate, which may damage the optic nerve, resulting in visual impairment or blindness.

Treatment for methanol poisoning? Give ethanol! This will saturate the alcohol dehydrogenase enzyme and slow the formation of formate. Ethanol has a greater affinity for the enzyme than methanol does.

Alternatively, inject patient with fomepizole, which inhibits alcohol dehydrogenase – combined with haemodialysis to remove methanol.

Question 29

Ethanol effects on the CNS

Answer 29

In total – general depressant.

Ethanol: -enhances GABAA- mediated inhibition by positive allosteric interaction

• inhibition of function of NMDA glutamate receptors thus also depressant
• inhibition of opening of voltage- dependent Ca2+ channels reducing excitation
• associated with disinhibition of the reward pathways of the brain, with an increase in DA in nucleus accumbens, euphoria and reduction of behavioural inhibitions.
• inhibits the release of antidiuretic hormone (ADH) from pituitary gland, therefore diuretic.
• wide variety of individual host (user) affects based on genetics and exposure.

Question 30

Cross tolerance of alcohol and other sedatives

Answer 30

Chronic ethanol use produces tolerance to alcohol and cross tolerance to Benzodiazepines and other sedatives, requiring the user to take much higher doses for effect.

Benzodiazepines are relatively safe in overdose, however are potentially lethal when combined with alcohol.

Chronic use of alcohol and other sedatives have been associated with depression and risk of suicide.

Question 31

Cannabis

Answer 31

Can be inhaled in cigarette smoke or taken orally. Smoking delivers 50% of THC to CNS within seconds, while oral route achieves 25-30%, due to metabolism in liver. Onset is delayed (0.5–2 hr), but duration is prolonged due to slow absorption from GI tract.
• Being very lipophillic, it can be stored in body fat, and excretion can take days; with detection in urine.

Question 32

Distribution of THC in the body

Answer 32

Once absorbed, distribution is dependent upon blood flow.

Being lipophillic, DTHC accumulates in fatty tissues, reaching peak concentrations in 4-5 days. They are then slowly released back into other body compartments, including the brain.

It can take up to 30 days to clear a single dose. Thus, repeated doses can cause significant accumulation.

Question 33

Pharmacological effects:

Answer 33

CNS: psychomimetic and depressant

• Relaxation, peace, euphoria
• Uncontrolled laughing
• Greater intensity of senses (taste, sound, sight)
• Impairment of memory
• Increased appetite
• Analgesia, antiemetic actions
• Slight bronchodilation, but more tar than tobacco
• High doses cause anxiety, paranoia, hallucinations

Question 34

Mechanism of action for cannabis: cannabinoid receptors (GPCRs)

Answer 34

CB1 receptors: abundant in hippocampus (memory), cerebellum (loss of motor coordination), hypothalamus (appetite stimulation), mesolimbic DA pathway. Positioned pre-synaptically, activation inhibits NT release. Very few receptors in brain stem, thus lack of cardiovascular and respiratory inhibition for most.

CB2 receptors: exist in immune tissues and may mediate cytokine release and modulate pain.

Question 35

Cannabis Tolerance and Drug Dependence

Answer 35

• Relatively minor, even in heavy users
• Withdrawal syndrome is also generally weak, with restlessness, confusion, sweating, tremor, sleep disturbances, and mild irritability.
• Long term effects with chronic use: decreased testosterone and sperm count, impaired memory, apathy.

Question 36

Medicinal uses of THC?

Answer 36

• Used for treatment of nausea and vomiting after chemotherapy treatment;
• Also for stimulation of appetite and prevention of weight loss in AIDS patients.
• Analgesia
• Glaucoma
• Treatment resistant epilepsy
• The use of these compounds is still controversial, but approval for use is slowly rolling out across the AU states.

Question 37

What is an overdose?

Answer 37

• “overdose”: an excessive and dangerous dose of a drug, can mild, moderate, severe or lethal.
• Most people who overdose are under the influence of more than one drug – on average 2.7 drugs are identified in fatal overdose cases.
• When overdose is lethal, it is common that no single drug is present at a lethal dose. Rather it is the synergistic effects of combining the drugs that is lethal.
• The majority of overdoses involve legal drugs.
• e.g., a combination of opiates (heroin or prescription painkillers) and alcohol can be especially dangerous. Both suppress breathing, but by different mechanisms.

Question 38

Death by respiratory failure

Answer 38

• Prescription opioids are the cause for more deaths by overdose than any other single drug.
• Like opioids, alcohol overdose can suppress breathing by either decreasing the excitatory effect of glutamate, such that high doses can result in passing out and reduced breathing;
• and/or an unconscious individual may inhale their own vomit, which further reduces breathing.

Question 39

Death by stimulants

Answer 39

• Cause of death is predominantly due to the indirect increases of noradrenaline. There are no clear antagonists to addresses overdose.

Brain damage: Microischemia caused by drugs such as cocaine.

Hyperthermia: differs by drug (up to 38.3C)
Some stimulants primarily impact on the temperature of the brain (amphetamines), whereas others are more systemic (cocaine). Being in a warm club or environment can make this even more dangerous.

Question 40

How stimulants kill:

Answer 40

• Brain damage (rising BP increases the risk of ruptured blood vessel in the brain - narrowing of blood vessels reduces blood flow)
• heart attack (with more activity, the heart needs more oxygen. Along with reduced blood supply due to narrowing of the blood vessels, this can lead to heart attack)
• overheating (dopamine regulates body temperature. Increasing dopamine levels with stimulants can affect the body’s ability to cool itself. Combined with increased activity, this can lead to a dangerous increase in body temperature, leading to organ failure and death)

Question 41

What is done in overdose?

Answer 41

First priority is support of cardiovascular and pulmonary functions.

If dependence is an issue or suspected, management of the withdrawal symptoms is next that may occur as the drug is eliminated from the body without being replaced.

Question 42

What are symptoms of withdrawal?

Answer 42

Symptoms of withdrawal are generally the opposite of the effects of the drugs. This “rebound effect” in terms of symptoms is due to the re-sensitisation and re-regulation of receptors of CNS and PNS.

Bear in mind that dependence on combinations of drugs is very likely, so management of CV aspects is crucial, perhaps requiring constant monitoring.

Question 43

Detoxification

Answer 43

• Detoxification: drug is cleared from the system and support measures are implemented, is overseen by a physician and nursing team. This can be physically dangerous.
• Generally speaking, this may require up to 30 days in hospital or care unit, depending upon the half life (lives) of the drug(s) of dependence.

Question 44

Rehabilitation

Answer 44

• Rehabilitation: In parallel, counseling and therapy processes are started. Through group sessions, users hear and share stories about reasons for drug addiction, how to avoid triggers, and how to successfully live a drug-free life – that this is possible.
• Removal of the user from their environmental cues of friends, family, places, and habits is crucial in this process. Psychological aspects may be identified and self-medication reduced.

Question 45

What strategies can be used in physical treatment of dependence?

Answer 45

• Substitution therapy combined with symptomatic relief, followed by weaning off of the element of substitution. Alone, this is usually insufficient to prevent relapse.
• Counselling can be used if helpful to the patient.
• Should substitution therapy not be possible, managing withdrawal symptoms is paramount.

Question 46

How can pharmacology assist?

Answer 46

Administer a prescribed opioid and then gradually reduce the dosage used each day. Switching user from short acting (heroin) to long acting (buprenorphine or methadone) is most useful, and depending upon response, gradually reducing dose over 6 week period.

Question 47

Benzodiazepine Withdrawal

Answer 47

Patients who have used high dose BNZs for long-term treatment will need to gradually reduce doses used over months. Withdrawal symptoms, if they occur, will be mild.

In the case of BNZ and opioid dependence, reduction of BNZ gradually while maintaining the opioid component with low dose methadone is possible. Alternatively, a long acting BNZ can be substituted.

If low dose BNZs have been used for long-term treatment, no adverse effects are usually seen.

If anxiety returns, non-BNZ drugs can be prescribed instead.

Question 48

Alcohol Withdrawal Syndrome

Answer 48

The level of physical dependence is reflected by the severity of the withdrawal symptoms experienced by the user.

The symptoms and severity are determined by the amount and duration of alcohol consumption, leading to possible sleep disruption, ANS activation, tremors, and in severe cases, seizures and cardiac arrest.

Two or more days after withdrawal, individuals may experience “delirium tremens”, with hallucinations, delirium, fever and tachycardia.

Hydration, electrolytes, vitamins (high dose thiamine) should be strongly encouraged.

• Sometimes, sedating medication might be used, such as benzodiazepines, but care needs to be taken due to possible cross-tolerance effects following long-term alcohol use.
• Ideally, a short-acting benzodiazepine is used according to the stage and severity of the withdrawal.
• Anticonvulsants, such as carbamazepine, may also assist. If there is a history of medical problems, seizures, or use of other drugs, hospitalization is required.

Question 49

Pharmacology of treating alcohol dependence: disulfiram

Answer 49

Disulfiram has been utilised to help cease alcohol consumption by users, but its side effects (flushing, tachycardia, hyperventiliation and stress) challenges with patient compliance has made it a third choice by many.
Abstinence is reinforced to avoid the resulting adverse reaction.

Question 50

3 phases in the psychostimulant withdrawal process:

Answer 50

• “Crash”: acute dysphoria, irritability and anxiety, increased desire to sleep, increased
  appetite, etc.
• “Withdrawal”: increased craving to use, poor concentration, some irritability and lethargy.
• “Extinction”: intermittent craving to use in response to external cues.

Question 51

Relapse: Aspects of Psychological Dependence

Answer 51

• During periods of drug withdrawal, individuals experience irritability, stress, anxiety, low mood and blunted responses to experiences that would normally be pleasurable. These aversive behavioural changes can be long-lasting and contribute to the drive to retake the drug to escape from what is a negative emotional state (negative affect).
• The memory of previous drug-induced experiences can be very intense and long lasting, giving rise to craving; it may drive an individual to take the drug again – referred to as relapse – even after a prolonged period of abstinence.
• Craving may be triggered by stress or by cues, such as experiencing the environment that a person associates with previously taking the drug or the sight of drug administration paraphernalia e.g. a crack pipe or syringe. This suggests that associative learning may be an important factor in psychological dependence.

Question 52

Psychological and social interventions

Answer 52

• Psychotherapies
• Social support interventions
• Self-help support groups
• Socio-cultural relevance

Question 53

Long term treatment of drug dependence

Answer 53

Once rehab has been successfully completed, the behavioural therapy that should follow is just as important as the pharmacology.

• There is no “cure”, and this is usually a life-long process. One is effectively in remission, and relapse is an ever- present possibility.