General principles of drug dependence and abuse
Drug dependence or addiction refers to the state when drug-taking becomes compulsive and starts to take precedence over other needs. There is an excessive craving for the drug. A common feature of dependence-producing drugs is the activation of the dopaminergic “reward” pathway, the mesolimbic pathway. Most dependence-producing drugs produce a rewarding experience, like an elevation of mood or a feeling of euphoria.
We distinguish physical and psychological dependence. If withdrawal from the drug causes physical symptoms (an abstinence syndrome), the drug causes physical dependence. If withdrawal from the drug causes drug-seeking behaviour from the affected person, the drug causes psychological dependence.
Positive reinforcement refers to how a stimulus makes you more likely to seek out the stimulus again later. Euphoria causes significant positive reinforcement, as the addict wants to experience the euphoria again later.
Drug abuse or substance abuse refer to the use of drugs unfairly or immorally.
Tolerance is defined as when a drug causes decreased pharmacological effects after repeated administration. It often accompanies dependence. Tolerance can occur by two important mechanisms:
- Pharmacokinetic tolerance – when enzymes that metabolize the drug are induced
- Pharmacodynamic tolerance – adaptive changes that alter the pharmacodynamics of the drug, such as changes in receptor density or changes in the signal transduction pathway of the receptors
The adaptive changes that occur during pharmacodynamic tolerance contribute to the development of physical dependence. In many cases tolerance develops because the body down-regulates the receptors the drugs bind to. When the affected person isn’t taking the drug, he or she has fewer receptors that can be stimulated by endogenous compounds. The person becomes dependant on using more the drug in order to compensate for the decreased number of receptors.
Opioids are mainly used medically for their use as analgesics, but they have major potential as drugs of abuse. Commonly abused opioids include morphine, heroin, fentanyl and methadone.
These drugs are taken IV, intranasally or by inhalation.
These drugs bind to κ, δ, and most importantly μ opioid receptors.
These drugs give a strong sense of euphoria, similar to that of an orgasm. This euphoria is followed by a calm, even-tempered mind (called a high), which is again followed by sedation and a deep sleep (called a nod). After waking up the person will crave the drug again.
Opioids also cause respiratory depression, myosis and convulsions.
Both psychological and physical dependence develop. Tolerance is mostly pharmacodynamic. The μ opioid receptor is a Gi-protein coupled receptor, so when it is activated it inhibits adenylyl cyclase, decreasing the intracellular level of cAMP. Tolerance develops because adenylyl cyclase is overactivated to compensate for the chronic inhibition of adenylyl cyclase by chronic opioid use.
In a non-tolerant person 60 mg of morphine will cause respiratory arrest and death. In a tolerant person 2000 mg of morphine is necessary to cause respiratory arrest. This shows that tolerance may decrease the effect of morphine by more than 30x.
Tolerance to the respiratory depression caused by morphine only lasts for a few days. If an addict has a short abstinence period of a few days, they will lose the tolerance to respiratory depression. If this addict then takes an equally large dose of opioids like he used to, he will develop respiratory arrest and death.
Opioid intoxication is characterised by myosis, shallow breathing (respiratory depression) and loss of consciousness or coma. It can be treated by naloxone, a μ opioid receptor antagonist.
Opioid abstinence (withdrawal):
The time it takes for withdrawal symptoms to start depends on the exact opioid. For morphine and heroin, they begin 6 – 10 hours after the last dose, and peak after 2 days and ends after 5 days.
Symptoms include, anxiety, hyperventilation, mydriasis, piloerection, muscle pain, spasms and vomiting. Opioid abstinence is rarely fatal.
Treatment of opioid abuse:
Methadone is a long-acting synthetic opioid. Unlike other opioids it does not cause euphoria. Buprenorphine is a semisynthetic opioid that also doesn’t cause euphoria.
By substituting addictive opioids with methadone or buprenorphine (which don’t cause euphoria), we can prevent withdrawal symptoms from appearing without causing euphoria. By slowly decreasing the dose the patient can become opioid-free without experiences withdrawal symptoms.
Naltrexone is a μ opioid receptor antagonist. It is usually given to people who are opioid-free but at risk for relapse. If a person taking naltrexone attempts to use opioids again, they will not experience any euphoria so there will be no positive reinforcement.
Both physical and psychological dependence develops. The mechanism of tolerance is both pharmacodynamic and pharmacokinetic.
Pharmacodynamic tolerance develops on the basis of various changes in CNS neurons. There is a reduction of GABAA receptors and an increase in voltage gated Ca2+ channels and NMDA glutamate receptors.
Pharmacokinetic tolerance develops as the level of the CYP2E1 enzyme, which biotransforms ethanol, is increased.
Alcohol abstinence (withdrawal):
Alcohol abstinence follows three phases and lasts for 5 – 10 days.
The first phase begins 8 – 24 hours after the last drink. Symptoms include:
- Sympathetic activation
The second phase begins after the first and last until 5 days after the last drink. It’s characterised by generalized tonic-clonic seizures.
The third phase begins after the second phase and lasts 1 – 5 days. This phase is called delirium tremens, and it’s characterised by:
- Sympathetic activation
Delirium tremens can be fatal.
Treatment of alcohol abuse:
During withdrawal it’s important to maintain homeostasis. Electrolytes and fluid should be monitored, and sympathetic activation should be blocked. Benzodiazepines can be given for sedation, and antipsychotics can be given for the delirium. Antiepileptics should be given if seizures occur. Thiamine should be given to prevent Wernicke-Korsakoff encephalopathy.
Disulfiram is an aldehyde dehydrogenase inhibitor. If a person consumes alcohol while taking this drug the level of acetaldehyde in the body will become very high, causing a very uncomfortable acetaldehyde syndrome.
Naltrexone is useful for treating alcohol abuse as well as opioid abuse, as it decreases the euphoria caused by drinking alcohol.
Acamprosate is an NMDA glutamate receptor antagonist. It reduces the craving for alcohol.
Abuse of benzodiazepines and barbiturates
Benzodiazepines are among the most commonly prescribed worldwide. Both barbiturates and benzos are subject to abuse.
Benzodiazepine overdose is rarely fatal by itself as it will simply induce a deep sleep. This usually requires no treatment. However, if the person is also under the influence of other CNS depressants like alcohol, a fatal respiratory depression can develop. This is unfortunately a combination often used in suicides.
Barbiturate overdose can be fatal as it causes significant respiratory and cardiovascular depression by itself. Treatment involves inducing diuresis and alkalinisation of the urine, which increases excretion of the drug.
Tolerance takes at least several months to develop for benzodiazepines. It’s a pharmacodynamic tolerance that develops due to downregulation of the GABAA receptor.
Tolerance of barbiturates develops earlier than for benzos. Tolerance does not develop to respiratory depression however, so if a person increases their dose to increase the sedation effect, they may develop respiratory arrest. This tolerance is both pharmacodynamic and pharmacokinetic.
Withdrawal of moderate doses of benzos causes a “rebound” anxiety. Withdrawal of high doses can cause seizures.
Withdrawal of barbiturates causes seizures.
Treatment of abuse:
Treatment of benzo or barbiturate abuse involves giving the affected person long-acting drugs and slowly decreasing their dose until the person is drug-free. Complete detoxification can usually be achieved in some months.
Abuse of inhalants
“Sniffing” organic solvents like gasoline, paint thinner, glue or shoe polish is a low-cost and easily available method to get high. The effect lasts only 5 – 15 minutes and involves euphoria and disorientation.
Acute toxicity of sniffing can cause lethal arrhythmias and sudden cardiac death.
Chronic sniffing can cause damage to many organs, especially the bone marrow.
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