Drugs of Abuse II Dr. Simran Kaur Simranjit.email@example.com
Commonly abused substances include: i. Opiates and narcotics • powerful painkillers with sedative and euphoric qualities • Include: Heroin, Opium, Codeine, Pethidine (meperidine), hydromorphone, oxycontin
ii. Central Nervous system (CNS) stimulants • Include cocaine, amphetamines, dextroamphetamine, methamphetamine and methylphenidate (Ritalin) • Most commonly used stimulants are caffeine and nicotine. • These drugs have a stimulating effect and produce tolerance
iii. CNS depressants - Include barbiturates (amobarbital, secobarbital, pentobarbital), benzodiazepines (diazepam, lorazepam, alprazolam), chloral hydrate and paraldehyde. • Most commonly used is Alcohol • Produce a soothing sedative effect and anxiety-reducing effect and can lead to dependence
iv. Hallucinogens • Include LSD (Lysergic acid diethylamide, derived from ergot, a grain fungus), mescaline (from cacti), psilocybin (‘magic mushrooms') and phencyclidine (PCP or Angel Dust) • Have hallucinogenic properties and produce psychological dependence
v. Tetrahydrocannabinol (THC) - Active ingredient in cannabis, marijuana and hashish. - Used for their relaxing properties but THC-derived drugs can also lead to paranoia and anxiety.
TREATMENT OF DRUG DEPENDENCE • Pharmacological Approaches 1. Substitution/Replacement treatment • to alleviate withdrawal symptoms/ long-term maintenance and detoxification or withdrawal -- Involves administration under medical supervision of a prescribed medicine with similar action to the drug of dependence
2. Blocking response • Use of antagonists 3. Aversive therapy • Induce unpleasant response to drug of abuse concerned 4. Modification of craving • Use of drugs to relieve withdrawal symptoms
Non-pharmacological approach 1. Cognitive- Behavioural Therapy (CBT) • short-term focused approach to helping drug-dependent individuals become abstinent from drugs
CBT CBT attempts to help patients recognize, avoid and cope • RECOGNIZE the situations in which they are most likely to use drugs • AVOID these situations in which they are most appropriate and • COPE more effectively with a range of problems and problematic behaviours associated with substance abuse
2. Cognitive Therapy • a system of psychotherapy that attempts to reduce excessive emotional reactions and self-defeating behaviour by modifying the faulty or erroneous thinking and maladaptive beliefs that underlie these reactions.
3. Community Reinforcement Approach • a broad-spectrum behavioural treatment approach for substance abuse problems, that utilizes social, recreational, familial and vocational reinforcers to aid clients in the recovery process.
4. Motivational Enhancement Therapy • based on principles of motivational psychology and employs motivational strategies to mobilize the client’s own change resources.
I. NARCOTIC ANALGESICS • Drugs that reduce pain without producing unconsciousness (cf Anaesthetics) • OPIATES (also opioids) : A class of very potent painkillers
From Opium – an extract from the poppy plant Papaver somniferum The major active ingredients include: Morphine Codeine Thebaine Narcocotine SOURCE
1. Natural narcotics Morphine Codeine Thebaine 2. Semi-synthetic narcotics Heroin Hydromorphone Oxycodone Etorphine 3. Synthetic narcotics Buprenorphine Fentanyl Methadone Pethidine (Meperidine) Pentazocine (Talwin) Propoxyphene (Dextropropoxyphene) TYPES OF NARCOTIC ANALGESICS
4. Endogenous opioids • Peptides which are produced in the brain and have opiate-like pharmacological effects • Derived from precursor peptides by protease cleavage • b-endorphin (Pro-opiomelanocortin, POMC) • met-enkephalin and leu-enkephalin (Proenkephalin) • dynorphin (Prodynorphin)
ADVERSE EFFECTS OF OPIATES • Dose-related and depend on rate of absorption a. Low or moderate doses of opiates: Effects on CNS • have an analgesic effect • depress respiration • cause constriction of pupils • impair ability to concentrate • suppress cough reflex • reduce appetite Effects on GI tract • reduce gut motility (leads to constipation – has been used to relieve diarrhoea and dysentery)
b. Higher doses or when drug is administered via intravenous/inhalation: • lead to state of euphoria • induce nausea and vomiting (due to effect on chemical trigger zone – the area postrema)
c. At the highest dose/ overdose: • lead to unconsciousness • fall in body temperature and blood pressure • respiratory pressure • ultimately death
Opioid receptor binding studies • Binding of radioactive 3H naloxone to rat brain show the classic saturation binding curve. • As the concentration of the opiate ligand increases, binding to receptors increases linearly until receptors are fully occupied.
Opiate Bioassay • Han Kosterlitz et al. (1970, 1975)
OPIOID AGONISTS AND ANTAGONISTS • Pure agonists • high affinity for m receptors and lower affinity for d and k receptors • include most morphine-like drugs: Morphine, codeine, dextropropoxyphene, methadone, pethidine, etorphine, fentanyl
2. Partial agonists (mixed agonists and antagonists) • Nalorphine (low dose antagonist at m receptors and partial agonist on d receptor and k receptors. • Pentazocine antagonist at m receptors and partial agonist on d receptor and k receptors.
3. Antagonists • Block m, d and k receptors • Naloxone (short acting 2-4 hours) and Naltrexone (longer duration of acting t1/2 = 10 hours)
Mechanism of action of Opioids • Reduction of membrane excitability (hyperpolarization due to increased K+ conductance) • Inhibition of neurotransmitter release (inhibition of Ca2+ entry) • Suppressing firing rate of inhibitory interneurons (increasing activity in some neuronal pathways)
All the opioid receptors are G-protein coupled receptors 1. They are coupled to the inhibitory G protein Gi : • Inhibition of adenylate cyclase • reduce cAMP • decreased function of cAMP-dependent protein kinases (partially responsible for ion channel changes)
2. Direct coupling to ion channels reducing synaptic transmission: a. Postsynaptic inhibition • Opioid binding to receptors activate G protein • Open K+ channel • Increase K+ conductance • Hyperpolarization (inhibitory post-synaptic potential IPSP) decreases rate of firing.
b. Axoaxonic inhibition • Opioid receptors on presynaptic terminal activate G protein • Closes Ca2+ channel • Decreases conductance of Ca2+ • Decreases release of neurotransmitters (e.g. noradrenaline, dopamine or glutamate and substance P released on afferent sensory neurons that transmit pain signals)
c. Presynaptic autoreceptors • Via G protein activation of K+ channel opening and Ca2+ channel closing: • Somatodendritic autoreceptors hyperpolarize cells and reduce cell firing • Presynaptic autoreceptors reduce the release of neurotransmitters
Rewarding effects of Opiates (Opioid reinforcement) Linked to the mesolimbic dopaminergic pathway • GABAergic cells inhibit this pathway by limiting dopamine release • b-endorphin and opiate drugs decrease the release of GABA by -opening K+ channels -reducing influx of Ca2+ on GABA terminals
The inhibition of GABA cells lead to: • increased firing • greater dopamine release into the nucleus accumbens By means of similar mechanisms, k receptor agonists (dynorphin) inhibit dopamine neurons and reduce dopamine release
b-endorphin stimulates the pathway In contrast, k receptor agonists reduce dopaminergic neuronal activity and suppress the pathway
Opioid Tolerance and Dependence • Himmelsbach Hypothesis (1943) • the nervous system adapts to the presence of opiates so tolerance develops • in the event of sudden withdrawal of drug, the adaptive mechanism continues to function, causing a rebound in physiological effects (withdrawal syndrome).
Pharmacological treatment of opiate addiction/dependence 1. Detoxification • Elimination of abused opiate from body by substitution therapy a. Methadone • with gradual dose reduction over a 5-7 day period
b. Symptomatic relief i. Clonidine, an a2 adrenoceptor agonist • to reduce noradrenaline activity • relieve withdrawal symptoms: chills, lacrimation, rhinorrhoea, yawning, sweating ii. Promethazine or hydroxyzine • for nausea and vomiting iii. Loperamide • for diarrhoea iv. Methocabamol • for muscle cramps and joint pain
2. Maintenance Therapy • Methadone, LAAM (L-alpha-acetyl-methadol), Buprenorphine or narcotic antagonist, Naltrexone have been used. • Methadone maintenance programmes are the most popular (Methadone Clinic) - Supervised daily administration of the oral form
II. CNS Stimulants (Pysvhomotor stimulants) • Substances which produce a sense of euphoria or a feeling of being more awake • Used as therapeutic drugs or recreational drugs to increase alertness • Used to suppress appetite • Also used and sometimes abused to boost endurance and productivity
Source Cocaine is an alkaloid found in the leaves of the coca shrub (Erythroxylon), which grows in the Andes (particularly Bolivia, Colombia and Peru in South America). Coca leaves contain 0.6-1.8 % cocaine. Coca paste contains ~80 % cocaine A. COCAINE
MECHANISMS OF ACTION Cocaine binds to the neurotransmitter reuptake transporters on presynaptic membranes of dopaminergic neurons and blocks reuptake of • Dopamine (DA) • Noradrenaline (Norepinephrine, NE) • Serotonin (5HT)
A build up of neurotransmitter levels in the synaptic cleft occurs. Subsequently leading to increased activation of the dopaminergic reward pathway and a sense of euphoria and arousal. • As the cocaine level decreases, so does the dopamine level in the pathway resulting in depression and a craving for the drug
Pharmacological effects Increased stimulation of the sympathetic nervous system: • By blocking the reuptake of NE Tachycardia Hypertension Mydriasis (pupil dilation) Tremors
Binding affinity of cocaine: • 5HT transporter > DA transporter > NE transporter Blockade of DA reuptake accounts for cocaine’s ability to: • STIMULATE • REINFORCE • CAUSE ADDICTION