Drugs of Abuse Management PDF

Drugs of Abuse Management Dr. Simón Q. Rodríguez Lara MD, PHD Adapted by : Dr. Patricia A. Romero MD, MSc WE MAKE DOCTORS Objectives To identify the clinical presentation of the intoxication with the US most commonly used...

Drugs of Abuse Management Dr. Simón Q. Rodríguez Lara MD, PHD Adapted by : Dr. Patricia A. Romero MD, MSc WE MAKE DOCTORS Objectives To identify the clinical presentation of the intoxication with the US most commonly used substance of abuse To identify the clinical presentation of withdrawal syndrome of substances of abuse To understand the pathophysiology of each substance of abuse To provide accurate treatment based on the potential substance of abuse.  Dependence vs addiction With repetitive exposure, addictive drugs induce adaptive changes such as tolerance (escalation of dose to maintain effect). Addiction consists of compulsive, relapsing drug use despite negative consequences, at times triggered by cravings that occur in response to contextual cues. Dependence is presented once the abused drug is no longer available, signs of withdrawal become apparent. A combination of such signs, referred to as the withdrawal syndrome.  Dependence vs addiction “Physical dependence” → Dependence. “Psychological dependence” → Addiction. Dependence invariably occurs with chronic exposure, only a small percentage of subjects develop a habit, lose control, and become addicted. Compulsive drug seeking and relapse to drug use are considered to be the hallmarks of addiction.  Dependence vs addiction Certain mechanisms seem to be common for many drugs: Dopamine (DA) mechanisms are center stage (as a general rule, all addictive drugs activate the mesolimbic dopamine system) Activation of the extracellular signal-regulated kinase (ERK) pathway. Decrease in Calmodulin-related genes. Increase transcription of genes related to lipid/cholesterol and Golgi/endoplasmic reticulum (ER) function. Glutamate and GABA receptor. Tolerance & withdrawal Tolerance Chronic exposure to addictive drugs, will lead to the brain adaptation (down-regulation/up- regulation). Withdrawal Adaptive changes become fully apparent once drug exposure is terminated. We make Doctors  Cocaine Alkaloid ester extracted from the leaves of Erythroxylum coca. Clinically → local anaesthetic and vasoconstrictor used particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects. Mechanism of action Reversibly binds and inactivates sodium channels. Binds differentially to the dopamine, serotonin, and norepinephrine transport proteins and directly prevents the re-uptake of dopamine, serotonin, and norepinephrine into pre-synaptic neurons. Effect on dopamine levels is most responsible for the addictive property.  Cocaine VGSC Targets Sodium-dependent dopamine transporter antagonist. VGCC Sodium-dependent noradrenaline transporter antagonist. Sodium-dependent serotonin SDDT transporter antagonist. SDNT SDST Sodium channel protein type 5, 10 and 11 subunit alpha antagonist. Muscarinic acetylcholine receptor M1 & M2 antagonist. M1 M2 We make Doctors  Cocaine Acute intoxication management: Effects - Benzodiazepines (diazepam) Euphoria (might be replaced by anxiety), hyperactiveness, - Phentolamine suppression of appetite, local anesthesia, and possible (cardiovascular sudden death due to cardiac arrest. management). Locomotor depression rather than stimulation. - Hypertermia → immersion in Sympathomimetic properties → potent vasoconstrictor of cold water. blood vessels in the brain (myocardial infarction or ischemic stroke). - If needed: - Nitroglycerine (refractory hypertension) Toxicity - Non-selective B-blockers? Intense agitation, convulsions, hypertension, rhythm disturbance, coronary insufficiency, hyperthermia, Closely evaluate → risk rhabdomyolysis, and renal impairment. of/ongoing MI, if yes → avoid B-blockers  Amphetamine type. Similar structure to the catecholamine neurotransmitters → long planar conformation, an aromatic ring and nitrogen in the aryl side chain. A compound discovered over 100 years ago, is one of the more restricted controlled drugs. It was previously used for a large variety of conditions and this changed until this point where its use is highly restricted. During World War II, amphetamine was used to promote wakefulness in the soldiers. This use derived into a large overproduction of amphetamine and all the surplus after the war finalized end up in the black market which produced the initiation of the illicit abuse. Amphetamine (AMPH), methamphetamine (METH), methylphenidate (MPH) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy).  Amphetamine type Mechanism of action Is taken into presynaptic nerve terminals by the association with two sodium ions and one chloride ion. The complex of the amphetamine with the ions is actively transported by monoamine reuptake transporters. As amphetamine acts competitively with the endogenous monoamines, the greater the number of amphetamines the more internalized amphetamine will be found. Displaces other monoamines to be stored by VMAT2 which produces the pumping of the neurotransmitters into the synapse by a process called retro-transport. Inhibition of the reuptake and of monoamine oxidase We make Doctors  Amphetamine Type Targets Synaptic vesicular amine transporter antagonist Vesicular monoamine transporter 2 (VMAT2) antagonist Sodium-dependent dopamine transporter modulator Sodium-dependent noradrenaline transporter modulator Sodium-dependent serotonin transporter modulator Monoamine oxidase antagonist Alpha adrenergic receptor agonist Beta adrenergic receptor agonist SET MAO NAT Amphetamine Type Effects Elevated catecholamine levels → arousal and reduce sleep, on the dopamine system → euphoria, may cause abnormal movements and precipitate psychotic episodes. Effects on serotonin transmission→ hallucinogenic and anorexigenic functions as well as in hyperthermia.  Amphetamine Type Toxicity Acute amphetamine overdose → hyperthermia, respiratory depression, seizures, metabolic acidosis, renal failure, hepatic injury, and coma. Neurologic effects → agitation, aggressive behavior, irritability, headache, and hallucinations. Cardiovascular → arrhythmia, cardiomyopathy, myocardial infarction or ischemic stroke. GI tract → abdominal pain, vomiting, diarrhea, cramps, anorexia, and GI hemorrhage. Amphetamines are neurotoxic. Neurotoxicity depends on the NMDA receptor and affects mainly serotonin and dopamine neurons.  Amphetamine Type We make Doctors  Amphetamine Type Metabolism: Liver under the action of the CYP2D6. Elimination: Urine 40%, 90% is eliminated 72 h after oral administration. Depends from urine pH; acidic pH will produce a higher excretion of amphetamine and basic pH produces a lower excretion.  Lysergic acid diethylamide (LSD) Mechanism of action Effects Activates the serotonin 5-HT2A receptor in Mood alteration, sleep the prefrontal cortex, enhancing glutamatergic disturbances and anxiety. transmission onto pyramidal neurons, Tachycardia, increase blood enhancing the perception. Repeated doses pressure and body temperature, induce rapidly down regulation. dizziness, decrease appetite, and Target sweating. The most troubling side 5-hydroxytryptamine receptor 1A, 2B, 6 effect are the lost of judgement agonist. and impaired reasoning (bad trip). Marijuana Cannabis sativa and Cannabis indica → evidence has demonstrated its potential usefulness in the management of chronic pain, spasticity, inflammation, epilepsy, and chemotherapy-induced nausea and vomiting among many others. Contains more than 400 different chemical compounds, of which 61 are considered cannabinoids, a class of compounds that act upon cannabinoid receptors of the body. Tetrahydrocannabinol (THC) and Cannabidiol (CBD) types of cannabinoids found naturally in the resin of the marijuana plant, both interact with the cannabinoid receptors.  Marijuana Mechanism of action The primary psychoactive component of Cannabis, delta 9-tetrahydrocannabinol (Δ9-THC) →weak partial agonist activity at Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R) receptors. CBD → acts as a negative allosteric modulator of the cannabinoid CB1 receptor, the most abundant G-Protein Coupled Receptor (GPCR) in the body. Effects Increased appetite, reduced pain, and changes in emotional and cognitive processes.  Marijuana Targets Cannabinoid receptor 1 & 2 modulator Glycine receptor subunit alpha-1, -3, alpha-1/beta. N-arachidonyl glycine receptor agonist  Nicotine Nicotine is the principal neuroactive alkaloid responsible for tobacco addiction. Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is a highly addictive substance.  Nicotine Mechanism of action Binds stereo-selectively to nicotinic-cholinergic receptors on autonomic ganglia, the adrenal medulla, neuromuscular junctions and in the brain. Nicotine exerts two effects, a stimulant effect exerted at the locus ceruleus and a reward effect in the limbic system. Causes release of acetylcholine, norepinephrine, dopamine, serotonine, vasopressin, beta-endorphin and ACTH.  Nicotine Targets Neuronal acetylcholine receptor subunit alpha- 3, -4, -5, -6, -7, -9, -10; beta-2, -3, -4 agonist Cytochrome P450 19A1 antagonist Choline O- acetyltransferase antagonist Nicotine Effects Nicotine addiction leads to increased risk of severe adverse health effects caused by tobacco. Distribution of nAChRs with different subunit combinations in various brain regions contributes to diverse mechanisms of plasticity. Mechanisms of nicotine-induced plasticities include upregulation and downregulation of nAChRs; interactions with catecholaminergic, GABAergic, and glutamatergic neurotransmission; and neurodegenerative structural changes in fasciculus retroflexus and cortex.  Ethanol A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. Is a two-carbon alcohol that directly affects many different types of neurochemical systems and signaling cascades and has rewarding and addictive properties. Ethanol The legally allowed blood ethanol concentration (BEC) for operating a motor vehicle is 80 mg% (80 mg ethanol per 100 mL blood; 0.08% w/v) in the United States, which is equivalent to a concentration of 17 mM ethanol in blood. The consumption of one standard drink (a 12-oz bottle of beer, a 5-oz glass of wine, or a 1.5-oz shot of 40% liquor) by a 70-kg person would produce a BEC of about 30 mg%.  Ethanol Absorption absorbed rapidly into the bloodstream from the stomach and small intestine and distributes into total body water (~0.65 L/kg body weight). Peak blood levels occur about 30 min after ingestion. First-pass metabolism by gastric and liver ADH Metabolism The main enzymes involved in ethanol metabolism are ADH and ALDH, followed by catalase and CYP2E1. Epithelial cells of GI tract and liver.  Ethanol Mechanism of action Affects the brain’s neurons in several ways. It alters their membranes as well as their ion channels, enzymes, and receptors. Alcohol also binds directly to the receptors for acetylcholine, serotonin, GABA, and the NMDA receptors for glutamate. The sedative effects of ethanol are mediated through binding to GABA receptors and glycine receptors (alpha 1 and alpha 2 subunits). It also inhibits NMDA receptor functioning. In its role as an anti-infective, ethanol acts as an osmolyte or dehydrating agent that disrupts the osmotic balance across cell membranes. Ethanol Ethanol Ethanol Teratogeni Neural Sexual c function Immune Bone Body Hematologic temperatu al re Ethanol effects Cancer Diuresis Cardiovascul Liver ar system Digestive Stroke system Skeletal Lungs muscle Ethanol Treatment