QG NP3.docx

Peak brain alcohol concentration is achieved at 15 minutes. Peak blood alcohol concentration is achieved at 75 minutes. During absorption, alcohol concentration in the brain is greater than alcohol concentration in the blood. During elimination, alcohol concentrations in blood are higher than alcoh...

Peak brain alcohol concentration is achieved at 15 minutes. Peak blood alcohol concentration is achieved at 75 minutes. During absorption, alcohol concentration in the brain is greater than alcohol concentration in the blood. During elimination, alcohol concentrations in blood are higher than alcohol concentrations in the brain. Therefore, blood alcohol does not exactly reflect psychomotor impairment. Blood concentration would be high even though the person would be acting normally, and would be more drunk than blood alcohol would predict in the beginning There are considerable polymorphisms for both alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). The variant ADH1B*2 increases vmax which means faster conversion of ethanol to acetaldehyde (would get drunk faster). ALDH2*2 is a variant that increases acetaldehyde. Having both of these variants would cause the person to feel effects much faster. Specific symptoms are flushing, nausea, headache, and hangover. Mechanisms of Action Acamprosate (Compral): weak NMDA receptor antagonist and GABAA agonist Disulfiram (Antabuse): inhibits aldehyde dehydrogenase, evoking unpleasant acetaldehyde syndrome when drinking: nausea, vomiting, palpitations, blurred vision, dyspnea Naltrexone (Vivitrol, Depade, ReVia): mu opioid receptor antagonist LSD: agonist/partial agonist of 5HT2A (increase EPSP) – G-protein coupled, closes K+ channels. Not addictive, but produces tolerance. Varenicline (Chantix): partial agonist selective for alpha-beta nicotinic acetylcholine receptor subtypes (major receptor in VTA); highly dependent on presence of agonist. If agonist is not present, will bump up activity and have partial effect. If agonist is present, will compete so will have decrease in response Bupropion (Zyban): inhibit NE and DA uptake; nicotinic receptor antagonist (less reward) Xylazine: Alpha-2 agonist, decrease release of NE THC: partial agonist at CB1R disinhibition of DA neurons mainly via presynaptic inhibition of GABA neurons in VTA Ketamine and PCP: NMDA antagonist Salvia: kappa receptor modulator psychotomimesis Nicotine: selective agonist of nAChR; nicotinic receptors on DA neurons on VTA/NAc Terminology Physical dependence: withdrawal syndrome arises if drug is discontinued, dose is substantially reduced, or an antagonist is administered Tolerance: greater amount of drug is needed to maintain therapeutic effect, or loss of effect over time. You can build tolerance to sedation, nausea, vomiting, urinary retention, and respiratory depression. You DO NOT build tolerance to hallucinations, pruritis, and constipation. Pharmacokinetically this is related to induction of enzymes and pharmacodynamically this is related to the downregulation or desensitization of receptors. Pseudo-addiction: behavior that is suggestive of addiction. It is caused by the undertreatment of pain. Addiction: psychiatric disorder characterized by continued compulsive use of substances despite harm. This is related to mesolimbic dopamine pathways which are also activated by food, water, and sex. Medicinal Chemistry: Cocaine There are eight possible stereoisomeric forms of cocaine, but only one is found in the active natural product of cocaine. 2 ester groups on cocaine make it vulnerable to hydrolysis, therefore it has a short half life. It is usually administered by snorting or injecting. Much of cocaine toxicity is attributed to oxidative stress. Ethanol increases toxicity by extending sympathomimetic activity. You only get cocathylene when used with ethanol. AEME is only formed when the user smokes crack or cocaine because heat promotes hydrolysis and condensation. Medicinal Chemistry: Hallucinogens Two major structures of hallucinogens are phenylalkylamines and indolalkylamines. Mescaline is a phenylalkylamine and is similar to catecholamines (one phenol ring). Amphetamine is the prototype phenylisopropylamine. Methylenedioxy is a 5 membered ring with 2 oxygens. When methylenedioxy is introduced to a phenylalkylamin, it induces hallucinogenic properties. Methyl increases the lipophilicity and decreases metabolism to produce highly potent psychoactive compounds. Hallucinogenic potency increases as hydrocarbon load increases. Hallucinogenic properties can be selected for by adding substituents to the aromatic ring (preferred: 4-,2-,5-). Benzofuran enhances stimulant effects (fused rings). Stimulant properties can be promoted by keeping the aromatic ring un-substituted or adding a ketone in the beta position. LSD and psilocybin are examples of indolealkylamines and are similar to 5-HT (fused rings). Medicinal Chemistry: Nicotine Nicotine is poorly water soluble. The addition of benzoic acid helps favor the salt form of nicotine. Co-solvents such as propylene glycol and glycerol are used to promote solubility. Thermal decomposition of flavoring compounds result in the formation of aldehydes Empiric therapies for meningitis include: Vancomycin, 3rd or 4th generation cephalosporins with or without Rifampin. 3rd generation cephalosporins include: ceftriaxone, ceftazidime, cefdinir, cefpodocime, cefotaxime, cefixime. Cefepime is a 4th generation cephalosporin. If CSF comes back with gram-negative diplococci, can d/c vancomycin. Prophylactic treatment for meningitis is indicated for close contacts of Neisseria and Hemophilus. We would use Ciprofloxacin 500mg one dose, or Ceftriaxone 250mg IM one dose, Rifampin 600mg every 12 hours for 4 doses, or Azithromycin 500mg one dose. In pregnancy, Ceftraixone 250mg IM one dose is indicated. Community acquired meningitis would be streptococcus pneumoniae. To treat this, we would use Ceftraixone 2g every 12 hours until it is ruled out Hospital acquired meningitis would be staph aureus or Enterobacteriaceae (ex. Enterobacter cloacae) Listeria meningitis treatment would include Ampicillin, Ceftriaxone, and Vancomycin Corticosteroids in meningitis is only indicated in children with Hemophilus and adults with pneumococcus (ex pneumococcal bacteremia). Remember that decrease in inflammation could decrease penetration. We would want to give dexamethasone prior to or with the first dose of antibiotics. DO NOT give corticosteroids if it is listeria. Nociceptive pain is characterized by sensory nerves identifying damage in tissues. It includes visceral and somatic pain. Visceral pain is deep, aching, gnawing, and is poorly localized. Visceral pain usually involves internal organs and is therefore ill defined, deep, and aching. Somatic pain is dull and well-localized. Somatic pain is usually characterized by musculoskeletal pain in skin, muscle, joints, and or ligaments. Pathologic pain is disengaged from stimuli, often chronic, and may not correlate to a physical exam or diagnostic finding. NSAID adverse events include bleeding risk. Acetaminophen adverse events include hepatotoxicity and is usually at greater risk with excessive intake at greater than 4 grams per day. Remember to account for acetaminophen in all products, especially combo products. Acute pain treatment: try non-opioids first and limit to minimal effective doses. Avoid long acting products. Morphine is contraindicated in renal impairment because morphine metabolites are excreted renally. 6-glucoronide metabolites can accumulate and be toxic. The following changes occur when you stop smoking: 20 minutes: BP and HR decrease 12 hours: CO decreases Weeks-Months: improved circulation, increased lung function Months: mucus clearance improves, decreased respiratory symptoms 1 year: heart disease cut in half 5 years: stroke risk cut to the rate of someone who never smoked 10 years: lung cancer rate cut in half: other cancer risks decrease 15 years: heart disease risk cut to rate of someone who never smoked Drug Interactions while smoking involves CYP1A2. CYP1A2 is induced when actively smoking, so substrates such as clozapine and caffeine will have decrease serum concentrations and therefore doses should be increased. Clopidogrel is also a substrate, and there would be an increase in serum concentrations of the metabolite, but no changes in dose are needed. When someone stops smoking, CYP1A2 will not be induced, so serum concentrations will increase and therefore dose should be decreased. Smoking interacts with estrogen, BZD, antidepressants, antispsychotics, beta blockers, inhaled insulin, and warfarin. Two important adverse events for varenicline (Chantix) that patient should always receive education about: nausea, so take with food and vivid dreams. Vitamins are a key component of alcohol withdrawal treatment. The three agents are daily multivitamin (PO daily), folic acid (1mg PO daily) to prevent megaloblastic or macrocytic folic acid deficiency anemia, and thiamine (100mg PO daily) to prevent Wernicke-Korsakoff syndrome. It is important to remember to give dextrose AFTER the first dose of thiamine. In supportive care, we give fluids for hydration support as D51/2 NS w/ 20mEq KCl/L as 50-100mL/hour AFTER the banana bag. Example dosing for initial treatment of alcohol withdrawal with BZD would be 1mg PO Q4HPRN, if severe: 2mg PO Q2HPRN Counseling points for Acamprosate (Campral): This drug is used to help keep you alcohol free. Take it three times a day. Common side effects are diarrhea. Call your doctor right away if you notice signs of allergy or withdrawal. Call your doctor if you experience suicidal ideation. Counseling points for Disulfiram (Antabuse): Do not take this for at least 12 hours after drinking alcohol or taking drugs that have alcohol in them. Do not take this drug if you are intoxicated. Avoid metronidazole and inform all providers you are taking this drug. You may experience abnormal or metallic taste and/or headaches. You can use this in high risk situations. Disulfiram reaction includes flushing, SOB, headache, nausea, tachycardia, palpitations and more severe reactions include MI, CHF, arrhythmia, respiratory depression, and convulsions. These can occur up to 2 weeks even after therapy has been discontinued. Counseling points for Naltrexone (Vivitrol, Depade, Revia): Some adverse events include nausea and low energy. Do not take this drug if you have used any opioid containing drugs in the past 7-14 days. Taking this drug while using opioids can lead to withdrawal. If patient is starting naltrexone, make sure they have been off opioids for 1 week before starting, otherwise could go into precipitated withdrawal. Antabuse dose is 666mg by mouth three times daily. If renally impaired (CrCl 30-50 mL/min), 333mg by mouth three times daily. Antabuse dose: 250mg by mouth daily Naltrexone (vivtrol) dose: 280mg gluteal IM every 4 weeks Naltrexone (Depade, Revia) dose: 50mg by mouth once daily OR 100-150mg by mouth three times per week. Topiramate dose: 200-300mg per day by mouth in divided doses. Titrate, taper, and renal adjust. Gabapentin dose: 900-1800mg per day by mouth in divided doses. Titrate, taper, and renal adjust. Buprenorphine has a ceiling effect on respiratory depression and for analgesia. This means it will only go so high for analgesia effect. You cannot overdose on BUP, so is considered to be safer. Use cautioning when transferring from a pure agonist to BUP because of precipitated withdrawal. Meperidine is no longer used because of the risk of accumulation of the active metabolite, normaperedine. In patients with impaired renal function, this can cause seizures. TCAs are used in fibromyalgia. If contraindicated, can use Duloxetine. TCAs are contraindicated if within 14 days of MAOI use and is contraindicated in acute recovery from MI. Side effects of TCAs include sedation, orthostatic hypotension, heart block, dry mouth, urinary retention, constipation. Amitriptyline has the most adverse effects, notriptyline and desipramine have the least ADEs. Anticholinergic drugs should be avoided in older adults, patients with: glaucoma, enlarged prostate, and seizure disorder. Anticholinergic effects include: blurred vision, cognitive changes, constipation, dry mouth, orthostatic hypotension, sedation, sexual dysfunction, tachycardia, urinary retention. When converting to another opioid, have to account for incomplete tolerance so decrease the dose (methadone decrease by 75%). Methadone is dangerous at initiation because analgesic effects are shorter than the dosing interval. If a patient takes an extra dose, it can quickly accumulate and cause respiratory depression. Methadone has a long half life and is lipophilic. CYP inducers decrease methadone levels and may lead to withdrawal. Breakthrough pain should be controlled with immediate release formulations and at a dose of 10-15% of daily dose. This can be the same medication patient is on or an equivalent MME dose. Opioids should not be used with benzodiazepine because of the risk of respiratory depression. Doses over 50 MME increases the risk of overdose. Methadone and BUP can be used in pregNancy. MOTHER trial outcomes include: number of neonates requiring treatment for NAS, peak NAS score, total amount of morphine needed to treat NAS, length of hospital stay for neonates, neonatal head circumference. The 4Cs of addiction include: compulsion, cravings, consequences, and control.