drugs final exam

Cognitive Models of Depression

Aaron Beck (1921- ) noted dysfunctional attitudes and negative mood states in depressed individuals. Helplessness theory: Idea that individuals who are prone to depression automatically attribute negative experiences to causes that are internal, stable, and global Beck updated cognitive model: Negative schema developed in depressed people through combination of genetic vulnerability and negative early life experiences Depressed individuals tend to have depressive biases in thinking and memory.

TCA pharmacokinetics

Absorbed well when taken orally Long elimination half lives: 10-20 hours for imipramine, 12-75 hours for desipramine, 20-35 hours for Amitriptyline Often taken at night helps with the drowsiness side effects In some patients (i.e., depression patients with insomnia), the drowsiness side effects are actually beneficial/therapeutic

Does chronic FLXdeplete 5-HT?

All mice receive acute FLX ½ mice had received chronic FLX as well Some as adults Some as adolescents Acute FLX led to more EC 5-HT in chronic FLX-treated rats

Interference with the HPA axis?

Alprazolam blocks short-term HPA axis responses to stress Alprazolam increases HPA axis activity at longer time points after stress Three days later the stress hormone level is much higher than the group that wasn't treated with Xanax Short tern it blocks that action of HPA - long term it increases stress HPA axis helps us deal with short term consequences of stress May be blocking the natural stress response

MAO inhibitors

Although they can be effective, potentially fatal food and drug interactions have limited their use Foods high in tryptamine >>cheese, wine, beer >>Too much tryptamine can increase blood pressure and cause heart attacks and aneurysms drugs that are epinephrine-like in structure >>cold and asthma mediations >>Nasal sprays

Barbiturates are not commonly used therapeutics

Although they promote sleep, they block REM sleep Upon drug discontinuation, REM-sleep rebound is frequently observed >>A significant increase in REM >>>>Vivid dreams, nightmares

Benzodiazepines as amnestics

Amnestics - induce anterograde amnesia Sometimes desirable during surgery Versed (midazolam) is a common example Misused as date-rape drugs (flunitrazepam - rohypnol) As are other drugs with similar mechanisms of action (GHB and "Mickey Finn's" - chloral hydrate in alcohol)

Naloxone

An opioid antagonist that is most typically used to treat opioid overdose This further limits abuse potential and helps prevent any euphoric effects of full agonists (heroin, morphine)

Drug addiction is associated with increased criminal activity

5-10-fold increase in violent crime 8-15-fold increase in property crime A majority of individuals arrested even for many non-drug related crimes test positive for drugs ~85% of female prostitutes test positive for drugs at the time of arrest

Selegiline (Eldapril)

A MAO-B inhibitor - particularly effective at increasing dopamine neurotransmission Initially used in the treatment of Parkinson's disease Emsam A transdermal patch of seligiline Bypasses the GI tract, does not result in blood levels that are high enough to increase blood pressure Relatively safe, and appears to be relatively effective

Belsomra (suvorexant)

A Merck drug FDA approved in 2014 Blocks orexin receptors $65 million in sales in 2015 Decreases sleep latency Increases nightly sleep time At the highest dose approved: >>Fall asleep 6 minutes faster >>Stay asleep 16 minutes longer All for only ~$10/pill!!

Clomipramine (Anafranil)

A TCA with a higher affinity for SERT than most TCAs >>Sometimes considered a mixed serotonin-norepinephrine reuptake inhibitor >>Used for OCD with 40-75% efficacy The first antidepressant that was observed to exhibit anxiolytic properties

Levomethadyl acetate (LAAM)

A longer-acting methadone derivative that was approved by the FDA to treat opioid addiction in 1993. Can be administered Monday-Wednesday-Friday and lasts throughout the week. >>In contrast, methadone is typically administered daily In most studies LAAM is either comparable or slightly superior to methadone in ensuring that patients refrain from taking other opioids Still used primarily as a second-line treatment behind methadone or buprenorphine >>Concerns about side effects have limited its use >>>>Not much evidence that the side effects are any worse than methadone

Buprenorphine

A mu opioid partial agonist (and kappa antagonist) It has a slow onset and long duration of action, which allows for alternate day dosing A schedule III drug - can take the drug home with you The fact that it is a partial agonist may limit its efficacy >>The max dose typically given of buprenorphine is ~24-32 mg, which is roughly the equivalent of 60-70 mg methadone (on the low side of effective methadone doses) Sometimes prescribed in combination with naloxone >>An opioid antagonist that is most typically used to treat opioid overdose >>This further limits abuse potential and helps prevent any euphoric effects of full agonists (heroin, morphine) Data comparing the efficacy of buprenorphine to methadone are mixed, with some studies showing that methadone works better

Varenicline (Chantix)

A nicotinic receptor partial agonist >>Reduces cravings when nicotine is absent >>Also reduces the pleasurable effects of cigarettes when smoked Thee US Food and Drug Administration (FDA) has issued warnings on varenicline, noting that it may increase the risk of serious neuropsychiatric or cardiovascular events

Propofol (diprovan)

A non-barbiturate GABAa agonist A sedative Used clinically in anesthesia Sometimes to inhibit a seizure Also leads to euphoria, sometimes hallucinations Can lead to injection-site pain >>Activates TRPA1 receptors >>Often co-administered with lidocaine

Methaqualone (Quaaludes)

A non-barbiturate sedative drug These were extremely popular in the 70s and early 80s >>Its popularity was similar to that of marijuana Legal until 1984 For some reason, people considered it to be an aphrodisiac >>Not true, but it might lead to behavioral disinhibition

Most frequently falsified prescriptions (France 2001-2012)

1. Zolpidem - 21.7% 2. Bromazepam (Lexotan) - 11.2% 3. Flunitrazepam (rohypnal) - 8.5% 6. Zopiclone (imovane) - 7% 7. Alprazolam (Xanax) - 6.7% 8. Clonazepam (Klonopin) - 6.2% 10. Lorazepam (Valium) - 3.5%

Detoxification Treatments for Opioid Addiction

Antagonists are used to accelerate detoxification and to prevent relapse >>Detoxification is often performed under sedation or anesthesia to reduce the negative experience of withdrawal Naltrexone: a long-acting opioid antagonist with a high affinity for mu opioid receptors A single dose of naltrexone (50 mg) will block the pharmacologic effects of 25 mg IV heroin for up to 24 hours, A 100 mg dose is effective for up to 48 hours 150 mg is typically effective for 72 hours. Neither tolerance nor dependence develops with naltrexone

Dr Kohls' claims

Antidepressants are effective in the short term, but lose their efficacy as serotonin is depleted >>Poop-out? >>Potentially due to receptor-level alterations SSRIs deplete serotonin from the presynaptic neuron Can only increase 5-HT by eating more tryptophan or 5-HTP Individuals become addicted to SSRIs and suffer withdrawal symptoms and craving

Barbiturate Pharmacodynamics

At low - medium doses, barbiturates are positive allosteric modulators at GABAa receptors >>Bind to a different site on a receptor than most agonists >>Do not directly activate the receptor (not agonists) >>Facilitate the activation of the receptor by an agonist At high doses, barbiturates can act as agonists at GABAa receptors Antagonists at AMPA receptors and kainate receptors Are somewhat non-selective in their binding >>Also bind to nicotinic AchRs and the 5HT3R >>>>Block current through these channels

Efficacy of benzodiazepines and related drugs

BZDs are highly effective in reducing anxiety symptoms acutely But when and how frequently should they be used? Would benzodiazepine treatment soon after initial stress exposure prevent the development of PTSD?

Conclusions from a recent meta-analysis (2015)

BZDs are ineffective for PTSD treatment and prevention >>Risks associated with their use tend to outweigh potential short-term benefits Risks include: worse overall severity, worse psychotherapy outcomes, aggression, depression, and substance use Benzodiazepines should be contra-indicated for PTSD

The original major classes of sedatives were named according to their chemical structure

Barbiturates

Other effects of barbiturates

Barbiturates increase the expression of cytochrome P450 enzymes (CYP450) CYPs metabolize thousands of chemicals >>Responsible for ~75% of all drug metabolism >>Drugs that increase or decrease CYP expression/activity are likely to lead to increased risk of drug-drug interactions >>>>Codeine and tramadol are opioid pain medications that become much more active after being metabolized >>>>>Barbiturates can lead to an increased risk of overdose from these drugs

Benzodiazepine therapeutics summary

Benzodiazepines are a major advance compared to barbiturates for promoting sleep or reducing acute anxiety >>Much safer They are highly effective in reducing acute anxiety Long-term benefits of chronic BZD use are essentially not accepted >>SSRIs are typically favored These drugs are fairly addictive, so alternatives are being sought

TCAs- Pharmacodynamics

Block presynaptic norepinephrine and serotonin transporters therapeutic effects Block postsynaptic histamine and acetylcholine receptors side effects >>Blocking histamine receptors drowsiness >>Blocking acetylcholine receptors confusion, cognitive impairments, dry mouth, blurred vision, urinary retention, increased heart rate If taken at high doses (suicide attempts), TCAs can be fatal due to cardiac arrhythmias >>Sometimes only dispense 1 week supply at a time >>At least 12 deaths have been reported from treating children with desipramine for ADHD or depression

Antidepressants work better than placebo

Both groups have strong reduction of symptoms over time Yes the antidepressant group is better than the placebo but only 3/10 weeks measured

Bupropion for cigarette addiction

Bupropion (Wellbutrin) is typically thought of as an antidepressant, but it is used for many other indications It is not selective for the serotonin transporter, and it inhibits the dopamine transporter as well >>Thus, its mechanism of action is a little closer to that of a psychostimulant, although it is not typically abused

Pharmacogenomics and bupropion responses

Bupropion is metabolized by CYP2B6 Could mutations in this gene affect the efficacy of bupropion in patient populations?

If given the choice, many patients prefer buprenorphine over methadone

But given the limited effectiveness of detoxification compared to maintenance therapy, these uses of methadone and buprenorphine are controversial

NRT, CNRT and Chantix are all commonly used, but which one is the best?

C-NRT is better at leading to initial abstinence than NRT and Chantix, but no long-term benefits were observed

Withdrawal from barbiturates

Can result in hallucinations, restlessness, disorientation, convulsions Can sometimes be fatal Because of these effects and the other risks of taking barbiturates, they have been replaced with benzodiazepines for most applications

Alpha-2-adrenergic agonists

Clonidine - an α-2 adrenergic agonist that is typically used to treat hypertension Also sometimes used to treat attention deficit hyperactivity disorder Within the context of opioid abuse, it is primarily used to enhance detoxification outcomes During detoxification, the sympathetic nervous system is overactive, and this is responsible for many of the symptoms of withdrawal Clonidine aims to inhibit the sympathetic nervous system Buprenorphine has been shown to be superior to clonidine (an alpha agonist) for reducing withdrawal.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Considered to be second-generation antidepressants Fluoxetine (Prozac - Eli Lilly) hit the US market in 1988 Annual sales were ~$2.6 billion/year prior to going off patent It is estimated that 1 in 8 American adults is taking antidepressants >>Most common are the SSRIs Six SSRIs were approved relatively quickly by the FDA >>Fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram >>Typically the FDA won't approve new SSRIs because there is little reason to believe new SSRIs would be any better than existing SSRIs

Diagnostic Criteria for Major Depression

Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others). AKA - ANHEDONIA Significant weight loss when not dieting or weight gain (e.g., a change of more than 5 percent of body weight in a month), or decrease or increase in appetite nearly every day. Insomnia or hypersomnia nearly every day. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). Fatigue or loss of energy nearly every day. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick). Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others). Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

Comparing the efficacy of Chantix and bupropion

Does this mean that Chantix and bupropion are equally effective overall? Does this suggest that Chantix and bupropion are equally likely to be effective in any given patient? Or it doesn't matter which drug is prescribed to which person? Or are there other variables that influence this? If so, what? Yes these are equally effective Genetic factors can influence this

"Side effects" of benzodiazepines

Drowsiness Mental Confusion and Amnesia >>Some of the cognitive impairments induced by benzodiazepines persist long after the use of benzodiazepines is discontinued, although significant cognitive improvements do occur. A side effect to one person might be another's therapeutic response

Lexapro

Escitalopram (s-citalopram) Approved by the FDA for depression in 2002 Made by Lundbeck pharmaceuticals Global sales of $2.5 billion in 2010 Lundbeck also made Celexa (citalopram) Celexa's patent expired in 2003 Were able to get another FDA approval for basically the same structure

Maintenance therapy

Essentially a drug replacement therapy >>Have patients switch from a more dangerous/more addictive drug to a (hopefully) less dangerous/less debilitating/less addictive drug Aims to help addicts by maintaining a level of drug in their system that will prevent the uncomfortable and often intense withdrawal symptoms caused by abstinence from the drug they are trying to quit Maintenance therapy can go on indefinitely Maintenance therapy is the preferred first-line option in most cases because it is associated with better long-term prognosis and fewer side effects than detoxification Basically they acknowledge they are addicted to drug but know its harmful Switch to a less harmful addictive drug Want to prevent withdrawal symptoms And maintain individual on drug that doesn't have as much cognitive problems Not thought of as a cure - reduces overall risk

Does adding counseling help patients on buprenorphine/naloxone?

Extra counseling doesn't make that much of a difference A lot of people stopped participating in the study ~60% are no longer participating EMM3 = given medications 3x weekly and extensive counseling SMM3 = given medications 3x weekly and brief counseling SMM1 = given medications once weekly and brief counseling No clear benefit of extensive counseling Substantial attrition

Overall efficacy of detox

For heroin, relapse rates are ~91%. Even among individuals who manage to stay clean for one year following detox, the lifetime relapse rate for heroin has been reported to be as high as 85% For methamphetamine, one year relapse rates are ~61% For benzodiazepines, relapse rates are 40-60% For alcohol, ~90% of individuals relapse within 4 years of completing treatment

Sedative/anxiolytic summary

GABAa agonists tend to be effective at inducing sleep and reducing anxiety >>Barbiturates, alcohol, benzodiazepines However, these drugs carry a relatively high risk for mental and physical side effects In addition to clinical uses, these drugs are frequently abused

Detoxification

Goals of detox: >>Eliminate the drug from the body completely >>Overcome withdrawal effects completely to reduce the risk of relapse Methods of detox: >>Cold turkey - no drugs at all >>Drug tapering - use a drug with similar pharmacodynamics and a longer half life to make detox less severe (but longer) >>Use unrelated drugs to reduce symptoms of withdrawal >>Precipitate withdrawal using antagonists >>>>Typically performed under anesthesia Trying to completely eliminate drug from body Drug tapering - wants to limit withdrawal affect If a person is going through heroin withdrawal after 12 hours they'll start to experience withdrawal - if you treat with antagonist - it will cause severe withdraw symptoms to happen quickly - ripping off the bandaid

Potential causes of depression

Heritability estimates for major depression range from 33% to 45%. No genes have been identified that account for more than a very small percentage of patients with depression.

Sedative use and abuse - by the numbers

In 2008, 5.2% of Americans filled at least one prescription for a benzodiazepine In 1996, approximately 1.1 kilograms of lorazepam equivalents were prescribed per 100,000 adults in the US By 2013, approximately 3.6 kilograms of lorazepam equivalents were prescribed per 100,000 adults in the US The percent of outpatient doctor's visits that led to a benzodiazepine prescription doubled between 2003 and 2015 The number of continuing benzodiazepine prescriptions increased by 50% from 2005 to 2015

FLX and 5-HT depletion

In WT mice, minimal 5-HT depletion occurs In mice with a mutation in Tph2, depletion of 5-HT does occur

Buprenorphine and methadone during opioid withdrawal

In addition to being used in maintenance therapy, buprenorphine and methadone have been used during withdrawal from opioids With longer half lives than heroin (and prescription opioids), buprenorphine and methadone can reduce the severity of withdrawal symptoms Utilizes a dose tapering paradigm >>For methadone, this can range from 2-3 weeks to 180 days >>>>Longer dose reduction periods are associated with better outcomes

Xanax Lethality

In animals, the dose of Xanax that kills half of all animals that take it is ~1 mg/kg, which would be the equivalent of 80 mgs for a 180 pound human BUT... this assumes equal metabolism in humans and animals (not typically the case) AND... it assumes that there are no other drugs on board >>This number likely decreases significantly if Xanax is taken with alcohol

Mini Summary

In general, SSRIs do not appear to lead to presynaptic serotonin depletion, but this does appear possible when serotonin synthesis is inhibited 5-HTP does appear to be relatively well tolerated, but additional studies are required to evaluate its therapeutic efficacy when added to SSRIs

Do different SSRIs lead to different effects on extracellular 5-HT?

In general, not really Zoloft's starting dose is often 50 mg Prozac's starting dose is often 20 mg These drugs have different potencies, but dosing can essentially equalize them

Is 5-HTP + FLX safe?

In mice, it seems to be Studies in humans are ongoing

Benefits of methadone maintenance therapy

Increase retention in treatment Reductions in IV drug use Reductions in criminal activity Reduced HIV rates Lowered mortality due to opioid abuse

Benzodiazepines more info

Introduced in the 1960s Positive allosteric modulators of GABAa Different allosteric site compared to barbiturates Do not have any intrinsic agonist activity Probably why they are safer than barbiturates Anxiolytic is a term that is most commonly used with benzodiazepines Benzodiazepines are less effective than cognitive-behavioral therapy (CBT) in reducing chronic anxiety CBT or antidepressants (SSRIs) are typically used for longer-term treatments

Controversies surrounding benzodiazepines

Lawyers have tried to argue that Halcion has led people to commit crimes (murders) that they otherwise would not have Sometimes successfully At least one individual had her murder charges dismissed due to her Halcion intoxication at the time She also was able to sue Upjohn, the maker of Halcion for $21 million Settled out of court

Maintenance Therapy - Summary

Maintenance therapy is controversial in that it does not eliminate addiction, it just changes what the person is addicted to. Negative health consequences of long-term methadone along with social stigma and other factors inspire many individuals to want to be completely drug free Maintenance therapy is typically more successful than detoxification Not trying to eliminate addiction

Major depression - background

Major depression affects ~ 15 million Americans each year >>Depression is the leading cause of disability among Americans aged 15-44. >>Approximately 1 in 6 Americans will meet the criteria for depression at some point Existing treatments (i.e., SSRIs) fail in 30-50% of patients. Women experience depression at nearly twice the rate of men Stress is a major risk factor for many psychiatric diseases, including depression and anxiety disorders >>The biological factors that influence depression risk/stress susceptibility remain unknown

Pharmacokinetics of benzodiazepines

Many benzodiazepines are metabolized to pharmacologically active intermediates In these cases, the half life of the drug administered will not match the timeline of the drug's effects Desmethyldiazepam (nordiazepam) has a half life of ~60 hours Shorter acting benzodiazepines are not metabolized into nordiazepam

Maintenance Pharmacotherapies for opioid addiction

Methadone - a full mu opioid agonist >>Generally considered the most successful treatment for chronic opioid dependence >>But, methadone maintenance can carry a fairly substantial financial cost to individuals participating in this therapy >>>>Cost varies widely, but can be anywhere from $4,000-30,000+ per year >>Has a slow onset of action >>24-36 hour half-life A schedule II drug - have to go to the clinic every day to get your dose Adequate dosing ranges from 80 - 150 mg, typically beginning with a daily dose of 20-30 mg with increases of 5 or 10 mg until the optimal dose is reached Access is a challenge for methadone - especially for people without money Want people to take the minimum amount of methadone needed

Nicotine replacement therapy (NRT)

NRT monotherapy features a single means of nicotine replacement C-NRT refers to combined nicotine replacement therapy (i.e., both the lozenge and the patch)

Benzodiazepines and barbiturates are not the only GABA agonist depressants available

Newer, "second-generation anxiolytics" were developed in the 1990s Lack the chemical structure to be classified as benzodiazepines or barbiturates, but work in very similar ways

Pharmacotherapies for tobacco addiction

Nicotine replacement therapy (e.g., the nicotine patch or nicotine lozenges) Varenicline (Chantix) Bupropion (Wellbutrin)

Ambien (Zolpidem)

Not a benzodiazepine (lacks the structural elements) >>But works in a similar manner A GABA1A agonist Used as a sleep aid Has a half life of 2-2.5 hours

More uses for benzodiazepines

Occasionally used to prevent seizures Sometimes given intravenously to reduce seizures Used in alcohol detoxification Chlordiazepoxide is one of the more common for this Due to its extremely long half life

Is naltrexone effective?

Only very weak support (Minozzi et al., meta analysis) If this drug prevents the rewarding effects of opioids, why wouldn't it be effective? The general consensus is that naltrexone doesn't work because patients don't take it. There are at least 9 different slow release forms of naltrexone Depot injection formulations are also now in use. >>Receive a single injection, it lasts for ~4 weeks. >>The major side effects observed with depot naltrexone are related to the injection site (inflammation and pain) Subcutaneous implants are also being investigated

Suicide and Depression

Only ~15% of individuals with major depression are suicidal >>Most suicide prone individuals are or have been depressed The likelihood of suicide is highest when coming out of a state of severe depression During an intense episode of depression, individuals frequently lack the energy or drive to attempt suicide

Does chronic FLX deplete 5-HT?

Perhaps when 5-HT synthesis is impaired This might contribute to the failure of SSRIs in some patients

Uses of Barbiturates

Promote sleep Reduce seizures Surgical anesthesia Reduce anxiety Induce euphoria Fairly similar to alcohol with respect to the acute psychological effects Death penalties and physician-assisted suicides (pentothol) >>Extremely dangerous when taken with alcohol

Prozac (Fluoxetine)

Prozac is unique among psychiatric drugs because it was the first to be designed in a rational manner Eli Lilly set out to synthesize a specific inhibitor of serotonin reuptake and succeeded. But is Prozac safe and effective? "I'm on this medication that's going to become a really big thing, because it's quite a breakthrough. You don't know what it's done for me." The author wanted the title to be I Hate Myself and I Want to Die

Anxiolytic/Sedative Terminology

Sedative-hypnotics Tranquilizers Antianxiety drugs (anxiolytics)

Major Classes of Antidepressants

Selective Serotonin Reuptake Inhibitors (SSRIs) Norepinephrine Reuptake Inhibitors (NRIs) Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) Serotonin Antagonist/Reuptake Inhibitors (SARIs) Tricyclic antidepressants (TCA) Monoamine oxidase inhibitors (MAOIs) 'Glutamatergic' Agents

Safety issues with methadone therapy

Several studies have found methadone to be associated with significant cardiac effects; >>Specifically, a prolonged QT interval in the ECG of methadone patients. >>>>16.2% rate of QT prolongation in hospitalized methadone maintained patients compared to 0% in non-methadone maintained, drug-injecting patients (Ehret et al., 2006) Fanoe and colleagues (2007) reported that patients treated with methadone for heroin dependence exhibited syncope and QT prolongation Syncope is a temporary loss of consciousness caused by a fall in blood pressure. BUT, you have to compare this to safety issues related to continuing heroin abuse...

Side effects of SSRIs

Sexual Dysfunction - difficulty achieving orgasm, erections, loss of sexual desire Sleep disturbance - typically insomnia SSRI discontinuation syndrome: Flu, Insomnia, Nausea, Imbalance, Sensory disturbances, Hyperarousal Least likely to occur with Prozac, due to its long half-life Serotonin Syndrome: Typically does not occur unless multiple drugs are taken Agitation, fever, diarrhea, hallucinations, sweating, ataxia Can be fatal

Uses of benzodiazepines vary based on pharmacokinetic properties

Short-acting: sleep aids Rapid onset and 2-3 hour half-life This enables a rapid induction of sleep and allows for waking up after ~8 hours Long-acting: anxiolytics One does not want to have to give multiple doses throughout the day or for feelings of anxiety to return after ~8 hours

Naltrexone (continued)

Side effects are fairly rare, but they include headache, nausea, abdominal pain, dysphoria, and depression It was initially feared that naltrexone might lead to liver toxicity, but this has not been a significant problem with naltrexone treatment

Tolerance and Physical dependence

Significant tolerance to barbiturates occurs for at least 2 reasons: 1. The induction of CYP enzymes in the liver >>Lead to increased breakdown of barbiturates, lessens their effects 2. Neural and receptor-level adaptations Tolerance occurs more readily to the sedative effects of barbiturates than to the respiratory depression induced by barbiturates This decreases the therapeutic index

Concerns about long-term benzodiazepine use

Small studies as early as 1990 have found no benefit of benzodiazepines in the treatment of PTSD >>Other than temporary reduction in anxiety Gelpin and colleagues studied recent trauma victims (experienced significant trauma within the past 18 days) and the effects of benzodiazepine treatment over the following 1-6 months

Antidepressants work better than placebo

Some textbooks claim that 65% of patients respond to antidepressants vs 35% for placebo. This is VERY optimistic.

Opioid addiction and its treatments

The need for treatment Estimates of the number of heroin addicts in the US varies widely Anywhere from 60,000 to 1 million Most say between 0.1-0.2% of the US population This is much less than some parts of the world (~2% in Southern Asia) Over 2 million Americans are addicted to prescription opioids There are two major approaches to opioid addiction pharmacotherapy: Maintenance therapy Detoxification Most opioid-dependent individuals engage in both types multiple times when trying to quit

Benzodiazepine overdoses

The overdose rate increased from 0.58 per 100,000 in 1996 adults to 4.4 per 100,000 adults in 2016 >>~7.5 fold increase in benzodiazepine overdose rate over ~20 years In 2013, benzodiazepines were involved in ~31% of all fatal prescription drug overdoses

Pharmacogenomics

The study of how genes affect a person's response to drugs.

Pharmacokinetics of barbiturates

Their half-lives vary widely From 3 minutes for thiopental to ~48 hours for amobarbitol, pentobarbital and secobarbital to as long as 120 hours for phenobarbital Ultrashort acting barbiturates (like thiopental) can induce sleep within seconds Barbiturates can be detected in drug tests for up to several weeks (depending on the drug)

Black market benzodiazepines

They are available as generic drugs The cost of Xanax is often 40 cents to a dollar per pill Street value of Xanax is often $2-5 per pill A bar of Xanax is 2 mg For anxiety disorders, patients are often instructed to take 0.25 - 0.5 mg at a time, up to 3 times a day For panic disorder, this can be increased to 2 mg at a time up to 3 times a day

Cigarette addiction treatment summary

Treatments for cigarette addiction are much more successful than treatments for opioid addiction >>Still most smokers require multiple attempts This likely stems less from better therapeutics and more from the fact that cigarettes are less rewarding and the withdrawal symptoms are not nearly as bad

First-generation Antidepressants

Tricyclic antidepressants (TCAs) - imipramine (Tofranil), desipramine (Norpramin), Nortriptyline (Aventil), Amitriptyline (Elavil), Clomipramine (Anafranil) Monamine Oxidase Inhibitors (MAOis) - Isocarboxazid (Marplan), Tranylcypromine (Parnate), Selegiline (Emsam) These drugs were developed in the 1950s and 60s These drugs are at least as effective as the current treatments, but they have many more side effects.

Common benzodiazepines

Valium = diazepam > used to treat anxiety Xanax = alprazolam > used to treat panic attacks and phobias Librium = Chlordiazepoxide > used to help alcoholics go through detox Halcion = triazolam > used as a sleep aid

Barbiturates - examples

Veronal - diethylbarbituric acid Luminal - phenobarbital Amytal - amobarbital - "truth serum" Seconal - secobarbital Pentothal - thiopental - was commonly used for executions, now it is difficult to obtain Nembutal - pentobarbital - has also been used for executions

Is 5-HTP a wonder drug?

Why isn't it used as an antidepressant? Poor pharmacokinetic properties? ~2 hour half life Not patented? Slow release 5-HTP as an adjunct to SSRIs is now patented and being investigated Would this lead to terrible side effects?

Benzodiazepines

a family of drugs that contain a benzodiazepine ring

Syncope

a temporary loss of consciousness caused by a fall in blood pressure.

Neuroendocrine Hypothesis

depression is cause by the chronic activation of the HPA axis (excess levels of cortisol)

Barbiturates

drugs derived from barbituric acid

Tranquilizers

induce feelings of peace and tranquility; reduce agitation

Clinical Uses of TCAs:

mood disorders (e.g., major depressive disorder (MDD) and dysthymia) - anxiety disorders (e.g., generalized anxiety disorder, social phobia (aka social anxiety disorder), obsessive-compulsive disorder, including trichotillomania, and panic disorder), and as an adjunct in schizophrenia - post-traumatic stress disorder (PTSD) - eating disorders (anorexia nervosa and bulimia nervosa) and body dysmorphic disorder - personality disorders, including borderline personality disorder - Neurological disorders (e.g., attention-deficit hyperactivity disorder, Tourette's syndrome and Parkinson's disease) - Chronic pain, neuralgia or neuropathic pain; fibromyalgia, headache, or migraine - smoking cessation - irritable bowel syndrome, interstitial cystitis, nocturnal enuresis, - narcolepsy, insomnia, pathological crying and/or laughing - chronic hiccups, ciguatera poisoning

Antianxiety drugs (anxiolytics)

more commonly used term for tranquilizer

Sedative-hypnotics

provide a sense of calm and promote sleep

Inflammatory Hypothesis

systemic or brain inflammation leads to depression

Neurogenesis Hypothesis

too little adult neurogenesis in the hippocampus leads to depression

Serotonin Deficiency Hypothesis

too little brain serotonin leads to depression