Exam 2

What are the features and symptoms of depression?

Features: depressed mood, loss of pleasure and interest

Symptoms: sleep disturbances, weight changes, fatigue, self doubt, guilt, worthlessness, inability to think, concentrate, suicidal thoughts or actions

What are the major classes of drugs used to treat depression?

Tricyclic antidepressants (TCAs) were the first developed antidepressant drugs

Selective serotonin reuptake inhibitors (SSRIs) are the most used antidepressants

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most used antidepressants

Monoamine oxidase inhibitors (MAOIs)

Atypical agents

Supplements

Mood stabilizers

What is the mechanism of action of tricyclic antidepressants?

Block the reuptake of norepinephrine and serotonin into nerves

What is the mechanism of action of selective serotonin reuptake inhibitors (SSRIs)?

Selectively block the reuptake of serotonin into nerves

What is the mechanism of action of serotonin/norepinephrine reuptake inhibitors (SNRIs)?

Selectively blocks the reabsorption of serotonin and norepinephrine in the brain

What is the mechanism of action of atypical drugs (bupropion)?

Block the reuptake of various monoamine neurotransmitters, but the relationship of these effects isn’t clear

What is the mechanism of action of monoamine oxidase inhibitors (MAOIs)?

Blocks the activity of monoamine oxidase (enzyme that breaks down norepinephrine, serotonin, and dopamine in the brain and other parts of the body)

What is the use of St. John’s Wort?

Can be effective in treating mild to moderate depression

What is the action of St. John’s Wort?

Does not act as an inhibitory of neurotransmitter transporters like other antidepressants, reduce sodium gradient in neurons and indirectly interfere with neurotransmitter transport, photosensitivity reactions affecting the skin are associated with relatively high doses

If you already take SSRIs, what can St. John’s Wort cause?

Can cause excess serotonin in one’s brain and may produce serotonin syndrome

What is the Black Box Warning for antidepressants?

Antidepressants increase the risk of suicidal thoughts/behavior in children, adolescents, and young adults with major depressive or psychiatric disorders

What does someone considering antidepressants need to do before starting?

They have to balance their risk with the clinical need

What is required for a patient starting antidepressants?

Patients are observed closely for worse/unusual behaviors

What drugs are commonly used in bipolar disorder?

Lithium

What are the adverse effects of lithium at therapeutic doses?

At therapeutic doses: teratogenesis; hand tremor, polyuria, GI upset, fatigue

What are the adverse effects of lithium at excessive doses?

At excessive doses: coarse tremor, confusion, sedation, incoordination, hypotension, seizures, coma, ECG changes

What is the basis for lithium as bipolar treatment?

It is a mood stabilizer that has high efficacy and disrupts the inositol phosphate signaling pathway that causes mania by blocking the neurotransmitter release, it also has a low therapeutic index so it can be easily toxic if increasing doses

What is the role of dopamine and acetylcholine in control of motor function?

Maintains chemical balance in the brain’s basal ganglia to coordinate smooth, voluntary muscle movements

How are dopamine and acetylcholine altered in Parkinson’s disease?

A drop in dopamine disrupts the chemical balance and makes acetylcholine overly dominant and causes tremors and stiffness

What are the goals of antiparkinson drug treatment?

Increase dopamine or stimulate dopamine receptors and block muscarinic receptors-blockers

What are nursing implications antiparkinson drug classes?

Avoid high protein meals and vitamin B-6 supplements

What is the role of dopamine in psychoses?

Increased dopamine → positive symptoms of schizophrenia

Decreased dopamine → negative and cognitive symptoms of schizophrenia

What are the positive symptoms of schizophrenia?

Hallucinations, delusions, disorganized speech and thoughts

What are the negative symptoms of schizophrenia?

Anhedonia (inability to experience joy), avolition (lack of drive or motivation), blunted affect

What are the pharmacokinetics of antipsychotics?

High rapid oral absorption, highly lipophilic with high apparent volumes of distribution, go through extensive phase 1 metabolism by CYPs and subsequent phase 2 conjugations, metabolized in the liver and excreted in the urine and bile, therapeutic effects take several days to six weeks to emerge but side effects emerge immediately, little to no tolerance or dependence has been noted

What are the key differences between typical and atypical drugs?

Typical: blockage of dopamine D2 receptors, only contains dopamine

Atypical: target serotonin and dopamine sites, absence of extrapyramidal motor disturbances, reduce the symptoms of schizophrenia in patients that don’t reply to typical antipsychotics, better at reducing negative symptoms, absence of hyperprolactinemia (too much prolactin), contains dopamine and serotonin

What is the effect of typical antipsychotics in mesolimbic pathways?

Blocks D2 receptors, leading to reduced positive symptoms of schizophrenia

What is the effect of typical antipsychotics in mesocortical pathways?

Block D2 receptors; is already deficient in schizophrenia, so it causes cognitive symptoms or worsen negative symptoms

What is the effect of typical antipsychotics in nigrostriatal pathways?

Block D2 receptors, which produces EPS such as motor abnormalities (parkinsonism), tardive dyskinesia or hyperkinetic movement disorder

What is the effect of typical antipsychotics in tuberoinfundibular pathways?

Block D2 receptors, causing hyperprolactinemia

What can too many antipsychotics lead to?

Parkinson’s

What does too much Parkinson’s treatment lead to?

Psychosis

What is the effect of atypical antipsychotics in mesolimbic pathways?

Block D2 receptors is more robust than 5-HT2A (serotonin) antagonism and can help reduce positive symptoms

What is the effect of atypical antipsychotics in mesocortical pathways?

More dopamine release. Dopamine deficiency causes negative and cognitive symptoms; there’s more 5-HT2A receptors than D2 receptors so 5-HT antagonistic property is more profound than D2 receptor blocking property which can help improve negative symptoms

What is the effect of atypical antipsychotics in nigrostriatal pathways?

5-HT2A antagonists bind to 5-HT2A receptors disinhibiting the dopaminergic neuron and causes more dopamine to be released which can reduce EPS

What is the effect of atypical antipsychotics in tuberoinfundibular pathways?

Dopamine and serotonin do opposite, serotonin = release. Dopamine blocks the release of prolactin but 5-HT2A causes release of prolactin. Antagonistic properties of atypical antipsychotics cancel dopamine and serotonin action on prolactin release

What are the major typical antipsychotic drugs?

Typical:

Phenothiazines - chlorpromazine, thioridazine, flyphenazine, flupenthixol, pericyazine, pimozide, trifluoperazine, zuclopenthixol

Butyrophenones - droperidol, haloperidol

What are the major atypical antipsychotic drugs?

Aripiprazole (abilify), asenapine maleate (saphris), brexpiprazole (rexulti), clozapine (clozaril), iloperidone (fanapt), lurasidone (latuda), olanzapine (zyprexa), olanzapine/fluoxetine (symbyax), paliperidone (invega), quetiapine (seroquel), risperidone (risperdal), ziprasidone (geodon)

What are the major adverse effects for typical antipsychotics?

Chlorpromazine - low clinical toxicity, medium extrapyramidal toxicity, high sedative action and hypotensive actions

Fluphenazine - high clinical potency and extrapyramidal toxicity, low sedative action, very low hypotensive actions

Thiothixene - high clinical potency, medium extrapyramidal toxicity, sedative action, and hypotensive action

Haloperidol - high clinical potency, very high extrapyramidal toxicity, low sedative action, very low hypotensive actions

What are the major adverse effects for atypical antipsychotics?

Clozapine - medium clinical potency and hypotensive actions, very low extrapyramindal toxicity, low sedative action

Risperidone - high clinical potency, low extrapyramidal toxicity, sedative action, and hypotensive actions

Olanzapine - high clinical potency, very low extrapyramidal toxicity, medium sedative action, low hypotensive actions

Quetiapine - low clinical potency, very low extrapyramidal toxicity, medium sedative action, low to medium hypotensive actions

Ziprasidone - medium clinical potency, low sedative action, very low extrapyramidal toxicity and hypotensive actions

Aripiprazole - high clinical potency, very low extrapyramidal toxicity and sedative action, low hypotensive actions

What are the 4 classes of extrapyramidal side effects and treatments?

Parkinson-like: bradykinesia, rigidity, variable tremor masked facial expression, shuffling/slowed gait and movement

Akathisia: motor restlessness, not “anxiety” or “agitation”

Acute Dystonias: spasm of muscles of tongue, face, neck, back; might mimic a seizure - treatment includes a reduced dose or switch of antipsychotic drug to an antiparkinsonian agent like benztropine or trihexyphenidyl (antimuscarinics) or diphenhydramine

Tardive Dyskinesia (TD): oral-facial dyskinesia, widespread choreoathetosis, or dystonia which worsens when the person is agitated but is not seen while they are sleeping and can’t go away. they need to get up and move but they can’t move quickly so they shuffle their feet - prevention is crucial because treatments are unsatisfactory but include drugs that are inhibitors of presynaptic vesicular monoamine transporter type 2

What are symptoms of neuroleptic malignant syndrome (NMS)?

Muscle rigidity, stupor, hyperthermia, unstable blood pressure, myoglobinemia, can be fatal if not treated

What is the time of maximal risk for NMS?

Weeks; can persist for days after stopping neuroleptic

Proposed mechanism of NMS

Too much/rapid antagonism of dopamine receptors may contribute

What is treatment for NMS?

Stop neuroleptic immediately. Use dantrolene or diazepam as muscle relaxants, or bromocriptine (D2 agonist for parkinson’s if you’re no longer worried about psychosis)

What does the D2 receptor block in antipsychotics?

Blocks tuberoinfundibular pathway causing increased prolactin

What are some endocrine side effects of antipsychotics?

Gynaecomastia in men (breast development), galactorrhoea (producing milky substance from breasts when not pregnant or breast feeding), amenorrhea in women (no more menstruation), sexual dysfunction or infertility in men

Are endocrine side effects more pertinent in typical or atypical antipsychotics?

Typical

What are the cardiac effects with antipsychotic drugs?

Blockage of cardiac potassium channels → prolonged WT in ECG → ventricular arrhythmia and sudden cardiac death

Atypical antipsychotic metabolic abnormalities

Block of hypothalamic H1 histamine receptors, block of 5HT2c receptors, block of pancreatic beta cell M3 muscarinic receptors, histamine, muscarinic, and serotonin receptors

What are some anticholinergic effects of typical antipsychotics?

Atropine-like side effects: constipation, dizziness, confusion, hallucinations, urinary retention, blurred vision, dry eyes, orthostatic hypotension, dry mouth/throat, feeling hot without sweating, tachycardic

What is epilepsy?

The 3rd most common neurological disorder affecting ~1% of the worlds population;

What is the incidence rate of epilepsy?

300,000 people/year have an initial seizure (120,000 under 18 years old); recurrence risk following first unprovoked seizures range from 27-76%; there are 200,000 new cases of epilepsy each year; the highest incidence rate is <2yrs and >65yrs

What is the meaning of medically refractory or pharmacoresistent epilepsy?

Define seizures

Seizures are hyper-synchronous, high frequency discharges by a large group of hyper-excitable neurons that is evident during electroencephalographic (EEG) recordings

What are the two broad categories of seizures

Focal (partial): seizures that have limited spread

Generalized: focal seizures that are rapidly conducted to both hemispheres of the brain

A seizure can begin as a focal seizure and spread to both hemispheres and end as a generalized seizure

What are two categories of anti-seizure medications?

Broad spectrum: reasonable initial choices in most adult patients regardless of the type of seizure or syndrome - valproate, lamotigine, topiramate, levetiracetam, clonazepam, zonisamide

Narrow spectrum: restricted to patients who have focal epilepsy with partial and secondary generalized seizures - carbamazepine, phenytoin, phenobarbital, bagapentin, tiagabine, oxcarbazepine, pregabalin

What are the channels that depolarize and hyperpolarize the neuronal membranes in anti-seizure medication?

Voltage-gated ion channels (I NEED TO DO THIS LATER WHEN I CAN RE LISTEN TO NICOLES EXPLAINATION OF PAGE 25 ON THE ANTISEIZURE NOTES)

Identify the primary mechanistic target of phenytoin, carbamazepine, phenobarbital, valproic acid, and ethosuximide

DO THIS WHEN I HAVE THE BRAIN POWER TO UNDERSTAND THE CHART ON PAGE 29 OF THE ANTISEIZURE NOTES

What is a common side effect of antiseizure drugs?

MAIN side effect: sedation

What is the relationship of metabolism of phenytoin with dose and the effects on toxicity?

Metabolism is saturable, half-life decreases, steady state is not achieved in routine fashion, quick development of toxicity symptoms

Describe metabolism of anti-seizure medications and the effect of anti-seizure medications on CYP450s

If cytochromes are inhibited, it increases the toxicity of the medication and visa versa, if cytochromes are induced, the toxicity of the medication decreases

Describe the impact of anti-seizure medications on oral contraceptives

Inhibiting cytochromes are inhibited, the birth control is more potent and visa versa if the cytochrome is induced, birth control is less potent

Describe the effect of aspirin on phenytoin and valproic acid

What are the differences between purified cannabidiol and Hemp and Cannabis oils

Cannabidiol: oral solution to treat seizures in Lennox-Gastaut syndrome and Dravet syndrome to reduce seizures and convusions; highly soluble and metabolized in the liver by CYP3A4 and CYP2C19

Oils: not all are the same, CBD concentration is dependent on plant strain, content is unregulated and may change from lot to lot and some components can indue or inhibit CYP450s

Identify 2 reasons why thiopental can be used during the induction phase of anesthesia

1. It has high lipid solubility, which leads to a very fast onset of action

2. It rapidly induces a state of unconsciousness from which the patient cannot be aroused

Describe the relationship between the dose and CNS effects and how this differs between barbiturates and benzodiazepines

General relationship: both drug classes show progressive, dose-dependent CNS depression (sedation → hypnosis → anesthesia → coma)

Barbiturates: have a steep dose-response relationship and a narrow therapeutic index of 2-4 (small dose increases can rapidly lead to severe toxicity, deep coma, and fatal respiratory depression)

Benzodiazepines: have a flatter/safer dose-response curve and a wide therapeutic index of 100. has a limited maximal ability to depress CNS function on their own (high doses rarely cause fatal coma unless combined with other CNS depressants)

Compare the relative efficacy between muscle relaxants, benzodiazepines, and barbiturates

Barbiturates: high efficacy as general CNS depressants (used for anesthesia induction, seizure control, and severe insomnia)

Benzodiazepines: high efficacy for anxiety, panic disorders, sleep, acute seizures, alcohol withdrawal, and muscle spasms

Muscle relaxants: specific efficacy targeted at reducing skeletal muscle hypertonicity/spasms

Compare the relative safety between muscle relaxants, benzodiazepines, and barbiturates

Barbiturates: very low relative safety (narrow margin of safety, high suicide potential, profound respiratory depression)

Benzodiazepines: high relative safety and wide therapeutic margin

Compare the relative drug interactions between muscle relaxants, benzodiazepines, and barbiturates

Barbiturates: potent inducers of hepatic drug-metabolizing enzymes (CYP450) and exhibit strong additive CNS depression with ethanol and other depressants

Benzodiazepines: substrates of CYP3A4 (susceptible to inducers/inhibitors) and show additive CNS depression with other depressants (alcohol, opioids)

Compare the relative dependence liability between muscle relaxants, benzodiazepines, and barbiturates

Barbiturates: high potential for tolerance, physical dependence, abuse, and addiction

Benzodiazepines: low dependence and abuse liability except with long-term, high-dose usage (can cause withdrawal and require slow tapering)

How do barbiturates and benzodiazepines act on the receptor?

Allosteric activators (allosteric agonists) at specific sites on the GABA receptor complex to enhance GABA-mediated chloride ion channel activity (inc opening frequency, while barbiturates inc opening duration)

What are the factors that alter the time course of drug action for benzodiazepines?

Onset of action: determined heavily by lipid solubility (higher lipid solubility = faster onset and quicker entry into the brain)

Duration of action: determined by hepatic metabolism; may undergo extensive metabolism into pharmacologically active intermediates or metabolites (and active metabolites can accumulate in body fat and prolong clinical half-life)

Similarities of diazepam combined with midazolam, lorazepam, or alprazolam

All are GABA allosteric activators

Severe additive effect: combining any of them with diazepam produces additive CNS and respiratory depression, drastically increasing the risk of profound sedation, coma, and fatal respiratory depression

Differences of diazepam combined with midazolam, lorazepam, or alprazolam

Midazolam + Diazepam: pairs an ultra-short-acting anesthetic (midazolam half-life of 2-5 hrs) with a long-lasting agent that accumulates in body fat (diazepam half-life of >20-100 hrs), causing unpredictable, prolonged sedation depths

Lorazepam + Diazepam: pairs a medium-acting drug that is directly excreted without active metabolites (lorazepam) with a long-acting drug that produces active metabolite accumulation (diazepam)

Alprazola + Diazepam: pairs a short-acting agent tailored mainly for panic/anxiety (alprazolam half-life of 11 hrs) with a versatile long-acting agent that also covers muscle spasms and seizures (diazepam)

Describe how diazepam acts on the CNS, cardiovascular system, and respiratory system.

CNS: causes dose-dependent central nervous system depression, including relief of anxiety, sedation, hypnosis, amnesia, and coma

Cardiovascular system: minimal direct cardiovascular effects at normal clinical doses, but can cause hypotension (esp. if medically unstable or given rapidly IV)

Respiratory system: can cause respiratory depression, particularly in patients with pre-existing respiratory issues, hypoxemia, or when given in high/anesthetic doses

Describe the effect of diazepam when used in combination with other CNS depressants.

It produces additive CNS and respiratory depression

Combining it with alcohol, opioids, antidepressants, or other depressants significantly exacerbates sedation, cognitive impairment, and the risk of fatal respiratory depression

List the precautions for the use of benzodiazepine drugs

Caution in patients with respiratory problems (sleep apnea, hypoventilation), cardiac issues/instability, pregnancy (category D is teratogenic and causes neonatal CNS depression), and history of drug abuse/addiction

List the adverse reactions for benzodiazepine drugs

Daytime drowsiness, fatigue, ataxia, incoordination, dizziness, confusion, anterograde amnesia, tolerance, and physical/psychological dependence

List the drug interactions for benzodiazepine drugs

Additive CNS depression with alcohol, opioids, and other depressants; levels are altered significantly by CYP3A4 inhibitors and inducers

Identify what would occur if a patient on a CYP3A4 inducer is administered a benzodiazepine

The CYP3A4 inducer increases the metabolic breakdown of the benzodiazepine. This decreases half-life, increases its clearance, and lower blood levels, which results in a reduced and shortened therapeutic (anxiolytic) effect

Identify what could occur if a patient on a CYP3A4 inhibitor is administered a benzodiazepine.

The CYP3A4 inhibitor slows down the hepatic metabolism of the benzodiazepine. Increases half-life, decreases clearance, and raises blood levels, leading to more profound, prolonged sedative/hypnotic effects and an increased risk of respiratory depression

Recognize the benzodiazepine antagonist flumaenil and state when it is used

What is it: competitive antagonist at the benzodiazepine-binding site on the GABA receptor that reverses benzodiazepine effects

When it is used: to facilitate rapid recovery after benzodiazepine anesthesia/sedation or to manage acute benzodiazepine overdose and toxicity

Identify whether benzodiazepine anti-anxiety agents are preferred in young, pregnant, and elderly patients

Young patients: not preferred as a first-line long-term therapy (used carefully for single-use procedures)

Pregnant patients: contraindicated/not preferred (category D; crosses placenta, causing teratogenic confenital malformations early and neonatal CNS depression/withdrawal late-term

Elderly patients: cautioned due to high risk of excessive sedation, confusion, ataxia, and falls. If a benzo must be used, lorazepam is preferred bc it lacks active metabolites

What are similarities of diazepam and the ‘z’ drug zolpidem.

Both are scheduled IV GABA-modulating drugs that cause central nervous system depression

What are differences of diazepam and the ‘z’ drug zolpidem.

Zolpidem binds selectively to a specific subgroup of GABA receptors, acts primarily as a hypnotic to quicken sleep onset and maintenance, has inactive metabolites resulting in less daytime drowsiness, and lacks significant anxiolytic, muscle-relaxant, or anti-seizure properties

Compare and contrast the effects of diazepam (valium) and buspirone (anxiolytic).

Diazepam: GABA receptor agonist; fast acting anxiolytic, sedative, muscle relaxant, and anti-seizure agent; has cognitive side effects, potentiates CNS depressants, and carries dependence/abuse liability

Buspirone: 5-HT serotonin receptor partial agonist sued as an anxiolytic; unlike diazepam, it isn’t a controlled substance, causes minimal psychomotor/cognitive impairment, doesn’t potentiate CNS depressants, and has no dependence or abuse potential. However, it requires multiple weeks of dosing work and can’t be used for acute/single-dose anxiety

Compare and contrast the effects of diazepam (valium) and ramelteon (sleep aid).

Diazepam: broad GABA agonist used for anxiety and sleep with strong sedative, amnestic, and dependence properties

Ramelteon: melatonin receptor agonist used to reduce sleep latency. unlike diazepam, it isn’t a controlled substance, does not cause daytime drowsiness, and lacks abuse/dependence potential

Compare and contrast the effects of diazepam (valium) and suvorexant (sleep aid).

Diazepam: GABA agonist with borad depressant profiles (anxiety, muscle relaxation, seizures, sedation) and high dependence potential

Suvorexant: orexin receptor antagonist (DORA) that blocks wake-promoting orexin signaling to improve sleep onset and maintenance. Schedule IV drug that is well-tolerated without daytime drowsiness, physical dependence, or abuse liability like benzos