IP8 Exam 3

List the normal values Peacock would like us to use in questions.

List the normal values Peacock would like us to use in questions.

• HR: 60-80 BPM

• Temperature: 36.5-37.3 degrees C

• BP: 90/60 to 120/80

• RR: 12-18 Breaths per minutes

• Pupils: 2-4mm (light) and 4-8mm (dark)

Define toxicology and toxicity.

Toxicology is the study of nature, effects, and detection of poisons.

Toxicity is the overexposure to a substance causing an undesirable effect

Answer the following T/F questions:

(1) Every poison exposure will result in toxicity.

(2) Just because something is a natural substance doesn’t mean it is safe!

(1) F—>not all

(2) T

Poisoning can be classified as _______ or _______. Define those terms.

Intentional: self-harm (mostly seen as this), suicide, assault, homicide

Unintentional: not intending to do harm by the following ways—>misuse and abuse of medication, adverse events

Define poison and where it can come from.

Any substance capable of causing illness or death.

Legal and illegal drugs, natural and synthetic susbtances

Answer the following questions about the background of toxicology:

(1) What is the leading cause of accidental death in the US? What did it surpass ~10 years ago?

(2) What type of life-years are lost and why?

(3) How many cases of human toxic substance exposure were reported in 2020? What are becoming a small but growing fraction of reported exposure (<0.5%)?

(4) When does exposure most frequently occur? When are fatalities most common?

(1) Poisoning; motor vehicle accidents

(2) disproportionate because most people who suffer from poisoning are not at the end of their lives yet.

(3) 2.13 million cases; fatalities

(4) Highest exposure is in 1-2 year olds, with teens and adult exposure tending to be more severe; ages 20-69

List & describe the most common reported ingestions, from highest to lowest.

1. Analgesics

   1. Mostly associated with opioids (fentanyl) due to respiratory suppression. Very common to see OTC meds in children.

   2. Also a high risk with taking large amounts of Tylenol to cause self-harm.

2. Sedatives

3. Cleaning products

   1. This is more accidental in children.

4. Antidepressants

   1. Some people who take antidepressants are also suicidal, could be taking to many to self-harm.

5. CV drugs

   1. In particular calcium channel and beta blockers.

6. Alcohols

7. Anticonvulsants

8. Cosmetics

9. Antihistamines

10. Pesticides

Answer the following T or F questions:

(1) Most of the time when a patient presents to you with toxicity, the substance will be unknown.

(2) If you do know a substance a patient with toxicity has taken, it is more than likely that other substances may be involved.

(1) T

(2) T

What should you do during a physical exam for a patient presenting with toxicity?

• Vital signs: HR, BP, RR, Temp

• CNS (mental status): agitation, confusion, obtunded (suppressed responsiveness, desensitize), lethargic, paranoid, seizure

• Skin (color & appearance): diaphoresis (sweating), dryness, cyanosis (blue), flushing (red)

• HEENT (pupils & salivation): miosis (contracted pupil), mydriasis (enlarged pupil), nystagmus (eyes not coordinated), hyper salivation, dry mucous membranes

• Chest (heart & lungs): arrthymia (could be highly fatal), bronchorrhea (wet lungs), wheezing

• GI: peristalsis (wave-like motion), absent bowel sounds, abdominal tenderness, diarrhea

• GU: urinary retention, incontinence

• Musculoskeletal: myoclonus (important part of serotonin syndrome where there is abnormal muscle contractions), hyperreflexia, tremor

________ informs the ________. Define these terms.

Symptomology: set of symptoms characteristic of a medical condition.

Toxidrome: constellation of features characteristic of the type of exposure.

• Benefit is that this is a category, so we don’t have to figure out the exact singular agent.

What are the key questions that need to be answered with toxicology?

• What is the toxidrome?

• What are the signs and symptoms of this toxidrome?

• What is the specific toxic agent?

• What is the MOA of the toxic agent?

• What is the MOA of toxicity?

• What is the etiology/epidemiology of toxicity?

Why does it matter to know if someone has opioid poisoning?

So you can give them naloxone. If it is sedative poisoning, then naloxone won’t do anything because it doesn’t compete with the binding of sedatives.

Describe anticholinergic agent toxicity.

Agents: antihistamines (1st gen), Antipsychotics (FGAs, clozapine, olanzapine)

MOA: muscarinic receptor antagonism

Atropine is a competitive, reversible antagonist of muscarinic acetylcholine receptors

• Often useful as a reversal agent for cholinergic poisoning.

• Doesn’t work at nicotinic receptors

• Get the airway working first and then add this on.

What are the signs and symptoms?

• Mental status: agitation, hallucination, delirium

• Increased HR & BP. RR is indifferent/increase

• Increased temp

• Mydriasis (enlarged pupils)

• Decreased bowel sounds

• Decreased sweat

  • Person has dry skin and mucous membranes

• Flushing (red)

• Urinary retention

• Delirium

  • Hallucinations

  • Agitation

  • Carphologia

    • Lint licking behavior on clothes or sheets.

Describe cholinergic agent toxicity.

Agents: organic phosphorus insecticides, chemical warfare nerve agents, and pesticides

MOA: inactivate esterase enzymes, including acetylcholinesterase, which leads to accumulation of acetylcholine @ nicotinic, muscarinic, and CNS synapses.

• Basically acetylcholine acting everywhere.

Physostigime: acetylcholinesterase inhibitor

• If inhibiting acetylcholinesterase, then the total amount of acetylcholine will increase.

• See this used with an anticholinergic overdose.

What are the signs and symptoms?

• Mental status: confusion

• Constant/decreased HR, no effect on BP, RR

• No effect on temperature

• Miosis (constricted pupils)

• Increased bowel sounds

• Increased sweat (very wet)

  • Extra fluid everywhere, could drown in your own fluids because it is just that wet.

Fill in the blanks below regarding cholinergic toxicity:

(1) _______ is very important with this toxicity.

(2) The action at muscarinic receptors will give a person the killer B’s, which are _______.

(3) The action at nicotinic receptors will produce ______.

(4) The action at sympathetic receptors will produce ______.

(5) _________ receptors are outcompeting ________ receptors here.

(1) Airway protection (need to intubate as soon as possible)

(2) bradycardia, bronchorrhea, and bronchospasm

• Lungs not working, lungs filling with fluid, and heart not beating often can lead to death quickly

(3) paralysis

(4) seizures

(5) Muscarinic; nicotinic and sympathetic

Describe opiate toxicity.

Agents: all the opiates (like codeine, fentanyl, morphine, etc.)

What is the classic triad of opiate toxicity?

• Decreased level of consciousness, bradypnea (respiratory depression), miosis (constricted pupils).

Naloxone half-life is about 30 minutes to 2 hours, may need to re-dose.

What are the signs and symptoms?

• Mental status: depression and somnolence

  • common cause of presenting unresponsive or altered

• Decreased HR, BP, and RR (very)

• Decreased temperature

• Constricted pupils

• Decreased bowel sounds (constipation)

• Sweating normal/decreased

What are the antagonists used for opioid overdose?

Naloxone

• Shorter half-life than most opioids and will precipitate withdrawal.

• This will not work for sedative (like benzodiazepines) toxicity.

Ventilation

Describe serotonin syndrome/sympathomimetics toxicity.

Agents & MOAs:

• MAOIs, linezolid

  • inhibition of serotonin metabolism

• SSRIs/SNRIs, TCAs, duloxetine

  • blockade of serotonin reuptake

• Ampethatmines, buspirone, cocaine

  • increased serotonin release

• Drug interactions between multiple agents that have serotonergic effects.

Clinical manifestations: myoclonus (muscle effects), rigidity, hyperreflexia, altered mental status, diaphoresis, hyperthermia (>38 C), lactic acidosis, rhabdomyolysis

Diagnosed with the Hunter criteria

Treatment:

1. Removal of offending agent

2. Supportive care (fluids, temperature management)

3. Benzodiazepines & Cyproheptadine (mostly H1 & some serotonin antagonism)

   1. Benzos more often used

4. Choose anti-emetics carefully due to some of them having serotonin signaling.

Fill in the blanks below regarding acetaminophen toxicity:

(1) Leading cause of _________ in the US.

(2) Recommended dose limits for outpatient are ______, and recommended dose limits for inpatient are _____.

(3) Refer to a health-care facility with ingestions of more than _______ in adults and _______ in children.

(4) Take _______ 4 hours post ingestion.

(5) Obtain the following at admission and then repeat at 24-hour intervals: ___________ and ________.

(6) A good way to decrease acetaminophen toxicity would be to _______ it.

(7) Toxicity is not an increase in acetaminophen’s ______, it is _________ from depletion of conjugate metabolites. This is what prevents people from feeling immediate effects.

(1) liver failure

(2) 3 g/day; 4 g/day

(3) 150 mg/kg (~10g); 200 mg/kg

(4) serum acetaminophen concentration

(5) baseline liver function tests (AST, ALT, bilirubin, INR); serum creatinine concentration

(6) blister pack

(7) action; hepatotoxicity

Recognize the phases of acetaminophen toxicity presentation.

1. Phase 1 (12-24 hours)

   1. N/V, diaphoresis, anion gap acidosis in massive ingestion only

      1. Kids are a little safer from overdoses because they have a higher risk of vomiting earlier and their metabolisms are different.

2. Phase 2 (24-72 hours)

   1. Seeing clinical improvement, might have some right upper quadrant pain. Will start to see lab abnormalities in hospital.

3. Phase 3 (72-96 hours)

   1. Hepatic encephalopathy, cerebral edema, coagulopathy, metabolic acidosis.

      1. Liver damage is not treatable, but you can survive.

4. Phase 4 (5-14 days)

   1. Death due to multi-organ failure

   2. If the patient survived, they will have hepatic dysfunction that will resolve slowly.

What is acetaminophen’s toxic metabolite? Explain how it is metabolized.

NAPQI. About 5% of acetaminophen will get metabolized into this by CYP450-2E1, which is what creates toxic reactions by saturating pathways, stealing sulfates wherever possible, and depleting glutathione.

How does NAPQI get cleared from the body?

Via enhanced sulfate conjugation by NAC.

What is a great example of a drug that will increase CYP450-2E1, which will thus increase the amount of NAPQI in the body.

Alcohol; very dangerous for a patient to take large amount of Tylenol if they also have alcohol use disorder.

Describe NAC.

This replaces glutathione in order to enhance sulfate conjugation with NAPQI to reduce it.

Most useful if given within 8 hours and won’t be as useful in liver failure.

Describe calcium channel blocker toxicity.

Dihydropine/nondihydropine selectivity is lost.

Decreased inotropy and chronotropy

• Inotropy is the strength and intensity of a heart contraction. Decreasing this leads to poor perfusion and lower ejection fraction.

• Chronotropy is associated with HR and speed. Decreasing this will lead to bradycardia.

Hyperglycemia is the most important prognostic and severity indicator.

• Get a BG on admission is this toxicity is suspected.

• Insulin is not being secreted because Ca2+ is not docking and releasing it, which increases the amount of glucose in the blood stream.

Giving a high dose of insulin will restore glucose active transport and prevent shock. Can also give a dose of epinephrine to get the heart beating again.

Describe beta-blocker toxicity.

Specificity for the different beta receptors is lost in overdose.

The lipophilicity of the agent will determine how impacted the CNS will be.

• Propranolol has the highest seizure risk because it is the most lipophilic.

These have a very low therapeutic index, so big risk in children.

• 1 pill could be too much in a child.

Causes hypoglycemia due to inhibition of glycogenolysis. Na+ channel blockade results in prolonged QRS interval and arrthymias. K+ blockade results in a prolonged QTc interval.

Differentiate calcium channel blocker toxicity and beta blocker toxicity.

Beta blockers

• Often present with altered mental status and hypoglycemia.

Calcium channel blockers

• Generally present without CNS effects and hyperglycemia.

Bradycardia, conduction block & heart failure at high doses are all shared symptoms.

What causes salicylate (aspirin) poisoning?

Not the MOA, the off-target effect of uncoupling of oxidative phosphorylation by salicylates and dinitrophenol. By this happening, we are separating energy generation process from the ATP synthesis process, and protons flow down without doing any work. This results in wasting energy and getting heat as a waste product (decrease in energy production & hyperthermia to give us a fever), and having to do glycolysis to scrape more energy from the system.

Glycolysis will result in lactic acidosis.

Many forms of salicylates, such as combination agents, oil of wintergreen, bismuth subsalicylate (pesto bismol—>especially concerning in children due to the pink color).

What are the clinical manifestations of salicylate toxicity, typically seen with levels > 30 mg/dL (like the whole bottle)?

• GI: abdominal pain and vomiting

• Respiratory alkalosis (hyperventilation) and metabolic acidosis (lactic acid production)

• CNS: tinnitus, brainstem-mediated hyperventilation, delirium

• Acute lung injury

  • This is secondary to hyperventilation

Explain the timeline of salicylate toxicity.

Serum salicylate levels may not peak for more than 24 hours post-ingestion, especially with enteric-coated forumlations.

T or F: it is important to consider herbal and other non-FDA approved supplements when taking a patient history.

T

Give an example of a scenario where multiple substances where ingested, which then complicates the clinical picture.

A patient comes in sedated, obtunded, not super responsive, and dry. Kind of low HR and BP, normal pupils. This sounds like a sedative toxidrome.

After patient gets admitted, their kids call and say they found Tylenol PM by bed. Now we have Benadryl in the equation, which is an anticholinergic agent.

We don’t have any symptoms of acetaminophen, yet that is the more dangerous substance taken. We see effects from the drug that was taken, but the highest risk comes from Tylenol, which we don’t see symptoms of.

Give supportive care (airway breathing), check BS, and do labs for acetaminophen toxicity. If it is acetaminophen toxicity, then give NAC.

What are pralidoxime and cyproheptadine used for?

Pralidoxime reactivates cholinesterase via dephosphorylation and is used in combination with atropine to reverse the nicotinic effects of organophosphate poisoning.

Cyproheptadine is a histamine H1R antagonist that is used off-label only for serotonin syndrome.

What is the poison help number?

1-800-222-1222

List the role of the pharmacist in toxicology.

• In triage, can help with monitoring vitals, pick up on toxidrome and assist with labs.

• In community, can inform patients of max doses of OTC meds.

• Help in predicting what could happen or symptoms that could arise.

• Give drug information—>patient took drug X, this is what will happen

• Take medication histories

• Identify medications based on characteristics via drug databases.

• Education about antidotes

• Poison prevention education

Explain what to do for the initial evaluation of the patient.

-For the primary exam, do the following:

• Airway

  • Wanting them to maintain their airway

• Breathing

• Circulation

  • Having a HR

• Disability

  • Could what they have took be affecting their organs?

• Exposure

  • Are they still being exposed, do they get something on their skin or eyes?

-Check the following vital signs:

• BP, HR, RR, Temp

• Mental status

-Take the following labs:

• Glucose

  • Helpful with hypoglycemia

• Electrolytes

• BUN

• CBC

  • Maybe not as helpful because might not see much of an effect in these values

• Acetaminophen/aspirin

  • Because you can get these OTC anywhere

• LFTs

• UDS

• Pregnancy test if they are of childbearing age and female

-Also do a scene check/pill count to be able to ballpark how long it’ll last:

• What agent, what time, and how much was taken.

What are the agents used for decontamination?

-Activated charcoal: down the throat or NG tube

• This prevents absorption of the toxic agent and should be used within the first hour of ingestion for maximum benefit, but some ER products or larger amounts may still benefit from delayed administration of activated charcoal.

• Does NOT work with charged particles, like iron or lithium.

• CIs:

  • If patient is unable to maintain their airway (intubation)

  • If patient has a GI perforation (like a tear in their stomach), then the charcoal might get out of the GI tract

  • If patient took a caustic agent (like bleach) and endoscopy is essential, then all the endoscopy will show is the black charcoal.

-Whole bowel irrigation: like a colon prep, give patient light PEG to sweep out system. Will work with charged particles.

-Gastric lavage: not recommended, but instilling saline in NG tube and sucking it down

-Ipecac: not recommended because it induces vomiting which could make a patient aspirate.

Describe enhanced elimination (dialysis).

Most patients don’t need this, but if they get AKI due to overdose then they will, and it is also very helpful with aspirin overdose.

Molecule size: smaller, those will be easier to remove.

Vd: smaller, as it will remain in the blood and won’t go into the tissues.

Protein binding: low

Lipophilicity: low (more hydrophilic)

List the supportive care options for a patient with toxicity.

-IVF (to help BP and kidneys), oxygen

-If hypotensive, then give vasopressors like NE

-If hypoglycemic, then give dextrose

-If having a seizure, give a benz like lorazepam

-If experiencing QTc prolongation, then discontinue the offending agent (hopefully this will resolve the prolongation), and replenish electrolytes (K, Mg, Ca)

-If experiencing a wide QRS complex, then give sodium bicarb, or lidocaine for refractory cases.

For a patient with beta blocker/calcium channel blocker overdose, recommend treatment.

Initial Supportive Care

• If patient is hypotensive, give IVF and vasopressors

  • If patient is having refractory hypotension/in combination with vasopressor therapy, then give high-dose insulin therapy (+ dextrose)

• If bradycardia, give atropine to increase the HR

• If having a seizure, give a benzo

Data to support calcium IV given with CCB overdose (can help overcome blockade) > BB overdose (this won’t hurt the patient if given)

Data to support glucagon in BB overdose > CCB overdose

What problems can arise with high dose insulin therapy?

• Hypoglycemia is the biggest risk, but giving dextrose with the insulin can help prevent that.

• If giving both insulin + dextrose and patient is still hypoglycemic, then maintain them on their high dose insulin dose and give more dextrose infusion.

• Hypokalemia can also result from this therapy, so treat that with supplementation prior to starting infusion.

• Volume overload

Glucagon leads to increased ________ and improved _______.

contractility; hemodynamics

Compare and contrast IV and PO NAC.

21-hour method for IV and 72-hour method for PO.

Given the APAP nomogram, assess the need for treatment for a given patient.

Treatment line: if a patient is below this, then no treatment is needed. If a patient is above this, then needs to be treated with NAC.

High-risk line: if patient falls here, then give a high dose of NAC.

The nomogram is used to predict the likelihood and severity of hepatotoxicity caused by an acute ingestion.

Levels are measured 4 or more hours after time of ingestion. Measurement between 1 and 4 hours after ingestion is helpful only to exclude ingestion of APAP. If time of ingestion is unknown, measure APAP level immediately and again 4 hours later.

Nomogram is most useful for immediate-release products.

How should you manage salicylate (aspirin) toxicity?

• Fluid replacement with IVF

• Urine alkalization

  • Salicyclic acid is a weak acid and is ionized an alkaline environment. The kidney has no specific uptake for salicylate ions and reabsorption of charged molecules is limited, leading to increased elimination.

  • Give sodium bicarb for this. Higher the urine pH, the more aspirin that is eliminated.

  • Complications that could prevent urine alkalization are hypokalemia and fluid depletion.

• Dialysis

  • This is 1st/2nd line and is very effective for salicylate poisoning.

What are some resources you can use if a patient presents with toxicity?

Goldfrank’s Toxicologic Emergencies

Lexi-Tox

Micromedex

Poison Center

Give examples of patient centered language with negative and positive connotations.

Negative

-Describing patients as crazy, shizophrenic, drug abuser/junkie, committed suicide

Positive

-Acutely psychotic or dysregulated, patient with schizophrenia, non-suicdial self-injury, completed suicide or died by suicide

Define schizophrenia.

A severe, chronic brain disorder that affects how a person interprets reality. It is characterized by extremely disordered thinking and behavior that impairs daily functioning.

T or F: A patient with schizophrenia will remain on treatment life-long.

T

Review schizophrenia epidemiology.

• Common in about 0.3-0.7% of patients (24 million)

• Equal prevalence in all genders

• Onset in late teens to mid-30’s

• Among the top 10 global causes of disability

Review schizophrenia pathophysiology.

Not fully understood, but multiple hypotheses like genetics (1st degree relative), environment (stress & illness in pregnancy), substance use (cannabis in teens/young adulthood), and neurobiology.

Review the schizophrenia diagnostic criteria.

Must have more than 2 of the following for 1-month: delusions, hallucinations, disorganized speech.

Must have overall symptoms for 6 months.

List the acute and maintenance goals of schizophrenia therapy.

Acute goals are: reduce the severity of psychosis and associated symptoms, return to the best level of functioning, and formulate short and long-term treatment plans.

Maintenance goals are: maintain or improve the patient’s level of functioning and quality of life, and continue to monitor for adverse treatment effects.

T or F: There is preference amongst 1st generation and 2nd generation antipsychotics.

F; no preference

Summarize the CATIE trial.

Purpose: test the effectiveness of antipsychotic drugs in patients with chronic schizophrenia.

Result: patient receiving olanzapine experienced a longer time to discontinuation (stayed on the med longer) compared with the other antipsychotic medications, but the patients on olanzapine experienced greater weight gain, hyperglycemia, and hyperlipidemia (metabolic syndrome).

Limitations: olanzapine dose used was 30 mg, while the FDA max approved is 20 mg.

Differentiate the dopamine (DA) pathways.

-Nigrostriatal: blockage may cause EPS, tardive dyskinesia.

-Mesocortical: blockade may worsen negative and cognitive symptoms.

-Tuberoinfundibular: blockage may increase prolactin (aids in lactation, development of breasts in men).

-Mesolimbic: blockage may decrease positive symptoms (movement).

What are all the symptoms that encompass EPS?

Dystonia: muscle contractions which can occur in any skeletal muscle.

Akathisia: feeling of anxiety and intense inner restlessness (“crawling out of my skin”).

Pseudoparkinsonism: tremor, shuffling gait, bradykinesia.

Tardive Dyskinesia: involuntary movement of the mouth and face, considered irreversible.

Differentiate FGAs and SGAs.

FGAs

• Typicals

• Dopaminergic activity, more likely to cause EPS

• Fewer drug-drug interactions

SGAs

• Atypicals

• Dopaminergic and serotonergic activity, more likely to cause metabolic symptoms

• More drug-drug interactions

BBW: Increased risk of death in older adults with dementia-related psychosis.

______ the Ki, the higher the binding affinity. ______ the Kd, the stronger the binding.

Lower; lower

What does looking at the receptor binding profiles help us do?

Come up with treatment recommendations.

Answer the following questions related to FGAs:

(1) Put the FGAs in order of highest potency to lowest potency.

(2) State the medication pearls for fluphenazine.

(3) State the medication pearls for haloperidol.

(4) State the medication pearls for loxapine.

(5) State the medication pearls for chlorpromazine.

(6) Which of them come in tablets?

(7) Which of them come in SAIs?

(8) Which of them come in LAIs?

(1) Fluphenazine, haloperidol (comes in a LAI), loxapine, chlorpromazine (this is NOT for maintenance).

(2) High risk for EPS & sexual dysfunction.

(3) High risk for EPS & sexual dysfunction; minimal risk for sedation, weight gain, anticholinergic effects, and hypotension.

(4) Has 5HT2A antagonism, which reduces the risk of EPS and improves negative/cognitive symptoms.

(5) Highest risk for hypotension, sedation, and weight gain; most commonly used in acute agitation.

(6) all

(7) fluphenazine, haloperidol, chlorpromazine

(8) fluphenazine, haloperidol

What should you always do first with shizophrenia therapy?

Establish safety and efficacy FIRST with a proper trial of oral medication(s).

Answer the following questions about SGAs:

(1) State the pearls of risperidone.

(2) State the pearls of paliperidone.

(3) State the pearls of olanzapine.

(4) State the pearls of quetiapine.

(5) Which of them come in a tablet?

(6) Which of them come in a SAI?

(7) Which of them come in a LAI?

(1) Has a moderate risk of EPS that is dose dependent (higher dose, higher risk); associated with hyperprolactinemia (affects fertility and sex drive); is a CYP2D6 substrate, so decrease dose by 50% in the setting of a strong CYP2D6 inhibitor like fluoxetine, paroxetine, or bupropion.

(2) Is an active metabolite of risperidone, but is NOT a CYP2D6 substrate because it is already active; must do renal dose adjustments; most associated with hyperprolactinemia (all patients will have elevated prolactin, but base medication decision off clinical symptoms—>if patient is fine, then the mildly elevated levels are okay!); high risk for hypotension.

(3) High risk of sedation and weight gain; often used as an adjunct for mania due to sedation properties to reset the sleep cycle; is metabolically offensive, has the highest incidence of DM—>not considered 1st line for maintenance treatment in antipsychotic naive patients due to its metabolic effects.

(4) High risk for sedation, weight gain, anticholinergic effects; metabolically offensive, increases LDL/TGs

(5) all

(6) olanzapine

(7) risperidone, paliperidone, olanzapine

What is partial agonism? Give an example of a medication that is a partial agonist.

-Will act as a functional antagonist in the mesolimbic dopamine pathway, where excessive dopamine activity is thought to cause positive symptoms, but show functional agonist activity in the mesocortical pathway, where reduced activity is thought to be associated with negative symptoms and cognitive impairment.

-Aripiprazole (Abilify)

What will Abilify worsen if added to an agent that tightly binds dopamine, like haloperidol?

It will worsen psychotic symptoms because haloperidol is already blocking dopamine.

Answer the following questions about SGAs/TGAs:

(1) State the pearls of aripiprazole.

(2) State the pearls of ziprasidone.

(3) State the pearls of lurasidone.

(4) Which of them comes in a tablet?

(5) Which of them comes in a SAI?

(6) Which of them comes in a LAI?

(7) State the pearls of clozapine.

(1) Has the highest risk for akathisia; is a CYP3A4 & CYP2D6 substrate, so decrease dose by 50% in the setting of a strong CYP2D6 inhibitor like fluoxetine, paroxetine, or bupropion, or a CYP3A4 inhibitor; can decrease prolactin levels; may decrease the effectiveness of other antipsychotics when used in combination

(2) Has a low-moderate risk of EPS due to the potent 5HT2A antagonism and 5HT1A agonism; must be taken with 500 or more kcal for proper absorption, so don’t dose if patient has food problems; BBW of QTC prolongation (~40 msec).

(3) Has a low-moderate risk of EPS due to potent 5HT2A antagonism and 5HT1A partial agonism; is a CYP3A4 substrate, so requires dose adjustments in the setting of strong CYP3A4 inhibits and inducers like carbamazepine; must be taken with 350 or more kcals.

(4) all

(5) aripiprazole, ziprasidone

(6) aripiprazole

(7) Is the most effective antipsychotic, BUT IS NOT 1ST LINE (indicated for treatment resistant—>failure of 2 APs); must be re-titrated if missed medication for 2 or more days due to risk of sudden cardiac collapse and respiratory arrest; REMS program for ANC monitoring; has minimal risk of EPS, drug of choice in tardive dyskinesia; common SEs—>QTc prolongation, weight gain, excessive drooling, constipation.

What is the #1 cause of clozapine-related deaths? What is the BBW for clozapine?

Constipation

Agranulocytosis, myocarditis (within 1st month), orthostasis, and seizure risk. Increased risk of death in older adults with dementia-related psychosis.

What is responsible for clozapine’s metabolic effects?

Norclozapine (this is not psychoactive)

What should you always before initiating clozapine? Why?

Assess cigarette smoking status because inhaling combusted substances induces CYP1A2 and can decrease serum clozapine levels by up to 50%. Conversely, a patient may develop clozapine toxicity if they suddenly stop smoking and remain on their previous dose.

Smoking is NOT a contraindication, it just must be accounted for.

What is the conclusion of adding fluvoxamine to clozapine?

Treatment with fluvoxamine can alleviate weight gain and metabolic abnormalities without sacrificing the clinical effect. Increases levels of clozapine and decreases levels of norclozapine.

Which APs have LAI options?

Fluphenazine, haloperidol, risperidone, paliperidone, olanzapine, aripiprazole

What APs are preferred in special populations?

Pregnancy

• Haloperidol and risperidone are often used as 1st line due to having the most data for use.

Parkinson’s Disease

• Quetiapine and clozapine are preferred

What are the common ADEs for FGAs and SGAs?

Sedation, headache, GI upset, QTc prolongation, NMS

What are the monitoring parameters for medication use in schizophrenia?

-Complete metabolic panel to asses renal (SCr) and hepatic function (AST, ALT, Alk phosphatase)

-CBC

-BP & HR

-UDS, particularly in the setting of new onset psychosis or psychiatric decompensation

-AIMS to assess for the development of tardive dyskinesia

What APs are the least likely to cause metabolic syndrome?

Aripiprazole, lurasidone, ziprasidone

What APs have a moderate risk of causing metabolic syndrome?

Risperidone, paliperidone, quetiapine

What APs are the most likely to cause metabolic syndrome?

Olanzapine, clozapine

What is the BBW for ALL antipsychotics?

Increased risk of death in older adults with dementia-related psychosis.

1.5-1.7x increased risk of mortality with their use in the setting of dementia

SGAs are linked to a ________ of cerebrovascular events.

2-3x fold higher risk

What concept should you understand regarding the general management of antipsychotic ADEs?

-If the ADE is not causing the patient distress, then there is no need to change the medication. Can offer treatment for the ADE.

-If the ADE is causing the patient distress, can decrease the dose, change AP, or offer treamtent for the ADE. If the ADE persists after a dose decrease, then change the AP.

What are the most intolerable ADEs reported for antipsychotics?

ED, amenorrhoea, sexual dysfunction, hyperprolactinaemia, constipation, and galactorrhoea (lactation from the breast unrelated to pregnancy or lactation).

What occurs in 30-80% of all people taking antipsychotics and has been identified as one of the main reasons people stop taking antipsychotics? Give treatment options for this.

Sexual dysfunction

Decrease AP dose, switch AP to an agent with less DA afinity/less serotonergic antagonism, or if ED is the issue then can offer a PDE-5 inhibitor (like Viagra).

Answer the following questions regarding the management of ADEs in schizophrenic patients:

(1) What is the management for dystonia (NOT ACUTE)?

(2) What is the management for pseudoparkinsonism?

(3) What is the management for tardive dyskinesia?

(4) What is the management for hyperprolactinemia?

(5) What is the management for akathisia?

(1) PO Benadryl or benztropine

(2) PO Benadryl or benztropine

(3) Decrease or stop the AP and switch to clozapine or a VMAT inhibitor (like valbenazine)

(4) No defined treatment options, could switch to another AP

(5) PO propranolol preferred if patient can tolerate, but can use lorazepam in refractory cases.

Describe TD.

Characterized by repetitive, involuntary, purposeless movements and considered irreversible.

Risk factors include long term use of APs and use of FGAs.

AIMS is used to monitor and assess for this.

Give examples and treatment options for the psychiatric emergencies mentioned in the lecture slides for schizophrenia pharmacotherapy.

Acute Dystonia

-Involuntary contractions of the muscles

-Treatment: benadryl 25-50 mg IV/IM x 1, may repeat OR benztropine 1-2 mg IV/IM x 1, may repeat.

NMS

-Autonomic instability and bradyreflexia (slow muscle movements)

-Can occur due to dopamine antagonist OR withdrawal from dopamine agonist

-Treatment: Stop all antipsychotics and give supportive care, like physical cooling (ice pack, fan, IV frozen fluids), hydration, and BZDs/dantrolene to relax the muscles

Fill in the blanks below regarding hints to proper medication selection in schizophrenia:

(1) If a patient has a BMI of 55, DON’T use ______ or _______ as 1st line.

(2) If a patient has a history of acute dystonia with low-dose haloperidol, DON’T use ______.

(3) If a patient has treatment-resistant schizophrenia and suicidal ideation, then suggest _______.

(1) olanzapine; quetiapine

(2) haloperidol

(3) clozapine

Define bipolar disorder (BPD).

A brain disorder that causes unusual shifts in mood, energy, concentration, and the ability to carry out day-to-day tasks.

Have period of extremely “up” elevated moods (mania or hypomania), and periods of extremely “down” sad moods (depression).

Review the epidemiology of BPD.

-Lifetime prevalence of 2.6-4.4% (more common than schizophrenia)

-Symptom onset typically occurs in late adolescence or early adulthood

-Bipolar I occurs equally in persons regardless of sex identified at birth

-Bipolar II disorder is more common in persons with uteruses

-11-20% of patients with BPD die by suicide (2nd most common)

Describe the clinical course of BPD.

-Episodic, lifelong illness with a variable course

-Patients with untreated BPD may have >10 episodes of mania and depression during their lifetime

-Variability is the hallmark of this illness

Fill in the blanks below regarding the BPD:

(1) Bipolar I is associated with _______.

(2) Bipolar II is associated with ________.

(1) mania and depression or hypomania

(2) hypomania and depression

Review the diagnostic criteria for BPD.

MDD: must have 5 or more symptoms (including depressed mood and decreased interest/pleasure in normal activities) in the same 2-week period.

Mania: marked impairment of social or occupational functioning, abnormally elevated mood for at least 1 week.

Hypomania: abnormally elevated mood for at least 4 days with NO marked impairment.

What are the most common misdiagnoses for BPD?

1. MDD

   1. Most people present first with depression and are put on a SSRI/SNRI, which will help the depression but will probably put the patient into mania or hypomania.

2. Schizophrenia

3. OCD

4. Other anxiety disorders

List the goals of therapy for BPD.

Mania/Mixed Episodes

• Control symptoms to allow a return to usual levels of psychosocial functioning.

• Provide education regarding bipolar disorder

• Enhance patient involvement in treatment

• Minimize functional impairments

Acute Depression (this is where we see life-ending attempts)

• Achieve remission of the usual symptoms of major depression and return the patient to usual levels of psychosocial functioning.

Maintenance

• Prevent relapse and recurrence

List examples of mood stabilizers and antipsychotics for BPD pharmacotherapy.

Mood stabilizers include lithium, VPA derivatives, CBZ/OBZ, lamotrigine

Antipsychotics include FGAs and SGAs

Answer the following questions regarding mood stabilizers for BPD:

(1) State the drug pearls for lithium.

(2) State the drug pearls for VPA derivatives.

(3) State the drug pearls for lamotrigine.

(4) State the drug pearls for CBZ/OXB.

(1) Effective for both I and II, also has anti-suicidality benefits. Dose depends on renal and drug interactions.

• Increases neurotoxicity

• Baseline monitoring includes CBC, TSH (for hypo or hyperthyroidism), BMP (for renal toxicity), UPT

• Has a very narrow therapeutic index (0.6-1.0) and can utilize linear kinetics to predict therapeutic levels with new doses.

  • If patient is not in this range but mania is controlled, then it is okay!

• Drug of choice for mania in pregnancy, found not to increase risk of Epstein’s anomaly.

(2) These are more effective for I (controlling mania) and does cause neural tube defects and ~10 points decreased IQ in babies.

• Baseline monitoring includes CBC, CMP (for hepatotoxicity), UPT (should not be used in patients with a uterus who can conceive).

• Has non-linear kinetics, so can’t predict a level based on a level.

• The different formulations ARE NOT EQUIPOTENT.

  • The ER formulation is about 25% less bioavailable than the DR formulation, so not getting enough if patient is switched from DR to ER, which could lead to de-stabilization.

  • Getting too much if switching from ER to DR.

(3) This is only approved for II, NOT approved for the acute treatment of mania. Follow a titration schedule because SJS/TENs risk.

• SLOW titration of about 6 weeks due to risk of SJS/TENs.

• Must be re-titrated if >5 days of meds are missed

• Mood stabilizer of choice (for depressive episodes) in pregnancy.

(4) Has a very high risk of SJS, so avoid in patients with HLA-B*1502. There are many drug-drug interactions, which has made these fall out of favor (like 3rd & 4th line). Hyponatremia is a big side effect, with OXB»CBZ.

• Requires hepatic and renal dose adjustments

• Baseline monitoring includes CBC, CMP, UPT

What are the adverse effects of Lithium?

• Acne, rash

• Increased thirst (polydipsia), N/V/D

• Hypo & hyperthyroidism

• AKI (typically not at therapeutic doses), nephrogenic diabetes insipidus, increased urination (polyuria)

List the drug interactions that will increase or decrease lithium concentrations.

Increase Li+ Concentrations

-Diuretics

-NSAIDs, EXCEPT ASPIRIN

-ACEi & ARB

Decrease Li+ Concentrations

-Caffeine (>8 cups, or 750 mg/day, of coffee/day)

-Acetazolamide (used for altitude sickness)

-Mannitol/urea

-Potassium sparing diuretics

Describe lithium toxicity.

Elevated serum drug levels (>1.2) DO NOT equal toxicity, toxicity equals symptoms! Toxicity can occur at any concentration, so look at the patient to see if they have a tremor, having seizures, etc.

Could result from:

• Excessive lithium intake

• Impaired excretion due to meds that reduce GFR like NSAIDs, diuretics, ACEi/ARBs

• Sodium/volume depletion which can increase lithium concentrations due to illness (diarrhea, vomiting), excessive sweating (like soaking through a shirt), and a low sodium diet (see this with HF patients; body will hold onto any salt, and only salt available is Li+).

Management of toxicity can be discontinue offending agents and give supportive therapy of fluid resuscitation with 0.9% NS @ 150-200 mL/hr.

What are the adverse effects of VPAs?

• Weight gain

• Very low platelet counts (thrombocytopenia)

• Hepatoxicity, pancreatitis, hyperammonemia

  • Hyperammonemia is elevated ammonia which contributes to confusion

  • Treated with lactulose

State the drugs that VPA derivatives have interactions with, and the effect those interactions have.

Carbapenems reduce VPA concentration to basically 0.

Lamotrigine’s concentration is increased 2-fold by VPA, so do a modified titration of lamotrigine.

Warfarin’s concentration is increased by VPA, which leads to increased INR and bleeding.

Phenytoin, but that is not totally understood.