Pharm. 2 Exam 3

development and persistence primarily based on basal ganglia, amygdala, and prefrontal cortex

state general neurobiology of SUD

- plays role in positive motivation and pleasure, with involvement in habits and routines in reward circuit

- euphoria of drug highs thought to produce overactivity in this circuit --> chemical surges and signaling of endorphins and other neurotransmitters in basal ganglia

- after repeated exposures, reward circuit adapts to drug, decreasing individuals ability to feel pleasure from anything EXCEPT the drug

describe basal ganglia role in SUD

plays role in anxiety, irritability, and apprehension as the euphoria fades and the individual seeks the drugs next high

describe amygdala role in SUD

- aids individual with ability to plan, solve problems, and demonstrate self-control

- one of the last areas of the brain to mature --> SUD highest in 18-24yo

describe pre-frontal cortex role in SUD

- main neurotransmitter in substance use

- reinforce pleasure rather than generating direct effect

- pleasurable activities cause changes in neural activity leading to formation of habit

describe role dopamine role in SUD

- impulsive drug use produces high, if experiences too often causes migration to compulsive use (addiction) to reduce the unpleasant effects of withdrawal

- substance use causes powerful surges in dopamine --> lead individual to repeat activity without thought, leading to drug habit

describe relation of neurobiology to SUD (how it all comes together)

epigenetic

development stage

gender

weight

ethnicity

state biological risk factors for developing SUD (5)

aggressive childhood behavior

lack of parental supervision

drug availability at school

drug experimentation

decreased peer refusal skills

community poverty

state risk factors for young adults to develop SUD (6)

heroin - < 30d

cocaine - 0-4y

cannabis - 1-6y

tobacco - 1-27y

alcohol - 3-15y

state time to progression to SUDs for heroin, cocaine, cannabis, tobacco, and alcohol

- addiction severity index

- screening, brief intervention, referral to Tx (SBIRT)

--- alcohol and tobacco use with increasing evidence of illicit drug use

- alcohol use disorders identification test (AUDIT)

- alcohol use disorders identification test-consumption (AUDIT-C)

- CAGE questionnaire (identifies problematic drinking)

- clinic institute withdrawal assessment alcohol-revised (CIWA-Ar)

- clinical opiate withdrawal scale (COWS)

state clinical tools for evaluation of SUDs (7)

- can be fatal (med emergency)

- 3rd day after reduction or cessation of alcohol

- mortality rate 20% if untreated

- demonstrate confusion, disorientation, hallucinations, delusions, autonomic hyperactivity, anxiety, fluctuating levels of psychomotor activity

alcohol withdrawal:

describe delirium tremens (DTs)

tremulousness

alcohol withdrawal:

state the classic sign

N/V

insomnia

transient visual, tactile, auditory hallucination or illusions

psychomotor agitation

anxiety

seizures

alcohol withdrawal:

state withdrawal Sxs (6)

hypoglycemia

hyponatremia

hypomagnesemia

state what long-term alcohol use can produce (3)

benzodiazepines

alcohol withdrawal:

state 1st line pharmacological tx

barbiturates - for those who are refractory to benzos

alcohol withdrawal:

state 2nd line pharmacological tx

- propofol in conjunction with benzos

- can be used in pts refractory to barbiturates

- requires ICU/monitored bed and mechanical ventilation

alcohol withdrawal:

state adjunct medication used

- wernicke encephalopathy

- characterized by ataxic gait, vestibular dysfx, confusion, horizontal nystagmus, lateral orbital palsy, gaze palsy

- is reversible but can progress to Karsakoff syndrome

state and describe the alcohol-induced encephalopathy

- chronic amnestic syndrome that follows Wernicke encephalopathy

- main feature is anterograde amnesia, with possible confabulation

describe Korsakoff syndrome

- thiamine IV/IM x3d then PO daily

- thiamine (vit B1) deficiency is patholophysiologic between both syndromes (Wernicke-Korsakoff syndrome)

state the Tx/Rx for Wernicke encephalopathy and Korsakoff syndrome

intervention medications usd to reduce the cravings for alcohol

alcohol use disorder:

describe antidipsotropic meds

- most effective med for abstaining from alcohol use disorder

- targets GABA and N-methyl-D-asparate glutamatergic receptor activity --> decreased cravings

- must be alcohol-free at initiation

- ADRs: D/N, weight-based dosing

- does not require titration

- CI severe renal disease

alcohol use disorder - antidipsotropic meds:

describe acamprosate

- 2nd line Tx ETOH-dependent individuals who are motivated to quit

- inhibits aldehyde dehydrogenase thereby inhibiting conversion of alcohol to acetate

- alcohol consumption increases serum acetaldehyde causing diaphoresis, palpitations, facial flushing, N/V, cramps, vertigo, hypotension, tachycardia

- ADRs: HA, skin rash, drowsiness, metallic aftertaste, hepatitis, peripheral neuropathy

alcohol use disorder - antidipsotropic meds:

describe disulfiram

- 1st line Tx for alcohol and opioid dependence by blocking opiate Mu receptor

- modifies HPA axis to suppress alcohol consumption

- oral absorption enarly 100% but undergoes substantial first-pass effect

- ADRs: N/abdominal pain

- caution: hepatic and renal impairment

alcohol use disorder - antidipsotropic meds:

describe Naltrexone

united states annually consumes more than 80% of all opioids supply

state U.S. epidemiology of opioid use disorder

- alcohol or marijuana abuse

- 1st degree relatives addicted to alcohol or other drugs

- friends addicted to heroin or opiates

state RF of developing opioid use disorder (3)

- for opiate use disorder

- partial agonist (Mu) and weak (k) - has ceiling effect so opioid effects level off even with dose escalation (reduces risk of misuse, dependency and side effects)

- reduces opioid withdrawal Sxs and cravings for opioid (without possessing full opioid effects/delayed withdrawal Sxs)

Buprenorphine:

state therapeutic use

poor bioavailability (high first pass effect)

accumulates in fat

slow redistribution

should be dissolved under tongue - do not swallow (first pass effect)

Buprenorphine:

describe pharmacokinetics

- combine with counseling and other support Rx

- buprenorphine/naloxone (Suboxone) is preferred over buprenorphine alone for opioid use disorder

Buprenorphine:

describe prescribing/preferred way to use

physical dependence and subsequent withdrawal effects will occur if buprenorphine is stopped abruptly (after long duration of use)

Buprenorphine:

what will happen if this med is stopped abruptly

- for opiate use disorder

- long acting Mu agonist (blocks euphoria, alleviates cravings, suppresses withdrawal)

Methadone:

state therapeutic indications

- well absorbed

- long variable t1/2 (accumulates in muscle and organs)

- CYP3A4 metabolism

Methadone:

state pharmacokinetics

- heroin addiction --> OUD and analgesia

- some clinics mix drug with fruit juices to discourage IV admin

- minimal effective dose about 40mg, some will require much greater doses

Methadone:

describe historical use and administration notes

sweating

decreased libido

weight gain

constipation

irregular menstrual periods

facial flushing

pruritus

euphoria or dysphoria

insomnia

urinary retention

bradycardia (rare)

biliary spasm

urticaria

syncope

overdose death

torsades de pointes (higher doses)

Methadone:

state ADRs (16)

smoking is single largest preventable cause of morbidity and mortality

describe smoking morbidity and mortality

- nicotinic stimulation intimately linked to dependence

- cholinergic (nicotinic) receptor a4b2: mediator of nicotine dependence

--- causes release of dopamine, glutamate and gamma-aminobutyric acid

describe role of nicotine in smoking

- recommend setting a target quit date (date at which complete abstinence to combustible cigarettes)

- general CI

--- light smokers

--- adolescents

--- women pregnant or breastfeeding

describe general pharmacotherapy guidance for smoking cessation

- nicotine replacement therapy (NRT): gum, lozenge, inhaler, nasal spray and patch

- bupropion

- varenicline

state the FDA-approved meds for smoking cessation

- as monotherapy, all equally effective (varenicline "appears to be more effective")

- combo NRT (patch + other NRT) > lone NRT or bupropion

- MC used approach = varenicline (alone)

- all pts should have behavioral modifications +/- pharmacotherapy

pharmacotherapy of smoking cessation:

describe prescription of these meds

oral mucosa (gum, lozenge, inhaler)

nasal mucosa (nasal spray)

skin (patch) - slowest onset of all

nicotine replacement therapy (NRT):

absorption of nicotine occurs through which 3 modalities

- not intended to be delivered via GI tract

- 1st pass metabolism

- nicotine irritating to esophagus and stomach

nicotine replacement therapy (NRT):

what is this not intended to be delivered via

- no formulation delivers nicotine as rapidly as smoking

- increases probability of quitting by 50-60%

nicotine replacement therapy (NRT):

describe the use of this for quitting

- light smokers

- adolescents

- women pregnant or breastfeeding

nicotine replacement therapy (NRT):

state general CI (3)

cardiovascular disease (esp within 2w of MI or serious event)

serious arrhythmias

unstable angina

nicotine replacement therapy (NRT):

state cautations (3)

irritability

anxiety

increased appetite

lack of concentration

restlessness

depressed mood

insomnia

Sxs start quickly and peak within 7d - gradually diminish over 2-4w

nicotine replacement therapy (NRT):

state nicotine withdrawal Sxs (8)

- dosing based on typical time to 1st cigarette (surrogate marker of dependence)

- if within 30min of walking dose=4mg, otherwise dose=2mg

- peak nicotine concentrations after 30min

- chew and park technique (park when tingling or peppery taste occurs)

nicotine replacement therapy (NRT):

describe nicotine gum

- should be placed in mouth and allowed to dissolve over 20-30min

- occasionally move from side to side

- do not chew or swallow whole

nicotine replacement therapy (NRT):

describe nicotine lozenge/mini-lozenge

- nicotine absorption occurs through buccal mucosa with very little reaching pulmonary circulation

- mouth and throat irritation MC and may cause bronchospasm in asthmatics

nicotine replacement therapy (NRT):

describe nicotine oral inhaler

- acidic environment reduces nicotine absorption

- drink only water during gum, lozenge, or oral inhaler (no coffee or soda)

nicotine replacement therapy (NRT):

state patient education for nicotine gum, lozenge or oral inhaler

- Rx only

- substantially more rapid peak nicotine concentrations at 10-15min

- 1-2 doses/hr up to max of 40doses (80 sprays) per day

- high rate of side effects limit use of this form

nicotine replacement therapy (NRT):

describe nicotine nasal spray

- nicotine concentration increase gradually over several hrs then remain steady for 16-24hrs

- cannot be used for cravings or withdrawal Sxs due to slow onset

- remove patch at bedtime (i.e. only 16hr application) if sleep disturbances occur with 24hr administration

- initial dose typically worn 4-6w then reduced at 2w intervals

nicotine replacement therapy (NRT):

describe the nicotine patch

buproprion

which antidepressant can be used for nicotine cessation

- unclear MOA, possible reuptake inhibition of DA and NE or nicotinic receptor agonist

- efficacy about = to nicotine patch but slightly less than varenicline

- found to significantly increase long-term (6m) cessation relative to control

Bupropion for nicotine cessation:

state therapeutic use

seizure disorders

black box warning: increased suicide risk in younger pts

Bupropion for nicotine cessation:

state CI (2)

lower dose daily x3d than increased dose BID separated by at least 8hr

Tx continue for at least 7-12w

Bupropion for nicotine cessation:

state dosing instructions

metabolized via CYP2B6

known CYP2D6 inhibitor

Bupropion for nicotine cessation:

state pharmacokinetics

varenicline

which drug is a partial agonist of a4B2 nicotinic acetylcholine receptor

- relieve Sxs of nicotine withdrawal while also blocking effects of nicotine from any cigarettes that are smoked

- more effective than either bupropion or NRT

- double NRT about as effective as varenicline

Varenicline:

state therapeutic use

Nauseua

abnL dreams

insomnia

Varenicline:

state MC ADRs (3)

neuropsychiatric SE

changes in mood (mania and depression)

psychosis

aggression

agitation

anxiety

suicide

Varenicline:

state less common ADRs (7)

- started a week before "target quit date"

- 0.5mg once daily x3d, 0.5mg BID x4d, 1mg BID duration of Tx

- recommended 12w duration but Rx can be extended

- adjust dose in severe renal dysfx

Varenicline:

state dosing instructions

What are the MAOIs?

- phenelzine

- selegine

- isocarboxazid

- tranylcypromine

- procarbazine

- furazolidone

What is the main contraindication to MAOIs?

Pheochromocytoma

Why are MAOIs not used much anymore?

risk of hypertensive crisis

What causes this hypertensive crisis in MAOIs?

tyramine containing foods

When do stimulants (MAOIs) need to be given?

in the morning

What do the TCAs end in, and what are the two additional drugs?

- -ipramine

- -iptyline

- trazodone

- doxepin

What are the ADRs of TCAs?

- anticholinergic

- orthostatic hypotension

- sedation

- cardiac arrhythmias

What kind of metabolism do TCAs undergo?

34A metabolism

What cannot be take within 14 days of TCAs?

MAOIs

What are the first-choice medications for depression?

SSRIs

What are the SSRIs?

- fluoxetine

- sertraline

- citalopram

- escitalopram

- paroxetine

- fluvoxamine

- vilazodone

What effects are SSRIs also known to have that we need to be cautious with?

mild antiplatelet effect (problematic if the patient is already on another anticoagulant)

What is a caution with starting all antidepressants in a new patient that we need to be aware of?

- there is a risk of hypomania/exacerbation of mania

- cut back on the dose if this is the case

- start low and go sloe

What is escitalopram (SSRI) an active metabolite of?

Citalopram

What SSRIs are LEAST likely to have DDIs?

Citalopram and Escitalopram

What SSRIs are MOST likely to have DDIs?

Fluvoxamine

What is special about citalopram?

it has a really long half life

What do ALL SNRIs and SSRIs have a risk for?

Serotonin syndrome

Do antidepressants ever completely remove the risk of suicide?

No

What are the SNRIs?

- Duloxetine

- Venlafaxine

- Desvenlafaxine

What are the ADRs of duloxetine?

- neuropathic problems

- depression

What are the atypical antidepressants?

- vortioxetine

- buproprion

- nefazodone

- vilazodone

- mirtazapine

What is a special indication for bupropion?

smoking cessation

What is the main indication for mirtazapine (besides an antidepressant)?

weight loss

What is the MOA of mirtazapine at low doses?

- H1 blocker

- sedating/appetite stimulating

What is the MOA of mirtazapine at high doses?

alpha-adrenergic effects

What are the low-potency, 1st generation antipsychotics?

- chlorpromazine

- thioridazine

What are the high-potency, 1st generation antipsychotics?

- fluphenazine

- haloperidol

- perphenazine

- prochloroperazine

- thiothixene

- trifluoperazine

What are the 2nd generation antipsychotics?

- aripiprazole

- lurasidone

- olanzapine

- quetiapine

- risperidone

- ziprasidone

- lumateperone

- pimavanserin

- brexpiprazole

- clozapione

What are the 1st generation antipsychotics used to treat?

positive symptoms (hallucinations, delusions, "sterotypical symptoms)

What are 2nd generation antipsychotics used to treat?

BOTH negative and positive symptoms, plus negative affect, social isolation, and illogical thinking

How are antipsychotics administered?

Given IM monthly

What generation of antipsychotics are used less frequently because of a higher risk for EPS and tardive dyskinesia?

1st generation

How do 1st generation antipsychotics cause EPS and tardive dyskinesia?

block dopamine

What is the BBW for 2nd generation antipsychotics?

increased mortality in elderly/dementia related schizophrenia psychosis

What is the long term concern with 2nd generation antipsychotics?

development of metabolic syndrome and diabetes

What is the special indication for pimavaserin?

it is an atypical antipsychotic for patients who develop schizophrenia related to parkinson's disease

psychosis

What is the special indication for clozapine?

refractory psychosis

Which atypical antipsychotic has a REMS requirement?

Clozapine