Pharmacology MNTH Flashcards
Indications for Antipsychotics
Manage Psychotic symptoms
(SCZ, Bipolar, etc)
Improve mood, reduce anxiety, reduce sleep disturbance
Antiemetic effect
Pruritis
Preoperative Sedative
Which drug can treat anxiety in autism disorder?
Risperidone
Where does the mesolimbic pathway go, and which receptors are there?
Where does the mesocortical pathway go, and what are its receptors?
To the nucleus accumbens and increase in DA cause positive psychosis symptoms
To the Prefrontal cortex, and DA hypoactivity causes negative symptoms of psychosis.
A blockade of the D2R will do what?
Block the mesocorticomesolimbic Pathway
-Alleviates psychosis symptoms
Block the nigrostriatal pathway
Produce EPS and Tardive dyskinesia
Block the tuberoinfundibular pathway
-Increases prolactin secretion
What action do most typical antipsychotics have vs Atypical?
Typical: D2R antagonism
Atypical: D2R antagonism and inverse agonism of 5-HT2A
What are EPS?
Treatment?
Extrapyramidal Symptoms
Come from block of D2R in the Nigrostriatal pathway
Dystopia
Parkinson’s-like symptoms
Akathisia (motor restlessness)
The higher potency (typical) antipsychotics will cause more EPS
TD: Antiparkinsonian agents, amantadine, benztropine diphenhydramine
Which potency will have more OFF-target effects in antipsychotics?
Low potency. High potency stay at the receptors for longer and can cause EPS or TD. The low potency will cause more off target effects.
What is Tardive Dyskinesia?
How do you treat it?
Caused by block of D2R of the nigrostriatal pathway
Fly-catching or worm-like tongue movements
Treat with VMAT inhibitors (valbenazine and deutertrabenazine)
What is neuroleptic malignant syndrome?
Resembles severe Parkinsonism with autonomic instability.
Leads to lead-pipe muscle rigidity altered mental status, fever and unstable BP.
Use Dantrolene or bromocriptine
If symptoms last longer than a week then it increases mortality risk
What are the times of onset of these antipsychotic ADRs?
Acute dystopia Akathisis Parkinsonism Neuroleptic malignant syndrome Personal tremor Tardive dyskinesia
1-5 days 5-60 days 5-30 days Weeks to months Months to years of Tx Months or year of Tx
What can be used to stop hyperprolactinemia if you can’t switch antipsychotics?
Bromocriptine
Chlorpromazine and Thioridazine
Typical Antipsychotics
Least potent of the class
Can cause EPS, increase serum TG and cause hyperglycemia
Wide range of CNS, autonomic, and endocrine effects
Fluphenazine
Typical Antipsychotic
Oral form has high risk for EPS
Low potential for weight gain, sedation, orthostasis, and antimuscarinic effects
Has injectable long acting form 2-3 weeks
Haloperidol
Typical Antipsychotic
Low potential for orthostasis, weight gain, sedation
Higher incidence of EPS
Can be used in acute psychosis
What are newer Atypical Antipsychotics good for generally?
Positive symptoms
Cause more metabolic syndrome, CAD, stroke, and HTN
Which are usually first line for psychosis, typical or atypical antipsychotics?
Atypical
Which antipsychotics cause the highest risk of developing diabetes?
Olanzapine and Clozapine
What needs to be monitored for those on atypical antipsychotics?
A1C Weight and heigh BP Glucose Lipids
What is the black box warning of atypical antipsychotics?
Elderly with dementia-related psychoses are at increased risk of stroke death.
Clozapine
Atypical Antipsychotic
Indicated for Tx of people with low threshold for EPS
Not first line because of hematological side effects
Will cause weight gain, myocarditis, diabetes, sedation
Constipation can also lead to deadly small bowel obstruction
Contraindicated when WBC is below 3000 or if Granulocytes are below 1500
Aripiprazole
Atypical Antipsychotic
Indicated: SCZ, Bipolar, Autism
Low occurrence of EPS, Low potential for weight gain, sedation, antimuscarinic effects
Partial agonist of D2
Antagonist of 5HT2A
Olanzapine
Atypical Antipsychotic
Indications: SCZ, Acute Mania, Maintenance of Bipolar 1
Antagonist of 5HT2A and D2
Quetiapine
Atypical Antipsychotic
Indications: SCZ, Acute Bipolar 1, Bipolar Depression
Weak antagonist of D2 and 5HT2A
Least likely to cause EPS (Best for Parkinson patients)***
Increase QT interval***
Risperidone
Atypical Antipsychotic
Indications: Maintenance of SCZ 13-17 and adults, Acute manic episodes
Antagonist of 5-HT2A and D2
Will elevate Prolactin
Low likelihood of EPS
Weight Gain, anxiety, vomiting, ED and rhinitis.
How are Antipsychotics metabolized?
Through the CYPs in the liver
First pass metabolism is significant.
The drug may last longer than planned because it can hide in adipose tissue (very lipophilic)
What are the three hypotheses for the pathophysiology of MDD?
Monoamine hypothesis
Glutamatergic Hypothesis: NMDAR Antagonists
Neurotrophic hypothesis: Depression associated with low BDNF. Tx of depression increases Neuro genesis.
How long does it take for antidepressant effects to work?
Why?
6 weeks
Acute treatment activates inhibitory autoreceptors to lower the firing rate of serotonergic and NE neurons.
This may increase suicide risk
With chronicity of Tx, the autoreceptors are downregulated.
What are the general differences between typical and atypical antidepressants?
Typical (SSRI, SNRIs, TCA, MOAIs) will inhibit reuptake or degradation of monoamines
Atypical target receptors and/or inhibit reuptake of monoamines
SSRIs
Fluoxetine, Sertraline, Citalopram, Paroxetine, Fluvoxamine Escitalopram
Safety during an overdose
Indications: GAD, PTSD, OCD, PMDD, Bulimia
ADR: anxiety nervousness, insomnia, sexual dysfunction, GI effects
- Specifics: Serotonin Syndrome
- No Cardio side effects
CYP2D6 metabolized: inhibition of CYPs will cause muscle rigidity and hyperreflexia
Quick withdrawal causes discontinuation syndrome:
- dizziness, HA, nervousness, Nausea, insomnia.
Which SSRIs cause the most discontinuation syndrome and least?
Most paroxetine (short 1/2 life)
Least Fluoxetine (Long 1/2 life)
Serotonin Syndrome?
Increase of serotonin usually because the CYP is block when using an SSRI or SNRI
Serotonin levels cause muscle rigidity, hyperthermia, hyperreflexia, and autonomic instability.
SNRIs
Venlafaxine, Desvenlafaxine, Duloxetine, Levomilnacipran
Indications: MDD, GAD, Stress unrinary incontinence, Fibromyalgia, binge-eating
ADR: Anxiety nervousness, insomnia, sexual dysfunction, increase in BP and autonomic effects due to excess NE
Which SNRI can be used to treat fibromyalgia?
Milnacipran
Which SNRI causes Orthostatic hypotension vs dose-related hypertension?
Duloxetine
Venlafaxine
Tricyclic Antidepressants
Amiltriptyline, nortriptyline, imipramine, desipramine
Not first line- risk of lethal overdose
Indications: MDD, Pain, Enuresis, Insomnia
Affects muscarinic R: Anticholinergic effects, alpha-1 adrenergic R: orthostatic hypotension and sedation, H1 R: Sedative effects and weight gain, Quinidine-like effects on cardiac conduction. Prolonged QTc
Seizure threshold is lowered
Eliminated by hepatic CYPs
What is the most serious ADR of TCA Antidepressants?
Prolonged QTc
Monoamine Oxidase Inhibitors
Selegiline, tranylcypromine, phenelzine, isocarboxazid
Indication: Depression (transdermal patch)
Avoid tyramine: inhibition of MAOs increases the Bioavailability of tyramine. Will cause a hypertensive crisis
(Transdermal may reduce HTN risk)
Slow CYP acetylators at higher risk for toxicity.
Takes up to 2 weeks to recover from MAO activity
5-HT2 Receptor Modulators
Trazodone
Indications: Major depression, Anxiety disorders
ADRs: Orthostatic hypotension, Prapism, Hepatotoxicity
Trazodone is contraindicated with MAOIs
Atypical Antidepressants
Mirtazapine, Bupropion, Amoxapine
Mirtazapine
Atypical Antidepressants
ADR: Somnolence (good for insomnia), Increased appetite, weight gain
Not as many sexual effects
Hepatic metabolism with long 1/2 life
Bupropion
Atypical Antidepressants
NET, DAT Blocker
Indications: Depression, smoking cessation, ADHD
ADR: anxiety, tachycardia, HTN, irritability, tremor, insomnia, Not commonly associated with sexual effects
Seizures are worst ADR
Should antidepressants should be used with what for Bipolar disorder?
Mood-stabilizers
Which antipsychotics are used for acute mania and bipolar depression?
Clozapine: Monotherapy or Adunctive, refractory mania
Olanzapine: adjunctive, Bipolar depression
Quetiapine : monotherapy, Bipolar depression
Lithium
Bipolar depression, acute mania, prophylaxis
ADR: HA, fatigue, GI disturbances, hypothyroid, Nephrogenic Diabetes Insipidus***** T-wave inversion
80% have ADRs
Neurotoxicity w/ antipsychotic, metronidazole, methyldopa
Eliminated Renally
Caffeine can enhance the renal elimination of lithium
Narrow therapeutic index. Need to stay within .6-1.2 mEq/L. Lower doses used for prophylaxis (600 mg/day), Higher for acute mania (900-1200 mg/day)
Altered Extracellular fluid volume can cause toxicity
Symptoms of lithium toxicity?
Ataxia
Slurred speech
Coarse tremors
Confusion
When do you need hemodialysis for lithium toxicity?
2.5 mEq/L and moderate-sever neurologic toxicity
More than 4 and renal impairment
More than 5 regardless of clinical status
Anticonvulsants
Valproate
Carbamazepine
Lamotrigine
Valproate
Used for bipolar mania not for bipolar depression
ADR: GI, CNS depression, alone is, thrombocytopenia, pancreatitis, teratogenicity
Highly protein-bound, CYP metabolized
Carbamazepine
Acute Mania
Not first-line agent
INDUCES CYPs
Lower efficacy for biplolar
ADR: Stevens-Johnson syndrome risk, agranulocytosis, aplastic anemia, hepatic failure
HLA-B 1502 and Asian must be screened for Stevens-Johnson syndrome
Acute overdose is potentially lethal above 15 mcg/mL
Ataxia, choreiform movements, diploid, nystagmus, seizures, coma
Lamotrigine
Maintenance Tx of bipolar 1 disorder and bipolar 2
Low rates of switching to mania, useful to prevent bipolar depression
ADRs: HA, nausea, Rash, Stevens-Johnson syndrome risk
What is the remission goal with depression in the STAR*D Trials?
Remission for more than 2 months
What were the levels of remission for each of the 4 levels
- 37%
- 31%
- 14%
4 13%
What is ECT?
Electroconvulsive therapy
Electrical current that produces a generalized seizure. Usually unilateral. Few contraindications. Needs 6-12 rounds for remission.
Very safe, even for pregnancy.
What is the first line treatment of a delusional disorder?
Risperidone
Antipsychotic
Which Anxiolytics can cause coma and which don’t?
Barbiturates, alcohol
Benzodiazepines and newer hypnotics don’t
What are the indications for anxiolytics/anxiety disorder?
GAD PTSD Acute Stress Disorder Panic Disorder OCD
What is the primary treatment for Anxiety disorders?
SSRIs
Benzodiazepines
Exposure Therapy
Explain the role of BDNF in anxiety
The higher the level of BDNF, it is essential for acquisition and extinction of anxiety.
What are the three theories of the pathogenesis of Anxiety?
Noradrenergic Model: ANS of anxious pts is hypersensitive
GABAa-Receptor Model: Inhibits 5-HT, NE, and DA
Serotonin Model: Lower serotonin function in those with anxiety
Are partial agonist for 5-HT1a effective agains GAD or panic disorder?
Yes for GAD but not panic disorder.
Benzodiazepines
Positive Allosteric modulators of GABAa Receptors
Indications: GAD, agoraphobia, Seizures, Insomnia, Operations
(Each one has different uses)
Alprazolam: GAD and Agoraphobia
Diazepam: Status Epilepticus, GAD
Lorazepam: Alcohol withdrawal, GAD
ADR: Drowsiness, Confusion, Ataxia, Seizures, Abuse
—Sudden withdrawal can be fatal.
What are the withdrawal symptoms for Benzodiazepines?
Anxiety, Insomnia, Tremor, Myoclonus, Delirium, Seizures
Barbiturates and Anxiety
Linked to fatal overdose
Not first line.
Low doses are positive Allosteric modulators of GABAa
High doses are agonists of GABAa, so they form a loop for themselves (dangerous)
Buspirone
5-HT1a Receptor Antagonist
Indications: GAD ***especially in elderly
Less abuse potential
CYP metabolized
Chloral Hydrate
Sedative Drug for Anxiety
Not usually used, schedule 4
Barbiturate-like effects on GABA
Metabolized by hepatic alcohol dehydrogenase
Meprobamate
Carisoprodol
Anxiety
Schedule 4
Meprobamate causes CNS depression
Carisoprodol has an active metabolite that is meprobamate.
What can be used for acute anxiety?
Can you overlap drugs?
Benzodiazepines and B-adrenergic antagonists
SSRIs and SNIS, Buspirone have delayed onset, but you can use a benzo first and overlap it with SSRI tx.
Transient
Short-Term
Long-term Insomnia
Less than tree days: low dose hypnotics for 2-3 nights. No Benzos before big events
3 days to 3 weeks: 7-10 nights of hypnotics
More than 3 weeks: Use sleep hygiene, hypnotics, and identification of other condition
What are the ADRs of Hypnotics in Insomnia?
Affect sleep quality
Barbiturates>Benzos>Z-drugs
Rebound anxiety, sedation
Can cause rebound insomnia with cessation.
Which Benzodiazepines are approved for Insomnia?
Flurazepam, ternazepam, quazepam, estazolam
Zolpidem, Zaleplon
Z-drugs for Insomnia
GABAa agonists
Sedative effects only, and less disruptive of sleep architecture
Less ADRs
Besides illicit drugs, what is the next most common used drug?
Marijuana
What is one of the most common, but one of the most addictive drugs?
Nicotine
What is a substance use disorder?
Maladaptive pattern of substance use despite continued adverse consequences
What is the DSM-5 for Substance Use Disorder?
Alcohol
Marijuana
Opioids
Problematic pattern of substance use leading to clinically significant impairment or distress. Needs 2 of 11 criteria occurring in a 12-month period
- Taken in larger amounts or over longer periods of time
- Persistent desire but unable to control use
- Great deal of time used to get, use, or recover from effects
- Craving
- Failure to fulfill obligations
- Continued use even with persistent interpersonal problems
- Activities given up for use
- Recurrent use even with physical hazardous conditions
- Continued use even with knowledge that use will cause hurt or problems
- Tolerance
- Withdrawal
2-3 Mild, 4-5 Moderate, 6+ Severe
Can you use lab values to diagnose a SUD?
NO
Good to know if drugs are in the system for a withdrawal or intoxication situation.
What do substances of abuse do in dopamine pathways?
Elevate dopamine in reward circuitry
Increase activity in Ventral Tegmental Area, and Nucleus Accumbens
Substance Intoxication Syndrome
Substance exerts behavioral or psychological changes on the central nervous system
Reversible, substance-specific.
Different substances may produce similar syndromes
Explain the general features and the effects of intoxication and withdrawal symptoms for
Sedatives (alcohol, hypnotics)
Stimulants
Pupil Dilation:
Intoxication: Stimulants and hallucinogens
Withdrawal: Opioids, Alcohol
Pupil Constiction:
Intoxication: Opioids
Withdrawal: Stimulants
Psychotic Symptoms:
Intoxication: Stimulants, Alcohol, Hallucinogens
Withdrawal: Sedatives and Alcohol
CV Symptoms:
Intoxication: Stimulants
Withdrawal: Sedatives and Alcohol
Which drug routedoes not following the finding of higher Cp=higher pharmacological effect?
Smoked
Explain addiction impulsivity and compulsivity?
Impulsivity: Early in drug use and is a risk factor for development of substance use disorder
Compulsivity: Later in addiction and contributes to maintenance of use disorder
Name the stages of the addiction cycle
Binge/intoxication
-high or reward
Withdrawal/Negative Affect
-withdrawal
Preoccupation/Anticipation
-craving
What is a stress-induced relapse
Stress signaling induces craving
Drug sought to alleviate stress
What is cue-induced relapse
Stimuli associated with either positive or negative reinforcement of the drug induces craving
Can cause an induced withdrawal as well
What are the receptors of marijuana, and what are their mechanisms?
CB1 and CB2, central and peripheral
G coupled (inhibition of adenylyl Cyclase) Can also inhibit Ca and K channels
Endogenous cannabinoids (anandamide) operate by retrograde signaling to decrease the effect on postsynaptic neuron
Why doesn’t cannabis cause respiratory depression?
There is an absence of CB1R’s in the Medulla
What does THC Agonism of CB1 receptors do?
Relaxes Hyperphagia (munchies) Tachycardia Decreased coordination Conjunctivitis Hallucinations Minor pain control
Explain the effect of THC
Agonism of CB1R stimulates the amygdala causing a sense of “novelty”
Heavy users have down-regulation of CB1R
Loss of motivation, and reduced IQ
Also causes loss of short-term memory due to imbalances of GABA in hippocampus.
What are the symptoms of Cannabis Intoxication
Euphoria, sensory intensification, or apathy, fear, distrust, and panic
Increased appetite, hallucinations, dry mouth
Sedation
Tachycardia
Conjunctival congestion
What are the symptoms of withdrawal of cannabis use?
Tx?
Restlessness Irritability Mild agitation Insomnia Sleep EEG Nausea, cramping Craving Pain
No pharm Tx available for all withdrawal
-depression and insomnia may be treated by zolpidem, buspirone, and Gabapentin
LSD
Partial agonism of 5-HT2A
Effects through serotonin, dopamine, and norepinephrine
Can induce psychosis
Toxicity is rare, cardiovascular collapse observed with very high doses
NO tolerance or withdrawal.
Hallucinogen Intoxication Syndrome
Pupillary dilation Tachycardia Sweating Palpitations Blurring of vision Tremors
Tx: Counseling, Benzos, antipsychotics
MDMA
Intoxication, and withdrawal symptoms
Hallucinogen and stimulant (amphetamine)
Increases concentration of serotonin by reversal of SERT function
Marked intracellualr 5-HT depletion for 24 hours after a single dose (causes depressive symptoms after use). Can cause increased aggression during these periods.
ADR:
Acute toxicity: hyperthermia, serotonin syndrome, seizures
Chronic Toxicity: Neurotoxicity
Toxicity: Pupillary dilation, Tachycardia, Sweating, Palpitations, blurring of vision, tremors
Phencyclidine
PCP
Antagonist of NMDA receptors, induces psychotic symptoms
Causes extreme Violence in intoxication syndromes
Tx: Non-stimulating environment, restraints, acidification of urine, antipsychotics
ADR Toxic events: Cardiovascular toxicity, neurological toxicity, Rhapdomyolysis
Intoxication syndromes: Violence, nystagmus, numbness, ataxia, dysarthria, muscle rigidity, muscle rigidity, seizures or coma
What are the therapeutic indications of stimulants?
ADHD
Narcolepsy
Anorexiant (obesity)
Obstruction/sleep apnea
Explain nicotine MOA
Agonists of neuronal nicotinic Acetyl cholinergic receptors
16/17 subtypes of the receptors are expressed in the autonomic ganglia and CNS
Explain how low doses and high doses of nicotine affect the body generally
Adrenal medulla
Neuromuscular junction
Low doses: euphoria, arousal, relaxation
High doses: tremors, convulsions
Small doses stimulate ganglionic cells, large block them
Adrenal medulla: small evoke discharge of catecholamines, large doses prevent release due to spinach ice nerve stimulation
Neuromuscular junction: stimulation is rapidly obscured by paralysis (toxic doses)
Explain the different kinds of nicotinic receptors nicotine affects
Mechanoreceptors: skin, mesenteric, tongue, lung
Chemoreceptors: carotid body
Thermal receptors: skin and tongue
Pain receptors
What are the physiological effects of nicotine?
Respiratory Depression
Sympathomimetic: vasoconstriction, tachycardia, HTN
Parasympathomimetic: GI tract and urinary. Increased bowel activity and urination
Acute Nicotine Toxicity
Tx
Central stimulation (convulsion, coma, respiratory arrest - diazepam
Respiratory paralysis
-Mechanical Ventilation
HTN and arrhythmia
-Atropine
How does nicotine affect metabolism?
Metabolized by CYP2D6
They induce expression of CYP1A2 (caffeine) and CYP2E1 (alcohol)
Nicotine Withdrawal
Tx
Irritability, impatience, anxiety, restlessness, increased HR, increased appetite
Tx:
Replacement therapy
Bupropion
Varenicline (chantix)
Rimonabant (CB1 inverse agonist) not approved in US
Cocaine MOA
Blockade of catecholamines neurotransmitter reuptake
Increased dopamine concentrations in reward circuitry
What are the physiological effects of cocaine?
Stimulant effects: excitement, euphoria, decrease fatigue
Higher doses: Seziure, CV complications
Behavioral risks: trauma while intoxicated, promiscuous sexual activity
Chronic cocaine use: reduced sexual drive, anxiety, violence
Acute Cocaine Toxicity
Tx
Seizure,
Hyperthermia
Chest Pain
Psych complaints
TD: Benzos
Explain metabolism and testing of cocaine
How long does the euphoria last
Hydrolysis by tissue esterases
- makes benzoylecgonine metabolite
Urine test can see it for up to 10 days
Snorting: 15-30 min
Smoking 5-10 min
Cocaine: Tolerance and Withdrawal
Tx
Chronic users experience less euphoric effects
Withdrawal symptoms: dysphoria, sleepiness, craving, bradycardia. For 1-3 weeks
Tx: psycotherapy, behavioral treatments. Can use antidepressants or modafinil for relapse
Amphetamines: MOA
Elevation of extracellular dopamine
Depletion of DA stores occurs due to inhibition of VMAT and reverse transport of dopamine by the DA transporter
Effects and toxicities are from increased DA and NE signaling
Physiological Effects of Amphetamine
Performance enhancing
Increased NE and DA
Wakefulness, improved attention, increased Resp rate, suppressed foo intake signaling, CV increased BP heart rate slows reflexively (reflex bradycardia)
Smooth muscle contraction increases (difficult urinating)
Amphetamine Intoxication
Tx
Euphoria, Insomnia, increased wakefulness, decreased appetite, aggression, anxiety, tachycardia, HTN, Tremors
Benzos for seizures
Amphetamine: Withdrawal
Tx
Depression, Altered mental status, Drug craving, sleep disturbances, fatigue
Supportive therapy. NO TCA for depression
Methamphetamine
Brief, intense euphoric effect (rush or flash)
Causes prolonged insomnia and extremely irritable and paranoid state
Long-lasting effects of discontinued use
-depression, fatigue, anergic, cognitive impairments
Mehylphenidate
ADHD
Low dopamine release, diminished reward in children
DDIs with CYP450: Warfarin, phenytoin, phenobarbital, TCA
ADR: GI discomfort, anorexia, insomnia, fever
