Exam 2 Flashcards
What is depression (definition, symptoms, diagnosis, and prevalence)?
An affective disorder consisting of Major Depressive Disorder (MDD) and related conditions; is a chronic, recurring, and potentially life-threatening illness. It worsens the health of people with other chronic diseases and is associated with increasing diability over time.
Symptoms involve energy, sleep, mood, self-concept, weight, and thoughts of suicide.
Diagnosis is based on a clinical interview and the presence of at least 5 symptoms daily (or almost every day) for at least two weeks.
It is the fourth most disabling disease worldwide.
What age group has the highest depression prevalence?
18-25
How many cases of depression lead to hospitalizations and suicide, and how many cases are adequately treated?
Depression is responsible for 70% of psychiatric hospitalizations
Depression is responsible for 40% of suicides
Only about 21% of yearly cases are adequately treated
What is Major Depressive Disorder (MDD)?
Type of depression characterized by a combination of symptoms that interfere with a person’s ability to work, sleep, study, eat, and enjoy once-pleasurable activites
How often do MDD episodes occur in those with the condition?
An MDD episode may occur only once in a person’s lifetime, but episodes often recur throughout a person’s life; acute episodes of MDD last about 6-14 months untreated
6 types of depression and related conditions
- Major Depressive Disorder (MDD)
- Psychotic depression
- Postpartum depression (10-15% incidence)
- Seasonal affective disorder
- Bipolar disorder
- Dysthymic disorder
What is the paradox of antidepressant medications?
Medications rapidly increase neurotransmitter levels but antidepressant action is slow onset; for this reason, the pathophysiology of depression is thought of as theory rather than fact
What is the current focus of theories of how antidepressants exert their effects (pathophysiology of depression)?
Current theories focus on the long-term effects of antidepressants on the second messenger systems
3 functions of second messenger systems
- Neuron protection from damage due to injury or trauma
- Promote and maintain the health and stability of newly formed neurons
- Promote and maintain synapses that connect neurons
Current theories of the pathophysiology of depression/antidepressants focus on the second messenger systems
How does depression affect the hippocampus?
Long-term depression is associated with a shrinking hippocampus (net loss of neurons); it is thought that this loss of neurons is a mechanism behind depression
What is the relationship between antidepressant drugs and neurogenesis (2 reasons for this)?
Antidepressant drugs increase neurogenesis, and it is thought this is one reason these drugs work.
We know this because:
1. The timing of neurogenesis and net neuron gains in response to antidepressant drugs fits with the time frame of therapeutic response in patients (unlike NT levels)
2. Blocking neurogenesis in mice also blocks the behavioral changes indiced by antidepressant drugs
What is the role of neurotransmitter levels in the pathophysiology of depression?
Role of neurotransmitter levels in the pathophysiology of depression is thought to be through affects on gene expression that alter neurogenesis and neuroprotection (CREB and BDNF interactions)
What is CREB (and relation to BDNF), and what is the relationship between depression and CREB?
Activation of adenylate cyclase and Ca2+ dependent kinase pathways enhance the activity of CREB, a transcription factor that binds to DNA to regulate the expression of other genes.
BDNF is thought to be a key transcriptional target for CREB.
Inadequate neurotransmitter activity for serotonin and/or norepinephrine thought to lead to less CREB and BDNF activity in individuals suffering depression.
What is the relationship between depression and BDNF (3 keys)?
Inadequate neurotransmitter activity for serotonin and/or norepinephrine thought to lead to less CREB and BDNF activity in individuals suffering depression (increased CREB = increased BDNF).
BDNF is thought to be key:
1. BDNF affects the normal development and health of the nervous system
2. Chronic stress decreases the production of BDNF
3. BDNF is decreased in blood levels in depressed patients (reversed with antidepressants)
What are the treatment options for depression (3 first-line drugs, 2 other drugs, and 2 additional approaches)?
First-line drugs:
1. Selective serotonin reuptake inhibitors (SSRIs)
2. Serotonin and norepinephrine reuptake inhibitors (SNRIs)
3. Norepinephrine-dopamine reuptake inhibitor (NDRI)
Other drugs:
1. Tricyclic antidepressants (TCAs)
2. Monoamine oxidase inhibitors (MAOIs)
Additional approaches:
1. Psychotherapeutic interventions
2. Light therapy
6 currently available selective serotonin reuptake inhibitors (SSRIs)
- Fluoxetine (Prozac)
- Paroxetine (Paxil)
- Sertraline (Zoloft)
- Fluvoxamine (Luvox)
- Citalopram (Celexa)
- Escitalopram (Lexapro)
How does serotonin affect different 5-HT (1, 2, 3) receptors?
Serotonin action at 5-HT1 receptors produces antidepressant and anxiolytic effects
Serotonin action at 5-HT2 receptors produces adverse effects including insomnia, anxiety, agitation, sexual dysfunction
Serotonin action at 5-HT3 receptors produces adverse effects including nausea
What are selective serotonin reuptake inhibitors (SSRIs)(mechanism, onset)?
First-line drug for the treatment of MDD, dysthymia, and all anxiety disorders that block the reuptake of serotonin, which increases the amount present in the synapse and magnifies its effects
Although serotonin levels increase quickly, all SSRIs have a slower 4-6 week onset of action
5 side effects and lethality of SSRIs
Side effects:
1. Sexual dysfunction (in up to 80% of patients)
2. Insomnia
3. Anxiety
4. Agitation
5. Nausea
SSRIs are not lethal in overdose
What are the similarities and differences between SSRIs?
Drugs are all considered equally effective, and within and between class switches are considered legitimate; individual differences in metabolism and possible drug interactions are important for patient-to-patient differences in responses to SSRIs
What is serotonin discontinuation syndrome?
Syndrome that occurs in 60% of patients upon abrupt cessation of SSRI drug intake, thought to be due to relative deficiency of serotonin
Onset is within a few days of cessation, usually lasting for 3-4 weeks
Includes 5 core somatic symptom sets:
1. Disequilibria
2. Gastrointestinal symptoms
3. Flu-like symptoms
4. Sensory disturbances
5. Sleep disturbances
What are serotonin norepinephrine reuptake inhibitors (SNRIs) (venlafaxine, duloxetine)?
First-line drugs for the treatment of depression that block the reuptake of both serotonin and norepinephrine (called dual-action antidepressants). May have modestly improved efficacy compared with SSRIs
2 types:
1. Venlafaxine (Effexor)
2. Duloxetine (Cymbalta)
Very similar onset as SSRIs; NT levels increase quickly, but SNRIs have a 4-6 week onset of action
How do the side effects and risk of SNRIs (venlafaxine, duloxetine) compare to those of other antidepressants?
Both side effects and risk of overdose with SNRIs is worse than SSRIs but better than TCAs and MAOIs
What is bupropion (Welbutrin) (mechanism, side effects)?
Bupropion (Welbutrin) is the only norepinephrine-dopamine reuptake inhibitor; it is a first-line drug for the treatment of depression that blocks the reuptake of both norepinephrine and dopamine (called dual-action antidepressants). This mechanism is similar to cocaine but it is not generally abused. It is also used for nicotine addiction, as it antagonizes certain nicotinic receptors.
Dopamine potentiation effects can also treat children with ADHD.
Side effects: it does not affect serotonin reuptake so it does not have the side effects of SSRIs, but…
- Produces effects of minimal sexual dysfunction or enhanced sexual functioning
- May result in weight loss
- General side effects include anxiety, restlessness, tremor, and insomnia
- Serious side effects include psychosis and seizures
What are first-generation antidepressants (TCAs, MAOIs)?
These agents, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) were introduced in the 1950s and 1960s to treat depression; both drug classes increase the levels of norepinephrine and serotonin in the brain
How do tricyclic antidepressants (TCAs) compare to SSRIs?
TCAs were created in the 1950s and 1960s, but newer drugs like SSRIs are no more effective
TCAs are cheaper but produce more undesirable side effects
What is different among the varying types of tricyclic antidepressants (TCAs)?
TCAs are named based on chemical structure, and all look and function similarly but vary in side groups
What is the mechanism of action of tricyclic antidepressants (TCAs)?
- Inhibit presynaptic norepinephrine and serotonin reuptake transporters
- Inhibit postsynaptic histamine, acetylcholine, and several other receptors
4 side effects of tricyclic antidepressants (TCAs)
- Anticholinergic activity can lead to confusion, memory and cognitive impairment, dry mouth, blurred vision, increased heart rate, and urinary retention
- Antihistaminic activity can cause drowsiness and sedation
- Antiadrenergic effects can cause postural hypotension
- Life-threatening effects are concerning, especially for overdose in a suicidal patient population:
- Cardiac effects like arrythmias
- Excitement and convulsions
- Respiratory depression and coma
What is the mechanism of action of monoamine oxidase inhibitors (MAOIs)?
MAOIs inhibit monoamine oxidases such as MAO-A, which metabolizes dopamine, norepinephrine, and serotonin; they also inhibit tyramine metabolism, leading to further increases in norepinephrine
What is phenelzine (Nardil)?
First-generation antidepressant, monoamine oxidase inhibitor (MAOI) that is used as a treatment of depression by inhibiting monoamine oxidases, thereby inhibiting metabolism of dopamine, norepinephrine, and serotonin; also inhibits tyramine metabolism, leading to further increases in norepinephrine
What is imipramine (Tofrenil) (mechanism)?
First generation antidepressant, tricyclic antidepressant (TCA) that is used as a treatment of depression by:
1. Inhibiting presynaptic norepinephrine and serotonin reuptake transporters
2. Inhibiting postsynaptic histamine, acetylcholine, and several other receptors
What is the relationship between tyramine and monoamine oxidase inhibitors (MAOIs)?
MAOIs inhibit tyramine metabolism; tyramine increases blood pressure, leading to potential interactions:
- Eating a high tyramine food like cheese while taking a MAOI can easily raise systolic blood pressure
- In extreme cases, ingesting tyramine-containing foods while taking MAOIs can cause an “adrenergic storm,” causing extreme tachycardia, extreme hypertension, and possibly death
What is trazodone (Desyrel) (mechanism of action, effectiveness, side effects)?
Trazodone (Desyrel) is a second generation antidepressant
Mechanism: Blocks 5-HT2 receptors and has a metabolite m-chlorophenylpiperazine that is a serotonin agonist
Trazodone is therapeutically as efficacious as TCAs
Side effects:
- Drowsiness most common
- Priapism is rare but serious effect, requiring surgery in about 33% of cases and can cause permanent impotence
- Modest effects on cognitive functioning even with overdoses
What is the goal of acute treatment of major depressive disorder (MDD)?
Remission of all symptoms
Are antidepressants intended for acute or long-term treatment?
Most antidepressants are approved for both acute and long-term treatment of major depression
What is the success rate of antidepressants?
Antidepressants achieve remission in about 30-40% of patients within a single trial of 8-12 weeks
There is improved response with sequenced augmentation or switching drugs in cases with inadequate response therapy; switching + augmentation leads to 70-80% of patients being able to achieve remission
Once an adequate response in achieved, therapy is continued for a minimum of 6-12 months
What is the recurrence rate of depression?
In patients who have a single episode of major depressive disorder (MDD), about 85% will have at least one recurrence, and many patients will have multiple recurrences
There is significant protective benefit when antidepressants are continued long-term for patients with recurrent MDD
What is esketamine (Spravato)?
Nasal spray with in-clinic adminisatration that was FDA approved in 2019 to treat depression (ketamine nasal spray); it can cause depression relief within hours and is intended for patients resistant to other treatments
2 general effects of psychostimulants (CNS stimulants)
- Augment monoamine neurotransmitter action (particularly dopamine, but also serotonin and norepinephrine)
- Increase dopaminergic activity in the brain’s central reward pathway (behavioral reinforcement, abuse, dependency, and craving)
5 main CNS stimulants
- Cocaine
- Amphetamines
- Methylphenidate
- Ephedrine and cathinone
- Synthetic cathiones (i.e., bath salts)
What is the history of cocaine?
- About 5,000 years ago: thought that leaves of coca plant were first used
- 1855-1860: cocaine identified and purified
- Mid-to-late 1800s: cocaine identified as local anesthetic, combined with wine, in Coca Cola, and other commercial products
- Sigmund Freud once recommended cocaine
- 1914 Harrison Narcotic Tax Act: cocaine baned in patent medicines and beverages
- 1918: procaine (novocaine) developed as synthetic local anesthetic
What is the mechanism of action of cocaine?
Blocks dopamine reuptake transporters (and other monoamine transporters) leading to an accumulation of dopamine in the synaptic cleft
3 acute neurotransmitter and biological effects of cocaine (and long-term effects)
Has actions in both the central and peripheral nervous systems:
1. Activates a “fight or flight” response due to increased norepinephrine (e.g., vasoconstriction)
2. Increased central arousal and a sense of energy; anorexia, hyperthermia
3. “Euphoria” (tolerance) and rewarding properties; dependency due to increased dopamine in reward pathway
After acute effects wear off: depression, dysphoria, sleepiness, craving
What is the dopaminergic central reward pathway?
Dopaminergic pathway involving neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NA) and prefrontal cortex (PFC) that is likely involved in sensing/processing reward; activated by drugs of abuse
What is the relationship between cocaine and sodium channels?
Cocaine is also a sodium channel blocker, and for this purpose can be used topically for ENT procedures, where vasoconstrictor activities can also reduce bleeding; possibly contributes to cardiac toxicity via this mechanism
Generally, this action is not thought to contribute to rewarding or addictive properties
3 forms of cocaine
- Coca leaves: chewed by native South Americans
- Cocaine salt as powder (cocaine hydrochloride, “snow”):
- Water-soluble
- May be administered orally, intravenously, or nasally
- Cannot be smoked - Cocaine in the base (crystal) form (crack; freebase):
- Insoluble in water but soluble in alcohol, acetone, or ether
- Heating the freebase converts cocaine to a stable vapor that may be inhaled
Why is smoking cocaine (crack, freebase form) especially concerning?
Cocaine in the base (crystal) form can be heated and inhaled, and smoking it has rapid onset of action; per the NIDA, this increases likelihood of misuse
Describe the distribution of cocaine (pharmacokinetics)
Penetrates brain readily; initial brain concentrations exceed plasma concentrations, but then it redistributes to other tissues
Crosses placenta (it and metabolites are also stored in uterine wall/placental membrane)
Describe the metabolism of cocaine (pharmacokinetics)
Half life in plasma is about 50 minutes, but it remains in the brain for 8+ hours
Metabolized by enzymes in plasma and liver; the major metabolite is benzoylecgonine, which is also used to test for cocaine use
What is benzoylecgonine?
Present in the plasma and liver, the major metabolite of cocaine; it is also used to test for cocaine use
What happens when cocaine and ethanol are co-used?
Creates cocaethylene, which is pharmacologically as active as cocaine, potentiating the euphoric effect and increasing the risk of dual dependency and the severity of withdrawal with chronic use
Cocaethylene is more toxic and the metabolite exacerbates cocaine toxicity
Cocaethylene has a half-life of 150 minutes
What are the pharmacological side effects of cocaine?
With long-term, high-dose use, cocaine can cause hallucinations and behavioral effects (impulsive or compulsive behavior and aggressive, homicidal behaviors)
6 mid-1900s clinical uses of amphetamines
- Schizophrenia
- Morphine addiction
- Tobacco smoking
- Severe hiccups
- Appetite suppression
- WWII pilot endurance
Abuse became a problem
3 current clinical uses of amphetamines
- ADHD
- Narcolepsy/IH
- Binge eating disorder (one FDA-approved drug)
3 forms of amphetamines
- Amphetamine pills/powder: can be taken orally or snorted nasally
- Amphetamine salts: can be dissolved and taken intravenously
- Methamphetamine in the freebase form (ice, crystal meth): can be smoked
What is the mechanism of action of amphetamines?
- Enter dopamine transporters (DAT) in the presynaptic neuron, preventing dopamine reuptake
- Interferes with the actions of the vesicular monoamine transporter (VMAT) within the cell, preventing the storage/packaging of dopamine and elevating intracellular levels; this causes the DAT to act in reverse, pumping cells into the synaptic cleft instead of reuptaking dopamine
Both of these actions lead to dopamine accumulation
Note: this can occur with other monoamines as well, similar to the actions of cocaine
Additional mechanims likely contribute to its ability to increase synaptic dopamine (and other monoamines)
Do amphetamines cross the placenta?
Yes, amphetamines cross the placenta
How long do amphetamines remain in the body?
The half-life of amphetamine is measured “in hours”
Methamphetamine has a half-life of about 11 hours
What is thought to be the pathophysiology of ADHD?
Thought that dysregulation of dopamine and norepinephrine in certain brain regions contributes to ADHD
How do CNS stimulants relate to ADHD?
Formulations of methylphenidate and amphetamine are considered first-line treatments for ADHD; they can improve symptoms but have some controversy and some potential issues with use
Note that non-stimulant drugs can also be used to treat ADHD
What is methylphenidate (mechanism, onset, half-life)?
CNS stimulant that is considered a first-line treatment for ADHD
Mechanism: Inhibits postsynaptic dopamine (and noreepinephrine) reuptake transporters, like cocaine; has other actions as well
Onset/half-life: Original dose form (Ritalin) has peak levels in blood about 2 hours after oral administration (it is slowly taken up into the brain after oral delivery); half-life is about 2-3 hours
Because of relatively short action, different dosage forms with slow release and even pro-drug forms were developed
What are amphetamine (Adderall) and lisdexamfetamine (Vyvanse)?
CNS stimulants that are first-line drugs for the treatment of ADHD
Lisdexamfetamine (Vyvanse) contains the amphetamine molecule coupled to lysine and may have less abuse potential; it is also approved for binge eating disroder
What are the side effects of CNS stimulants (psychostimulants) for ADHD?
- Appetite reduction, possible growth suppression
- Night-time insomnia
- BP, heart rate increases (concerns for patients with cardiac issues)
- Psychiatric problems
3 reasons ADHD drugs (CNS stimulants) are abused, and 3 possible issues with this abuse
Abused for:
1. Study aids
2. Weight loss
3. High (euphoria)
Possible issues:
1. Side effects from “reformulation”
2. Side effects from stimulants themselves
3. Legal implications (schedule II drugs)
When were antipsychotics first created?
Effective antipsychotics weren’t created until about 1950
What are first generation antipsychotics (FGA),and what are 2 common examples?
“Typical,” “conventional,” neuroleptic, “older drugs” that induce antipsychotic effects through D2 antagonism; specifically, binding affinity to D2 receptors is very strongly correlated with antipsychotic potency (positive symptom amelioration) and a high risk of side effects due to D2 blockade
Less commonly used than SGAs, and have a higher risk of side effects from D2 antagonism
2 common examples:
1. Haloperidol (Haldol)
2. Chlorpromazine (Thorazine)
What are second generation antipsychotics (SGA)?
“Atypical” antipsychotics or “newer drugs” that are typically characterized by 5-HT2A antagonism and D2 antagonism or partial antagonism; SGAs as a group have higher affinity for 5-HT2A receptors than D2 receptors
More commonly used than FGAs, and there is generally a lower risk of causing side effects via D2 antagonism
Treat positive symptom clusters, and although controversial, might have some impact on negative symptoms (or at least not make them worse)
What is psychosis?
Condition characterized by loss of contact with reality; can have multiple causes
What is schizophrenia, and how are its symptoms classified?
Complex mental illness with psychotic and other symptoms
Symptoms can be:
- Positive: excess or distortion of normal function
- Negative: decrease or loss of normal function
- Cognitive: defects in memory and attention
Positive symptom clusters are thought to be the most responsive to antipsychotic drugs
Medications can help, but there is a high rate of medication non-compliance/discontinuance, and some patients have refractory disease
How prevalent is schizophrenia?
Most common psychotic disorder, about 0.3% of the population
Peak incidence is at 15-24 years
Is schizophrenia genetic?
Schizophrenia can have a genetic basis:
- 10% of people who have a first-degree relative with the disorder will develop schizophrenia
- Having a second-degree relative with the disease also increases risk
- If someone has an identical twin with schizophrenia, they have about a 50% chance of also developing the disease
However, it is not purely genetic; complex trait and genetic/environmental interactions possibly contribute to neurodegeneration or dysfunction
What is the dopamine hypothesis of schizophrenia?
The dopamine hypothesis posits that “out of tune” dopaminergic activity (primarily in parts of the striatum and cortex) likely contributes to schizophrenia
This is the earliest concept for the pathophysiology of schizophrenia, and it is important for understanding schizophrenia symptoms, but it does not explain everything
This is why many antipsychotics act at D2 receptors, for drugs that increase dopaminergic activity aggravate/produce psychosis
Where do schizophrenia symptom clusters manifest in the brain?
Positive symptoms:
- Striatum
- Nucleus accumbens
Negative/cognitive symptoms:
- Frontal cortex (DLPFC, VMFC)
What are functions of dopamine/D2 receptors in different parts of the brain (pituitary, striatum, nucleus accumbens)?
Pituitary: limits prolactin release
Part of striatum: regulate movement/motor control (extra pyramidal nervous system)
Nucleus accumbens: reward
Also involved in receiving/processing some emetic (vomiting) signals
What is the serotonin hypothesis of schizophrenia (and 3 underlying reasons for this hypothesis)?
The serotonin hypothesis of schizophrenia suggests that dysregulation of serotonergic systems contributes to the pathophysiology of depression
This originated because:
1. Serotonin (5-HT) receptor agonists, like LSD, produce schizophrenic-like symptoms
2. Atypical antipsychotics (SGAs) have greater affinity for 5-HT2A than D2
3. 5-HT can modulate dopamine signaling
What is the glutamate hypothesis of schizophrenia, and what is one reason for and against this hypothesis?
The glutamate hypothesis of schizophrenia posits that dysfunction in glutamergic signal transduction contributes to the pathophysiology of schizophrenia
A reason for this hypothesis is that phencyclidine (PCP) and ketamine are NMDA antagonists and can heavily mimic the effects of schizophrenia; they also exacerbate psychosis and cognitive symptoms of schizophrenia
However, so far, drugs directly modulating glutamate receptors have failed in clinical trials
What is the acetylcholine hypothesis of schizophrenia (and 3 supports for this hypothesis)?
The acetylcholine hypothesis of schizophrenia suggests that dysfunction in acetylcholine signaling contributes to the pathophysiology of schizophrenia
This has some support because:
1. M4 acetylcholine receptor “knockout mice” had schizophrenia-like behaviors
2. An M4 agonist had efficacy in a phase II clinical trial
3. Clozapine (Clorazil) is a second generation antipsychotic (SGA) that has M4 agonist activities
On what receptors do antipsychotics typically act?
Varies from drug to drug, but all act at D2 receptors; many antipsychotics actually impact several neurotransmitter receptors
What are haloperidol (Haldol) and chlorpromazine (Thorazine), and how do they compare?
First generation antipsychotics (FGAs), AKA typical antipsychotics, that induce antipsychotic effects via D2 receptor antagonism; specifically, D2 receptor antagonism in parts of the striatum is highly correlated to the amelioration of positive cluster symptoms
Haloperidol (Haldol):
- Strong D2 antagonistic activity (high potency)
- Most commonly used FGA
- Higher risk for side effects due to D2 antagonism
Chlorpromazine (Thorazine)
- Not as strong a D2 antagonist as haloperidol (low potency)
- Has actions at other neurotransmitter receptors and can cause side effects due to actions at these other receptors (weight gain, sedation, orthostasis, anti-cholinergic effects)
What are the respective effects of D2 antagonism in the striatum and cortex of those with psychosis?
Striatum: though that dopaminergic activity is too high in psychosis, causing positive symptoms; benefit of reducing D2 activity via D2 antagonism is amelioration of these positive symptoms
Cortex: thought that dopaminergic activity is too low in psychosis, causing cognitive and negative symptoms; it is possible that reducing dopaminergic activity via D2 antagonism has no effect or exacerbates these symptom clusters
5 extrapyramidal side effects (EPSE) associated with D2 antagonism in parts of the striatum
D2 antagonism in parts of the striatum can induce extrapyramidal side effects (EPSE), which can manifest as:
1. Acute dystonia (true EPS)
2. Parkinsonism (true EPS)
3. Akathasia (possible EPS, unclear cause)
4. Tardive dyskinesia (true EPS)
5. Neuroleptic malignant syndrome (possible severe EPS)
What is akathisia, and how does it relate to antispychotic drugs?
D2 antagonism in parts of the striatum can lead to extrapyramidal side effects (EPSE), including the manifestation of akathisia; this is a possible EPS, as the cause is not clear
Akathisia is the most common movement disorder and is characterized by feeling of motor “restlessness”
Rates are thought to be higher with first generation antipsychotic (FGA) drugs than with SGA drugs
What is neuroleptic malignant syndrome, and how does it relate to antipsychotic drugs?
D2 antagonism in parts of the striatum can lead to extrapyramidal side effects (EPSE), including the manifestation of neuroleptic malignant syndrome; possibly an extreme EPS
Neuroleptic malignant syndrome is rare but life-threatening and is often identified early in treatment, though it can be seen after years; severe cases can last for a week after discontinuance
It is characterized by fever, rigidity, mental status changes, and autonomic instability
What is tardive dyskinesia (TD), and how does it relate to antipsychotic drugs?
Tardive dyskinesia (TD) is caused by receptor upregulation in the nigrostriatal tract, leading to involuntary hyperkinetic movements
D2 antagonism in parts of the striatum can lead to extrapyramidal side effects (EPSE), including the manifestation of TD, but only with long-term D2 blockade (late occurring)
The risk of antipsychotics causing this EPSE mirrors that of acute dystonias/Parkinson’s-like effects
What is acute dystonia, and how does it relate to antipsychotic drugs?
D2 antagonism in parts of the striatum can lead to extrapyramidal side effects (EPSE), including the manifestation of acute dystonias
Acute dystonia is a movement disorder caused by D2 antagonism in the nigrostriatal tract, so it is a true EPS
It is characterized by muscle spasms and abnormal postures
What are Parkinson’s-like effects, and how do they relate to antipsychotic drugs?
D2 antagonism in parts of the striatum can lead to extrapyramidal side effects (EPSE), including the manifestation of Parkinson’s-like effects
A Parkinsonism reaction is caused by D2 antagonism in the nigrostriatal tract, so it is a true EPS
It is characterized by slow movement, rigidity, variable tremor, masked facies, and shuffling gait
What is hyperprolactinemia, and how does it relate to antipsychotic drugs?
Hyperprolactinemia is marked by abnormally high levels of prolactin, and is caused by lack of dopamine/D2 action in the pituitary; normally, dopamine/D2 limit prolactin release by the pituitary
In women, this condition causes amenorrhea-galactorrhea and sexual side effects
In men, this condition causes sexual side effects and gynecomastia
D2 antagonism correlates with hyperprolactinemia risk (FGA), but most SGA drugs have low risk of hyperprolactinemia
What are the effects of antipsychotic action in the nucleus accumbens?
The nucleus accumbens is part of the central reward pathway, and D2 blockade in the central reward pathway may lead to “secondary” negative cluster symptoms
How do antipsychotic drugs relate to emesis?
D2 antagonism as caused by antipsychotic drugs has anti-emetic (anti-vomiting) effects in the chemo-receptor trigger zone
Other neurotransmitter receptors involved in emesis are also targeted by some antipsychotics (including SGA drugs)
3 most commonly prescribed second generation antipsychotic (SGA) drugs
- Risperidone (Risperdal) and paliperidone (Invega)
- Clozapine (Clozaril)
- Aripiprazole (Abilify): D2 partial agonist
What are risperidone (Risperdal) and paliperidone (Invega)?
Second generation antipsychotic (SGA) drugs; risperidone is rapidly metabolized to 9-hydroxyrisperidone by CYP-2D6 (except in about 10% of patients), and 9-hydroxyrisperidone is paliperidone (Invega)
Both act as an antagonist at both 5-HT2A and D2 receptors
The two drugs have similar clinical responses and side effects, but there is a higher risk than other SGAs for EPS/TD/hyperprolactinemia, especially at higher doses
May also cause orthostastis
What is clozapine (Clozaril), what are its side effects, and why is it still used?
Clozapine (Clozaril) is a commonly prescribed second generation antipsychotic (SGA) drug that acts as an antagonist at both 5-HT2A and D2 receptors
It has lots of side effects due to actions at multiple neurotransmitter receptors, including:
- Anti-cholinergic effects (constipation), orthostasis, sedation
- Weight gain and other metabolic issues (including dyslipidemia, impaired glycemic control)
- Agranulocytosis (rare but fatal)
- Seizure risk
- Myocarditis
- Sialorrhea
Despite these concerns, it is still used due to:
- People refractory to other drugs
- Suicide risk reduction in those with schizophrenia
What is aripiprazole (Abilify) (mechanism and side effects)?
Aripiprazole (Abilify) is a second generation antipsychotic (SGA) drug that is a 5-HT2A antagonist + D2 partial agonist
It is the most used SGA and has a favorable side effect profile; however, there is a warning for rare situations of uncontrollable or compulsive urges (e.g., gambling)
Some consider this “third generation” due to D2 partial agonism
What is the QT interval of an electrocardiogram (ECG)?
The QT interval approximates the time for heart ventricles to contract and relax; some antipsychotics prolong QT, which can be incredibly dangerous and lead to cardiovascular side effects
Why do some antipsychotics cause cardiovascular effects?
Some antipsychotic drugs inhibit Ikr, a potassium channel important for proper heart activity. Inhibiting Ikr extends repolarization and therefore extends the QT interval (time for heart ventricles to contract and relax)
QT prolongation is a risk factor for torsade or other serious arrythmias, and there are concerns for additive impacts on QT prolongation (other risk factors, other QT prolonging drugs, anything that decreases metabolism of antipsychotic)
Note that some, but not all, antipsychotic drugs have not been found to prolong QT
Describe the metabolism (pharmacokinetics) of antipsychotics
Many antipsychotics are metabolized by liver cytochrome P450 enzymes
Antipsychotics are highly lipid-soluble and protein-bound, so they are retained for many weeks after cessation; for this reason, can be months to relapse (clozapine may be an exception)
Potential interaction: smoking induces CYP1A2, which metabolizes clozapine (Clozaril)
What is the relationship between clozapine (Clozaril) and smoking?
Smoking induces CYP1A2, which metabolizes clozapine (Clozaril); this is a potentially relevant pharmacokinetic interaction
What are the effects of antipsychotic drug use in pregnancy/lactation?
Antipsychotics cross the placenta, but available studies indicate little to no toxicity
Some antipsychotics may be excreted in breast milk, but not many studies and some drugs are more studied than others
6 disorders that can be treated via antipsychotic drugs
- Schizophrenia (except catatonic form)
- Bipolar disorder
- Schizoaffective disorder
- Adjunct therapy in depression
- Tourette’s syndrome (for tics)
- Autism spectrum disorders (for irritability)
Can the elderly use antipsychotic drugs?
FDA warns against use in elderly dementia patients with psychosis
There is a slight but statistically significant increase in mortality in the elderly
What determines antipsychotic drug choice?
Most antipsychotics are, across a broad group of patients, equally effective for treating positive cluster symptoms
However, some patients may response to one drug but not another, and clozapine (Clozaril) may have unique properties that make it the drug of choice for some
What is the first line of antipsychotic pharmacological treatment?
The use of second generation antipsychotic (SGA, “atypical”) drugs as the first line of treatment is suggested because of their superior adverse-effect profile and their low to absent risk of tardive dyskinesia
What is the goal of immunization?
To protect against disease upon subsequent exposure to the infection
Which diseases have been eradicated as a result of vaccines?
Small pox and polio (near-eradication)
Measles and rubella in the Western Hemisphere
Plans to eliminate hepatitis A and B
4 qualities of the ideal vaccine
- Induces protective immune response in all individuals
- No adverse events
- Cheap to produce
- Not temperature sensitive
What is active immunity?
Stimulates the host to produce a protective response to a pathogen
Active immunity can be gained from natural infection or immunization (i.e., relies on immunologic memory)
What are live attenuated vaccines?
Vaccines that contain live organisms, undergo limited replication in host, and produce immune response without causing disease; a single dose produces long-lasting immunity
I.e., these are weakened viruses
What is the issue with live vaccines?
Live vaccines are not used in pregnancy, or in those who are immunosuppressed (e.g., elderly)
What are inactivated vaccines?
Vaccines containing an inactivated virus; the virus is grown in culture and exposed to heat/chemicals to inactivate it
Sometimes these vaccines are purified to contain only portion of virus needed to induce immunity
What is the issue with inactivated vaccines?
Multiple doses required to produce protective immunity, and generally require booster doses
What are fractional vaccines?
Vaccines that contain only portion of pathogen that induces protective immunity; this reduces adverse effects associated with vaccine administration
2 examples of live attenuated vaccines
- Measles, Mumps, and Rubella
- Varicella
4 examples of inactivated vaccines
- Polio
- Rabies
- Most influenza
- Pertussis
5 examples of fractional vaccines
- Polysaccharide vaccines
- Recombinant DNA vaccines
- Toxoids
- Influenza
- Acellular pertussis
How is recombinant technology used for vaccine production (recombinant vaccines)?
- Insert gene for antigen in microorganism (yeast, bacteria)
- Microorganism produces antigenic protein
- Antigenic protein harvested and purified for use as vaccine
What is the advantage and disadvantage of recombinant vaccines?
Advantage: large amount of pure antigen generated
Disadvantage: expensive
6 examples of recombinant vaccines
- Hep. B
- HPV
- Influenza
- MenB
- Zoster
- COVID-19 (Novavax)
What are toxoid vaccines?
Vaccines containing inactivated bacterial toxins that yield an immune response to toxins produced by infecting bacteria
2 examples of toxoid vaccines
- Tetanus
- Diphtheria
What are nucleic acid vaccines?
Vaccines that contain the gene for the antigenic portion of a pathogen and yield an immune response to the protein encoded by plasmid DNA or mRNA; induces cell mediated and antibody responses
When a virus enters the body, the host cell takes up this foreign DNA or mRNA. It then uses the pathogen’s gene (that the vaccine provided) to produce an antigenic pathogen protein, which can then combat the pathogen.
4 advantages of nucleic acid vaccines
- Induces complex immune responses
- Pure
- No infectious risk
- Easy and inexpensive to produce
6 examples of nucleic acid vaccines
Candidate infections:
1. Hep. C
2. Herpes
3. HIV
4. Parasites
5. Cancer
6. COVID-19 (first successful NA vaccine)
How are mRNA (nucleic acid) vaccines formulated?
Naked mRNA is rapidly degraded by extracellular processes, so it is coated with lipid nanoparticles that protect mRNA from degradation and facilitate entry into the cell
What is the mechanism of action of mRNA (nucleic acid) vaccines?
- mRNA encodes some of the coronavirus spike protein
- mRNA in lipid coat (to prevent degradation) enters cell and is translated into viral spike protein (mRNA quickly broken down)
- Immune system recognizes viral protein and initiates B cell (antibody) and cytotoxic T cell response
What are recombinant viral vector vaccines?
Vaccines with live vaccine engineered into carriers or vectors of antigens from other pathogens (i.e., using virus to deliver vaccine)
May induce immune response to vector and targeted pathogen, but pre-existing immunity to vector limits effectiveness
Common example is Ebola vaccine
Describe the relationship between Rotashield and intussusception
Rotashield was a vaccine for rotavirus that was introduced in August 1998. 15 cases of intussusception were reported d/t the administration of this vaccine, so the use of the vaccine was halted.
In 1999, it was found that Rotashield induces a 20-30x increased risk of intussusception following the first dose of the vaccine. 1-2 cases per 10k infants attributed to vaccine.
Describe the relationship between J&J COVID-19 vaccine and thrombosis
The J&J COVID-19 vaccine was linked to central venous sinus thrombosis (CVST) with thrombocytopenia, with 7 cases reported in about 8 million doses.
Estimated 7 cases of thrombosis with thrombocytopenia among females aged 18-49 years for every million doses of vaccine.
Vaccine no longer used in the US.
3 waves of the opioid epidemic in the US
Wave 1 (1999): Rise in prescription opioid overdose deaths
Wave 2 (2010): Rise in heroin overdose deaths
Wave 3 (2013): Rise in synthetic opioid overdose deaths (fentanyl)
What are the odds of dying from opioid overdose in the US?
1 in 96, this ranks as the 5th most likely cause of death
What are analgesics?
Drugs that relieve pain; can be opioids (narcotics) or nonopioids (nonnarcotics; includes NSAIDs)
3 medical uses of opioids
- Treat moderate to severe pain
- Suppress cough
- Suppress diarrhea
What are the most effective pain-relieving drugs (and 2 prominent examples)?
Opioids are the most effective pain-relieving drugs
Morphine remains the benchmark for all pain relievers
Codeine is thought to be the most commonly used drug worldwide today
opiate vs. opioid
opiate = a drug present in opium extract
opioid = any drug that acts as an opiate receptor agonist
What is pain?
Sensation resulting from any tissue-damaging stimulus that is essential for survival; contains emotional and sensory components
3 explanations for analgesic effectiveness
Analgesic effectiveness may be due to:
1. Reduced sensation
2. Reduced process of recognition
3. Altered process of discrimination, memory, or judgement that follows recognition
How do NSAID drugs and opioid drugs exert their specific effects?
NSAID drugs reduce the sensation of pain mostly through changes in peripheral sites of pain stimulus
Opioid drugs reduce pain via multiple actions in the Central Nervous System (CNS)
Describe the pain relay pathway
- Noxious (painful) stimuli activate nociceptors
- Nociceptors activate neurons in the dorsal horn of the spinal cord that release Substance P, the NT which relays the pain signal
- From spinal cord, pain info is transmitted to brain stem + thalamus and is processed/interpreted in higher brain centers (limbic system and somatosensory cortex)
- Descending (brain stem to spinal cord) pain-inhibitory systems modulate pain via serotonin and norepinephrine-releasing neurons
3 sites of action of opioids
- Activate endorphin neurons in dorsal horn of spinal cord (descending pain-inhibitory systems include serotonin and NE-releasing neurons)
- Inhibit release of transmitters from the primary afferent nociceptive neurons
- Exogenous opioids activate opioid receptors in the CNS
How many opioid receptor agonists are there?
> 50 natural, semisynthetic, and synthetic compounds
What are endorphins (and 3 examples)?
Endorphin is a generic term that applies to any endogenous substance that exhibits pharmacological properties of morphine (endogenous opioid peptides)
Endorphins are responsible for “runner’s high” and are critical to the therapeutic efficacy of acupuncture
This includes:
1. Enkephalins
2. Dynorphins
3. Beta-endorphins
How do endorphins relate to acupuncture?
Beta-endorphins levels are significantly elevated during acupuncture
Describe opioid receptors (type, what they bind, where)
Opioid receptors are G-protein coupled receptors that are widely distributed throughout the CNS and are present in peripheral nerves and GI tract; they bind endogenous endorphins and exogenous opioids
There are at least 4 specific types of opioid receptor (e.g., Mu)
What is the Mu opioid receptor?
Best and strongest analgesic action occurs at Mu; has highest abuse liability as a result
Mu is responsible for respiratory depression, spinal analgesia, bradycardia, physical dependence, and euphoria
Describe the 4 classifications of opioid receptor binding brugs
- Pure agonists: have an affinity for cell receptors to induce changes in the cell characteristic of the natural ligand (e.g., endorphins)
- Pure antagonists: have an affinity for cell receptors but elicit no change in cellular function; block both endogenous ligands and exogenous drugs
- Mixed agonist-antagonist: produce an agonist effect at one receptor and an antagonistic effect at another; clinically useful mixed drugs are kappa agonists and mu antagonists; display ceiling effect for analgesia (decreased efficacy)
- Partial agonists: bind receptors but with low intrinsic activity
What is morphine?
A pure agonist opioid that is the most effective analgesic
Most common use is by IV injection, but many routes of administration are possible
Inhalation of smoke from crude opium delivers morphine
Describe the distribution of morphine
Morphine is “ok” at crossing the blood-brain barrier (other opioids like heroin and fentanyl cross more readily); 20% of morphine reaches CNS
Describe the metabolism of morphine
Metabolized by the liver, and its metabolite (morphine-6-glucuronide) is 10-20x more potent
Half-life of both are 3-5 hours
Urine-screens can detect morphine, codeine, other opioids, and metabolites for 2-4 days after discontinuation (poppy seeds have small amount of morphine and can cause false positives)
Describe the 8 pharmacological effects of morphine
-
Analgesia and indifference to pain:
- Reduces pain intensity and associated distress
- Perception of pain is altered
- No LOC and no affects on other sensory modalities - Euphoria induces strong feeling of contentment, well-being, and lack of concern; Mu receptors activated within limbic dopamine reward system cause this
- Sedation and anxiolysis not as deep as CNS depressants; produces mental clouding
- Depression of respiration by decreasing respiratory center’s sensitivity to higher levels of CO2 in the blood; this is the single most important side effect and cause of death from OD
- Suppression of cough via brain’s cough center
- Pupillary constriction (miosis)
- Causes constipation/relieves diarrhea
- Nausea/vomiting
What is the significance of opioid’s depression of respiration?
Depression of respiration by decreasing respiratory center’s sensitivity to higher levels of CO2 in the the blood is the single most important side effect and cause of death from OD.
The combination of morphine (or any opioid) + ethanol, benzodiazepines, or barbiturates is especially dangerous.
What is the relationship between morphine and white blood cells?
Morphine affects white blood cells and thus should be avoided in patients with a compromised immune system
What is the relationship between morphine and histamines?
Morphine can induce histamine release, resulting in localized itching or more severe allergic reactions (including bronchoconstriction)
Describe morphine/opioid tolerance
Repeated administration of morphine results in marked tolerance…clinical morphine doses go from 50-60mg/day to 500mg/day in 10 days!
Tolerance to one opioid leads to cross-tolerance to all
Describe morphine/opioid dependence and withdrawal
Acute withdrawal in drug-dependent individuals includes symptoms that are generally opposite that of the pharmacological effects
Acute withdrawal is not life-threatening and can be precipated by injection of naloxone (Narcone)
What is heroin?
Semi-synthetic pure agonist opioid that is a drug of abuse and is not used medically in the US
Semi-synthetic because it is created from morphine, and first-pass metabolism converts it back to morphine
Lipid soluble, causes intense rush of euphoria when smoked or injected
Responsible for the 2nd wave of the opioid crisis (heroin deaths)
What is codeine?
Most commonly prescribed opioid, often combined with aspirin or acetaminophen for relief of mild to moderate pain; used to treat cough in Rx cough syrup
Commonly abused (lean/purple drank)
What is loperamide (Imodium) (effect, mechanism, aborption/metabolism)?
Goal: anti-diarrheal
Mechanism: Mu opioid receptor agonist that does not reach the CNS
Absorption is reduced by multidrug resistance protein 1 (MDR1) pump and first pass metabolism; MDR1 pump also blocks passage of blood-brain barrier
What is fentanyl?
Synthetic pure agonist opioid used medically for pain, typically as transdermal patches or lozenges
50-100x more potent than morphine
Illicit use increasing and associated with 3rd wave of opioid overdose deaths
What is oxycodone (Percodan, Oxycontin)?
Pure agonist opioid that is an oral agent used to treat pain
Abuse is common
Responsible for the 1st wave of opioid overdose deaths
What is methadone (dosing, half-life, administration)?
Methadone is a pill used to treat recovering heroin addicts; it relives craving and prevents withdrawal, but dose is not high enough to produce euphoria or sedation (addictive but milder withdrawal symptoms)
Common dose is 100mg, but some addicts have such high tolerance that they get 500mg/day
Has been reported to cause death at 1.4mg/kg in a naive user (80mg for a 150lb person) so diversion of pills intended for addicts is very dangerous
Long half-life allows it to block withdrawal for 24 hours
In current regulatory environment, daily clinic visits are required
Describe psychological treatment programs for opioid dependence
Traditional psychotherapy is the least effective opioid dependence treatment, unless paired with other treatments
“Self-help” or “communal” therapy run by former addicts can be very effective (think Jesse’s therapy in Breaking Bad)
This often involves going cold turkey w/ emotional support
What is buprenorphine (mechanism, administration, and comparison w/ methadone)?
Buprenorphine is a partial agonist opioid receptor modulator that can also relieve craving and withdrawal from opioids.
There is less potential for dependence than methadone and not a significant risk for respiratory depression upon overdose.
In current regulatory environment, outpatient treatment is allowed for physicians with special training (~8 hour course)
What is naltrexone?
Opioid antagonist that is the most commonly used antagonist for opioid withdrawal; most commonly used because of long duration of action, high oral bioavailability, and minimal side effects
Available as a once-per-month injectable formulation
What is naloxone (Narcan)?
Opioid antagonist used for acute treatment of opioid OD; minimal oral bioavaiability and short half-life make it less useful for addiction programs
What is the main psychoactive drug in marijuana?
delta-9-tetrahydrocannabinol (THC)
Describe the 2 plants that make THC
Cannabis sativa and Cannabis indica plants make delta-9-tetrahydrocannabinol (THC)
All parts of these plants contain THC, but it is most concentrated in a sticky resin
THC is secreted by the flowering tops of the female plants
What is hemp?
Cannabis sativa strains with very low THC, used to produce several industrial products like paper, cloth, biofuels, etc.
Hemp has higher cannabidiol (CBD) levels, and the 2018 Farm Bill federally legalized hemp cultivation
What is the mechanism of action of THC?
THC mimics the action of a family of endogenous substances called endocannabinoids (anandamide and 2-arachidonolylglycerol).
These substances, and THC, act as presynaptic inhibitory neuromodulators via activation of CB1 receptors. Specifically, they inhibit the release of glutamate and GABA, increasing dopamine release and leading to euphoric effects.
2 main endocannabinoids
- Anandamide
- 2-arachidonolylglycerol
THC mimics the action of these endogenous substances to elicit its effects
What is the role of CB1 receptors in different parts of the brain (frontal cortex, hippocampus, cerebellum, basal ganglia, brain stem)?
THC activates CB1 receptors to act as presynaptic inhibitory neuromodulators.
Frontal cortex: psychoactive drug effects
Hippocampus: THC-induced disruption of memory
Cerebellum: Movement and postural control
Basal ganglia: Movement and postural control
Brain stem: NONE in brain stem; this explains the relative nonlethality of THC
How is marijuana prepared, and what is the resulting THC concentration?
The preparation most often used in the US consists of dried, crushed leaves, and flowering tops and stems/seeds of the plant. The seeds and stems are usually shaken out before use.
THC concentration is typically 3-4%, but highly potent varieties may contain 10-15%. Hemp concentration is <0.3%.
What is relatively concerning about oral marijuana consumption?
“Overdose” risk may be higher because slow absorption leads user to take higher dose
Describe the absorption of smoked/vaped marijuana
The absorption and crossing of the BBB with smoked or vaped marijuana is very fast due to the very high lipid solubility of THC (lung tissue great for absorption).
Peak intoxication achieved by 10-20 min, and effects usually last 2-4 hours after a dose.
Describe the absorption of orally consumed marijuana
Aborption is slower and highly variable among persons, onset may take 30-120 minutes, and peak effects may not be reached for 1-3 hours after a dose. It may be 12 hours after ingestion before the effect is over.
The delay in onset is a major cause of toxicity in the inexperienced user.
What is the relationship between marijuana and tachycardia?
Time course correlates well with THC blood levels; a substantial increase of 20-100% is typical
2 peripheral vasomotor effects induced by marijuana
- Marijuana produces generalized peripheral vasodilation, especially in skeletal muscles and conjunctiva
- Causes vasoconstriction in fingers and toes
Describe marijuana tolerance
There is strong tolerance to the desired effects of THC, typically only in those who use several times/day.
Tolerance is noticeable after 1-2 weeks of daily use and is lost at about the same rate on discontinuation.
Is marijuana psychologically addictive (psychological dependency)?
Many people do become psychologically dependent, and discontinuation may be very difficult; 3 studies including 55k people found a prevalence of dependence ranging from 6-9%.
Cannabis has a lower tendency to produce compared to many other drugs of choice.
Is marijuana physically addictive?
Even very heavy chronic use is unlikey to produce serious physical withdrawal symptoms
What is the time course of marijuana withdrawal?
Onset is 1-3 days
Peak is 2-6 days
Duration is 7-14 days
Describe massive overdose with regard to marijuana
The risk of severe toxicity or death due to cannabis is extremely low, and there are no well documented deaths in humans.
Massive overdose, however, can produce a toxic psychosis that dissipates in a few days.
Describe the 8 dangers from moderate recreational use of marijuana
“Moderate recreational use” equals about a “few” joints per week or less. For healthy individuals there are relatively few dangers, but certainly this is not totally risk-free.
- There is risk of progression to heavy use or dependence.
- Impaired driving ability does occur and is additive with alcohol.
- Acute panic reaction is probably the most frequent adverse reaction.
- Mobilization of latent psychosis is very rare, but may occur as an acute psychotic reaction
- Cannabis use associated with a ~2.4 fold increase in risk of schizophrenia
- Flashbacks occur
- Postural hypotension is common and can lead to falls
- Peripheral vasoconstriction may lead to cold fingers and toes
What is the relationship between marijuana and psychosis/schizophrenia?
Mobilization of latent psychosis is a very rare event, but may occur as an acute psychotic reaction to cannabis; this occurs in a person with a pre-existing psychopathology and can persist for a long time.
Cannabis use is associated with a ~2.4-fold increase in risk of developing schizophrenia; the cause vs. effect is unclear, but the relationship between cannabis use and schizophrenia is dose-dependent.
4 cardiovascular effects of marijuana joints
- Tachycardia and peripheral vasodilation
- Risk of heart attack for those with significant CV risk factors increased ~5-fold in the first hour after use in one study
- Risk of mortality for those with significant CV risk factors increased ~3-fold over a 4 year period
- Lung cancer
What is the relationship between marijuana and lung cancer?
Lung cancer is a possible lethal effect of smoking marijuana. Marijuana smoke “tar” contains many of the same carcinogens as tobacco smoke, and the concentration of carcinogens is three times higher than in tobacco smoke.
The way people smoke joints doesn’t help, as there is 33% more tar deposited in the lungs than with tobacco.
What is unique about the pulmonary effects of smoking joints relative to tobacco smoking?
Acute and chronic respiratory problems observed in chronic cigarette smokers are seen, but it takes fewer joints than tobacco cigarettes
What are the pulmonary effects of marijuana vaporizer use vs. joint use?
Some studies have found improved pulmonary symptoms and lung function associated with vaping vs. smoking. Vaping is suggested to reduce risk of lung cancer, but this is a theoretical benefit without scientific support.
Moreover, 2019 saw an outbreak of lung injury and deaths associated with vaporizers and e-cigarettes.
What is chronic intoxication with regard to marijuana?
Chronic intoxication (stoned all the time) is another risk of chronic heavy use; this has significant effects on social functioning and learning
Is marijuana a gateway drug?
There is risk of progressing to the use of other, more harmful, illict drugs.
Cannabis users are more likely to layer use heroin and/or cocaine than non-users. This might be d/t common actions on the reward center in the NA, and might be d/t ease of access since other drugs are supplied by the same illegal black market.
Describe THC accumulation in the body, and its effects on drug tests
THC and some of its metabolites are highly lipophilic and tend to partition into body fat stores, with heavy use correlated with greater degree of accumulation.
The main consequence of this is that THC can be detected in urine drug tests for up to 72 hours after a single joint and as long as 30 days after discontinuation of daily smoking.
Describe medical cannabis in the US (3 cannabis-derived drugs)
Pure THC (dronabil) and a synthetic analogue (nabilone) are FDA approved in the US for treatment of anorexia in AIDS patients and for refractory nausea and vomiting of patients undergoing chemotherapy.
Pure cannabidoil aka CBD (EPIDOLEX) is also FDA approved in the US for certain types of epilepsy.
However, medical cannabis advocates assert that these drugs are not as effective as natural cannabis for many medical conditions.
Is cannabis superior to THC-only or CBD-only for treatment of medical conditions?
It is currently unclear. Cannabis does contain hundreds of additional compounds that might be pharmacologically active, but politico-legal issues made it very difficult to conduct robust clinical trials.
What is delta-8-THC?
There is very little delta-8-THC in natural cannabis, and most products in marketplace are mostly semi-synthetic chemical modifications of CBD.
Psychoactive properties and adverse effects less studied than delta-9-THC.
There are multiple warnings from FDA about lack of regulation and safety concerns for delta-8-THC products.
What is the prevalence of caffeine use?
Most commonly used psychoactive drug in the world, used by 80% of adults
Describe the absorption of caffeine
Significant absorption occurs in 15-20 minutes, almost all is absorbed by 45 minutes
Describe caffeine metabolism
Caffeine is metabolized in the liver by CYP1A2, a member of the cytochrome p450 enzyme family.
People who are “slow metabolizers” of caffeine can be at increased risk for caffeine-related adverse effects.
Half-life of caffeine is about 5 hours.
What is CYP1A2?
Member of the cytochrome p450 enzyme family that is found in the liver and breaks down many drugs, including caffeine.
It is inhibited by many drugs, and is induced by many drugs (smoking included).
What is the mechanism of action of caffeine?
Caffeine acts as an antagonist at adenosine receptors; adenosine is a neuromudulator that normally results in sedative, depressant, and anticonvulsant actions
What are the “positive” and “negative” effects of caffeine?
“Positive” effects: “awakening,” elevates mood, enhances performance of simple motor tasks
“Negative” effects: low doses may adversely impact delicate motor skills, arithmetic skills, or skills involving accuracy timing; high doses can cause agitation, anxiety, insomnia, rapid breathing, and shakiness
3 cardiovascular effects of caffeine
- Slight transient increase in blood pressure
- Slight stimulant action in heart, also dilates coronary arteries
- Constricts cerebral blood vessels
What are the pulmonary, GI, and urinary effects of caffeine?
Pulmonary: bronchial relaxation
GI: Increased secretion of gastric acid
Urinary: diuretic effect (controversial)
Describe the tolerance and dependence of caffeine
Chronic use (as little as a cup of coffee/day) can lead to habituation, tolerance, and some withdrawal symptoms, and some craving
Describe caffeine distribution
Caffeine is distributed throughout the body, and it freely crosses the placenta
How many chemicals are released by burning tobacco, and how many are toxic?
Burning of tobacco releases about 4000 chemicals, and at least 250 are known toxins or carcinogens. Smokeless tobacco also puts toxins/carcinogens into the body.
Describe the morbidity and mortality of tobacco use
Tobacco use is the single largest preventable cause of death and disease in the United States, though rates of use are declining.
In 2021 about 11.5% of 18+ in the US smoke.
There are more than 480,000 US deaths every year from cigarette smoking.
Describe the absorption of nicotine
Nicotine is readily absorbed, and smoking nicotine reaches the brain in 7 seconds
Describe the metabolism of nicotine
Most nicotine is metabolized by the enzyme CYP2A6 in the liver, generating cotinine (primary metabolite with 18 hour half-life).
Nicotine half-life is about 2 hours.
Does nicotine cross the placenta?
Yes, nicotine crosses the placenta (multiple impacts on developing fetus)
What is the mechanism of action of nicotine?
Nicotine acts as an agonist at nicotinic acetylcholine receptors (NAChRs), facilitating release of dopamine, ACh, glutamate, and other neurotransmitters
How many smokers want to quit and attempt to quit?
70% want to quit, and 40% attempt to quit each year
2 FDA approved medications for nicotine withdrawal
- Bupropion (Zyban)
- Varenicline (Chantix)
What is varenicline (Chantix) (goal, mechanism of action, side effects)?
Varenicline (Chantix) is an FDA approved drug for smoking cessation/nicotine withdrawal. It is thought to both help withdrawal and make smoking less satisfying.
It is a partial nAChR agonist, agonizing the nAChR during the quit stage to reduce craving during a quit attempt. In the context of nicotine use, varenicline acts as a nAChR agonist to compete with nicotine at the binding site.
Main side effect is reports of increased alcohol intoxication.
What is the relationship between nicotine withdrawal medications and neuropsychiatric events?
Bupropion (Zyban) and varenicline (Chantix) previously had FDA boxed warnings about neuropsychiatric events.
Larger studies found rates lower than first thought, especially for patients w/o a history of psychiatric disorder (labels still indicate to observe patients for these events).
Are e-cigarettes a proper treatment for smoking cessation?
No, not FDA approved. Scientists still have a lot to learn about whether e-cigarettes are effective for quitting smoking.
4 potential issues with e-cigarettes
- Most adult e-cig users do not quit cigs (dual-use)
- Known negative effects of nicotine still present
- Vapors contain harmful chemicals
- Other issues such as accidental fires, poisonings by liquid
6 peripheral effects of nicotine at nAChRs
- Increase in epinephrine
- Raises blood pressure
- Raises heart rate/cardiac contractility
- Decrease in muscle tone
- Multiple actions on GI tract
- May alter taste bud sensitivity
What is dementia (and 2 types)?
Dementia is the progressive deterioration of memory and cognitive function; it is NOT a single disease.
2 types:
1. Reversible dementia: theoretically can treat underlying cause and reverse dementia
2. Irreversible dementia: caused by an incurable condition
What is early onset Alzheimer’s disease?
Approximately 5-10% of all AD, defined as AD diagnosed before age 65 (can be much earlier).
Approximately half of cases are familial, from inheritance of a mutant gene: APP, PSEN1, PSEN2, but other cases have no obvious cause.
What is the relationship between Down syndrome and Alzheimer’s disease?
Increased risk for early onset AD in Down syndrome
What is late onset Alzheimer’s disease?
Most common type of AD, defined as AD diagnosed after age 65.
May be influenced by genetic factors (e.g., APOE4), and may also be influenced by environmental factors, lifestyle, other health factors, and even trauma.
What is the prevalence of Alzheimer’s disease in the US?
Ages 65-74: 5%
Ages 75-84: 13.1%
Ages 85+: 33.3%
People under 65: 200k in US
By 2060, it is predicted that almost 14 million people in the US will suffer from Alzheimer’s disease.
How does Alzheimer’s disease affect brain size?
AD causes brain atrophy (neurodegeneration)
What are amyloid plaques?
Neuropathological component of Alzheimer’s disease, aggregated (fibrillary) forms of beta-amyloid extracellularly
What are neurofibrillary tangles?
Neuropathological component of Alzheimer’s disease, contain primarily abnormal tau proteins in neurons
Describe the Alzheimer’s continuum?
AD is proposed to be a continuum of severity, with lesser forms as MCI and higher forms consisting of increasingly severe AD
3 types of drugs to treat Alzheimer’s disease
- Acetylcholinesterase inhibitors (3 drugs)
- Glutamate receptor partial antagonist (1 drug)
- Abeta targeting antibodies (immunotherapy) (2 drugs, recently approved, some controversy and limitations, 1 going to be discontinued
What is the cholinergic hypothesis of AD?
Hypothesis: AD is due to a decrease in acetylcholine (ACh) levels and dysfunction of cholinergic neurons in the brain.
This is believed because neuronal death is prevalent in AD, a result of decreased ACh.
What is donepezil (Aricept)?
Acetylcholinesterase inhibitor FDA approved to treat Alzheimer’s disease. Prevents the breakdown of ACh.
What is the pharmacologic effect of acetylcholinesterase inhibitors, like donepezil (Aricept)?
Only modest impacts on cognition, function, and behavior in Alzheimer’s disease patients, DO NOT impact disease course.
Not all patients will see benefit.
Can cause side effects some of which due to effects in periphery.
How is glutamate activity altered in Alzheimer’s disease?
There is elevated glutamate activity in AD; this is why memantine (Namenda), a glutamate receptor partial antagonist, is used to treat AD
What is memantine (Namenda) (mechanism, administration, efficacy, side effects)?
Glutamate NMDA-type receptor non-competitive partial antagonist that is FDA approved to treat Alzheimer’s disease. It may have actions at other receptors as well.
Usually given in combination with AChE inhibitor, called Namzaric (combination of memantine and donepezil).
Has modest effects, DOES NOT alter disease course.
Side effects (less than 7% of patients): headache, confusion , constipation
Describe immunotherapy for Alzheimer’s disease (goal, what is an antibody, what is lecanemab-irmb)?
Goal: clear (or prevent worsening of) Abeta forms that are proposed to cause the disease
Antibody: a protein complex made and used by the immune system to neutralize foreign invaders. Each antibody recognizes a specific protein sequence (antigen or epitope). Can be engineered in a lab.
Lecanemab-irmb (Leqembi): antibody that binds with high affinity to Abeta oligomers/protofibrils. It was FDA approved in early 2023 in AD, and treatment is initiated in MCI with confirmed amyloid presence.
What is lecanemab-irmb (Leqembi) (mechanism, clinical trial efficacy, 3 side effects)?
Antibody treatment for Alzheimer’s disease that binds with high affinity to Abeta oligomers/protofibrils.
FDA approved in 2023, and treatment is initiated in MCI or early dementia only with confirmed amyloid presence.
Mechanism:
1. Antibody binds with high affinity to Abeta oligomers/protofibrils
2. Antibody recruits macrophages and encourages the “eating” of Abeta
In 2023 clinical trial, lecanemab-irmb (Leqembi) significantly reduced amyloid plaque burden relative to those who received the placebo.
In this same trial, the drug also had modest improvements with regard to cognitive decline (slowed decline).
Side effects:
- Risk for amyloid related imaging abnormalities (ARIA) (edema, microhemorrhage) in about 20% of patients
- Rare fatal brain hemorrhage in some patients
- Infusion reactions
4 controversies surrounding lecanemab-irmb (Leqembi)
- Not enough racial and ethnic diversity in trials
- Difference in cognitive decline was only 2.7% (0.45 on 18 point scale)
- ARIA and hemorrhage risk
- Does modest efficacy justify cost and patient burden?
