Week 1 (Mood Disorders and Addiction) Flashcards
1
Q
Dopamine neurons effect on both motor function and behavior
A
1) Dopamine neurons from substantia nigra to caudate and putamen are important for motor function
2) Dopamine neurons from ventral tegmental area (VTA) to frontal cortex, striatum (nucleus accumbens, caudate, putamen), limbic cortex (temporal lobe) and amygdala, hippocampus are important for behavior
2
Q
Basal ganglia circuit loops influenced by dopamine
A
1) Motor cortex
2) Frontal cortex (dorsolateral prefrontal cortex)
3) Limbic cortex
Note: dopamine acts at putamen and anterior caudate
3
Q
Major depressive disorder (MDD)
A
Unipolar, “clinical” depression
10% of the population
17% will have MDD at some point
Leading cause of disability for age 15-44
Females more than males
Onset in 20s/30s, another peak in perimenopausal women, another peak >65yo
Diagnosis made by presence of critical number of symptoms
Heterogeneous disease
Several pathophysiologic models, not one etiology for all
Treatment works, but not one-size-fits-all
4
Q
How is treatment for MDD?
A
Many not treated at all, some treated pooly
Treatment rates vary by ethnic group (whites treated best and mexicans treated worst)
5
Q
Diagnosis of MDD
A
Clinical syndrome
Symptoms present for >/= 2 weeks
Must have major impact on person
Must not be explained by something else (substance abuse, medication side effects, other illness)
No diagnostic biomarker, must use diagnostic interview (“structured interview”)
6
Q
Major depression symptoms
A
Depressed mood
Diminished interest or pleasure in most activities
Significant weight loss or gain (>5%) or appetite change
Insomnia or hypersomnia
Psychomotor agitation or slowing
Fatigue or loss of energy
Worthlessness or guilt
Impairments in attention or decisiveness
Recurrent thoughts of death
7
Q
Comorbidities with depression
A
Diabetes: poor metabolic control, poorer adherence to medication and diet regimens, lower quality of life, higher medical expenditures
Cardiovascular disease: 1/5 with CVD have MDD also, and another 1/5 have minor depression; 1/3 get depression 1 year after MI and then have higher mortality than non-MDD; MDD predicts development of CVD also
8
Q
Mechanisms of MDD
A
Behavioral: diet, exercise, meds
Autonomic: heart rate variability less in people with MDD (bad!)
Inflammatory signaling: cytokines increased by 3x in MDD
Molecular mechanical: platelet adhesion increased (serotonin in serum sticks to platelets and increases adhesion –> can cause clot or MI)
9
Q
Screening for suicidality
A
Highest rate of completed suicide are older, unmarried, white males
First ask about suicidal ideation (have you ever felt that life is not worth living?), then follow up on nature, frequency, extend, timing of suicidal thoughts, especially the context (job loss, death of loved one)
See if there is a plan (details, lethality, practicing, firearms in the home)
Degree of intent (motivation, extent of aim to die, associated behapiors or planning for suicide)
10
Q
Neurobiology of MDD
A
Catecholamine hypothesis: monoamine, biogenic amine, abnormal signaling with 5HT, NE, DA
Neurotrophin hypothesis: deficits in neurotrophins (BDNF) lead to withered neurons, reduced plasticity and neurotransmission impairments
Vascular hypothesis: microvascular disease in white matter disrupts circuits leading to symptoms
Inflammatory hypothesis: cytokines and cortisol disrupt neuronal function
Psychological: cognitive, behavioral, psychosomatic, social, personality, psychosomatic; mind not tied to physical brain?
11
Q
Candidate gene x environment interactions (cGxEs)
A
Are not as robust as they appear because of publication bias
12
Q
Effective treatments for MDD
A
Antidepressant medications
Psychotherapy
Brain stimulation: electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS)
No one treatment works for everyone
May take several weeks for benefits to emerge
Side effects occur first but fade with time (reason for patients stopping tx before it starts to work!)
13
Q
How to assess treatment success in MDD
A
Remission (symptom resolution) instead of response (>50% improvement) leads to less disability and less risk of relapse
Simple rating scale (“measurement based care”) can give reliable benchmark (don’t just ask how’s your hypertension, you measure it)
14
Q
Failure of treatment
A
Less than 1/3 of patients remit with initial treatment (so treatment fails in more than 2/3)
Can be because of biological factors, patient couldn’t tolerate getting to appropriate dose, patient didn’t see benefits so stopped taking med, misconceptions or stigma derailed treatment
15
Q
Next step treatments for MDD
A
Combined medications: SSRI plus bupropion; antidepressant plus T3 or lithium; antidepressant plus aripiprazole
Medication plus therapy
TMS
ECT
16
Q
Complementary and alternative medicine for MDD
A
Folate and 5-methyltetrahydrofolate (MTHF) (Deplin)
Vitamin B12
Omega-3 fatty acids
S-adenosyl-L-methionine (SAMe)
St John’s Wort
Yoga
Tai Chi
Acupuncture
17
Q
DSM
A
Diagnostic and Statistical Manual of Mental Disorders
Collection of diagnostic criteria used as a standard for communication, billing, and research into psychiatric disorders
Organized by major symptoms (not etiology) and is primarily descriptive
18
Q
Disorders we will study that are in the DSM
A
Mood disorders: major depressive disorder, dysthymic disorder, bipolar I disorder, bipolar II disorder
Substance related disorders: dependence, abuse, intoxication
Anxiety disorders
Somatic distress disorders
Sleep disorders
Personality disorders
Adjustment disorders
Schizophreniform disorder
Schizoaffective disorder
Delirium
Dementia
Other cognitive disorders
Disorders usually first diagnosed in infancy, childhood or adolescence: autism, learning disorders, communication disorders, ADD, disruptive disorders, mental retardation)
Eating disorders: anorexia nervosa, bulimia nervosa
Sexual and gender identity disorders
19
Q
Factors necessary for diagnosis
A
Meet specific criteria (or number of symptoms from a list)
Meet duration or age of onset requirements
Have clinically significant distress or impairment in social, occupational or other important areas of functioning
Not have exclusionary disorders
20
Q
Etiology is important in which disorders?
A
PTSD requires a specific event
Adjustment disorders are a response to an event
Mental disorders due to specific general medical condition
21
Q
Biopsychosocial model for coding
A
Axis I: clinical disorders and other conditions which may be a focus of clinical attention; typically require immediate attention from a clinician (usually we have medications for these disorders)
Axis II: personality disorders/mental retardation;maynot require immediate carebut cancomplicatetreatment so should be taken into account by the clinician
Axis III: general medical conditions (diabetes, CVD, etc)
Axis IV: psychosocial and environmental problems (poverty, dysfunctional families, other factors in patient’s environment that might have impact on person’s ability to function)
Axis V: global assessment of functioning (overall rating of person’s ability to cope with normal life in school, work, social settings; 10 is persistent danger of severely hurting self or others and 100 is superior functioning)
22
Q
Cerebral cortex receives brainstem projections of which biogenic amines?
A
Dopamine (from substantia nigra and VTA)
Norepinephrine (from locus coeruleus)
Serotonin (from raphae)
These regulate many aspects of behavior including mood
23
Q
Fast acting amino acid neurotransmitters
A
Glutamate (excitatory)
GABA (inhibitory)
24
Q
Glutamate signaling
A
Excitatory, fast acting
Important in long distance, point to point connections
Receptors are AMPA (ion channel), NMDA (ion channel), metabotropic (second messenger)
Mechanism for synaptic plasticity via LTP
Basis for excitotoxicity (mechanism for neuronal death in CNS trauma, ischemia and neurodegenerative disease)
25
Memantine
Glutamate **antagonist**
Drug for **Alzheimer's** disease
26
GABA
**Inhibitory, fast acting**
Important in local **interneuron** connections
Important in many behavioral syndromes (anxiety, etc)
27
Drugs that act on GABA receptor
**Benzodiazepine**
**Barbiturates**
**Alcohol**
This can be additive so don't drink while taking benzos/barbiturates!
28
Biogenic amines
Neuromodulators with effects on many behaviors and mood disorders
Catecholamines: **DA, NE, E**
Indoleamine: **5HT**
Imidazoleamine: **histamine**
29
Amine inputs to the cerebral cortex
**Diffuse** (NT released from varicosities), and target **ALL cortical layers**
30
Where else (other than synapses) do aminergic neurons release NTs from?
Aminergic neurons release NTs from **varicosities** along the **axon fibers** in a **paracrine** fashion (act on target molecules on neurons (?) nearby, but not at a synapse)
31
Receptor subtypes for aminergic neuromodulators
**Multiple** receptor subtypes are generated from different genes or RNA splice variants
Different receptor subtypes can mediate **different effects** and can be **selectively targeted** by pharmacological agents
32
How do many aminergic receptors work?
Many are **metabotropic** receptors that activate **G-proteins**, which then modulate **ion channels** or trigger **intracellular second messenger** systems
**NE** --\> **beta adrenergic** receptor --\> G-protein --\> adenylyl cyclase --\> cAMP --\> PKA --\> **increase** protein phosphorylation
**DA** --\> dopamine **D2** receptor --\> G-protein --\> adenylyl cyclase --\> cAMP --\> PKA --\> **decrease** protein phosphorylation
33
Conventional anti-psychotic therapeutic drugs
**Blockers of D2 receptors** (have Parkinsonian motor side effects!)
Have other actions as well (**Chlorpromazine**, **Haloperidol**)
34
Dopamine synthesis
**Tyrosine** turned to DOPA by **tyrosine hydroxylase** (rate limiting enzyme in both DA and NE synthesis!)
DOPA durned to **dopamine** by **DOPA decarboxylase**
35
Homovanillic acid (HVA)
Major **metabolite** of **dopamine**
Can be measured in urine, plasma and CSF
HVA is **increased** in **psychosis** (DA) and **pheochromocytoma** (NE)
HVA is **decreased** in **depression, Parkinson's** (DA), when taking **anti-psychotics**
36
Where are DA neurons located?
In the midbrain:
**Substantia nigra**
Ventral tegmental area **(VTA)**
37
Dopamine terminal fields
**Caudate, putamen** (nigro --\> striatal) for **motor**
**Nucleus accumbens** (ventral striatum) important in **reward** (VTA) (meso --\> limbic)
38
How does DA influence behavior?
**Dopaminergic** projections to **frontal cortex, limbic cortex, amygdala, hippocampus**
39
How are biogenic amines cleared?
**Reuptake**
Note: this can be target of psychoactive agents and drugs
40
Transporters that regulate levels of DA release and re-uptake
Vesicular monoamine transporter (**VMAT**)
Dopamine transporter (**DAT**)
41
Which drugs target DAT (dopamine transporter)
**Ritalin** (methylphenidate): stimulant
**Bupropion**: antidepressant
**Cocaine**
These all **block reuptake** and increase dopamine concentrations at synapses
42
NE synthesis
Tyrosine turned to DOPA by tyrosine hydroxylase (rate limiting enzyme in both DA and NE synthesis!)
DOPA durned to dopamine by DOPA decarboxylase
**Dopamine** turned to **NE** by **dopamine-beta-hydroxylase**
43
Vanillylmandelic acid (VMA)
Major **metabolite** of **NE**
Can be measured in urine, plasma, CSF
VMA is **increased** in **pheochromocytoma**
VMA is **decreased** in **depression**
44
Where are NE neurons?
**Locus coerulus** of the brainstem (pons)
45
Where do NE pathways project?
**All neocortical areas** (frontal, etc)
**Limbic cortex** (temporal lobe)
**Amygdala**
**Hippocampus**
46
Transporters that regulate levels of NE release and re-uptake
Vesicular monoamine transporter (**VMAT**)
Norepinephrine transporter (**NET**)
47
Drugs that target norepinephrine transporter (NET)
**Ritalin** (methylphenidate): stimulant
**Tricyclic antidepressants**: imipramine, nortriptyline, desipramine
These **block reuptake**
48
Epinephrine synthesis
**NE** turned into **Epi** by **phenylethanolamine N-methyltransferase**
49
Targets of epi pathways
More **restricted** projections to **subcortical regions**
50
Serotonin (5HT) synthesis
**Tryptophan** turned to 5-hydroxytryptophan by tryptophan-5-hydroxylase
5-hydroxytryptophan turned to **serotonin** (5HT) by aromatic L-amino acid decarboxylase
51
5-hydroxyindoleacid (5-HIAA)
Major **metabolite** of **serotonin**
Can be measured in urine, plasma and CSF
5-HIAA **increased** in **autism**
5-HIAA **decreased** in **depression, suicide, aggression** and **violence**
52
Where are serotoninergic neurons located?
**Raphe** nuclei along midline of brainstem (medulla, pons and midbrain)
53
Major targets of serotinergic pathways
**All neocortical areas** (frontal, etc)
**Limbic cortex** (temporal lobe)
**Amygdala**
**Hippocampus**
54
SERT
Serotonin transporters (SERT) regulate levels of **5HT** **reuptake**
55
Drugs that target SERT (serotonin reuptake transporter)
**SRI** (serotonin reuptake inhibitors) **antidepressants**: **fluoxetine** (Prozac), peroxatine
**Tricyclic antidepressants**: imipramine, nortriptyline, desipramine
**MDMA** (ecstasy)
These **block reuptake** and increase serotonin concentrations at synapses
56
Monoamine oxidases (MAO) and MAO inhibitors
MAOs enzymatically **degrade catecholamines**
**MAO inhibitors** block catecholamine breakdown (so increase concentrations) and are used as **antidepressants** and in **anxiety** disorders (**Phenelzine, Selegeline**)
**Two forms** of monoamine oxidase have different specificities: **MAO-A** (5HT, NE, DA), **MAO-B** (DA)
57
Histamine synthesis
**Histidine** turned to **histamine** by **histidine decarboxylase**
58
Major targets of histamine pathways
**All neocortical areas** (frontal etc)
**Limbic cortex** (temporal lobe)
**Amygdala**
**Hippocampus**
59
What does histamine influence?
**Sleep** and **wakefulness**
**Appetite**
Drugs that **increase** histamine (increase release or receptor agonist) **promote wakefulness and reduce appetite:** **modafinil** (promotes histamine release)
Drugs that **decrease** histamine (decrease release or block H1 receptors) **promote** **drowsiness** and sleep (anti-histamines) and **promote** **appetite**: diphenhydramine (Benadryl which is anti-histamine, H1 blocker)
60
What are the targets of Ach pathway?
**Basal nucleus** (forebrain) cholinergic system sends projections to **all cortical regions** including **hippocampus** and **amygdala**
61
Which neuron terminals are lost in Alzheimer's?
**ACh** terminals in the **hippocampus** and **cerebral cortex**
62
Cholinomimetic drugs
Promote **memory** and **attention**
Approved treatment for Alzheimer's disease
63
Neuromodulatory peptides that have effects on behavior
**Enkephalins**: endogenous **opiates**; pain modulation; reward
**Leptin**: appetite regulation
**Oxytocin** and **vasopressin**: social bonding
**CRH**: stress response
64
Demographics of Bipolar Disorder
1-2% lifetime prevalence (up to 5% if broader definitions)
Onset of clear episodes in **20s** but some report **teen/childhood onset**
**25% attempt suicide** and 15% complete
65
Diagnosis of bipolar disorders
Family of clinical diagnoses defined by presence of symptoms of these states: **depressed, manic, hypomanic, mixed**
Have major impact on the person (**impairment**)
Not explained by something else
No diagnostic biomarker; **diagnostic interview** is gold standard
66
Symptoms of a manic episode
**Elevated, expansive** or **irritable** mood for at least **one week** (or any duration if **hospitalized**) along with **\>/= 3** of:
Inflated self-esteem or **grandiosity**
**Decreased** need for sleep
**More talkative** than usual (pressured speech)
**Racing thoughts** or **flight of ideas** (thoughts only tangentially related to each other)
**Distractibility**
Increase in **goal-directed activity**
Excessive involvement in **high risk activities**
67
Symptoms of a hypomanic episode
**Elevated, expansive** or **irritable** mood for at least **4 days**, clearly different from a person's usual mood, and **\>/= 3** other symptoms of mania (**\>/= 4 if only irritable**)
**Non-subtle change** in functioning (ex: sufficiently more productive in a way noticeable to others)
**Not severe enough** to cause serious **impairment** in social or occupational functioning, or to necessitate hospitalization and there are **no psychotic features**
68
Symptoms of a mixed episode
"Black Mania"
Meet criteria for both **manic** and **depressed** episodes, except duration of **depression need only be one week**
Severe, causing marked **impairment**
Rule out substance induced, general medical condition, etc
69
DSM-IV-TR classification of Bipolar Diagnoses
**Bipolar I Disorder**: at least one lifetime episode of **mania** or **mixed** state; although not required for diagnosis, one lifetime episode of major depression occurs in the majority
**Bipolar II Disorder**: at least one lifetime episode of **hypomania**; at least one lifetime episode of **major depression**
**Bipolar NOS**: not otherwise specified
**Bipolar disorder with "rapid cycling"**: meets criteria for bipolar I or bipolar II; **4 or more episodes** of major depression, (hypo)mania, or mixed state in any **one year**
70
Possible triggers for depression and (hypo)mania
**Depression triggers**: **stressful** event, **poor social support**, negative cognitions, poor nutrition, sedentary lifestyle, medication effects, alcohol/substance misuse
**(Hypo)mania triggers**: poor/reduced **sleep pattern**, **stressful** life event, severe **emotional stress**, drug misuse or abuse, "**switching" from medication**, natural rhythmicity of the disorder
71
Co-morbidities with bipolar disorder
**Psychiatric** co-morbidities: 77% have some disorder; 44% have \>/= 3; 63% **anxiety** disorder (50% panic); 37% **substance** disorder (34% alcoholic); 45% behavioral disorder (20% **ADHD**)
**Medical** co-morbidities: cardiovascular (**HTN**, **hyperlipidemia**), endocrine/metabolic (**obesity**, **thyroid**, **T2DM**)--can occur within first decade of illness
72
Course of bipolar disorder
37% relapse within one year
**73% relapse** within **5 years** despite treatment
Question is not whether or not they'll have another episode, but when
73
Pathophysiology of bipolar disorder
Neuroimaging studies show key regions of the brain that differ in **volume** and/or **activity** (ex: **medial prefrontal cortex, putamen, amygdala** more active when processing emotionally expressive faces)
Signaling cascades are affected by drugs (lithium, etc), so these may be involved in pathophysiology
Family pedigree and GWAS studies duggest specific genes, but replication is problematic
**Gene x Environment** interaction is likely
74
What can lead to dysregulation of mood in the brain?
**Diminished prefrontal modulation** of subcortical and medial temporal elements (amygdala, anterior striatum, thalamus)
75
What signaling pathways/molecules are targeted by mood stabilizers (lithium and divalproate) for treating bipolar disorder?
**BDNF** pathway
Extracellular signal-regulated kinase pathway
Glycogen synthase kinase-3-mediated pathway
Bcl-2
76
Genetic factors important in bipolar disorder
Not yet known, but being investigated by GWAS (genomewide association studies)
77
Challenges to treating bipolar disorder
Manic episodes are more responsive to treatment than depressive, but **people LIKE their manias**
**Depressive** episodes account for much of the **disability**
**Loss of insight** interferes with receiving effective treatment
Psychotherapeutic interventions **improve outcomes** but require willing participation
78
Treatments for mania or mixed episodes
**Lithium**
Anticonvulsant agents: **valproate, lamotrigine, carbamazepine**
Antipsychotic agents: **olanzapine, risperidone, quetiapine, ziprasidone, aripirazole**
Adjunctive **benzodiazepines** commonly used
**ECT** or **clozapine** for refractory cases
If psychotic symptoms, include **antipsychotic**
**Psychoeducation**
79
Treatments for depressive episodes
**Lithium** and **lamotrigine** are first-line
Antidepressants remain controversial: olanzapine-fluoxetine combo has FDA approval (Zyprexa plus Prozac = **Symbax**)
**Quetiapine** has FDA approval
**Psychotherapy** (cognitive behavioral therapy, interpersonal therapy, social rhythm therapy)
**ECT** for refractory situations
Be watchful for potential **"switch" into mania**
If psychotic symptoms, include an **antipsychotic**
80
Maintenance treatment for bipolar disorder
**Lithium** (dose once per day to give renal cells a chance to regenerate)
Valproate
Lamotrigine
Aripiprazole
Quetiapine, Ziprasidone as adjunct to lithium or valproate (FDA approved)
Need to **monitor for long-term toxicities** (thyroid, renal, hepatic impact) and side effects (diabetes, dyslipidemias)
81
Complementary and alternative medicine for bipolar disorder
Omega-3 fatty acids
**BCAA** (branched chain amino acids)
**N-acetylcysteine**
**Folic acid**
Magnesium
**Inositol**
Acupuncture
82
Harmless use
Use patterns that **do not predispose** to harm or risk of harm
Perceptions of harm vary according to cultural norms (alcohol normal in US but opiates normal in Middle East)
83
At-risk use
**Elevated risk** for substance-related **problems** (exceeding recommended limits, non-medical use, illicitly obtaining drug)
**No long-lasting harm**
84
Substance abuse
**Maladaptive use** --\> **impairment**
**\>/= 1 within 12 months** and **recurrent**: failure to fulfill obligations, use in hazardous situations, legal problems, social problems
Criteria for dependence **not** met
85
Substance dependence
**Maladaptive use** --\> **impairment**
**\>/= 3 within 12 months**:
Tolerance
**Withdrawal**
Larger amounts or period than intended
**Unable to decrease** use
Excessive time spent
Decrease important activities
Use despite physical or psychological problems
86
What is addiction?
**Chronic**, **relapsing** brain disease characterized by **compulsive** use despite **harmful consequences**
87
How does neurobiology affect diagnosis/treatment of addiction?
Addiction is a brain disease so we need to give therapy
Engage personal responsibility for disease management
**Biopsychosocial** model in practice
Combination of **pharmacotherapy** plus **behavioral therapy** and **social support** is recommended as the standard of care
88
Clinical course of addiction
Volitional at first
**Chronic**
**Relapsing** (loss of control)
Never "cured" but **controllable**
Same condition, different targets
Natural recovery possible
89
How many people have dependence on drugs, alcohol or nicotine?
3% drugs
8% alcohol
21% nicotine
90
Biological risk factors for addiction
**40-60%** of vulnerability is **genetic** (metabolism, reinforcing effects, responses to the environment)
Neurochemicals
Neurocircuits
91
NTs involved in addiction
**DA**: in nucleus accumbens and substantia nigra; role in **motivation** and **pleasure**
**5HT**: in dorse raphe; role in **mood**, **pain**, **impulsivity**
**Opioid**: everywhere; role in **pain** and **pleasure**
**Glutamate** (+): in hippocampus; role in **learning** and **memory**
**GABA** (-): everywhere; role in **alertness**
92
Psychological risk factors
Risk-taking
Sensation-seeking
Impulsive
Unhealthy coping skills
Psychiatric conditions
Self-esteem issues
93
Environmental risks
Drug availability
Cultural values
Lack of parental support/family dysfunction
Drug-using peers
Life stressors
Lack of structure
Poorly developed social skills
94
NTs and alcohol
Alcohol **increases DA** --\> pleasure, reward, craving
Alcohol **decreases** **serotonin** --\> impulsivity, disinhibition
Alcohol **increases** **opiates** --\> euphoria
Alcohol **increases** **GABA** --\> sedation, hypnotic
Alcohol **inhibits** **glutamate** --\> amnesia, learning impairments
95
Alcohol intoxication depending on BAC
0-100 mg/dl: euphoria disinhibition
100-200: slurred speech, incoordination
200-300: confusion
300-400: stupor
400-500: coma
\>500: death
96
Maximum drinking limits
**Men**: 2 drinks per day and **14 per week**
**Women**: 1 drink per day and **7 per week**
**One episode** of heavy drinking past 1 month (\>5 for men; \>4 for women)
97
Methamphetamine
**Synthetic**
High lasts **8-24 hours**
Half life 12 hours
Causes **DA release**
Limited medical uses
**Neurotoxic**
98
Cocaine
**Plant-derived**
High lasts **20-30 minutes**
Half life 1 hour
**Blocks DA reuptake** (?)
Used medically
**Not directly neurotoxic**
99
Methamphetamine intoxication
**Rush** (5 to 30 minutes): adrenal gland release of **epi**, rapid release of **DA**, intensely **euphoric**, **tachycardia**, **BP** spike, heart rhythm abnormalities
**High** (4 to 6 hours): continuation of the physical and mental **hyperactivity**
**Binge** (3 to 15 days): **larger doses required** to achieve same intensity, little or **no rush or high felt**, physical and mental **hyperactivity**
100
Methamphetamine withdrawal
**"Crash"** (1 to 3 days): follows a binge, **tired, lifeless**, and **sleepy**, feelings of emptiness and **dysphoria**, often repeat use of this drug or alcohol/other drugs to self-medicate withdrawal symptoms
**Withdrawal** (several days to weeks): **depressive** symptoms, **lethargy**, **cravings**, and **suicidal** thoughts
101
Long term effects of methamphetamine use
**Addiction**
**Psychosis** (paranoia, delusions, hallucinations, repetitive motor activity)
Changes in brain structure and function
**Memory loss**
**Aggressive** or violent behavior
**Anxiety** and mood disturbances
**Fatigue**
**Dental** problems
**High BP, tachycardia, tachypnea**
**MI, stroke**
Skin lesions
**Dehydration, weight loss**
**Death**
102
Marijuana
**THC** (delta-9-tetrahydrocannabinol)
**Euphoria**, attention/short term memory, **impulsiveness**, **time distortions**, conjunctival injection, **impaired coordination**
Association with psychosis with frequent users
103
Medical marijuana
Compassionate Use Act 1996
SB 420 (2003) establishes ID card, county level "regulation"
Explosion (2007-2010; 439 in LA)
Legalization in 2013?
104
Screening for nicotine dependence
**How long from the time you wake up** is your first cigarette?
\< 5 min = severe nicotine dependence
\< 60 min = moderate nicotine dependence
\> 3 hours = mild nicotine dependence
105
Opioid intoxication
Initial **euphoria** followed by **apathy, sedation, retardation, impaired function**
**Pupillary constriction**
**Drowsiness, slurred speech, inattention, memory impairments**
106
Opioid withdrawal
**Dysphoria**
**N/V**
**Myalgias**
**Lacrimation**
**Yawning**
**Insomnia**
**Diarrhea**
**Craving** and **anxieties**
107
Highest risk for problem/pathological gambling
**AA, disabled, unemployed**
108
Physical health issues of pathological gamblers
**Heart disease, liver disease, HTN,** stress-related physical problems (**migraines**, tension **headache, IBS, ulcers, insomnia** and **sexual dysfunction**)
More likely to have had a **physical injury**
More likely to have needed **ER visit**
3.5x more likely to have **sleep problem**, poorer sleep quality and increased daytime sleepiness
109
What does problematic sleep cause?
**Impaired self-control** and decision-making
Increases **impulsivity**
Attenuate responses to losses and increase expectations of gains
**Degrade cognition** in executive functioning tasks
SO we need to become aware whether client is also suffering sleep problems and include that in management!
110
Psychotropic (psychoactive) drug
Crosses BBB and acts primarily on CNS
Affects brain function, resulting in alterations in perception, mood, consciousness, cognition and behavior
111
Catecholamine Hypothesis of affective disorders (mood)
Dysfunction in **NE** and/or **5HT** systems
**Depression** is **deficiency** in NT activity (alterations in receptor sensitivity/function?)
**Mania** is **excessive** NT activity
112
Do people usually respond to antidepressant drugs?
Response in **50-60%** of adults with major depression
**Remission in 30%**
**80%** of patients will **eventually** respond to drug therapy
113
Tricyclic antidepressants (TCAs)
**Inhibit reuptake** of biogenic amines (**NE**, **5HT**): inhibition of reuptake occurs immediately but takes 2-3 weeks to see antidepressant activity and 8-10 weeks for maximal effect
**Block** **muscarinic** cholinergic receptors (are antimuscarinic)
**Block alpha-1 adrenergic** receptors
**Block H1** **histamine** receptors
Note: muscarinic, alpha1 and H1 actions not wanted--just because of structure of drug
114
Binding affinities of TCAs
TCAs have high binding affinity for **NET** and **SERT** (not as much DAT)
Also may have high affinity for unwanted receptors (like 5HT2A which is responsible for psychosis?!)
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Pharmacologic effects of TCAs
**CNS** effects
**Sedation**: can be used to induce sleep; contraindicated in combination with other CNS depressants (ethanol, sedating antihistamines)
Normal subjects do not show mood elevation, and may feel unpleasant or dysphoric
Can produce **seizures** at high doses
**Weight gain**
**Withdrawal** if stopped abruptly (nausea, dizziness, headache, increased perspiration, salivation)
Patients should be slowly tapered off drug
ANS: anticholinergic (**antimuscarinic**) activity causes dry mouth, blurred vision, constipation, **urinary retention**
CV: **tachycardia** and **arrhythmias** due to increased NE in cardiac tissue and antimuscarinic activity; **orthostatic hypotension** due to alpha-adrenergic block; bundle branch block and signs of impaired conduction due to local anesthetic activity
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What do you do if you OD on antidepressants?
OD can be fatal!
Treat by controlling **arrhythmias** w/**lidocaine** and **propanolol**
Control **seizures** with **diazepam** or **lorazepam**
Reduce CNS **antimuscarinic** effects with **physostigmine**
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Clinical uses for antidepressant drugs
**Depression**
**Enuresis** = bed-wetting (imipramine is most commonly used)
**Chronic pain** (amitriptyline is most commonly used)
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Drug interactions of antidepressants
**Potentiate** effects of other **CNS depressants**
**Potentiate** **hypertensive** effects of sympathomimetic amines
**Additive** effects with other **antimuscarinic drugs**
Cause **severe** **reaction** when administered with **MAOIs**
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Mirtazapine (Remeron)
Second generation antidepressant
**Blocks** **5HT2** and **alpha2** adrenergic receptors
**Does not inhibit reuptake**; very sedative and associated with weight gain
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Bupropion (Wellbutrin/Zyban)
Second generation antidepressant
**Inhibits reuptake** of **NE**, **DA**; **nAChR antagonist**
Does **not** cause weight gain or sexual dysfunction
Also used for **smoking cessation**
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Trazodone (Desyrel)
Second generation antidepressant
**Inhibits 5HT reuptake** and **blocks 5HT2 receptors**; little antimuscarinic and autonomic activity
Very **sedative**; frequently used to promote sleep nondepressed patients (?)
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St. Johns Wort
**Herbal** treatment (Hypericum perforatum) for depression
**Induces CYP450** (so decreases concentrations of other drugs!)
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Examples of selective serotonin reuptake inhibitors (SSRIs)
**Fluoxetine** (Prozac): long half life (2-3 days) and active metabolite norfluoxetine has 7-9 day half life
Paroxetine (Paxil)
Fluvoxamine (Luvox)
**Sertraline** (Zoloft)
**Citalopram** (Celexa)
Escitalopram (Lexapro)
Note: no evidence that any SSRI is superior to any other, but some patients who fail to respond to one SSRI will respond to another because of differences in tolerability
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SSRIs
Little effect on NE reuptake
Produce few **CV** and **antimuscarinic** side effects
Metabolism: fluoxetine and paroxetine metabolized by CYP2D6, and paroxetine by CYP3A4 also
Adverse effects: **nausea**, diarrhea, headache, insomnia, jitteriness, fatigue and **sexual dysfunction**, hyponatremia (SIADH especially in elderly)
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Serotonin Syndrome
Triad of **mental** status changes, **autonomic** hyperactivity, **neuromuscular** abnormalities
Signs: **tremor**, **hyperreflexia**, muscular **rigidity**, **ocular** **clonus**, **hyperthermia**, **agitation**
Drugs that cause excess serotonin: **MAOIs**, **TCAs**, **SSRIs**, **opiate** analgesics, OTC cough medicine, antibiotics, weight-reduction agents, antiemetics, antimigraine agents, drugs of abuse, herbal products
Management: removal of precipitating drugs, provision of **supportive** care, control of agitation, administration of **5HT2a** **antagonists**, control of autonomic instability, control of hyperthermia
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Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
**Duloxetine** (Cymbalta): blocks both **5HT** and **NE** reuptake
**Venlafaxine** (Effexor): primarily blocks 5HT reuptake at lower doses, and both 5HT and NE reuptake at higher doses; may cause more **restlessness** and **insomnia** than the SSRIs
Desvenlafaxine (Pristiq): desmethyl version of venlafaxine
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Adverse effects of SSRIs and SNRIs in children
Similar to those in adults but **increases in motor acivity** more common
Long-term safety of these drugs (effects on growth, personality development and behavior) is unknown
Greater risk of **suicidal** **thoughts** or behaviors (but not actually suicide) when children or adolescents take SSRIs and SNRIs --\> **black-box warnings** on all antidepressant drug labels
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CYP450 metabolism of SSRIs, TCAs
**Metabolite** of parent compound is **active**, with pharmacology similar (but not identical) to parent compound
Duration of clinical activity associated with AUC of parent compound and active metabolite (not just plasma half life of drug) defined by total time above threshold plasma levels assumed for efficacy
Long half-life of metabolites provides drug-generated **"tapering"** effect contrasts with drugs with shorter half lives and inactive metabolites that require continued drug administration with increasingly lower dosages (both strategies **minimize drug withdrawal** symptoms that can be observed if the parent drug is discontinued abruptly)
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Examples of Monoamine Oxidase Inhibitors (MAOIs)
**Isocarboxazid** (Marplan): hydrazide; non-selective MAOI; irreversible or slowly reversible; no tyramine-containing food
**Phenelzine** (Nardil): hydrazide; non-selective MAOI; irreversible or slowly reversible; no tyramine-containing food
**Tranylcypromine** (Parnate): non-hydrazide structurally similar to d-AMPH; non-selective MAOI; irreversible or slowly reversible; no tyramine-containing food
**Selegiline** (Deprenyl): selective irreversible **MAO-B** inhibitor; used for **Parkinson's disease**
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MAOIs
Can inhibit both MAO-A and MAO-B or just one
MAO is enzyme responsible for intracellular oxidative deamination of **catecholamines** and **5HT**
Metabolism: hydrazides metabolized by acetylation; rate of metabolism variable
Since new enzyme must be synthesized to overcome inhibition, it lasts days after drugs gone from plasma
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Lithium as a mood stabilizer
Mechanism not yet known but may change electrolyte conductance, may be due to interference with phosphatidylinositol signaling cascade in brain
Pharmacologic effects: CNS effects are small in normal people but **calms** manics and **dampens mood swings** in bipolar patients; no peripheral autonomic blocking activity
Absorbed rapidly and well
**Not metabolized**
**Renal excretion** (clearance reduced by diuretics so must decrease lithium dose if taking diuretics)
Adverse reactions: **low TI** (adverse effects at therapeutic levels, must monitor), fine **tremor** (treat w/propanolol), **N/V/D**, **polyuria** and **polydipsia** (Li+ blocks action of ADH on distal tubule), decreases thryoid function, cardiac **arrhythmias**, **weight** **gain**, fluid retention
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Mood stabilizers (other than lithium)
**Valproic acid**: monitor liver function
**Carbamazepine**: do CBC
**Lamotrigine**
Some **atypical antipsychotic** drugs: olanzapine, aripiprazole, ziprsaidone, risperidone, quetiapine
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Choice of drug for major depression
**SSRI** is initial treatment: citalopram or sertraline in adults, fluoxetine for children or adults
**SNRI** or **bupropion** or **mirtazapine** can also be first-line
Secondary treatment after 2-4 weeks of SSRI with only partial response (use a different antidepressant or 2 different classes like SSRI and bupropion)
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When people abuse drugs or are addicted to gambling, what is happening in their brains?
**DA** released from **VTA** into **nucleus accumbens** (in ventral striatum)
Then, leads to changes in homeostasis of **DA regulation**
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Which two systems converge on medium spiny neurons in the nucleus accumens?
Cortical (**glutamatergic**)
VTA (**dopaminergic**)
**Coincident** activity in these two pathways lead to "reward" sensation
When **DA present**, accumbens medium spiny neurons become **more responsive** to **glutamate** inputs from amygdala, frontal cortex, cingulate cortex and other limbic areas
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Endogenous neural transmitters and their receptors that are involved with VTA-accumbens circuitry (reward circuitry)
**VTA** using **dopamine** on **D1** and **D2** receptors
**Cortex** using **glutamate** on **AMPA** and **NMDA** receptors
**Interneurons** using **GABA** on **GABA-A** receptors
**Raphe** using **5HT** on 5HT receptors
**Interneurons** using **ACh** on **nicotinic** receptors
**Interneurons** using **enkephalins** on **mu** and **delta** opioid receptors
**Interneurons** using **anandamide** on **cannabinoid** (**CB1**) receptors
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What other neurons affect DA neurons that lie in the VTA?
**GABA** neurons (stim by **enkephalins**)
**Cortex** neurons (which have **glutamate** inputs)
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What other neurons affect GABA neurons that lie in the nucleus accumbens?
**Cortex** neurons (with **glutamate** inputs)
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Hedonistic substances and their NTs and receptors
**Cocaine**, **amphetamine**, **ritalin** --\> DA --\> **DA reuptake inhibitor**
**Alcohol** --\> GABA --\> **GABA-A agonist** (increase DA in accumbens)
**Alcohol** --\> **glutamate** --\> **NMDA** **antagonist** (increase DA in accumbens)
**Nicotine** --\> **ACh** --\> **nicotinic** **agonist** (increase DA in accumbens)
**Opiates** --\> **enkephalins** --\> **mu and** **delta** opioid **agonist** (inhibit GABA in VTA to activate DA neurons of VTA)
**Ketamine**/**PCP** --\> **glutamate** --\> **NMDA** **antagonist** (disrupt signaling at NMDA receptors on medium spiny neurons)
**Benzodiazepines**/**barbiturates** --\> GABA --\> **GABA-A agonist**
**Marijuana** --\> **anandamide** (2-AG) --\> **cannabinoid** (CB1) **agonist** (trigger DA release in accumbens and have direct effects on medium spiny neurons)
**Hallucinogens** (LSD, etc) --\> 5HT --\> **5HT2A agonist**
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Nicotinic ACh receptor
Ligand gated ion channel (**Na+**) with multiple potential combinations of different types of subunits
Alpha 4 beta 2: post-syn, **DA** release from nucleus accumbens, primary target of nicotine
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3 stages of progression to addiction
1) **Intoxication** stage: pleasure from substance of behavior, involves normal circuitry
2) **Negative** **affect** stage: gradual dysphoria, negative emotional state, stress--gradual changes and adaptations in circuitry, tolerance, involvement in stress systems and amygdala
3) **Craving** stage: preoccupation with addiction--substantial cellular and molecular adaptations in circuitry
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What happens in the reward circuit when you're addicted?
"Opponens" compensatory adaptations in VA-accumbens circuitry
**Decreased** basal **glutamate** and basal **DA**
**Increased** stimulated (**phasic**) glutamate and increased stimulated DA
Substances are **required** to balance opponens processes and achieve "normalcy"
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Phases of addiction (dependence) behavior
1) **Compulsion** to seek substance
2) **Loss** **of** **control** in limiting intake
3) Emergence of a **negative** **state** (dysphoria, anxiety, irritability)
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Caffeine
**Antagonist** at **adenosine** receptors (A1, A2)
Adenosine receptors implicated in regulating **sleep** and **arousal**
Certain adenosine receptors coupled to, and inhibit, D2 receptors
Caffeine promotes activity at those D2 receptors!
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NIDA treatment principles for treatment of addiction
**No single treatment** appropriate for everyone
**Remaining in treatment** for adequate period of time important
**Counseling** and other behavioral therapies commonly used
**Medications** may be important especially when **combined** with counseling
Treatment must be **assessed** continually and modified
Treatment does **not** need to be voluntary
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Treatment approaches for addictive disorders
1) **Medications** (Bio)
2) **Therapy** (Psycho)
3) **Lifestyle changes** (Social)
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Medications for treatment of addiction
Manage **detox**, target **urges**/cravings, increase likelihood of **abstinence**, reduce **harm** from addictive behavior, lay the groundwork to do recovery
For **alcohol**: Antabuse (**disulfiram**), Vivitrol (**IM** **naltrexone**), Revia (naltrexone), Campral (**acamprosate**)
For **opiate** addiction: **Suboxone** (buprenorphine + valoxone), Subutex (buprenorphine), **methadone**, Revia (naltrexone), Vivitrol (IM naltrexone)
For nicotine addiction: nicotine replacement therapies (patch, lozenge, inhaler, gum), Chantix (varenicline), Zyban (bupropion)
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Disulfiram (Antabuse)
Mechanism: **inhibits aldehyde dehydrogenase**, increasing acetaldehyde (causes flushing, tachycardia, etc?)
Most likely to benefit **highly motivated** and directly observed patients
Side effects: nausea, metallic taste, dysphoria, fatigue, hepatitis, psychosis (DA)
Effects can last 72 hours after last dose
**Second/third line** treatment for alcoholism, won't see many patients on this
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Naltrexone (Revia)
**Opiate antagonist**
**Decreases positive** **reinforcing** effects, increases negative aspects, decreases craving from first dose (prime), decrease craving from cues
Side effects: dysphoria, nausea, increased LFTs, expensive
Only shows modest effect: **decreased** **time** to relapse, # of drinks, cravings
"Curbs your enthusiasm for alcohol"
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IM Naltrexone (Vivitrol)
**Opiate antagonist**
**Injection** once per **month** (so internal med or family med doctors do this, not psychiatrists!)
No oral lead-in
Decreases drinking days and decreases heavy drinking days
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Acamprosate (Campral)
Mechanism: made from taurine; **restores NMDA receptor** tone in the glutamate system; **GABA properties**
Targets "negative reinforcement"
Higher **abstinence**, higher % of days abstinent and increased time to first drink
Side effects: diarrhea, rash
Start once detox is complete
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How does medical treatment for opiate addiction (using subtex or suboxone) work?
**Office-based**
**Sublingual** administration
Manages withdrawal
Used as **maintenance** therapy
Limited abuse potential
Great because meant people didn't have to go to methadone clinics every day at 5am!
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Naltrexone for opiate addiction
Supposedly **reduces pleasure** from opiates
Doesn't seem to reduce cravings in opiate dependents
Some evidence for "highly motivated" patients or directly observed
OD risk increased after discontinuation
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Nicotine patch
Slow onset, **continuous** delivery
**24-16 hour** dosing
Easy compliance
With or without taper
OTC
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Nicotine gum
Use **every 1 hour**
**Bite and "park"**
Slow, buccal absorption
Acidic foods decrease absorption
OTC
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Bupropion SR (Zyban/Lobutrin?)
**Nicotinic receptor antagonist**
Nonsedating/activating
Affects NE and DA
Side effects: headache, insomnia
Contraindicated in seizures/eating disorders
Start 10-14 days prior to quit date
300mg dose has least weight gain
Note: "side effect" of antidepressant trial was that people smoked less
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Varenicline (Chantix)
**Partial nicotinic agonist** of receptors JUST in **nucleus accumbens** limbic system (mimics and blocks receptors)
Attenuates withdrawal
Decreases craving
40 continuous abstinence at 12 weeks
Starter Pak then Continuing Pak
Side effects: nausea, H/A, insomnia, psych
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Are there medications for cocaine, methamphetamine, MJ, gambling or sexual addictions?
**None** that are FDA approved
For **marijuana**: Rimonabant (cannabinoid antagonist, but increased suicidal ideation); Marinol + Lofexidine (synthetic THC plus adrenergic modulator)
Considered for **cocaine**: modafinil, disulfiram, propanolol (WD), GVG (vigabatrin), topiramate, DHEA, TA-CD vaccine, buprenorphine, N-acetylcystine, d-amphetamine
Considered for **meth**: bupropion, mirtazapine, naltrexone, d-amphetamine, methylphenidate
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Psychosocial treatments
**Residential** treatment programs (30 day)
Intensive **outpatient** programs
**Family** treatment
**Individual** counseling
**12-step** support (not treatment because not a physician!)
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Evidence-based treatments
**Motivational** interviewing
**Relapse prevention** therapy
**Cognitive-behavioral therapy**
**Contingency** manageent
12-step facilitated groups
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Typical treatment plan for addiction
Bio: **medication** for SUD and psychiatric disorder, address medical consequences
Psycho: begin **individual** therapy; educate and motivate
Social: attend **12-step**; make lifestyle changes
Supervise and monitor: **urine drug screen**, recovery check-ups
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Therapeutic indications for CNS depressants
Produce **sedation**
**Reduce anxiety**
Promote **sleep**
Induce **anesthesia**
Treat **seizure** disorders
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GABA receptors
**GABA-A**: ligand-gated **Cl- channel**; activation of GABA-A causes **Cl- influx** then **hyperpolarization** of postsyn membrane then **neuronal inhibition**
**GABA-B**: **G-protein coupled receptor i**ncreases K+ conductance and **decreases Ca2+ conductance** (increases firing of GABA neurons?)
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Barbiturates mechanism
Barbiturates bind to specific site on **GABA-A** receptor to increase GABA-mediated neuronal inhibition
Absorption in small intestine
Distribution: all highly lipid soluble and the more **lipid soluble** it is, the faster it gets into the **CNS**
Metabolism: slow (18-96hr half life); **inducers** so increase metabolism of other drugs that are metabolized by hepatic enzymes; induces aminolevulinic acid (**ALA**) synthetase (motor disturbances and peripheral neuropathic disturbances)
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Examples of barbiturates
**Thiopental**, thiamylal: ultrashort-acting (consequence of its initial distribution to brain followed by subsequent redistribution to other tissues)
Secobarbital, **pentobarbital**: short-intermediate
**Phenobarbital**: long-acting
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Pharmacologic effects of barbiturates
Cause **CNS dose-dependent depression** (from slight sedation to coma and death); **low TI**
Dependence: psychological and physical **dependence**, and serious **withdrawal** symdrome (restlessness, anxiety, insomnia, weakness, orthostatic hypotension, convulsions, death)
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Clinical uses of barbiturates
**Anxiety**
**Insomnia**
**Anticonvulsant** (phenobarbital)
**Anesthesia**: thiopental, thiamylal used for induction
Adverse reactions: death from OD due to respiratory depression, CV collapse, pulmonary edema, pneumonia
Drug interactions: **additive** effects and **cross-tolerance** with other CNS depressants; induction of hepatic microsomal enzymes (accelerates metabolism and decreases conc of other drugs)
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Ethanol absorption, distribution, etc
Absorption: from **GI** tract, and food in stomach will delay absorption
Distribution: distributed throughout body and can cross placenta
Metabolism: **two enzyme systems**; primarily by **liver** so metabolism decreased in liver disease
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Metabolism of ethanol
This is the **PRIMARY** pathway of alcohol metabolism
Ethanol turned to **acetaldehyde** by alcohol dehydrogenase (**ADH**)
Acetaldehyde turned to **acetic acid** by aldehyde dehydrogenase (**ALDH**)
In each step, **NAD+ turned to NADH**
ADH has multiple isoforms, one of which has HIGH activity and is found in asians
ALDH has 2 forms, and Aisans have type II which has LOW activity (thus **Asians** build up **acetaldehyde** and get red!)
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Secondary pathway for metabolism of ethanol
Microsomal ethanol oxidizing system (**MEOS**) metabolizes some alcohol under **high alcohol** conditions and is due to **CYP2E1**
Ethanol turned to acetaldehyde by MEOS in this pathway, and then like normal acetaldehyde turned to acetic acid by ALDH
After **chronic ethanol consumption**, activity of MEOS increases, associated with rise of **CYP2E1**
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Zero order kinetics
When **substrate** concentration is much **higher** than **Km**
V = Vmax
**Vmax** is **independent of substrate concentration**
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Buprenorphine
**Partial opioid agonist**
In **Suboxone** an **Subutex**
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Is alcohol metabolism first order or zero order kinetics?
At doses we drink, it is **zero order** (pharmacologic concentration range greater than 200 mg/L)
Note: ethanol metabolism is **~10g/hr** (1 drink per hour) and any dose frequency that exceeds this causes alcohol accumulation and effects of alcohol
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Pharmacologic effects of ethanol
CNS: depression; **GABA**-mediated neuronal **inhibition** (but apparent stimulatory effects if decrease inhibitory control mechanism)
CV: **vasodilation**, depress myocardial contractility
GI effects: stimulate gastric secretions, **inhibit** intestinal brush border enzymes involved in **absorption** of nutrients
Endocrine: decrease testosterone, **inhibit ADH** (diuresis), sexual dysfunction
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Chonic adverse effects of alcohol
Nervous system: peripheral neuropathy (**paresthesias**, **tingling**), **cerebellar** cortical degeneration, **motor** dysfunction, **mammillary body** atrophy
**Sleep** disturbances
**Amnesia** for recent events (alcoholic blackouts)
**Wernicke-Korsakoff** syndrome: ivolve **thiamine** (vitamin B1) **deficiency**; confusion, oculomotor dysfunction, ataxia, polyneuropathy (**Wernicke** part); learning and memory problems (**Korsakoff** part)
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Alcohol effects of CYP2E1
**Acute**: alcohol sits on CYP2E1 so **decreases** rate of **metabolism** of other drugs (enzyme **competition**)
**Chronic**: **increases** rate of drug **metabolism** because alcohol **induces** CYP2E1 (enzyme induction)
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NADH/NAD+ ratio in alcoholism
Increased NADH/NAD+ in alcoholics
Reduces gluconeogenesis, causes hypoglycemia and ketoacidosis
Fatty acid synthesis requires NADH so get **fatty liver**
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Liver and pancreatic effects of alcohol
Can get **cirrhosis** which causes liver damage that slows metabolism of other drugs
**Pancreatitis**
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Acetominophen metabolism in the liver
Major pathway: **phase II metabolism** to produce inactive metabolites (nontoxic **glucoronide**, nontoxic **sulfate**)
When phase II pathway saturated, or when CYP450 induction, use **CYP450 system** (CYP2E1) which creates **toxic intermediate**, which can still be **metabolized by GSH** (yay!)
However, **alcoholics** are **depleted in GSH** so cannot metabolize toxic intermediate and instead get buildup of **toxic intermediate** which reacts with **liver proteins** and causes **hepatotoxicity** and acute renal failure
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Alcohol withdrawal
Begins right after you stop drinking
**Anxiety**, insomnia, **tremor**, **palpitations**, **nausea**, anorexia
Withdrawal **seizures**
Alcoholic hallucinations
**Delirium tremens** (tachycardia, hypertension, low-grade fever, tremor, diaphoresis, delirium, agitation)
Note: **d****etox**with**benzodiazepines** because work on GABA channel also
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Treatment of alcohol withdrawal/detoxification
Adjunctive to behavioral modification
**Disulfiram**: **aldehyde dehydrogenase inhibitor**; build-up of acetaldehyde causes headache, nausea, vomiting --\> acts as negative reinforces
**Naltrexone**: **opioid receptor antagonist** --\> associated with reinforcement and craving
**Acamprosate**: **NMDA** receptor **antagonist**; **GABA** **agonist**; increases abstinence; may restore balance between excitation and neuronal inhibition altered by chronic alcohol
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Methanol
Metabolized to **formaldehyde** and formic acid by the same enzyme systems that metabolize ethanol
Poisoning due to metabolites (formaldehyde cross-links protein)
Causes severe acidosis, **optic nerve damage** and blindness
Treatment: sodium bicarb for acidosis; use ethanol as competitive substrate inhibitor; **fomepizole** is **alcohol dehydrogenase inhibitor** to prevent methanol metabolism to formaldehyde
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Ethylene glycol
Colorless, sweet tasting solvent used in antifreeze solutions
Metabolism by alcohol dehydrogenase too, then generates oxalates which are very insoluble, especially w/Ca2+ (**calcium oxalate salts**) so can cause **renal stones** and **renal failure**
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