Exam 5: Psych, Pain, SUD Flashcards
Comorbidities of Bipolar Disorder
- alcohol and substance use common (50-60%)
- anxiety disorders are common and can significantly impact remission of mood episodes if left untreated or inadequately treated
What mood pole is experienced most often in bipolar disorder and can lead to misdiagnoses?
Depression
DSM-5 Classification of Bipolar I Disorder
≥ 1 manic episodes, depressive or hypomanic may have occurred
episodes generally last ≥ 1 week
DSM-5 Classification of Bipolar II Disorder
major depressive and hypomanic episodes
hypomanic episodes generally lasts ≥ 4 days
Target Symptoms of BPD: Mood
- euphoria, elation, happiness
- depression
- lability
- irritability
- hostility
- dissatisfaction
Target Symptoms of BPD: Cognitive/Perceptual
- flight of ideas
- racing thoughts
- grandiosity
- delusions
- hallucinations
- ideas of reference
- fragmented thoughts
Target Symptoms of BPD: Activity/Behavior
- pressured speech
- impulsivity
- insomnia
- aggression, outbursts, violence
- increased sexual dysfunction
- panic
Pharmacotherapy Overview for BPD
- mood stabilizers are the foundation of acute and maintenance treatment
- 1st line: usually lithium or valproic acid
- atypical antipsychotics can also be used 1st line as monotherapy or in combination with lithium or valproic acid
- many patients will take polytherapy with mood stabilizers
What is lithium associated with a decrease in?
- suicidality, especially in BPD
- narrow therapeutic index, evaluate if patient has a plan, and if it does involve overdose via pill ingestion
Lithium Dosage Forms
some difference in lithium content, but use 1:1 conversion
Therapeutic Level of Lithium for Acute Treatment
0.9-1.2 mEq/L
Therapeutic Level of Lithium for Maintenance
0.6-0.9 mEq/L
Therapeutic Level of Lithium for Toxicity
1.5 - >3.0 mEq/L
When should you draw lithium levels?
draw trough serum concentration 72 hours after dose initiation, 12 hours after last dose
Toxicities of Lithium
- GI
- ataxia
- coarse hand tremor
- AMS
- seizure
- lethargy
- confusion
- agitation
Side Effects of Lithium
- fine hand tremor
- hypothyroidism
- polyuria
- polydipsia
- acne (upper body, chest)
- dry mouth
- weight gain
- ECG changes
- diabetes insipidous
Teratogenic Effects of Lithium
- cardiac structural abnormality that requires surgery
- avoid in 1st trimester, use with caution in 2nd and 3rd trimester
- BPD gets worse in pregnancy, might need to increase dose
Lithium Lab Monitoring
- SCr, BUN (almost entirely renally excreted)
- urine specific gravity
- Na, K, Ca
- ECG (especailly if age > 40 or cardiac risk factors)
- Thyroid Function (TSH, T4)
- Parathyroid hormone
- CBC w/ differential
- Weight
- Pregnancy Test
How is lithium metabolized?
Mostly renally excreted
Decreased Li Renal Clearance Causes
due to ACEi, ARBs, thiazides, NSAIDs, dehydration
Increased Li Renal Clearance
lower Li levels
- caffeine
- osmotic diuretics
- loop diuretics
Increased Li Excretion Causes
- lower Li levels
- sodium bicarb
- high sodium intake
Toxicity Related to Na Depletion with Lithium
- thiazide diuretics
Valproate Dosage Forms: ER
- ER dosage form is ~ 10-15% less bioavailable than delayed release dosage from
- 1:1 converstion, expect lower serum concentration with the ER dosage form, usually not clinically significant
Valproic Acid Syrup and Capsule Sprinkle Form
higher risk for GI ulcerations (usually esophageal)
Serum Levels for Efficacy w/ Valproate
- 80-125 mcg/mL associated with most efficacy in mania
- obtain level at least 96 hours (4 days) after first dose or dose increase
Valproic Acid in Pregnancy
- unsafe in any trimester of pregnancy
- obtain baseline pregnancy test
- use contraceptive
Valproic Acid and PCOS
- PCOS occurs in up to 50% of women
- may treat with metformin
- refer to endocrinologist
Valproic Acid Side Effects
- GI: anorexia, N/V/D, dyspepsia, ulceration
- throbocytopenia, platelet dysfunction
- teratogenic neural tube defects, enduring negative effects on IQ of offspring
- increased appetite, weight gain (~6-8 kg)
- hyperammonemia
Valproate Lab Monitoring
Baseline
- pregnancy test
- LFTs
- CBC w/differential
- Serum Ammonia if suspected hyperammonemia
Drug Interactions with Valproic Acid
- signficant concern with combo use with lamotrigine (increased lamotrigine serum concentration and increased risk of SJS
- drug dosing cut in half
Carbamazepine in BPD
- thrombocytopenia/hematologic effects
- induce nearly all CYP450 enzymes
Oxcarbazepine in BPD
- CYP450 3A4 inducer
- associated with hyponatremia
Lamotrigine in BPD
- not useful for acute treatment or for manic episodes
- 1st line treatment for DEPRESSIVE symptoms
Topiramate in BPD
- may cause weight loss
- heat intolerance/hypohidrosis
- metabolic acidosis and kidney stones
- possible teratogen
- DRESS
Antipsychotics in BPD
- atypicals (except brexpiprazole, clozapine, iloperidone, and paliperidone) are FDA approved for acute and/or maintenance treatment (manic/mixed episodes) with and without psychosis
Seroquel in BPD
- FDA approved for bipolar depression
- dose at least 300 mg/day
Abilifiy/Brexpiprazole in BPD
- FDA-approved for adjunctive treatment in depression in combination with antidepressants treatment
- may see increased use for bipolar disorder
Symbyax for BPD
- olanzapine/fluoxetine
- FDA-approved for bipolar depression and treatment-resistant depression
Latuda in BPD
- FDA approved for bipolar depression
Clinical Pearls: Antipsychotics in BPD
- atypical antipsychs may be used as monotherapy or can be used combo with other mood stabilizers (VA or Li)
- all monitoring parameters for metabolic syndrome and movement side effects apply when used for BPD
Treatment Considerations of BPD
- mood stabilizers treatment is long-term and considered to be maintenance treatment to reduce time to subsequent mood episodes
- suicide attempt risk is high in both poles of bipolar disorder, monitor closely, use lithium cautiously
Treatment in Pregnancy: BPD
- lithium, VA, carbamazepine and topiramate are known or possible teratogens
Antidepressants in Bipolar Disorder
- need to have maintenance mood stabilizer therapy in combo with antidepressant therapy
- will use serotenergic antidepressants to treat anxiety
Functions of Pain
- warning system (avoid injury)
- aid in repair (hypersensitivity)
- can be maladaptive (irreversible neuropathy)
Temporal Features of Pain
- onset
- duration
- course
- pattern
Intensity of Pain
- average
- least
- worst
- current pain
Location of Pain
- focal
- multifocal
- generalized
- referred
- superficial
- deep
- opioid induced hyperalgesia (generalized)
Quality of Pain
- inflammatory: throbbing, pulsating
- neuropathic pain: stabbing, shooting, burning
- visceral: squeezing
Pain Transmission
- trauma in the periphery will transmit signal to spinal cord (activation of PNS)
- activation of CNS at spinal cord
- spinal cord sends input to the brain
- processed in the brain
- descending modulation to the spinal cord
Temperature Sensitive Receptors and Channels (in the skin)
- transient receptor potential cation channel (TRP
- TRPV (vanniloid) = heat
- TRPM (melastatin) = cold
Acid Sensitive Ion Channel
ASIC activated by H+ and conducted by Na+
Chemical Irritant Sensitive Receptors and Channels involved in Pain Signaling
histamine
bradykinin
Reflex Upon Painful Stimuli
- bypasses CNS, goes right back toward the muscle
- transmission via afferent nerve to the spinal cord
- modulation back to muscle via efferent nerve
- does not go to brain!
Sodium Channels responsible for conduction of pain signal that are non-opioid
Nav1.1, Nav1.6, Nav1.7, Nav1.8
Neurotransmitter released at the end of afferent neuron
glutamate (conduction of pain in spinal cord)
A-beta fibers
- non-noxious (touch, pressure)
- innervate the skin (thicker myelin)
- faster (35-75 m/s)
A-gamma fibers
- pain, cold
- myelinated
- fast (2-35 m/s)
- first pain, reflex arc
- sharp prickly pain
C fibers
- pain, temp, touch, pressure, itch (polymodal)
- unmyelinated
- slow (0.5-2 m/s)
- second pain
- dull aching
Substance P’s Role in Pain
- repeated stimuli reduces firing threshold
- increase expression of pain receptors via sensitization
- sunburn is a good example
Substance P MOA
- injury occurs at periphery
- substance P is released
- stimulates areas of the blood to degranulate mast cells
- vasodilation and release of bradykinin, prostaglandins, histamines (inflammatory markers)
- increase in receptors in the periphery to send more signals into the spinal cord
Neuropathic Pain Sensitization
- spontaneous afferent activity: possibly enhanced expression of sodium channel subtypes contributing to enhanced cellular excitability and generation of ectopic action potentials
- spinal sensitization leading to increased AMPA and NMDA expression and sensitivity
- A-beta afferent fibers that cause light touches to hurt due to cord sensitization
Neurotransmitters released in neuropathic pain signalling
- neuropeptides
- CGRP
- Substance P
_____ expression of opioid receptors in the brain stem along the _______ pathway
high, descending
Mu Opioid Expression Effects on Brain
- alter mood
- produce sedation
- reduce emotional reaction
Mu Opioid Receptor Expression on Brainstem
- increase activity of descending fibers
- decrease activity of input in ascending pathway via afferent neuron
Mu Opioid Receptor Expression on Spinal Cord
- inhibit vesicle release
- hyper-polarize post-synaptic membrane
Mu Opioid Receptor Expression on Periphery
- reduce activation of primary afferent
- modulate immune activity
What do Mu opioid receptors do?
influence ascending pathway and perceivement of pain
Amygdala and Pain
anticipates pain and reacts to perceived threats
Somatosensory Cortex and Pain
- registers which body part is in pain and the intensity of that pain
- less activity here when patients focus their attention away from their pain
Prefrontal Cortex and Pain
- processes pain signals rationally and plans action
- active when trying to consciously reduce pain
Right Lateral Orbitofrontal Cortex
- evaluates sensory stimuli and decides on response, particularly if fear is involved
- mindfulness meditation calms down this response
Opium contains which two types of Alkaloids
- phenanthrenes
- benzylisoquinolines
- opiates are only those opioids that are naturally occuring
Codeine SAR
3 position substitutions ether or ester produces decreased potency
Hydromorphone or Hydrocodone SAR
6 position increases activity
Oxycodone SAR
14 position OH has increased potency
Naloxone or Naltrexone SAR
N-allyl gives antagonists
Opioid SAR Overview
- 3 ring structure
- 3, 6, N position
- bulky group on N decreases potency
Where are peptides active?
endogenously
What are cleaved into more opioid subtype selective peptides?
large precursor proteins
Pro-opiomelanocortin (POMC)
cleaves beta-endorphin to Mu opioid
Preproenkephalin
- Leu-enkephalin –> delta opioid
- met-enkaphalin = mu and delta opioid
Preprodynorphin
- dynorphin –> kappa opioid
G protein coupled opioid receptor
- Family A peptide receptors
- Gi/o- coupled inhibition of cAMP production
- open GIRK potassium channels
- close calcium channels
Mu Opioid Receptors
- morphine
- endogenous opioid = endorphin
Kappa Opoid Receptors
- endogenous opioid = dynorphin
Delta Opioid Receptors
endogenous opioid = enkephalin
Nociceptin/Orphanin FQ Receptor
endogenous opioid = nociceptin
Sigma Receptors
not an opioid receptor
Opioid Receptor Signal Transduction
- presynaptic = inhibit calcium channel (Gi) decrease in neurotransmitter release
- postsynaptic = activate GIRK channel, efflux of K+ –> hyperpolarization
Endogenous peptides associated with Mu receptor
- beta-endorphins via POMC (endogenous morphine)
- component of runners high
Therapeutic Use of Mu
- analgesia (cancer pain, palliative, PCA)
- sedation
- antitussive (suppression of cough center in the medulla oblongata)
Opioid Induced Side Effects are mostly what?
on-target effects
Opioid Induced Side Effects
- respiratory depression in brain stem and pre-botzinger complex in the ventrolateral medulla
- constipation (GI tract)
- pruritus (itch) which is a side effect, not allergic response
- addiction
- urinary retention (opioid-induced ADH release)
- Nausea/Vomiting via chemoreceptor trigger zone in medulla
- miosis in oculomotor nerve (PAG)
Kappa opioid receptor endogenous peptide
- dynorphins natural ligand
- preprodynorphin
Kappa opioid receptor activation
- dysphoric
- aversive
- potential use for treatment of addiction by reducing dopamine release
- counterbalance mu opioid receptor effects
Delta opioid receptor endogenous ligand
- enkephalins
- proproenkephalin
Delta opioid receptor expression
- more dynamic expression
- intracellular
- externalized upon chronic stimuli
Role of Delta Opioid Receptor
- hypoxia/ischemia/stroke
- hibernation release of enkephalin like opioid
- reduce anxiety
- reduce depression
- treat alcoholism
- relief hyperalgesia, chronic pain
Side effect of delta opioid receptor
seizures
FDA approved delta opioids
None available
Opioid Site of Action
Ventral Tegmental Area and Nucleus Accumbens
Depressants can cause what neurotransmitter release
- dopamine release
Opioid MOA
- binds to mu receptor
- Gi signaling inhibits neurotransmitter release
- less GABA to activate GABAa
- less inhibition of dopamine neuron activity
- increase dopamine release
- increased activation of dopamine receptors in nucelus accubens
oral administration of opioids pk
- slow rise, long duration
- does not reach side effect region
Where is morphine absorbed?
- readily absorbed in GI
- first pass metabolism
Metabolism of Morphine/Phenanthrenes
- CYPD 2D6 and 3A4
- elimination T1/2 increased with liver disease
Morphine and Phenanthrenes undergo what type of metabolism?
- glucuronidation at 3’ and 6’ position
- morphine 6 glucuronide is still potent
Excretion of Morphine/PHenanthrenes
- glomerular filtration (renal)
- 90% excreted in 24h
Opioids that are prodrugs
- heroin
- codeine
- tramadol
CYP3A4 impact on opioid metabolism
- responsible for converting opioids to “nor” metabolites
- makes them less active
CYP 2D6 impact on opioid metabolism
- converts prodrug to active metabolite (morphine, hydromorphone, oxymorphone)
Which phenotype of 2D6 metabolizers is of high relevance
UM
- up to 50% higher plasma concentrations of morphine than EM when given codeine
- frequency 40% in North Africa
PM
- more common in caucasians
- no therapeutic effect from codeine
- same incidence of adverse effects
Use of Fentanyl
- 100x potent over morphine
- 50x potent over heroin
- used for palliative care breakthrough pain
Sufentanil, Remifentanil, Alfentainil
- agnoists
- anesthesia/sedation
- breakdown by plasma esterases due to ester linkage
Fentanyl Dosage Froms
- iv
- patch
- lollipop
Hydromorphone and Oxymorphone active metabolites
- no opioid active metabolites
Morphine use
- covered by medicare –> preferred over oxycontin
- extended release (MScontin)
- long acting, lower rush, M6G contribution to pain relief. risk for abuse if IV injected at once
Non-phenanthrene opioids
- tramadol
- meperidine
Tramadol use
- mild opiate anelgesic
- has SNRI properties (5HT/NE reuptake inhibitor, stimulates 5HT release)
- management of mild neuropathic pain
- painkiller used when you dont want to prescribe a stronger opioid
- schedule IV
Meperidine Use
- used to treat rigors (shivering)
- has toxic metabolite normeperidine (3A4)
- metabolite is devoid of analgesic activity
- neurotoxic causing nervousness, tremors, muscle twitches, and seizures
- renally excreted, do not use in patients with decreased renal function
Methadone MOA
block NMDA receptors
Methadone use
- primarily used for opioid dependence
- prolonged QTc
Opioids for Cough
- usually codeine
- DM has limited opioid activity (not scheduled)
Opioids for Diarrhea
- dephenoxylate with atropine
- Loperamide is strong pgp substrate (low BBB penetration)
- eluxadoline for IBS with diarrhea, mu/kappa agonist and delta antagonist
Pentazocine and Butorphanol
- k agonist
- partial agonist/antagonism at mu
- parenterally administered
- side effects include less dysphoria, hallucinations, increase in BP, HR
Nalbuphine
- full agonist at K
- antagonist at mu
- antagonism produces withdrawal
- parenterally administered
Buprenorphine
- partial mu agonist
- weak k agonist and gamma antagonist
- primary use in opioid replacement therapy
Prevention of constipation due to opioid use
Senna
- irritates colon
- cause fluid secretion/colonic contraction
Miralax
- stool softner via osmotic increase in GI water content
Docusate
- stool softener
opioid tolerance
- analgesic effects
- nausea
- urinary retention
- respiratory depression (biggest risk of death in withdrawn patients/users)
- euphoria
limited/no tolerance of opioid
- constipation
- itch
- miosis
Treatment for Opioid Dependence: Methadone
- full mu opioid receptor agonist (cross tolerance)
- provide relief from withdrawal
- slow acting (2-4 hours)
- accumulates with repeated dose
- NDMA antagonist racemic mixture
Treatment for Opioid Dependance: Buprenorphine
- mu opioid receptor partial agonist
-blocks full agonist effect of heroin, oxycodone (antagonist) - provides some activation (agonist) with less withdrawal