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Block 4: Musculoskeletal > Opioids, Glucocorticoids, Anesthetics, Adjuvants (Week 2--Melega) > Flashcards

Opioids, Glucocorticoids, Anesthetics, Adjuvants (Week 2--Melega) Flashcards

1
Q

WHO analgesic ladder

A

Way to approach how to give pain medication

1) Non-opioid +/- adjuvant
2) Opioid for mild to moderate pain + non-opioid +/- adjuvant
3) Opioid for moderate to severe pain +/- non-opioid +/- adjuvant

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2
Q

Opium

A

Extract of the juice of the poppy

Consists of 20 different compounds, including morphine and codeine

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3
Q

Opiates vs. opioids

A

Opiates are natural compounds isolated from opium (morphine and codeine)

Opioids are generic name for natural, semi-synthetic and synthetic compounds related to opium

(opiates ARE opioids)

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4
Q

Narcotics

A

Strictly refers to psychoactive compound with morphine-like effects

Inaccurate term because implies narcosis which is not necessarily produced by therapeutic doses

Narcotics are by law illegal or designated as controlled substances

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5
Q

Do we have endogenous opioid-like compounds in our bodies?

A

Yes, that’s why we have receptors for opioids

Beta-endorphin

Leucine- and methionine-enkaphalin

Dynorphins

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6
Q

How are opioids effective analgesics?

A

Opioids act as agonists and mimick analgesic activity endogenous compounds have

Bind to receptors on neuronal elements which allow them to function as NTs or neuromoduators

Modulate pain transmission at peripheral nociceptive afferents in spinal cord and brain

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7
Q

Endogenous opioid peptide receptors

A

All have inhibitory functions (however, can inhibit an inhibitory neuron to activate a process), all are G protein-coupled

Mu receptors

Kappa receptors

Delta receptors

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8
Q

3 mechanisms of opioid inhibition

A

1) Inhibit adenylate cyclase (decrease cAMP)
2) Reduce Ca2+ influx (thus reduce NT release)
3) Increase K+ efflux (hyperpolarized postsynaptic neuron)

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9
Q

Which neurons do opioids bind to?

A

Opioids bind to ascending pain transmission neurons to inhibit ascending nociceptive activity

Opioids bind to inhibitory neurons to cause disinhibition (activation) of descending pathways that then inhibit ascending nociceptive activity

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10
Q

CNS efects produced by Mu opioid agonists

A

1) Analgesia: symptomatic relief of pain that does not produce hypnosis (sleep) or impair sensation
2) Euphoria: mood elevation, sometimes frank euphoria, sometimes dysphoria
3) Sedation and drowsiness: dose-dependent drowsiness, feeling of heaviness, difficulty concentrating are common at first
4) Miosis: (NOT directly on PNS) Edinger-Westphal nucleus of third nerve contains para pre cell bodies and is inhibited by local interneurons, but opioids bind these and inhibit interneurons to activate E-W nucleus and cause too much para pre stimulation
5) Respiratory depression: decreased sensitivity of respiratory center in medulla to increases in blood CO2 (this is always cause of death from OD)
6) Nausea and vomiting: stimulate CTZ
7) Cough suppression: (antitussive) by acting on “cough center” in medulla
8) Inhibition of neuroendocrine factors: inhibit GnRH, CRH in hypothalamus (decrease plasma LH, FSH, ACTH, beta-endorphin)

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11
Q

Peripheral nervous system effects produced by Mu opioid agonists

A

1) Constipation: increased resting tone in GI
2) Constriction of sphincter of Oddi
3) Urinary retention: decreased force of detrusor muscle contraction
4) Histamine release from tissue mast cells and circulating basophils: causes itching, flushing, wamer skin, bronchoconstriction; morphine/codeine/meperidine can cause non-immunologic displacement of histamine from tissue mast cells
5) Truncal rigidity: only with large IV doses of a few drugs (fentanyl and congeners)

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12
Q

Classification of opioid medications

A

Agonist (strong, moderate, weak)

Mixed agonist-antagonist

Antagonist

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13
Q

Strong Mu agonists

A

Morphine

Hydromorphone (Dilaudid; “moderate to strong” but more potent than morphine!)

Fentanyl (Sublimaze; mu and kappa agonist, 80x more potent than morphine)

Methadone (also NMDA antagonist; good ORAL)

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14
Q

Moderate Mu agonists

A

Codeine

Oxycodone (Oxycontin; “moderate to strong”)

Meperidine (Demerol; “moderate to strong” but 6x less potent than morphine)

Hydrocodone

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15
Q

Weak Mu agonists

A

Propoxyphene (taken off market)

Tramadol (works at opioid receptors but not actually an opioid derivative)

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16
Q

Anti-diarrhea Opioids

A

Loperamide (Immodium)

Diphenoxylate (Lomotil)

Act as mu receptor agonists in myemteric plexus of large intestine to decrease GI motor activity and increase sphincter tone

Don’t affect CNS like other opioids do, don’t cross BBB much and whatever does is effluxed from brain by P-glycoprotein

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17
Q

Mixed opioid agonist-antagonists

A

Ex: pentazocine

Point was to make drug with analgesic but less addictive qualities (people still abused these though)

Occasional dysphoria or hallucination with kappa agonists

Ceiling effect for respiratory depression

Competitive antagonists or agonists at mu receptor and agonists at kappa or delta receptor

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18
Q

Symptoms of opioid overdose

A

Toxic triad: coma, pinpoint pupils, depressed respiration

Hypotension, hypothermia (skin cold and clammy), urinary retention, skeletal muscles flaccid, pulmonary edema, bradycardia, seizures (rarely)

Most signs of opioid intoxication reversed by naloxone

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19
Q

Classifications of opioid drugs

A

Agonists: morphine, codeine, heroine, hydromorphone, oxycodone, hydrocodone, meperidine, fentanyl, methadone, propoxyphene, tramadol

Mixed agonist-antagonist: pentazocine

Partial agonist: buprenorphine

Diarrhea treatment: loperamide, diphenoxylate

Opioid antagonists: naloxone, naltrexone

Antitussive: dextromethorphan

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20
Q

3 types of tolerance

A

1) Pharmacokinetic (dispositional): changes in absorption, metabolism or elimination so plasma AUC lower than observed initially
2) Pharmacodynamic: down-regulation of receptors, changes in receptor-effector coupling, compensatory physiological changes; desensitization
3) Cross-tolerance: resistance to one or several effects of a compound as a result of tolerance developed to a pharmacologically similar compound

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21
Q

Opioid tolerance

A

Can develop when large doses of opioids administered at short time intervals

First indication of tolerance is decreased duration of analgesia then decreased intensity of effect

Little or no tolerance for constipating effects of opioid agonists

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22
Q

Physical dependence

A

When drug is needed for normal physiological homeostasis (is universal with prolonged opioid therapy)

Must taper off opioids to avoid withdrawal syndrome

Cannot directly assess physical dependence but know they have it if there is withdrawal syndrome upon discontinuation of drug then elimination of symptoms upon readministration of drug

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23
Q

Opioid withdrawal

A

Like the worst symptoms of a bad cold

Yawning, lacrimation, rhinorrhea, sweating, gooseflesh/piloerection (“go cold turkey”), chills, anxiety, nausea, vomiting, diarrhea, hyperactive bowel sounds, abdominal cramps

Without treatment, get insomnia, anorexia, muscle crapms/spasms in legs and back (“kicking the habit”), dilated pupils, tachycardia, HTN

Withdrawal symptoms begin after 8-10 hours and last 7-10 days

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24
Q

Pseudoaddicton

A

Drug seeking, increased focus on obtaining medications, patients with poorly managed pain mimic the signs of psychological dependence, but pseudoaddiction resolves with effective pain management

Can be exacerbated by curtailing opioid therapy (because person will be in more pain)

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25
Q

Addiction

A

Defined by WHO as behavioral pattern of drug use, characterized by involvement with compulsive use of drug, securing its supply, high tendency to relapse after withdrawal

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26
Q

Who is at risk for drug addiction and how do we tell?

A

History: personal, family hx drug abuse, current addiction, hx problems with prescriptions, comorbid psychiatric disorders

Screening instruments: scored clinical surveys like opioid risk tool (ORT)

Behavioral checklists

Therapeutic maneuver (if functioning improves upon increased opiod dose it’s fine, but if not probably addicted)

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27
Q

What should we document in the patient’s chart?

A

Why opioid is prescribed

What reduction in pain has been achieved

What functional improvement has occurred

Document acceptable side effects

Document responsible medication use and absence of aberrant behavior

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28
Q

Corticosteroids

A

Anti-inflammatory and immunosuppressive

Inhibit synthesis of inflammatory proteins, cytokines, by inhibiting phospholipase A2 (eicosanoid pathway completely inhibited, so no prostaglandins and no leukotrienes)

Use is limited by systemic side effects

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29
Q

Glucocorticoid action on gene expression

A

GC enters cell and binds to cytoplasmic glucocorticoid receptor that is complexed with two HSP molecules –> GR translocates to nucleus where binds as a dimer to glucocorticoid recognition sequence (GRE) upstream of promoter –> increased transcription of anti-inflammatory genes

Similar pathway to inhibit transcription of inflammatory genes (cytokines, enzymes, receptors, adhesion molecules) using nGRE upstream sequence

Note: both increases and decreases in transcriptional rates of genes associated with inflammation

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30
Q

Non-genomic effects of glucocorticoids

A

Rapid effects which occur within a few minutes, actions do not require de novo protein synthesis

Modulate degree of activation and responsiveness of target cells (monocytes, T cells, platelets)

Unclear how these effects contribute to therapeutic efficacy of GCs in controlling vascular inflammatory pathology

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31
Q

Cortisone and prednisone

A

Inactive prodrugs with no GC activity

Require metabolism in liver to cortisol and prednisolone (by reducing C=O at carbon 11 to hydroxyl)

Joint injections and topical steroids must be active (11 beta hydroxyl) compounds bc won’t get transformed in liver!

Note: hydrocortisone is pharmaceutical term for cortisol (active)

32
Q

Different ways glucocorticoids can be classified

A

1) Duration of activity (short, med, long) based on duration of ACTH suppression following a single dose
2) Affinity of binding to GR (correlates with potency)
3) Extent of mineralcorticoid activity

Note: observed potency is measure of intrinsic potency and duration of action

33
Q

Hydrocortisone (cortisol)

A

Naturally occurring glucocorticoid

1/4 potency of prednisone, but has mineralcorticoid effect when used in pharmacologic doses (parenteral supplementation in patient believed to have adrenal suppression)

Biologic half life: 8-12 hours

34
Q

Prednisone

A

Most widely prescribed GC

Short half-life, low cose, negligible mineralcorticoid effect (inactive until metabolized by liver)

Useful for most immunosuppressive and anti-inflammatory indications

Biologic half life: 18-36 hours

35
Q

Prednisolone

A

Active hepatic metabolite of prednisone

Useful in liver failure (??)

36
Q

Methylprednisolone (Medrol, Solu-Medrol)

A

Used to treat wide range of conditions (allergies, arthritis, lupus, ulcerative colitis)

Biologic half life: 18-36 hours

37
Q

Dexamethasone

A

Long-acting glucocorticoid

7x more potent than prednisone

Biologic half life of 26-54 hours

38
Q

Biologic half life vs. plasma half life

A

Biologic half life: elimination from the body

Plasma half life: time required for plasma concentration of drug to decrease by 50%

39
Q

Epidural glucocorticoid injections for back pain

A

Anti-inflammatory: inhibit C-fiber conduction, decrease synthesis of COX2, iNOS, cytokines

3 types: interlaminar, transforaminal, caudal

40
Q

Anesthetic

A

Drug that causes loss of sensation

General: IV or inhalation; body-wide anesthesia

Local: acts only locally; loss of sensation in area of application without loss of consciousness and without impairment of CNS control of vital functions

41
Q

How do local anesthetics block sensation?

A

Work on all nerve fibers (not just C fibers like analgesics!) and block Na+ influx through Na+ channels so AP cannot propagate an impulse

Local anesthetics bind reversibly to Na+ channels to cause loss of sensation in that area because those peripheral nerve endings cannot be excited anymore

42
Q

Properties of local anesthetics

A

Lipid soluble, diffusible, affinity for protein binding, vasodilating, % ionization at physiologic pH

43
Q

Why is it so important that most local anesthetics are weak bases?

A

pKa of local anesthetics is 8-9 so most is ionized BH+ form at physiological pH

However, when in uncharged B form, it can pass through cell membrane, where it becomes protonated again and THAT reversibly blocks voltage-gated Na+ channels from the inside

44
Q

Three basic components of local anesthetic

A

1) Lipophilic aromatic portion
2) Intermediate connecting chain (ester or amide)
3) Hydrophilic amine portion

45
Q

Why do local anesthetics preferentially target neurons that are more active?

A

Local anesthetics have higher affinity for Na+ channels that are in the intermediate closed/open/inactivated conformation (NOT resting conformation)

Thus, LAs preferentially bind channels that are being more activated relative to “resting” channels

46
Q

Two types of Na+ channel inhibition

A

Tonic inhibition: same fraction of channels remain blocked when time between action potentials is long compared to time for dissociation of the local anesthetic from the Na+ channel

Phasic inhibition: action potential conduction is increasingly inhibited at higher frequencies of impulses (this is the main action of local anesthetics!)

47
Q

Which nerve fibers are targeted by local anesthetics?

A

Nociceptors fire at high rate and are therefore preferentially inhibited by local anesthetics (phasic inhibition) than are the slower firing sensory and motor impulses

48
Q

What determines the extent of absorption of local anesthetics?

A

Local vascularity

Local anesthetics in the systemic circulation can produce serious adverse reactions (usually accidental)

Note: don’t apply local anesthetic to nasal mucosa, oral mucosa, scalp, skin of head and neck because they’re well-vascularized and have potential for rapid absorption!

49
Q

How can you ensure that local anesthetics don’t get into systemic circulation?

A

Add vasoconstrictors to local anesthetics to decrease blood flow and reduce absorption to reduce systemic toxicity (rate of recovery from local anesthesia is a function of the blood supply moving the drug away from the application site)

Vasoconstrictors also keep anesthetic in contact with the nerve longer and increase duration of action

They also reduce bleeding in the surgical field

50
Q

What are the systemic toxic effects of local anesthetics?

A

Seizures (CNS)

Arrhythmias (CV)

51
Q

What is used for vasoconstriction?

A

Epinephrine

Don’t use EPI in extremities because circulation rate is low and can cause local ischemia

52
Q

Modes of administration of local anesthetic

A

Topical

Local infiltration (intradermal)

Peripheral/specific nerve or field block

Epidural anesthesia

Spinal anesthesia (subarachnoid space, intrathecal)

53
Q

What determines a nerve fiber’s sensitivity to local anesthetics?

A

Size

Degree of myelination

54
Q

Different types of nerve fibers and different sensitivity to local anesthetics

A

C fibers are small diameter (high SA:V ratio means absorption is favored), unmyelinated so are very sensitive to LA (easy for LA to get in!)

A fibers are large diameter, myelinated so are less sensitive to LA

Remember though, all nerves can be blocked by local anesthetics (even motor to respiration–bad!)

55
Q

Two types of local anesthetics

A

Esters: metabolized quickly by plasma cholinesterases, short half life, make PABA as metabolite (allergy concern); ex: cocaine, benzocaine, tetracaine, chloroprocaine–always have only 1 “i”

Amides: metabolized by hepatic P450 system, longer half life, allergy rare; ex: lidocaine, mepivacaine, bupivacaine, ropivacaine, articaine–always have 2 “i’s”

56
Q

LET (lidocaine, epinephrine and tetracaine)

A

Liquid or gel formulation which is topical anesthetic used on cut

57
Q

Lidocaine patch 5% (LIDODERM)

A

Relief of pain associated with postherpetic neuralgia

Reduces abnormal ectopic activity produced by damaged/dysfunctional nerves

No systemic activity; analgesic but not anesthetic (numbness)

Adverse effects: might have erythema, burning sensation, dizziness, rash

58
Q

Excitatory neurotransmission

A

Excitatory amino acids: glutamate (Glu) and aspartate (Asp)

4 major glutamate gated ion channel subtypes: NMDA, KA, AMPA (quisqualate), APB

59
Q

Inhibitory neurotransmission

A

GABA is major inhibitory NT in the CNS

2 receptor types: GABAA and GABAB

GABA-A receptor: ligand-gated Cl- channel that lets Cl- in to hyperpolarize postsynaptic membrane and inhibit neuronal transmission

GABA-B receptor: G-protein coupled receptor that increases conductance of associated K+ channel to let K+ in and blocks voltage-activated Ca2+ channel (K+ out and no Ca2+ in causes hyperpolarization and inhibition of neuronal activity)

60
Q

Peripheral sensitization

A

Increased nociceptor activity

61
Q

Antiepileptic drugs (AEDs)

A

Na+ channel blockers used as AEDs, so AEDs can actually be used off-label to counter effects of peripheral sensitization that is a critical component of neuropathic pain

Ex: topiramate, lamotrigine, carbamazepine (for trigeminal neuralgia)

62
Q

Tricyclic antidepressants (TCAs)

A

To treat depression and neuropathic pain

Amitriptyline: NE and serotonin reuptake inhibitor, Na+ channel blocker, NMDA antagonist

Tertiary amines with potent antimuscarinic adverse effects because they are metabolized to secondary amines which have weaker antimuscarinic side effects

Ex: amitriptyline, imipramine

Note: these drugs work as analgesics at lower concentrations and don’t change a person’s affect

63
Q

Mechanism of analgesia of TCAs

A

Descending axons from brain release NE and 5-HT in dorsal horn, and TCAs block reuptake here so increase firing of descending neurons from brain (which inhibit ascending C fibers???)

Block peripheral sensitization

64
Q

Central sensitization

A

Increased activity in dorsal horn of spinal cord

65
Q

Adjuvant medications used to counter effects of peripheral sensitization

A

Idea is to block Na+ channels and/or reduce primary afferent activity by raising the threshold for firing of peripheral neurons –> make it so peripheral neurons can’t fire so you can’t feel the pain

AEDs and TCAs do this

66
Q

Adjuvant medications used to counter effects of central sensitization

A

Idea is to inhibit/reduce transynaptic activity between nociceptor afferents, interneurons, cell bodies and their ascending neuronal inputs to the brain

Block NMDA receptors, block Ca2+ channels on presynaptic terminals

Use gabapentin, pregabalin, NMDA receptor antagonists (ketamine, methadone, dextromethorphan)

67
Q

Does gabapentin act on the pre- or post-synaptic neuron?

A

Presynaptic neuron

Binds a voltage-gated Ca2+ channel on the pre-synaptic terminal to block Ca2+ entry and thus decrease release of excitatory NTs which would then cause nociception

68
Q

NMDA receptor antagonists

A

NMDA receptor activation at the level of the spinal cord can evoke central hyperexcitability (“wind up” that allows increases in nociceptive transmission that ascends to brain)

NMDA antagonists block the action of glutamate at synapses in the spinal cord

Prophylactic use of NMDA antagonist inhibits central sensitization but still requires use of analgesic for complete abolishment of pain perception

Ex: ketamine, methadone, dextromethorphan

69
Q

Drugs that inhibit ascending nociceptive transmission or activate descending inhibitory neuronal pathways

A

Opioid

TCAs

70
Q

Drugs that inhibit or reduce transynaptic activity between nociceptor afferents, interneurons, cell bodies and their ascending neuronal axons to brain (inhibit central sensitization)

A

Ca2+ channel blockers

NMDA antagonists

NSAIDs

Opioids

71
Q

Drugs that block Na+ channels and/or reduce primary afferent activity by raising threhold for firing (inhibit peripheral sensitization)

A

Na+ channel blockers (AEDs), TCAs, LAs

Capsaicin

NSAIDs

72
Q

What is the highest (most cephalad) interspace at which a spinal (subarachnoid) needle can be inserted in adults?

A

L2-L3 because that’s where conus medullaris of spinal cord ends and don’t want to get near spinal cord because could damage it

73
Q

Difference between spinal injection and epidural injection

A

Spinal (subarachnoid) blocks motor and sensory fibers (paralyze)

Epidural analgesia is just sensory fibers (can still move, like when giving birth). Remember this is where internal vertebral venous plexus is (epidural space)

74
Q

“Breakthrough” pain

A

Temporary moderate to severe flare in pain that occurs even though analgesic medications are taken regularly

To treat breakthrough pain, give immediate release morphine

75
Q

Opioid tolerance vs. dependence vs. addiction

A

Opioid tolerance: effect of drug decreases when same dose given chronically, so dose needs to be increased over time to achieve same effect

Opioid dependence: drug needed for normal physiological homeostasis, is revealed as abstinence (withdrawal) syndrome upon discontinuation of drug

Opioid addiction: impaired control over drug use, compulsive use, continued use despite harm, craving, high tendency to relapse after withdrawal

76
Q

Opioid-induced hyperalgesia (OIH)

A

Opioid administration actually causes more pain, hyperalgesia

Pain threshold is lowered by opioids

Presents as opioid tolerance, worsening pain despite an increase in opioid dose, abnormal pain symptoms like allodynia

This pain is usually diffuse, less defined

Block 4: Musculoskeletal (37 decks)

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