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

Question 1

WHO analgesic ladder

Answer 1

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

Question 2

Opium

Answer 2

Extract of the juice of the poppy

Consists of 20 different compounds, including morphine and codeine

Question 3

Opiates vs. opioids

Answer 3

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)

Question 4

Narcotics

Answer 4

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

Question 5

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

Answer 5

Yes, that’s why we have receptors for opioids

Beta-endorphin

Leucine- and methionine-enkaphalin

Dynorphins

Question 6

How are opioids effective analgesics?

Answer 6

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

Question 7

Endogenous opioid peptide receptors

Answer 7

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

Question 8

3 mechanisms of opioid inhibition

Answer 8

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

Question 9

Which neurons do opioids bind to?

Answer 9

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

Question 10

CNS efects produced by Mu opioid agonists

Answer 10

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)

Question 11

Peripheral nervous system effects produced by Mu opioid agonists

Answer 11

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)

Question 12

Classification of opioid medications

Answer 12

Agonist (strong, moderate, weak)

Mixed agonist-antagonist

Antagonist

Question 13

Strong Mu agonists

Answer 13

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)

Question 14

Moderate Mu agonists

Answer 14

Codeine

Oxycodone (Oxycontin; “moderate to strong”)

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

Hydrocodone

Question 15

Weak Mu agonists

Answer 15

Propoxyphene (taken off market)

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

Question 16

Anti-diarrhea Opioids

Answer 16

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

Question 17

Mixed opioid agonist-antagonists

Answer 17

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

Question 18

Symptoms of opioid overdose

Answer 18

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

Question 19

Classifications of opioid drugs

Answer 19

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

Question 20

3 types of tolerance

Answer 20

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

Question 21

Opioid tolerance

Answer 21

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

Question 22

Physical dependence

Answer 22

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

Question 23

Opioid withdrawal

Answer 23

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

Question 24

Pseudoaddicton

Answer 24

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)

Question 25

Addiction

Answer 25

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

Question 26

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

Answer 26

**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)

Question 27

What should we document in the patient's chart?

Answer 27

**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

Question 28

Corticosteroids

Answer 28

**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

Question 29

Glucocorticoid action on gene expression

Answer 29

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

Question 30

Non-genomic effects of glucocorticoids

Answer 30

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

Question 31

Cortisone and prednisone

Answer 31

**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)

Question 32

Different ways glucocorticoids can be classified

Answer 32

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

Question 33

Hydrocortisone (cortisol)

Answer 33

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

Question 34

Prednisone

Answer 34

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

Question 35

Prednisolone

Answer 35

**Active** hepatic metabolite of prednisone Useful in liver failure (??)

Question 36

Methylprednisolone (Medrol, Solu-Medrol)

Answer 36

Used to treat wide range of conditions (allergies, arthritis, lupus, ulcerative colitis) Biologic half life: 18-36 hours

Question 37

Dexamethasone

Answer 37

Long-acting glucocorticoid **7x more potent** than prednisone Biologic half life of 26-54 hours

Question 38

Biologic half life vs. plasma half life

Answer 38

**Biologic** half life: **elimination** from the **body** Pl**a**sma half life: time required for **plasma concentration** of drug to decrease by 50%

Question 39

Epidural glucocorticoid injections for back pain

Answer 39

**Anti-inflammatory**: inhibit C-fiber conduction, decrease synthesis of COX2, iNOS, cytokines 3 types: interlaminar, transforaminal, caudal

Question 40

Anesthetic

Answer 40

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

Question 41

How do local anesthetics block sensation?

Answer 41

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

Question 42

Properties of local anesthetics

Answer 42

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

Question 43

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

Answer 43

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

Question 44

Three basic components of local anesthetic

Answer 44

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

Question 45

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

Answer 45

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

Question 46

Two types of Na+ channel inhibition

Answer 46

**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!**)

Question 47

Which nerve fibers are targeted by local anesthetics?

Answer 47

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

Question 48

What determines the extent of absorption of local anesthetics?

Answer 48

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!

Question 49

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

Answer 49

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

Question 50

What are the systemic toxic effects of local anesthetics?

Answer 50

**Seizures** (CNS) **Arrhythmias** (CV)

Question 51

What is used for vasoconstriction?

Answer 51

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

Question 52

Modes of administration of local anesthetic

Answer 52

**Topical** **Local infiltration** (intradermal) **Peripheral/specific nerve** or field block **Epidural** anesthesia **Spinal** anesthesia (subarachnoid space, intrathecal)

Question 53

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

Answer 53

**Size** Degree of **myelination**

Question 54

Different types of nerve fibers and different sensitivity to local anesthetics

Answer 54

**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!)

Question 55

Two types of local anesthetics

Answer 55

**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"**

Question 56

LET (lidocaine, epinephrine and tetracaine)

Answer 56

**Liquid** or gel formulation which is **topical** anesthetic used on **cut**

Question 57

Lidocaine patch 5% (LIDODERM)

Answer 57

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

Question 58

Excitatory neurotransmission

Answer 58

Excitatory amino acids: **glutamate** (Glu) and **aspartate** (Asp) 4 major glutamate gated ion channel subtypes: **NMDA**, KA, **AMPA** (quisqualate), APB

Question 59

Inhibitory neurotransmission

Answer 59

**GABA** is major inhibitory NT in the CNS 2 receptor types: **GABA_A** and **GABA_B** **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)

Question 60

Peripheral sensitization

Answer 60

Increased **nociceptor** activity

Question 61

Antiepileptic drugs (AEDs)

Answer 61

**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)

Question 62

Tricyclic antidepressants (TCAs)

Answer 62

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

Question 63

Mechanism of analgesia of TCAs

Answer 63

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

Question 64

Central sensitization

Answer 64

Increased activity in **dorsal horn of spinal cord**

Question 65

Adjuvant medications used to counter effects of **peripheral sensitization**

Answer 65

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

Question 66

Adjuvant medications used to counter effects of central sensitization

Answer 66

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)

Question 67

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

Answer 67

**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

Question 68

NMDA receptor antagonists

Answer 68

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

Question 69

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

Answer 69

**Opioid** **TCAs**

Question 70

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

Answer 70

**Ca2+ channel blockers** **NMDA antagonists** **NSAIDs** **Opioids**

Question 71

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

Answer 71

Na+ channel blockers (**AEDs**), **TCAs**, **LAs** **Capsaicin** **NSAIDs**

Question 72

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

Answer 72

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

Question 73

Difference between spinal injection and epidural injection

Answer 73

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)

Question 74

"Breakthrough" pain

Answer 74

Temporary moderate to severe flare in pain that occurs even though analgesic medications are taken regularly To treat breakthrough pain, give immediate release morphine

Question 75

Opioid tolerance vs. dependence vs. addiction

Answer 75

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

Question 76

Opioid-induced hyperalgesia (OIH)

Answer 76

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