Opioids, Glucocorticoids, Anesthetics, Adjuvants (Week 2--Melega) Flashcards
WHO analgesic ladder
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
Opium
Extract of the juice of the poppy
Consists of 20 different compounds, including morphine and codeine
Opiates vs. opioids
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)
Narcotics
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
Do we have endogenous opioid-like compounds in our bodies?
Yes, that’s why we have receptors for opioids
Beta-endorphin
Leucine- and methionine-enkaphalin
Dynorphins
How are opioids effective analgesics?
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
Endogenous opioid peptide receptors
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
3 mechanisms of opioid inhibition
1) Inhibit adenylate cyclase (decrease cAMP)
2) Reduce Ca2+ influx (thus reduce NT release)
3) Increase K+ efflux (hyperpolarized postsynaptic neuron)
Which neurons do opioids bind to?
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
CNS efects produced by Mu opioid agonists
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)
Peripheral nervous system effects produced by Mu opioid agonists
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)
Classification of opioid medications
Agonist (strong, moderate, weak)
Mixed agonist-antagonist
Antagonist
Strong Mu agonists
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)
Moderate Mu agonists
Codeine
Oxycodone (Oxycontin; “moderate to strong”)
Meperidine (Demerol; “moderate to strong” but 6x less potent than morphine)
Hydrocodone
Weak Mu agonists
Propoxyphene (taken off market)
Tramadol (works at opioid receptors but not actually an opioid derivative)
Anti-diarrhea Opioids
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
Mixed opioid agonist-antagonists
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
Symptoms of opioid overdose
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
Classifications of opioid drugs
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
3 types of tolerance
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
Opioid tolerance
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
Physical dependence
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
Opioid withdrawal
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
Pseudoaddicton
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)
Addiction
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
Who is at risk for drug addiction and how do we tell?
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)
What should we document in the patient’s chart?
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
Corticosteroids
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
Glucocorticoid action on gene expression
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
Non-genomic effects of glucocorticoids
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
Cortisone and prednisone
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)
Different ways glucocorticoids can be classified
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
Hydrocortisone (cortisol)
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
Prednisone
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
Prednisolone
Active hepatic metabolite of prednisone
Useful in liver failure (??)
Methylprednisolone (Medrol, Solu-Medrol)
Used to treat wide range of conditions (allergies, arthritis, lupus, ulcerative colitis)
Biologic half life: 18-36 hours
Dexamethasone
Long-acting glucocorticoid
7x more potent than prednisone
Biologic half life of 26-54 hours
Biologic half life vs. plasma half life
Biologic half life: elimination from the body
Plasma half life: time required for plasma concentration of drug to decrease by 50%
Epidural glucocorticoid injections for back pain
Anti-inflammatory: inhibit C-fiber conduction, decrease synthesis of COX2, iNOS, cytokines
3 types: interlaminar, transforaminal, caudal
Anesthetic
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
How do local anesthetics block sensation?
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
Properties of local anesthetics
Lipid soluble, diffusible, affinity for protein binding, vasodilating, % ionization at physiologic pH
Why is it so important that most local anesthetics are weak bases?
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
Three basic components of local anesthetic
1) Lipophilic aromatic portion
2) Intermediate connecting chain (ester or amide)
3) Hydrophilic amine portion
Why do local anesthetics preferentially target neurons that are more active?
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
Two types of Na+ channel inhibition
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!)
Which nerve fibers are targeted by local anesthetics?
Nociceptors fire at high rate and are therefore preferentially inhibited by local anesthetics (phasic inhibition) than are the slower firing sensory and motor impulses
What determines the extent of absorption of local anesthetics?
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!
How can you ensure that local anesthetics don’t get into systemic circulation?
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
What are the systemic toxic effects of local anesthetics?
Seizures (CNS)
Arrhythmias (CV)
What is used for vasoconstriction?
Epinephrine
Don’t use EPI in extremities because circulation rate is low and can cause local ischemia
Modes of administration of local anesthetic
Topical
Local infiltration (intradermal)
Peripheral/specific nerve or field block
Epidural anesthesia
Spinal anesthesia (subarachnoid space, intrathecal)
What determines a nerve fiber’s sensitivity to local anesthetics?
Size
Degree of myelination
Different types of nerve fibers and different sensitivity to local anesthetics
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!)
Two types of local anesthetics
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”
LET (lidocaine, epinephrine and tetracaine)
Liquid or gel formulation which is topical anesthetic used on cut
Lidocaine patch 5% (LIDODERM)
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
Excitatory neurotransmission
Excitatory amino acids: glutamate (Glu) and aspartate (Asp)
4 major glutamate gated ion channel subtypes: NMDA, KA, AMPA (quisqualate), APB
Inhibitory neurotransmission
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)
Peripheral sensitization
Increased nociceptor activity
Antiepileptic drugs (AEDs)
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)
Tricyclic antidepressants (TCAs)
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
Mechanism of analgesia of TCAs
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
Central sensitization
Increased activity in dorsal horn of spinal cord
Adjuvant medications used to counter effects of peripheral sensitization
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
Adjuvant medications used to counter effects of central sensitization
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)
Does gabapentin act on the pre- or post-synaptic neuron?
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
NMDA receptor antagonists
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
Drugs that inhibit ascending nociceptive transmission or activate descending inhibitory neuronal pathways
Opioid
TCAs
Drugs that inhibit or reduce transynaptic activity between nociceptor afferents, interneurons, cell bodies and their ascending neuronal axons to brain (inhibit central sensitization)
Ca2+ channel blockers
NMDA antagonists
NSAIDs
Opioids
Drugs that block Na+ channels and/or reduce primary afferent activity by raising threhold for firing (inhibit peripheral sensitization)
Na+ channel blockers (AEDs), TCAs, LAs
Capsaicin
NSAIDs
What is the highest (most cephalad) interspace at which a spinal (subarachnoid) needle can be inserted in adults?
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
Difference between spinal injection and epidural injection
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)
“Breakthrough” pain
Temporary moderate to severe flare in pain that occurs even though analgesic medications are taken regularly
To treat breakthrough pain, give immediate release morphine
Opioid tolerance vs. dependence vs. addiction
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
Opioid-induced hyperalgesia (OIH)
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
