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Fundamentals of Pharmacology > Pain and Opioids > Flashcards

Pain and Opioids Flashcards

1
Q

What are the Effects of Pain: Parasympathetic Responses?

A
  • Lowered B.P
  • Lowered Pulse
  • Nausea & vomiting
  • Weakness
  • Pallor
  • Loss of consciousness
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2
Q

What are the Effects of Pain: Sympathetic Responses?

A
  • Pallor
  • Increased B.P
  • Increased Pulse
  • Increased Respiration
  • Skeletal muscle tension
  • Diaphoresis (excessive sweating)
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3
Q

What are the results of untreated pain?

A
  • Depression, anxiety, decreased socialisation
  • Sleep disturbances
  • Impaired movements
  • Increased healthcare use and costs
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4
Q

What are nociceptors?

A

Specialised nerve endings that respond to painful stimuli

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5
Q

What does mechanical stress or damage to the tissues do to mechanosensitive nociceptors?

A

Excite them

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6
Q

Chemosensitive nociceptors are exited by what?

A

Various chemical substances released during the inflammatory response

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7
Q

Chemical irritation of nerve endings may produce what?

A

A severe pain response without true tissue destruction

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8
Q

What is role of the ascending pathway?

A
  • Come from periphery up to CNS
  • Pain signal is activated
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9
Q

What is the role of the descending pathway?

A
  • From CNS to periphery
  • Pain signal is inhibited
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10
Q

What are the sequence of events in pain formation?

A
  • Tissue damage occurs
  • Synthesis of inflammatory and pain mediators is initiated
  • Inflammatory mediators (including prostanoids) are released from damaged tissues
  • These mediators activate their receptors on nociceptor nerves
  • Pain signal is created and propagated
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11
Q

What are neuromodulators?

A
  • Inhibitory pain mediators
    • Endorphins and dynorphins - morphine-like substances
      • Located in brain, spinal cord & GIT
      • Produce analgesia when attached with opiate receptors in the brain
      • Activate μ receptors (endogenous opiates)
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12
Q

What is hyperalgesia?

A

Increased pain response

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13
Q

What is allodynia?

A

Pain response to stimuli that normally do not cause it

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14
Q

What do NSAIDs do?

A

Block the synthesis of prostanoids

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15
Q

What is the MOA of NSAIDs?

A
  • Inhibit COX
    • Inhibition of COX-1 causes
      • impaired gastric cytoprotection
      • anti-platelet effects
    • Inhibition of COX-2 causes
      • anti-inflamatory action
        • decreases prostaglandin in tissue, decreases inflammation
      • analgesic action
        • decreases prostaglandin in tissue, decreases nociception
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16
Q

What are the three major actions of NSAIDs?

A
  • Analgesic
  • Antipyretic
  • Anti-inflammatory
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17
Q

Describe Prostanoids

A
  • Unsaturated fatty acids (20 carbons)
    • precursor of eicosanoids is present in phospholipids of cell membrane
      • arachidonic acid
    • liberated by Phospholipase A2 (PLA2) - rate limiting step
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18
Q

Describe COX-1

A
  • Present in constant quantities in all tissues
    • all the time
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19
Q

Describe COX-2

A
  • Inducible to about 50-100 fold during inflammation
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20
Q

What are the physiological roles of prostaglandins?

A
  • Inflammatory processes
    • vasodilators (synergise with histamine, bradykinin)
    • indirectly contribute to increased permeability
  • Sensitise nerves to bradykinin (increase pain)
  • Fever ‘induction’
  • Platelet aggregation
  • Renal Function (renal blood flow regulation)
  • Gastric mucosal integrity (mucosal protection)
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21
Q

What is the role of Paracetamol?

A

Anti-pyretic

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22
Q

What are the characteristics of prostaglandin receptors?

A
  • Prostaglandin receptors are specified by the class and subtype
    • e.g. EP2 is the E Prostaglandin receptor subtype 2
  • G-protein coupled receptors
  • Depending on the cell type in which the receptor is expressed and the receptor type/subtype, varying signal transduction cascades can result in activation of stimulatory or inhibitory G-proteins
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23
Q

What is the MOA of prostaglandins?

A
  • Prostaglandins don’t cause pain by themselves but they increase pain-producing effects of other mediators
    • any receptor that increases cAMP in nerve cell would increase pain signal
24
Q

Major NSAIDs Adverse Effects: Describe GI intolerance and ulceration

A
  • Nausea
  • Mild dyspepsia
  • Heartburn
  • Ulceration
25
Q

Major NSAIDs Adverse Effects: Describe Bronchospasms

A
  • Synthesis of prostaglandins starts from arachidonic acid, through action of COX-I and COX-II gets into precursor prostaglandin and then different thromboxanes and prostaglandins are synthesised
  • Alternate pathway - synthesise leukotrienes (potent vasoconstrictors)
    • if you block COX pathway, this pathway becomes predominant
26
Q

Major NSAIDs Adverse Effects: Describe Renal Failure

A
  • Two blood vessels control how much blood is let in and out
  • By inhibiting PG production, NSAIDs cause afferent arteriole vasoconstriction and reduce GFR
27
Q

Major NSAIDs Adverse Effects: Describe Prolongation of Bleeding Time

A
  • Prevent formation of Thromboxane A2
  • Accounts for tendency of NSAID to increase bleeding time
  • Can make patient more susceptible to haemorrhage
28
Q

How do you decrease the incidence of GI complications from NSAIDs?

A
  • Paracetamol should be used as an alternative analgesic or to allow lower doses of NSAID use
  • NSAID with lower relative risk of GI complications should be used e.g. diclofenac
  • Lowest effective dose for the shortest period of time should be used in high risk patients that must have a NSAID
    • Proton pump inhibitors (PPIs): suppresses acid production
    • H2-receptor antagonists: suppresses histamine-induced acid increase
    • Muscosal cytoprotective (e.g. misoprostol)
29
Q

Describe how Misoprostol works for NSAIDs long term therapy?

A
  • Drug to protect against GI problems
    • prostaglandin E1 analogue
    • sometimes co-administered with NSAID therapy to prevent NSAID-induced ulcers
30
Q

Describe the toxicity of Paracetamol and what is its maximum daily dose?

A
  • Phase I metabolism
    • if NAPQ1 accumulates, this causes toxic reactions with proteins and nucleic acids
    • damages liver - irreversible
  • Max. daily dose = 4g
  • Glutathione = natural paracetamol detoxifier
  • N-acetylcysteine = drug used to speed-up paracetamol detoxification
31
Q

Describe the pathophysiology of Osteoarthritis (OA)

A
  • Progressive loss of cartilage in the joints
  • Inflammation does NOT play a predominant role
32
Q

What are drug therapy options for OA and drug classes used?

A
  • Paracetamol
  • Topical pain relievers
  • Corticosteroids
  • Hyaluronic acid
  • Opioids (last resort)
  • NSAIDs
33
Q

Describe Topical Treatments for OA

A
  • Heat and ice
  • Lidocaine patches
  • Topical NSAIDs (not long term)
  • Capsaicin
    • a skin cream made from hot peppers that relieves pain
34
Q

Describe Hyaluronic Acid Therapy for OA

A
  • Used by injection into the joints in patients with severe disease
  • Must be used sparingly
  • Used to replace lost fluid in the joint spaces and keep the joint working to cushion the bones in the joint
35
Q

Describe the characteristics of Ascending Pathway

A
  • Pain signal carried from periphery to CNS
  • Morphine acts on μ receptors
    • create conditions in which adenylyl cyclase attached to the receptor, has inhibitory Gi subunits (cAMP levels decrease as a result)
36
Q

What do opiods do to the ascending pathway?

A
  • Blocked by opioids, pain suppressed
37
Q

Describe the characteristics of Descending Pathway

A
  • Pain signal carried from CNS to periphery
  • Opiods prevent reuptake of NA and therefore increase the level of NA at the synapse
  • This pathway is activated by NA and pain is suppressed
38
Q

Describe the Characteristics of Opioids

A
  • Opioids inactivate pain signal through increase in NA in descending pathway
  • Opioids block ascending pathways by depolarisation and neurotransmitter release inhibition
  • A group of G-protein coupled receptors
  • Act on natural opioid receptors in cerebrum and medulla of the CNS
39
Q

What are the Three Opioid Receptor Types

A

μ, K, δ

40
Q

What are the actions of μ receptors?

A
  • Most highly concentrated in brain, responsible for most of the analgesic effect of opioids
  • Analgesia
  • Sedation
  • Respiratory Depression
  • Hypothermia
  • Reinforcing effects
  • Euphoria
  • Pupil constriction
  • Decreased GI motility
  • Nausea and vomiting
  • Urinary retention
41
Q

What are the natural ligands of μ receptors?

A

beta-endorphin, endomorphins

42
Q

What are the actions of k receptors?

A
  • Contribute to analgesia at the spinal level
  • Produce few unwanted effects (don’t contribute to dependence)
  • Analgesia
  • Sedation
  • Dysphoria
  • Diuresis
43
Q

What are the natural ligands of k receptor?

A

Dynorphins

44
Q

What are the actions of δ receptors?

A
  • More potent in the periphery but may also contribute to analgesia
  • Respiratory depression
  • Reinforcing effects
  • Nausea and vomiting
45
Q

What are the natural ligands of δ receptors?

A

Enkephalins

46
Q

What are the roles of endogenous opioids?

A
  • Modulation of
    • pain
    • response to stress
    • respiration
    • emotional response
  • For each of these, the effect of opioids is to decrease response, but they also increase pleasure (‘runners high’)
47
Q

What is the analgesic ladder?

A
  • Non-opioid analgesics such as NSAIDs and/or paracetamol
  • Weak opioids (e.g. codeine)
  • Strong opioids (e.g. morphine)
48
Q

What is the opioid classification?

A
  1. Original opiate - opium (from poppy seeds)
  2. Morphine, codeine - natural derivatives of opium
  3. Chemical derivatives e.g. heroin
  4. Synthetic opiates which resemble the morphine (e.g. methadone)
  • Could be agonists, antagonists and partial agonists
49
Q

What are the characteristics of opioid μ receptor?

A
  • Gi
  • Inhibits adenylate cyclase leading to reduced levels of cAMP
  • Reduces cellular excitability (K+ channels open)
  • Found at presynaptic sites (reducing neurotransmitter release via Ca2+ channel blocking)
50
Q

What are the direct effects of opioids?

A
  • Analgesia
  • Reduced emotional distress
  • Sedation
  • Eurphoria
  • Nausea and vomiting
  • Respiratory depression
  • Reduced GI motility
  • Pupil constriction
  • Decreased body temperature
  • Dry mouth
  • All of these effects are consequences of nerve transmission inhibition
51
Q

What are the Acute Adverse Effects of Opioids?

A
  • Respiratory depression (overdose, lung nerves)
  • Sedation (overdose, CNS effect)
  • Nausea/vomiting (GI nerves blocking)
52
Q

What are the Chronic Adverse Effects of Opioids?

A
  • Constipation (GI nerves blocking)
    • μ opioid receptor agonists inhibit gut motility
  • Endocrine effects (hormonal changes)
  • Osteoporosis (hormonal changes)
53
Q

What is tolerance?

A
  • Decreased effects with prolonged exposure to the drug (or increased dose required to achieve given effect)
    • leads to increased pain - may need to increase dose
    • affected by dose, frequency, regularity
    • doesn’t indicate addiction
    • normal if taken for a long perioid of time
54
Q

What are the Mechanisms of Tolerance development?

A
  • Tolerance is due to adaptations that reduce or oppose the opioid effect
  • Changes include:
    • decreased number of receptors
    • decreased production of endogenous ligand
    • compensatory changes in signalling cascades e.g.
      • increased expression of adenylate cyclase
      • increased expression of calcium channels
55
Q

What is the withdrawal and addiction process?

A
  • Adaptations to opioid drugs can also result in a withdrawal syndrome on cessation of use
  • Occurs because the adaptations don’t immediately reverse:
    • when no drug is present, the adaptations produce effects opposite to those of the opioid drug
  • Withdrawal occurs in people who are and aren’t addicted
  • In patients treated for pain, the manifestation of withdrawal is pain of greater intensity than prior to opioid use
56
Q

Describe Important Drug Interactions with Opioids

A
  • Other sedatives
    • high risk of respiratory depression (in combination with alcohol or other CNS depressants, have additive effects that could be lethal)
    • Impairment of cognitive, psychomotor function
    • Commonly observed with benzodiazepines and barbiturates
  • Drugs that lower blood pressure
    • Hypotensive effect of opioids is not strong at normal doses but can become significant in combination with other BP lowering drugs
57
Q

Describe Osteoporosis effects with Opioids

A
  • Elevated risk of fractures in elderly taking opioids
  • Decrease in bone mineral density in people taking opioids chronically
  • Two main mechanisms:
    • Secondary to endocrine disruption
    • Inhibitory effect on osteoblasts (involved in bone formation)

Fundamentals of Pharmacology (21 decks)

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