5.4 Opioid analgesics.

Local anesthetics

MODULE: SENSATION AND PERCEPTION

Valdas Liukaitis, PhD

LHSU FFI

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Contents
• WHO classification of CNS affecting substances
• short overview of neural mechanisms of pain
• classification of pain reducing medicines
• analgesic drugs
• opioid analgesics
• non-opioid analgesics
• anesthetics
• local anesthetics
• general anethetics

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CNS affecting substances
• General anesthetics: inhaled, intravenous
• Anxiolytics and hypnotics (tranquillizers): BDZ, B, new...
• Antipsychotic drugs (neuroleptics): typical, atypical
• Antidepressants: TCA, HCA, MAOI, SSRI
 Opioid analgesics: agonists (strong, moderate, weak), mixed
agonist-antagonists, antagonists
• Mood stabilizing agents: lithium, other...
• CNS stimulants: amphetamines, other...
• Psychotomimetic substances (hallucenogenes): LSD, other...
• Cognitive function improving drugs (nootropes): donepezil,
piracetam, memantine...

• Anti-epileptic drugs, drugs used in parkinsonism and other

movement disorders, other groups...
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 Pain
• unpleasant subjective sensitive experience with strong
emocional (affective) component
• associated with existing or possible tissue damage

• causes:
• chemical, mechanical, thermal stimuli...
• pathological proceses...

• protective reaction → indicates about problem

• Negative → affects the quality of people’s social and working lives

• → should be relieved → symptomatic treatment

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 Pain pathways
3. Perception
2.Transmission

4. Modulation

1. Nociception
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Brenner GM, Stevens CW. Pharamcology 3rd edition. Saunders Elsevier, Philadelphia 2010.
Pain management
• Analgesia – relief of pain

• Opioid analgesics
• Non-opioid analgesics (NSAIDs)
• Anti-epileptic drugs (AED)
• Tricyclic antidepressants (TCA)
• Tramadol with opioid agonist and TCA properties

• Anesthesia – temporary induced loss of all sensations

• Local anesthetics (LAs) block the initiation and propogation of sensory

and motor impulses from periphery to the CNS
• General anesthetics (GA) block activation of brain neurons →
suppression of consciousness and all sensations → loss of perception of
stimuli and response to them

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Opioid analgesics

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Definitions
• Narcotic analgesics = opioid analgesics (term more
appropriate for medicines)

• Opiate – a drug derived from opium poppy alkaloids

• Opioids – the class of drugs that includes:

• Opiates
• Opiopeptins
• All synthetic and semisynthetic drugs that mimic the opiate action

• Endogenous opioid peptides (opiopeptins)

• Endogenous peptides that act on opioid receptors

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 Endogenous opioid peptides

• Endogenous opioid peptides

(= opiopeptines = endorphins) – substances found at
the brain regions, where opiates exert their actions
• involved in pain modulation
• can be released in stressful conditions (pain / anticipation of pain) – diminish
the sensation of noxious stimuli
• most widely distributed: pentapeptides methionine-enkephalin and leucin-
enkephalin

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Effects of endogenous opioid peptides

Katzung B.G., Trevor A.J. Basic & clinical pharmacology, 15th ed. 2021
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Origin of opioids
• Natural opioids
 Synthetic opioids
 similar pharmacological
properties

• Semisynthetic opioids

Rang and Dale’s Pharmacology 8th ed., 2016 (modified)11

 Opiates
• Morphine – isolated 1803 by Friedrich Sertürner (DE)

• from crude opium (opium poppy)

• Morpheus – Greek god of dreams Morpheus

Jean-Bernard Restout (1771)
Morphine:
• effective relief of severe pain
• standard for “opioid analgesic” evaluation
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Source
• Crude opium – a brown gum, formed
after incision of a poppy seed pod (from
the white substance, revealing after
incision)
• contains many alkaloids
• ~10% - morphine

• Codeine – (methylmorphine) standard

for weak opioids

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Classification by manufacturing process

Lippincott Illustrated Reviews, Pharmacology - Whalen Karen, 7th ed., 2019

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 Classification by mode of action and alagesic
activity

• Full agonists
• strong agonists:
• morphine, meperidine, methadone, fentanyl etc.
• moderate agonists:
• hydrocodone, oxycodone etc.
• weak agonists:
• propoxyphene, dextrometorphan...

• Mixed agonist-antagonists and partial agonists:

• buprenorphine
• pentazocine, nalbuphine etc.

• Antagonists:
• naloxone, naltrexone

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 Classification by therapeutic usage
• Analgesics:
• morphine, codeine, meperidine, methadone, fentanyl etc.

• Antitussive:
• propoxyphene, dextrometorphan, codeine etc.

• Antidiarrheal:
• diphenoxylate, loperamide

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Pharmacokinetics of opioid drugs (1)
• Absorption
• mostly – good absorption s/c, i/m, p/o
• oral – 1st pass metabolism – higher doses (e.g. – morphine)
• high interpatient variability of 1st pass – difficult to predict effective dose
• codeine, oxycodone – low 1st pass
• nasal use – possible in some cases
• oral mucosal application, transdermal patches – delivery over days
• Distribution
• all bind to plasma proteins – varying affinity
• rapidly leave blood compartment to highly perfussed tissues:
• brain, lungs, liver, spleen
• lower concentration in muscles – but big reservoir due to greater bulk
• accumulation in fatty tissue – low, but important for chronically used lipophilics
(ex.-fentanyl)

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 Pharmacokinetics of opioid drugs (2)
• Metabolism, elimination and excretion
• large part → glucuronisation → glucuronides are excreted by kidneys, and
small portion with bile
• e.g. morphine →
• to morphine 3-glucuronide (M3G) → neuroexcitatory properties!
• ~10% - M6G – active metabolite → x2-4 stronger analgesic properties!
• in kidney failure and/or very high dosage → seizures (M3G) or prolonged
& enhanced opioid action (M6G)
• esters (heroin, remifentanil) → hydrolysis by plasma/tissue esterases: heroine
→ to morphine + conjugation
• phenylpiperidines (fentanyl, alfentanil, sufentanil) → oxydation in liver
• only small amount is excreted unchanged, no active metabolites
• CYP3A4: dealkylation of fentanyl (in liver, mucosa of small intestine)
• CYP2D6: codeine,
• CYP3A4 +CYP2D6: oxycodone, hydrocodone – metabolites have greater
potency – but little clinical importance
• demethylated meperidine → normeperidine: possible accumulation in kidney
failure / high doses → seizures!

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Properties of opioid analgesics

Katzung B.G., Trevor A.J. Basic & clinical pharmacology, 15th ed. 2021

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Mechanism of action
Opioid receptors
• Analgesia: by binding to specific receptors in brain and spinal
cord regions, responsible for pain transmission/ modulation

• -, -, - receptor classes:

• subtypes: 1, 2, 1, 2, 1, 2, 3
• belong to the family of Gi/Go protein-coupled receptors:
• inhibit adenylyl cyclase
• activate potassium channels
• suppress calcium currents
• different drugs – different potency on different subtypes
 diverse pharmacological effect

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Mechanism of action (2)

• Effects on different receptor types

• most of opioids – act primarily at - receptors

• supraspinal and spinal analgesia
• euphoria
• respiratory depression
• physical dependence
• pupil constriction
• -, - receptors
• spinal analgesia
• - receptors: dysphoria and hallucinations

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Mechanism of action (3)

• Ionic mechanism:
• on presynaptic nerve terminals:
• close voltage-gated Ca2+ channels → reduce transmitter
release:
• Glu, A/Ch, 5-HT, substance P;
• on postsynaptic nerve:
• inhibit postsynaptic neurons by opening of K+ channels →
hyperpolarization

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 Mechanism of action (4)

 neural mechanisms of
analgesia
 spinal actions (site B) –
all 3 receptor types –
inhibit dorsal horn pain
transmission neuron
(spinal administration
possible)
 supraspinal actions–
() inhibit transmission
and activate inhibitory
(GABA-ergic)
modulation neurons
(Sites D, E)

• exogenous opioid can stimulate the release of endogenous opiopeptides

• selective drugs may have non-selective effect

• peripheral opioid action (non-CNS) – inflamed/damaged site (Site A)

• - receptors are discovered on the peripheral terminals of sensory neurons
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 Central pharmacological effects (1)

• Analgesia – opioids act on sensory and on emotional

components of pain:
• continous dull pain vs sharp and intermittent
• without loss of consciousness
• pain less intense, less discomforting or entirely gone;
• commonly: drowsiness, difficulty in thinking, apathy, lessened
physical activity

• Euphoria and tranquility – pleasant floating sensation,

lessened anxiety and distress
• possible dysphoria (unpleasant) with restlessness and malaise
• to normal individual – unpleasantness

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 Central pharmacological effects (2)

• Sedation – drowsiness
• little or no amnesia
• sleep induction
• elderly > young
• morphine like > synthetic (ex. Fentanyl)
• can be easily aroused from sleep
• Respiratory depression
• all opioids, incl. mixed agonist-antagonists
• usual doses cause rarely
• depressed response to CO2 challenge
• produce depression of all phases of respiration (rate, minute
volume etc.), irregular and periodic breathing
• can be problematic in patients having increased intracranial
pressure, asthma, COPD

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 Central pharmacological effects (3)
• Cough suppression
• direct action on cough center in the medulla
• beneficial in strong cough, intubation
• Miosis (constriction of the pupil)
Poppy seels – pupils like seels
• excitatory action on
parasympathetic nerve of pupil
• all opioids
• can be blocked by atropine
• little tolerance to the effect
• Nausea, vomiting
• activation of chemoreceptor trigger zone
• all - receptors agonists can produce
• nausea in 40% and vomiting in 15%
• Convulsions
• excitation of hypocampal pyramidal neurons by high doses
and inhibition of GABA release by interneurons

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Peripheral pharmacological effects (1)

• Cardiovascular effects

• No significant direct effects on heart rate or rhythm

• rarely bradycardia
• except meperidine: antimuscarinic properties → tachycardia

• No significant effect on blood pressure

• rarely hypotension due to peripheral venous and arterial dilation
(several mechanisms, including CO2 accumulation due respiratory
depression and histamine release from mast cells caused by
morphine)

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Peripheral pharmacological effects (2)

• GI tract – constipation
• high density of opioid receptors in GI tract
• Stomach
• decrease of gastric acid secretion (rarely stimulation!)
• decrease of motility → prolonged gastric emptying time
• passage through duodenum may be delayed for 12 hr.!
• Small intestine
• decrease biliary, pancreatic and intestinal secretion → delay food
digestion
• water absorption is more complete → viscosity of bowel content
increased
• increase resting tone
• upper part is affected more than the ileum
• Large intestine
• peristalsis is diminished and tone is increased to the spasm
• passage of bowel content is delayed
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 Peripheral pharmacological effects (3)

• Biliary tract
• sphincter constricts
• billary smooth muscle constricts tenfold
• biliary collica possible
• Renal
• depressed function due to decreased renal plasma flow
• increased bladder tone
• increased sphincter tone → urinary retention
• Uterus
• possible prolongation in labor
• central and peripheral mechanisms are responsible

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Clinical uses of opioid drugs

• analgesia
• severe, constant pain
• p/o, i/m, s/c, transdermal form of fentanyl (>72h)
• acute pulmonary edema, MI
• parenteral morphine
• both suppression of pain and improvement of emotional state are
important
• cough suppression
• codeine, propoxyphene, dextrometorphan (p/o)
• diarrhea
• difenoxylate, loperamide (p/o)
• for analgesia during anesthesia
• premedication and adjuncts to other anesthetics

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Adverse effects of opioid analgesics

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Tolerance
• After frequent administration → loss of effectiveness =
tolerance
• larger doses are needed to produce the same response
• usually after 2 to 3 weeks of repeated dosage
• morphine > methadone
• agonists > mixed-receptor-effect drugs
• i/v > p/o
• possibility of tolerance to the effects of opioids:

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 Dependence
• physical dependence
• withdrawal / abstinence syndrome after stopping of
administration
• exaggerated rebound from the acute opioid effects, rhinorrhea,
lacrimation, yawning, chills, gooseflesh (piloerection),
hyperventilation, hyperthermia, mydriasis, muscular aches,
vomiting, diarrhea, anxiety, hostility
• Start and duration
• Start 6-10h after last dose of morphine
• peak 36-48h, ends ~ 5 days
• meperidine – start 24h,
• methadone – start 2 weeks after last dose

• mechanism: up-regulation of cAMP system, down-regulation of -

receptors

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Opiate withdrawal syndrome

Lippincott Illustrated Reviews, Pharmacology - Whalen Karen, 7th ed., 2019 34

 Methadone
• No active metabolites.
• Racemic mixture:
S isomer: NMDA antagonist; aids in preventing opioid tolerance and
treatment of neuropathic pain.
R isomer: agonist in treatment of nociceptive pain.
• Long and variable half-life increases risks of overdose.
• Very lipophilic and redistributes to fat stores.
• Duration of analgesia is much shorter than elimination half-life. Repeated
dosing can lead to accumulation.
• Can prolong QT interval and cause torsades de pointes.
• Warning: Conversion to and from methadone and other opioids should be
done with great care, since equianalgesic dosing varies dramatically.

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See Lippincott Illustrated
Reviews: Pharmacology, 7th
Ed., Whalen, Karen, Figure
14.5

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Other opioids
Tramadol

• Central acting analgesic with dual effect

• weak - receptor agonist
• reabsorption inhibitor of 5-HT and NE
• enhanced spinal inhibition

• toxicity – seizures, nausea, dizziness

• no effect on respiration and CV suppression

• Therapeutically for relief of severe pain and neuropathic

pain

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Partial agonists

• Agonists binding to inactive receptors (R) causes the

equilibrium to shift from R to active receptors (R*) - to
produce a biologic effect.
• Antagonists occupy the receptor but do not increase the
fraction of R* and may stabilize the receptor in the inactive
state.
• Partial agonists cause similar shifts in equilibrium from R to
R*, but the fraction of R* is less than that caused by an
agonist (but still more than that caused by an antagonist).
The magnitude of biological effect is directly related to the
fraction of R*.

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Mixed agonist-antagonists

• Mixed agonist–antagonists (MAA) - drugs that stimulate

one receptor but block another.
• In patients who have not received opioids (naive patients),
MAA show agonist activity and are used to relieve pain.
• In the patient with opioid dependence, MAA may show
primarily blocking effects (that is, produce withdrawal
symptoms).

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 Mixed agonist-antagonists
• Buprenorphine
• partial - agonist (transdermal patch used for moderate pain)
• weak - and - antagonist (for opioid dependence)
• half-life ~12 h and high potency
• Naloxone added to prevent the abuse of buprenorphine via IV administration

• Pentazocine
• - agonist (for moderate pain)
• weak - and - antagonist (for opioid dependence)
• psychomimetic action: hallucinations, nightmares, anxiety:
• action on  receptors
• additional action on σ (sigma) receptors

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Antagonists (1)
• Naloxone
• also – naltrexone
• highest affinity to - receptors
• lower affinity to - and - receptors
• PK (naloxone)
• poor p/o availability
• short parenteral action (1-2h)
• substrate to glucuronisation

• PK (naltrexone)
 p/o - well absorbed, but – rapid 1st pass metab.
 T ½ = 10h ; effect - ~48h

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Antagonists (2)
• Naloxone
• also – naltrexone

• PD
• in the absence of opioid – inert
• in morphine-treated – reversal of opioid effects in 1-3’ after i/v
injection

• Therapeutic usage
• Acute opioid overdose
• short duration compared to opioids
• (ex. - administer naloxone every 1-2h)!

• Naltrexone
• heroin addict treatment
• alcohol abuse treatment (reduced craving)

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Local anesthetics

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 Concepts
• Local anesthesia – the condition that results when
sensory transmission from a local area of the body to
the CNS is blocked.

• Primary action is nerve impulse inhibition via sodium

channels block of excitable membranes.

• Cocaine - the first agent, isolated by Niemann in 1860

and used by dr. Koller in 1884 as an ophthalmic
anesthetic.

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 Properties of ideal local anesthetic
• Ideal local anesthetic should has:
• low systemic toxicity
• quick onset of action
• duration of action sufficient to allow time for the surgery
• water solubility and stable in solution
• effective when injected into tissue and when applied topically to mucous
membranes
• completely reversible effect.

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Chemistry
The structure basic
components:
• lipophilic aromatic
portion (a benzene
ring)
• intermediate chain
(ester or amide)
• hydrophilic amine
portion

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Classification of local anesthetics

The commonly used local anesthetics can be classified basing

on the structure of this intermediate chain:
• esters:
• long duration (tetracaine)
• medium duration (cocaine)
• short duration (procaine)
• surface-active (benzocaine, cocaine)
• amides:
• long duration (bupivacaine, ropivacaine)
• medium duration (lidocaine)
• short duration (articaine)

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Pharmacokinetics of local anesthetics

• Well absorbed from administration site into blood;

• Highest concentrations appear in the more highly perfused

organs (i.e., brain, kidney and lung);

• Esters extensively and rapidly metabolized in plasma (by

pseudocholinesterase);
Paraaminobenzoic acid (PABA) metabolite – allergen;

• Amides - resistant to hydrolysis and almost completely

metabolized in the liver.

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Pharmacokinetics of local anesthetics

•Lippincott Illustrated Reviews, Pharmacology - Whalen Karen, 7th ed., 2019

49
Pharmacodynamics (mechanism of action) of local
anesthetics (1)

• LA block voltage-dependent sodium channels and reduce

the influx of ions:
• therefore prevents depolarization of the membrane and
block conduction of the action potential;
• Bind to the receptors from cell inside:
• non-ionized (uncharged) lipid soluble LA reaches
cytoplasm more rapidly;
• Ionized (charged) anesthetic produces more effective
block of the channel

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Pharmacodynamics (mechanism of action) of
local anesthetics (3)

•Lippincott Illustrated Reviews, Pharmacology - Whalen Karen, 7th ed., 2019

51
Clinical uses

 For minor surgery:

 advantage: the patients can remain awake and
protective airway reflexes remain intact

 Forms of local anesthesia:

 infiltration anesthesia (infiltration of the tissue)
 conduction anesthesia (injection next to the nerve
branch)
 spinal anesthesia (injection into segmental dorsal
roots, subarachnoidal space)
 Epidural anesthesia
 surface anesthesia (application to the surface of the
skin or mucosa

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 Clinical uses

Katzung B.G. Basic & clinical

pharmacology, 14th ed. 2018 53
Systemic effect
Blood levels of Local anesthetics

Katzung B.G. Basic & clinical

pharmacology, 14th ed. 2018 54
 Side effects
• CNS effects: sedation, restlessness, nystagmus, convulsions,
severe – coma and respiratory and cardiovascular depression;

• Cardiovascular: vasodilatation, heart block or other conduction

problems;
• bupivacaine most cardiotoxic (arrhythmias and hypotension)
• cocaine produce hypertension arrythmias and myocardial infarction (via
NE reuptake inhibition);

• Blood effects: methemoglobinemia (benzocaine, prilocaine);

• Allergy (mostly by esters).

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Literature

https://meded-lwwhealthlibrary- https://accessmedicine.mhmedical.com/
com.ezproxy.dbazes.lsmuni.lt/book. book.aspx?bookid=2988
aspx?bookid=2486 56