6th lecture - opioids Flashcards
In high doses, narcotic analgesics can cause
general central nervous system depression
another couple terms for narcotic analgesics
Opioids or
opioid receptor agonists
If they are used repeatedly, they cause medicine dependence or drug addiction.
narcotic analgesics can be classified as follows: (2)
Natural opium alkaloids
&
Synthetic analgesic drugs
(not chemically related to opium, but act as opiate receptor agonists)
Nociceptive receptors are
free nerve endings distributed throughout the body, which detect a nociceptive stimulus.
nociceptive = relating to pain
Opiate =
Opioid =
Opiate = a drug derived from opium
Opioid = a drug that is not derived from opium but interacts at the opioid receptor.
Both terms used for both narcotic analgesic subgroups interchangably despite definition difference.
Opioid receptors are located in the
brain,
autonomic nervous system,
gastrointestinal tract,
heart, kidneys, pancreas,
fat cells, lymphocytes,
adrenal glands, other tissues.
Endogenous ligands to opioid receptors (2)
enkephalins and endorphins,
they have a morphine-like effect. They are released as a reaction to pain and stress.
Opioid receptors are denoted with the greek letter..?
“mu”
μ-opioid receptor
Opioid receptor subtypes (2)
There are two subtypes: μ1 and μ2.
In addition, there are delta (δ), kappa (κ), sigma (σ) receptors (significance of sigma recptor is not understood).
non-μ-opioid receptors (3)
delta (δ),
kappa (κ),
sigma (σ) receptors
(significance of sigma recptor is not understood)
Full agonists produce?
Partial agonists produce?
Full agonists produce a dose-dependent increase in effect until maximum stimulation of the receptor is achieved.
Partial agonists produce a dose-dpendent increase in effect, but less than the maximum effect of full agonist.
An antagonist binds to a receptor and
inhibits the binding of agonists and displace previously bound agonists due to the greater receptor affinity of the antagonist.
Which has a greater affinity for opioid receptors - agonists or antagonists?
antagonists
Natural opium alkaloids are categorised into two chemical groups.
Derivatives of phenanthrene (morphine, codeine etc.) that have an analgesic effect.
&
Derivatives of isoquinoline (e.g. papaverine) that have a spasmolytic effect.
Opium is obtained from
poppy.
give examples of Semi-synthetic opioids (min. 4)
Hydromorphone
Buprenorphine
Butorphanol
Apomorphine
Oxymorphone
Ethylmorphine
Nalorphine
(Heroin)
give examples of Completely synthetic analgesic drugs (min. 3)
Fentanyl
Methadone
Trimeperidine, also known as Promedol
(the earliest and mostly studied opioid analgesic)
Piritramide
Estocin
Pentazocine
Completely synthetic analgesic drugs are Not substantially different from
morphine.
They are absorbed poorly if administered orally, do not cause vomiting, do not cause miosis.
The suppressant effects are equally strong,
the euphoric effect is weaker.
Pharmacokinetics of opioids
Lipophilic compounds, are capable of diffusing throughout the body.
are absorbed enterally & parenterally however absorption from the GI tract is slower and less complete.
penetrate the placenta well (unsuitable for pain relief in labour)
P-glycoprotein efflux pump can efflux absorbed drug from CNS back into the vasculature, in part, limiting central effects.
The primary site of effect for opioids?
What type of effects?
the CNS
for analgesia,
antitussive effects
and sedation.
what type of drug is loperamide
μ agonist,
antidiarrheal drug (immodium)
the P-glycoprotein efflux pump transports it back into the vasculature from CNS, limiting its central effects in most animals.
What is the P-g pump?
also known as multidrug resistance protein 1 (MDR1)
the P-glycoprotein efflux pump is a transmembrane unidirectional efflux pump that uses ATP to actively transport xenobiotics out of the cell against their concentration gradients
likely evolved as a defense mechanism against harmful substances.
Name the situation in which deficiency of functional P-g pump is relevant to small animal medicine.
P-g pump is also known as multidrug resistance protein 1 (MDR1)
Certain herding breed dogs (collies, aussies, shelties!) with homozygous mutations in the gene (MDRI) expressing P-g pump have a deficiency of these P-g efflux pumps.
"”ivermectin sensitive“ Collies”
These dogs show significant CNS effects of e.g. loperamide (among others) including heavy sedation.
opioids are metabolised in the liver into
into glucuronides.
Glucuronidation is often involved in drug metabolism.
glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond.
what is glucuronyl transferase?
Glucuronyl transferase is a drug-metabolizing enzyme that is produced and used in the liver.
What species lacks glucuronyl transferase?
Cats lack glucuronyl transferase, but they still rapidly and efficiently eliminate morphine by sulfate conjugation.
nonetheless, lower opioid doses should be used in cats.
Codeine (cough supressant) and synthetic analgesic drugs go through what process in the liver?
they go through demethylation in the liver and the byproduct is morphine (in humans).
in the case of opioids, potency refers to
the capability of attaching to receptors (and not the strength of the analgesic effect)
main therapeutic effect of opioids
Analgesia
name up to 6 Full μ agonists
morphine,
hydromorphone,
fentanyl,
remifentany,
alfentanyl,
methadone
Full μ agonists produce what type of effects?
the most profound analgesic effects.
(morphine, hydromorphone, fentanyl, remifentany, alfentanyl, methadone)
Opioids effect on the CNS
opioids produce a Dose- dependent sedation.
More profound sedation in combination with other sedatives (phenothiazines, α2 agonists).
Species dependently produce CNS inhibition or stimulation. However, In large doses the CNS will be inhibited in all cases.
Higher doses and rapid IV administration may produce excitation.
opioids produce inhibition of the CNS in what species? (3)
Inhibition of the central nervous system in dogs, monkeys, humans.
opioids produce stimulation of the CNS in what species? (6)
stimulation in cats, horses, goats, sheep, pigs and cows
However, In large doses the central nervous system will be inhibited in all cases.
Emetic/antiemetic effects of opioids
Opiates irritate the vomiting centre, particularly in dogs and cats.
Effect also occurs in low doses.
But Opioids can produce either emetic or antiemetic effects depending on the opioid, dose, and route of adminisration.
Opioids can produce either emetic or antiemetic effects depending on the opioid, dose, and route of adminisration.
Low doses cause?
Higher or multiple doses cause?
Low doses have an emetic effect, through D2 receptors.
Higher or multiple doses have an ANTIemetic effect.
emetic drug in dogs
apomorhpine (derivative of morphine)
effect of opioids on thermoregulation
Effects the thermoregulatory centre.
Hypothermia in dogs, rabbits, monkeys;
hyperthermia in cats, horses, cows, swine and goats.
A dual reaction may be experienced - hyperthermia in case of low doses and hypothermia in case of high doses – observed in mice and rats.
opioids produce Hypothermia in (3)
dogs, rabbits, monkeys;
opioids produce Hyperthermia in (5)
hyperthermia in cats, horses, cows, swine and goats.
opioid effect on the eyes
species dependent.
Mydriasis is experienced by monkeys, cats, sheep and horses.
miosis is experienced by dogs, rats, rabbits and humans.
however, The effect on the pupil may be masked by concurrent administration of other drugs, therefore pupillary effects are not specific and are quite variable.
opioids cause mydriasis in which species (4)
monkeys, cats, sheep and horses
opioids cause miosis in which species (4)
dogs, rats, rabbits and humans
Antitussive effects of opioids
Opiates strongly suppress the cough centre.
They are effective in case of a dry non-productive cough.
The antitussive effects are independent of respiratory depressant effects and analgesic effects.
give 2 examples of opioid antitussives
Butorphanol, hydrocodone
opioid Effect on the respiratory centre
Depression of the respiratory centre (dose-dependently).
The sensitivity of the respiratory centre to CO2 is weakened.
Respiratory difficulties are exacerbated as consciousness is lost.
Breathing can be maintained through the sensitivity of blood vessel chemoreceptors to deficiency in the amount of oxygen. If oxygen is inhaled, respiratory depression may increase.
large doses of opioids require mechanical ventilation.
animals at increased risk for respiratory depression (3)
Animals administered potent respiratory depressants (anesthetics),
animals with respiratory disease,
animals with increased intracranial pressure (head trauma)
opioid effects on the cardiovascular system
Clinically relevant doses produce minimal effects.
Morphine depresses cardiac output in dogs, but increases it in horses.
Hypotension in dogs caused by increases in plasma histamine concentrations (short term).
The effects of opioids on myocardial blood flow are variable.
opioid effects on the urinary tract
Effects on urinary tract are not frequently recognized, but can occur.
Excretion of urine is reduced, as opioids may stimulate release of ADH.
The tone of the bladder is increased, spasm of sphincters, urinary difficulties.
opioid effects on the GI tract
Vomiting (irritation of the vomiting centre).
Increase in tone of intestines and intestinal sphincters, reduction of peristalsis (loperamide!), constipation.
Secretion of the gastric glands is reduced.
Some investigations indicate the risk of colic in horses.
opioid Tolerance and dependence
Associated mainly with opioid use in humans.
However, opioids administered for a period 5-7 days may result in dependence in dogs.
Signs of withdrawal – nausea, aggression, vocalization, vomiting, hyperactivity, hypertermia, tremors, salivation.
name min. 7 full Opioid agonists
Morphine
Fentanyl
Methadone
Oxymorphone
Hydromorphone
Hydrocodone
Codeine
Meperidine (pethidine)
Sufentanil, alfentanil, remifentanil
Etorphine, carfentanil, thiafentanil
what drug has similar effects and potency to morphine.
methadone
describe Morphine (5)
analgesic,
does not always lead to CNS depression.
emetic effect in cats and dogs (similar to the effect of apomorphine).
an excellent antitussive, unsuitable as cough medicine due to other effects.
Thermoregulation effect differs depending on the animal species.
Fentanyl Causes less nausea and vomiting than
morphine.
describe what type of drug Meperidine (also known as pethidine) is
Antispasmodic, analgesic sedative.
Meperidine (pethidine) has
antimuscarinic effects so it is antispasmodic, however it may still cause what in dogs
bronchoconstriction
Meperidine (pethidine) may clinically be used for?
as premedication before anaesthesia, also in the treatment of colic.
Hydrocodone can be used as a what in dogs?
as an antitussive
Codeine clinical uses
Rarely indicated for use in veterinary medicine.
In human 10% of codeine is metabolized to
morphine.
Apomorphine may also act as what type of agonist
D2 agonist
At high concentratsions, Apomorphine acts as an
paradoxially as an antiemetic.
name a common Partial opioid agonist
Buprenorphine
Buprenorphine is what type of drug?
a partial μ agonist
Effects similar to morphine, but lower maximal efficacy.
Produces less nausea and vomiting
Butorphanol is what type of agonist?
μ antagonist to partial agonist; and κ agonist
Butorphanol Effects
dose dependent, has an analgesic effect in higher doses, but the effect is less than with morphine so not effective for severe pain.
More effective antitussive than codeine.
Antiemetic, can be used to prevent chemotherapy-indused emesis.
Tramadol is a
central analgesic drug, muscarinic antagonist Effective for mild or moderate pain, mainly in dogs.
why do opioids trigger the emetic center frequently?
because mu receptors are dense within th emetic center
toxicity of opioids
Strong depression of the central nervous system,
Comatose state,
Respiratory depression (death from respiratory arrest, paralysis of the respiratory centre).
antidotes to opioids (3)
opioid antagonists:
nalorphine,
naloxone and
naltrexone.
these are Antidotes for both natural and synthetic opiates.
define Neuroleptanalgesia
is joint administration of a tranquilizing drug and an analgesic especially for relief of surgical pain.
Contraindications for opioid use
acute uremia
Animals susceptible to seizures
(tetanus, epilepsy).
Animals with brain trauma
(increase in intracranial pressure).
Caution with large animals (long recovery period, drowsiness or agitation).
why is acute uremia a Contraindication for opioid use
because opiates stimulate release of ADH, oliguria occurs and is very bad during uremia.
why is brain trauma a Contraindication for opioid use
opioids may increase in intracranial pressure
