Lecture 24: Analgesic drugs 1 Flashcards
What are the effects of Opiods/Opiates Analgesics
- Analgesia (pain relief)
- A state of impaired consciousness
What are the types of pain after injury?
- Nociceptive pain: tissue damage
- Inflammatory pain: inflammation due to tissue damage
- Neuropathic pain: nerve damage (difficult to treat)
Opioids are usually used for Noiceptive and inflammatory pain
What are possible routes of administration of opioids?
- Oral
- Parenteral (injection): intramuscular, intravenous, intermittent, continuous, patient controlled (PCA)
- Trans-mucosal (mucosal membrane absorption)
- Transdermal (skin absorption)
Opium is the dried latex from ______ containing:
Opium is the dried latex from opium poppies containing:
1) Narcotic alkaloids:
- Morphine (12%), an opiate alkaloid (which processed chemically to produce heroin)
- Codeine
2) Non-narcotic alkaloids (not covered):
- papaverine,
- thebaine
- noscapine
What is the difference between Opiates and Opioids?
- Opiates (not chemically synthesized) are compounds present in the opium poppies extracted and refined.
- Opioids (chemically manufactured) are synthetic or semi-synthetic compounds which have similar chemical or pharmacological effects to opium poppies.
In this overview, the word opioid will be used.
Describe the Mechnaism of Action of Opioids Receptors
Opioids receptors are essentially pre-synaptic, belong to G protein coupled family of receptors
- Presynaptically, opioids activate Gi proteins → Inhibition of adenylate cyclase enzyme → ↓Ca channels permeability (→ Block transmitter release to interrupt pain conduction)
- Postsynaptically, ↑K conductance (out of the cell) → Hyperpolarization of postsynaptic neurone → ↓Response
What are the different tpyes of Opioid Receptors?
Opioid Receptors
Anatomical Distribution (CNS)
mu (μ) OP3
- μ1, μ2, μ3
- Spinal cord; Brainstem (periaqueductal grey)
- Thalamus; Cerebral cortex
kappa (κ) OP1
- κ1, κ2, κ3
- Spinal cord; Brainstem (periaqueductal grey), Limbic system; Hypothalamus
delta (δ) OP2
- δ1, δ2
- Olfactory bulb; Cerebral cortex, Nucleus accumbens; Amygdala; Pontine nucleus
Describe the process of Opioid Receptor Synthesis In Peripheral Inflammation
Although opioids traditionally have been considered centrally acting drugs, there is evidence for the action of opioids on peripheral nociceptor terminals after tissue damage.
- Opioid receptors are synthesized in cell body (Dorsal Root Ganglion) and transported toward central terminal in dorsal horn and toward periphery.
- Peripheral receptors become active within hours of local tissue damage. This occurs with unmasking of opioid receptors and the arrival of immunocompetent cells that possess opioid receptors and have the ability to s_ynthesize opioid peptide_s (endogenous opioids/ opioid-like substances).
This finding has led to an interest in the peripheral administration of exogenous opioids for postoperative analgesia, both at the site of surgery and as supplements to local anesthetics in nerve and plexus blocks.
Systematic review of these techniques demonstrates that intra-articular administration of opioids following knee surgery or arthroscopy may be efficacious.
If Mu-1 is activated, what are the effects?
Analgesia
If Mu-2 is activated, what are the effects?
1) Analgesia
2) Respiratory depression
3) Euphoria
4) Decrease GI motility
5) Physical dependence
If Kappa receptors are activated, what the effects?
1) Analgesia
2) Dysphoria
What are Opioid Agonists and what are their actions on opioid receptors?
Stimulate all of the receptors together
e.g.
Morphine
Fentanyl
Pethidine
Activation of all receptor subclasses though with different affinities
What are Opioid Antagonists and what are their actions on opioid receptors?
E.g.
Naloxone
Pentazocine
(e.g. for overdose of opioids)
Devoid of activity in all receptor classes
What are Agonist-antognists and Partial agonists?
Agonist-antagonist: e.g. nalophrine, pentazocine (Agonist activity on one type and anatongist activity on another).
Partial agonist: e.g. bup-re-norphine (Activity at one or more, but not all receptor types)
What drugs are administered for Severe, moderate and mild pain?
- Severe pain is given injective opioids for efficient relief, e.g. right after operation
- Moderate pain is given oral opioids, NSAIDs, paracetamol
- Mild pain is NOT given opioids
What are the effects, uses of opioids in general?
Effects
- Supra-spinal/spinal analgesia
- Sedation (impaired conscious)
- Marked individual variations (dose difference)
Uses
- For severe to moderate pain
- Relatively ineffective for neuropathic pain (pain due to nerve damage)
What are the Adverse Effects and Precautions around Opioid Administrations?
Adverse Effects
- Respiratory depression (need to monitor)
- Somnolence (drowsiness)
- Dizziness
- Constipation
- Ileus (lack of intestine movement cause blockage)
- Itching (histamine)
- Nausea and vomiting
- Vagally mediated bradycardia
- Hypotension (morphine) (histamine cause vasodilation)
Precautions
- Sleep apnea
- Chronic Obstructive Lung Disease patients (COPD)
- Elderly
What are the types of Opiates?
- Natural Opiates
Alkaloids contained in the resin of the opium poppy including:
- Morphine (tablet, injection)
- Codeine (tablet)
- Semi-Synthetic Opioids
Created from the natural opiates
- Bup-re-norphine (suboxone, contains naloxone)
- Oxycodone (oxycontin),
- Di-acetyl morphine (heroin)
- Fully Synthetic Opioids
- Fentanyl (pain relief injection)
- Pethidine (not frequently used)
- Methadone (dolophine) (tablet, injection)
- Tramadol (tablet more common, injection)
- Endogenous Opioid Peptides
Endogenous opioids are produced naturally in the body: (opioid-like subtances, prefer different receptors)
- Endorphins (mu-opioid receptors).
- Endomorphins (endomorphin-1 and endomorphin-2, mu-agonists) (mu-opioid receptors).
- Enkephalins (delta-opioid receptors).
- Dynorphins (kappa opioid receptors).
What are some things you need to consider when using Opioids?
- To be administered through the most _effective & comfortable route (_injection in severe pain)
- _Round the clock f_or severe to moderate pain (usually given continuously)
- Consider i_nter-patient variability_ (if there is pain, there is no respiratory depression)
- Use of adjuvants for enhancing opioids analgesia and reducing side effects e.g. NSAIDs
Opioids have two main effects:________-
analgesic and euphoric.
It is their euphoric effect which can lead to abuse
What are the different types of symptoms of Drug Abuse?
1) Physical dependence
- Withdrawal symptoms after abrupt discontinuation of large doses of opioids over extended period
2) Psychological dependence
- Craving for an opioid, resulting in drug-seeking behaviour at any cost
3) Drug tolerance
- The necessity to increase the dose to achieve the same effect
- Consider opioid rotation (change opioids), and NMDA receptors antagonists (increase NMDA receptors in chronic pain and inflammation, faster transmission)
4) Opioid Addiction
- Loss of control over drug use, compulsive use despite harm
What are some Opioid Withdrawal Symptoms?
BP
HR
RR
GI
Nuero/Msucular
Ophthalmic
Skin
How can you manage opioid withdrawal symptoms? (Slow)
1) Medication
- Methadone or Bup-re-norphine
- (principle of cross-tolerance in which one opioid is replaced with another then slowly withdrawn)
- These are less eurphoric, but also have less cognitive side effects.
2) Adjunctive (treatment of side effects)
- Clonidine (Centrally acting alpha2 adrenergic agonist, reduces adrenergic neurotransmission from locus ceruleus reducing autonomic symptoms of withdrawal
- Promethazine (a phenothiazine) (for Nausea, Vomiting)
- Diazepam (for Muscle cramps)
- Anti-diarrheal (for Diarrhea)
How can you manage opioid abuse (Rapid Opiate Detoxification Treatment)
(≈2 Hours)
A technique of detoxification under general anaesthesia to rapidly induce detoxification while blocking the severe symptoms of opiate withdrawal.
- Under general anaesthetic, the patient is not subject to withdrawal discomfort
- _High doses of nal tre xone (_opioid antagonist) are used
- Oral naltrexone maintenance can be initiated immediately after anaesthesia and continued to reduce the risk of relapse.
Name some weak and strong opioids
Weak Opioids
- Codeine
- Morphine
Strong Opioids
- Tramadol
- Diamorphine (heroin)
- (diacetyl-morphine)
- Pethidine
- Fentanyl
- Remifentanyl
- Buprenorphine
What are some relative potenticies across different opioids
Drug (IV Potency for Strong Opioids)
Morphine (1)
Methadone (1x)
Pethidine (high dose for same effect) (0.1x)
Fentanyl (lower dose for same effect) (50x-100x)
Describe Morphine
Introduction/Effects
Side effects
Routes of administration
Metabolism
Introduction
- Powerful analgesia
- Anxiolysis/sedation
- Cough suppression
- Miosis (constrict pupil)
- Altered mood (euphoria and tranquility)
- Large volume of distribution (only ⅓ bound to plasma proteins)
- Half-life of approximately 3 hours
Side Effects
- Respiratory depression
- Nausea and vomiting
- Constipation
- Addiction
- Pruritis (itching caused by histamine release)
- Biliary colic (constricts sphincter of Oddi)
- Bradycardia (vagal)
- Hypotension (histamine)
Routes of Administration
(Morphine has a slower onset and longer duration due to its low lipid solubility.)
- Oral (bioavailability 25%) undergoes substantial hepatic first-pass effect (need high oral dose)
- Intravenous (IV): bolus, or continuous IV infusion, or p_atient controlled analgesia_ (PCA- self administratable device)
- Intramuscular (IM)
- Intrathecal (CSF) / epidural
Metabolism:
In liver:
- 70% to morphine 3-glucuronide (M3G) (no analgesic property)
- 30% to morphine 6-glucuronide (M6G) (at least half as potent an analgesic as morphine and longer half life)
Excretion mainly in urine
Describe Pethidine
- Introduction/Effects
- Side effects
- Routes of administration
- Drug interactions
- Metabolism
Synthetic
Originally designed as anticholinergic- block parasympathetic (less marked miosis, dry mouth, tachycardia)
Long half-life
Oral bioavailability is 50%- much better than morphine and has very fast onset of action
One of the bi-products is norpethidine. This can cause hallucinations and seizures and can result in renal failure. Careful for patients taking MAOI (anti-depressant)
See pic.
Describe Fentanyl
- Introduction/Effects
- Side effects
- Routes of administration
- Drug interactions
- Metabolism
Introduction
- Strong mu receptor agonist.
- 80 - 100 times more potent than morphine.
- Used as an analgesic and in anaesthesia.
Side effects
- Similar to other opoids.
Routes of Administration
(Fentanyl has fast onset of action due to high lipid soluability.)
- IV
- IM
- Transdermal patches (in chronic pain) (25 mcg/hour, 50 mcg/hour, 75 mcg/hour, 100 mcg/hour)
- Disadvantages include slow onset (due to skin absorption)
- Also inability to rapidly change doses
- Transmucosal lozenges (200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, 1600 mcg)
- Nasal & sublingual spray (paediatric)
- Sublingual tablets
- Iontophoresis- method of transfermal PCA administration of _ionizable drugs in which the electrically charged component_s are propelled through the skin by external electric field
Describe Methadone
Introduction/Effects
Side effects
Routes of administration
Drug interactions
Metabolism
Introduction: Fully synthetic
- Rapid onset of analgesia effect (30–60 min.)
- It is used in:
- Chronic pain patients (due to its NMDA antagonism)
- For neuropathic pain
- For opioid withdrawal
- For detox
Side Effects:
Similar to other opioids. But:
- No significant cognitive impairment.
- No euphoria.
- Safe in renal and liver failure.
Adminstration:
Well absorbed from all routes:
- Oral (bioavailability 70%)
- Rectal
- Subcutaneous
- IV
- Sublingual
Describe Tremadol
- Introduction/Effects
- Side effects
- Routes of administration
- Drug interactions
- Metabolism
Introduction:
Synthetic codeine analogue. Weak μ-opioid receptor agonist.
- Inhibits uptake of noradrenaline and serotonin (5HT)
- Stimulation of inhibitory interneurons (DRG and DH), which release encephalin (both stimulate the inhibitory neurons- refer to pain physiology)
- Weak mu-opioid receptor agonist (for moderate pain)
Side effects:
Similar to other opioids (nausea and vomiting, dizziness, sedation, constipation etc.). But:
- Little respiratory depression
Routes of Administration:
- Oral (bioavailability >70%)
Drug Interactions:
- May cause serotonin syndrome (↑↑5HT) (agitation, ataxia, increased sweating, diarrhoea, fever, hyperreflexia, myoclonus, or shivering) if administered with antidepressants (SSRI)
- Used with caution in patients with e_pilepsy history (_increased risk)
Describe Codiene
Introduction/Effects
Side effects
Routes of administration
Drug interactions
Metabolism
Uses:
Codeine is used to treat:
- Mild to moderate pain (mu opioid receptors)
- Supress cough
- Anti-diarrhoea
Marketed as both a single-ingredient drug and in combination preparations with paracetamol (as co-codamol); with aspirin (as co-codaprin).
Side Effects
- Drowsiness and constipation
- Less common are itching, nausea, vomiting, dry mouth, miosis, respiratory depression
- Prolonged use can cause physical dependence
Metabolised:
Codeine is metabolised to morphine by cytochrome P450 2D6.
- Some patients are u_ltra-rapid metabolisers_ and are at higher risk of toxic opioid effects (increased morphine).
- Some patients are slow metabolisers and these patients may not experience adequate analgesic effect with codeine.
You should not give _____ to paitents with a history of epilepsy
Tramadol
You should not give _____ to patients on SSSRI
Tramadol
You should not give ____ to patients with renal fialure
Pethidine (and morphine?)
Codeine is metabolised to ______ by ______
what is the clinical significance of this?
Codeine is metabolised to morphine by cytochrome P450 2D6.
- Some patients are u_ltra-rapid metabolisers_ and are at higher risk of toxic opioid effects (increased morphine).
- Some patients are slow metabolisers and these patients may not experience adequate analgesic effect with codeine.
Name 2 opioid antagonists
Devoid of activity at all receptor classes
1) Naloxone (narcan)
2) Nal tre xone (longer duration)
What are co-analgesics?
Medications whose primary indication is for a purpose other than pain relief, but they demonstrate some analgesic enhancement
e. g. tricyclic antidepresants
e. g. anticonvulsants
e. g. corticosteroids
What is the word for “dilation of the pupil of the eye.”
mydriasis
