PHARMACOLOGY - Analgesic Drugs Flashcards
Describe the pain pathway
Stimulation of nociceptors generates an action potential which is transmitted along afferent (sensory) neurones to the dorsal horn of the spinal cord, where the information is then transmitted to several regions of the brain to achieve the conscious perception of pain
What is peripheral sensitisation?
Peripheral sensitisation is when there is increased stimulation of nociceptors by inflammatory mediators which increases neuronal firing and decreases neuronal firing threshhold, resulting in sensitisation and an amplified pain response being transmitted to the central nervous system (CNS)
What is central sensitisation?
Central sensitisation is when the neurones in the dorsal horn of the spinal cord have an increase in neuronal firing and a decrease in neuronal firing threshhold (sensitisation) due to repetitive or prolonged noxious stimulation
What is hyperalgesia?
Hyperalgesia is an increased sensitivity to noxious stimuli
What is allodynia?
Allodynia is the perception of non-noxious stimuli as noxious
What is the mechanism of action of opioids?
Opioids activate μ (mu) κ (kappa) and δ (delta) receptors to decrease neuronal excitability
What are the two desired effects that opioids have on the central nervous system (CNS)?
Analgesia
Sedation
What are the seven side affects of opioids?
Euphoria
Nausea/vomiting
Respiratory depression
Antitussive (suppresses cough reflex)
Miosis (pupil constriction) Mydriasis in cats
Decrease gastrointestinal motility
Histamine release
Why is oral administration of opioids unreliable?
Oral administration of opioids is unreliable due to first pass metabolism
What are the five indications to administer opioid drugs?
To reduce moderate to severe acute pain
To provide sedation
To reduce the dose of general anaesthetic required
To treat diarrhoea
To control excessive coughing
What are the contraindications for opioids?
Hypoventilation
Increased intracranial pressure (ICP)
Why are opioids contraindicated in patients with existing hypoventilation?
Opioids decrease the sensitivity of the respiratory centre in the brainstem to changes in PaCO2 which can result in hypercapnia. Patients with hypoventilation are already at an increased risk of hypercapnia and this can be exacerbated by opioids
Why are opioids contraindicated in patients with increased intracranial pressure (ICP)?
Opioids cause respiratory depression through decreasing the sensitivity of the respiratory centre in the brainstem to changes in PaCO2 which can result in hypercapnia. Hypercapnia triggers cerebral vasodilation to increase blood flow to flush out the excess CO2, however this can further increase intracranial pressure (ICP)
(T/F) Opioids which act on the κ (kappa) receptor have the most profound analgesic effect
FALSE. Opioids which act on the μ (mu) receptor have the most profound analgesic effect
What are the three classifications of opioids?
Agonists
Partial agonists
Antagonists
Which classification of opioids has the most efficacious effect?
Agonists
What are partial agonists?
Partial agonists are drugs which induce a submaximal response (i.e. lower efficacy)
Why is it ineffective to use an agonist opioid following the administration of a partial agonist opioid?
Partial agonist opioid have a very high affinity for opioid receptors, reducing the number of receptors that the full agonist opioid would have to bind to, reducing its desired effect
Give six examples of opioid drugs
Methadone
Pethidine
Bupremorphine
Butorphanol
Fentanyl
Tramadol
Give three examples of full μ (mu) agonists
Methodone
Pethidine
Fentanyl
(T/F) Pethidine has a long duration of action
FALSE. Pethidine has a short duration of action
Give two examples of partial μ (mu) agonists
Buprenorphine
Tramadol
Why should pethidine not be given IV?
IV pethidine can cause histamine release
Give an example of a partial κ (kappa) agonist
Butorphanol
Butorphanol is also a mu antagonist
Which opioid is most commonly used for opioid infusions?
Fentanyl
Why is fentanyl the best opioid for infusions?
Fentanyl has a very short duration of action (approx 30 mins) which reduces the risk of drug accumulation in the body
Be aware fentanyl is expensive
What can be used to reverse opioids?
Opioid antagonists
Give an example of an opioid antagonist
Naloxone
(T/F) Opioid antagonists are not liscenced in food producing animals
TRUE.
What is the mechanism of action for NSAIDS?
NSAIDS inhibit the production of proinflammatory mediators prostaglandin and thromboxane A through reversible inhibition of the cyclooxygenase (COX) enzyme
What are the two main isoforms of cyclooxygenase (COX)?
Cyclooxygenase-1 (COX-1)
Cyclooxygenase-2 (COX-2)
Which cyclooxygenase isoform is mainly involved in physiological function?
Cyclooxygenase-1 (COX-1)
Which cyclooxygenase isoform is up-regulated in response to inflammatory stimuli?
Cyclooxygenase-2 (COX-2)
What are the five useful effects of NSAIDS?
Analgesic
Anti-pyretic
Anti-inflammatory
Anti-thrombotic
Anti-tumour effects
What are the four indicators to administer NSAIDS?
Long term, chronic management
Management of inflammatory disorders
Management of pro-thrombotic states
Management of specific tumours
What are the seven contraindications to NSAID administration?
Patients with gastrointestinal tract disease
Patients with acute or chronic renal disease
Patients with impaired hepatic function
Patients with haemostatic disorders
Patients being concurrently treated with steroids
Breeding, pregnant or lactating animals
Patients with unstable asthma
What are the physiological roles of prostaglandins within the gastrointestinal tract?
Within the gastrointestinal tract, prostaglandins inhibit gastric secretion and cause vasodilation to increase blood flow to the stomach and increase mucus production to protect the gastric mucosa
Why are NSAIDS contraindicated in patients with gastrointestinal disease?
NSAIDS inhibit cyclooxygenase-1 (COX-1) and thus reduce prostaglandin synthesis which will cause a reduction in blood flow to the gastrointestinal mucosa, resulting in mucosal ischaemia followed by impairment of the protective mucus barrier which will expose the gastric mucosa to the gastric acid causing ulceration
Why should NSAIDS always be given with food?
NSAIDS should always be given with food to protect the gastrointestinal mucosa as the contact area of the tablet will receive a high localised concentration of the drug which will increase the risk of ulceration in that area
Which cyclooxgenase (COX) isoform is primary involved in physiological renal function?
Cyclooxygenase 2 (COX-2)
Important to note that COX-2 specific NSAIDS will not have any less adverse affects on the kidneys
What are the physiological roles of prostaglandins in the kidneys?
Renal prostaglandins have a vasodilatory effect and thus increase renal blood flow, improving renal function and excretion. Prostaglandins also provide compensatory vasodilation i.e. maintain blood flow in the presence of vasoconstrictors
Why are NSAIDS contraindicated in patients with acute or chronic renal disease?
NSAIDS inhibit cyclooxygenase and thus reduce prostaglandin production which will impair renal blood flow putting these patients at a higher risk of dehydration and acute renal failure
Why are NSAIDS contraindicated in patients with impaired hepatic function?
NSAIDS are metabolised by the liver and thus in patients with impaired hepatic function there is an increased risk of drug accumulation and therefore an increased risk of side effects
Why are NSAIDS contraindicated in breeding, pregnant or lactating animals?
NSAIDS are teratogenic. Furthermore, NSAIDS inhibit prostaglandin production and since prostaglandins have a role in ovulation, embryo implantation and parturition, this can have adverse effects
Why are NSAIDS contraindicated in patients with unstable asthma?
NSAIDs inhibit the cyclooxygenase pathway which can result in a shift to increase arachidonic acid metabolite production via the lipoxygenase pathyway which results in the production of lipoxins and leukotriens. Leukotriens trigger bronchoconstriction which exacerbates asthma
Which species is more prone to asthma?
Cats
What are the three classifications of NSAIDS?
Non-selective COX inhibitors
Preferential COX-2 inhibitors
Specific COX-2 inhibitors
Which classification of NSAIDS has reduced side effects?
Specific COX-2 inhibitors
Give two examples of non-selective COX inhibitors
Flunixin
Ketoprofen
Give two examples of preferential COX-2 inhibitors
Meloxicam
Carprofen
Give two examples of specific COX-2 inhibitors
Fibrocoxib
Robenacoxib
Give an example of a non-COX inhibiting NSAID
Grapiprant
What is the mechanism of action for Grapiprant?
Grapiprant is an EP4 prostaglandin receptor antagonist. EP4 receptors mediate pain caused by inflammation, thus inhibition of this receptor prevents the binding of prostaglandin resulting in an analgesic effect
Why does grapiprant have fewer adverse effects than other NSAIDS?
Grapiprant does not inhibit the physiological production of prostaglandins resulting in fewer adverse effects
What is the mechanism of action for local anaesthetics?
Local anaesthetics prevent the initiation and conduction of action potentials through blocking the voltage-gated sodium channels of nociceptive afferent (sensory) nerve fibres
What are the two desirable effects of local anaesthetics?
Analgesia
Antiarrhythmic
Which local anaesthetic is antiarrhythmic?
Lidocaine
Are local anaesthetics weak acids or weak bases?
Local anaesthetics are weak bases
Why are inflamed tissues resistant to local anaesthetics?
Inflammatory tissue has an acidic environment, which means the equilibrium will shift to the left and more of the local anaesthetic will exist in its charged form, reducing the quantity of uncharged drug available to cross the cell membrane
How does protein binding influence the duration of action of local anaesthetics?
Local anaesthetics have the ability to bind to local structural proteins. The higher degree of protein binding increases the duration of action as there will be a larger reservoir of drug available
Why is bicarbonate sometimes added to local anaesthetics?
Bicarbonate increases the pH causing the equilibrium to shift to the right to increase the quantity of local anaesthetic in its unionised form (uncharged) to increase the quantity of drug that can cross the cell membranes and carry out it’s effect - increasing speed of onset
Why is adrenaline sometimes added to local anaesthetics?
Adrenaline acts on α1 adrenoreceptors on vascular smooth muscle which causes a local vasoconstriction which will limit the blood flow to the area which will decrease the volume of blood that can wash the drug away. This will increase the length of time the local anaesthetic can enter surrounding cells, prolonging it’s effect
When are harmful side affects to local anaesthetics most likely to occur?
Harmful affects are most likely to occur following an overdose of local anaesthetics or accidental intravenous administration
What are the harmful affects that local anaesthetics can have on the central nervous system?
Convulsions
Depression
Coma
Death
What are the harmful affects that local anaesthetics can have on the cardiovascular system?
Bradycardia
Hypotension
What are perineural anaesthetic blocks?
Perineural anaesthetic blocks involve injecting local anaesthetic around the nerves to provide desensitisation to the surrounding structures
What kind of perineural anaesthetic block could you do to desensitise the forelimb?
Brachial plexus block
What kind of perineural anaesthetic block could you do to desensitise the hindlimb?
Femoral and sciatic block
Good for hindlimb amputations
What kind of perineural anaesthetic block could you do to desensitise the digits?
Digital block
Why are α2 agonists useful adjunctive drugs when used with local anaesthetics?
α2 adrenoreceptor agonists can be used adjunct to local anaesthetics in perineural blocks to prolong their effect
α2 agonists cause vasoconstriction which will limit the blood flow to the area which will decrease the volume of blood that can wash the drug away which will increase the length of time the local anaesthetic can enter surrounding tissues
What are the two main regions used for local anaesthetic epidurals?
Lumbosacral
Coccygeal
Which regions of the body are desensitised by a lumbosacral local anaesthetic epidural?
Abdomen (depending on drug dose)
Hindlimbs
Perineum
Which regions of the body are desensitised by a coccygeal local anaesthetic epidural?
Perineum
Tail
When is epidural administration of local anaesthetics contraindicated?
Patients with haemostatic disorders
Patients with pyoderma
Why is epidural administration of local anaesthetics contraindicated in patients with haemostatic disorders?
If you cause bleeding when introducing the needle into the epidural space, a patient with a haemostatic disorder won’t be able to clot which can result in blood accumulating and haematoma formation in the epidural space causing spinal cord compression
Why is epidural administration of local anaesthetics contraindicated in patients with pyoderma?
In patients with pyoderma you can introduce bacteria into the epidural space when injecting the local anaesthetic
How do you carry out intravenous regional anaesthesia?
Inject the local anaesthetic distal to a tourniquet to prevent the local anaesthetic from spreading into the systemic circulation
Which local anaesthetic drug can you use for intravenous regional anaesthesia?
Adrenaline free preparation of lidocaine
Which local anaesthetic drug should you NEVER use for intravenous regional anaesthesia?
Bupivicaine
When are lidocaine infusions indicated?
Lidocaine infusions are indicated to manage visceral pain
Why should you never use lidocaine infusions in cats?
Cats are more prone to drug accumulation and toxicity
What is emla cream?
Emla cream is a local anaesthetic cream made by a mix of lidocaine and prilocaine. This is especially useful for patients with very sensitive skin such as rabbits
What is oral transmucosal administration?
Oral transmucosal administration is the absorption of a drug through the buccal mucosa into the systemic circulation
What is the main benefit of oral transmucosal administration compared to oral administration?
Oral transmucosal administration reduces the impact of first pass metabolism so the bioavailability is greater than it would be following ingestion
What is transdermal administration?
Transdermal administration is when lipid soluble, potent drugs are absorbed through the skin into the systemic circulation
Give an example of an opioid drug that can be administered transdermally
Fentanyl patch
What are the two main advantages of a fentanyl patch?
Allows for opioid treatment at home
Long duration of action (three days)
What are the four disadvantages of a fentanyl patch?
Takes time to reach peak effect
Variable uptake
Problems with adhesion of the patch
Risk of recreational abuse by owners
How long does it take a fentanyl patch to reach it’s peak effect in dogs?
24 hours
How long does it take a fentanyl patch to reach it’s peak effect in cats?
12 hours
Which three analgesic drugs are commonly used for combined infusions?
Morphine
Lidocaine
Ketamine
Which factors should you consider when choosing analgesic drugs?
- Patient pain severity, health status and temperament
- Procedure invasiveness and possible complications
- Environment in which the drug is being given (i.e. at home? at the practice?)
- Convenience/practicality and affordability for the client
- Controlled drug legislation and veterinary medicine register
