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Flashcards in Analgesia Deck (89)
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1
Q

What is pre emptive analgesia? Why is this a useful strategey?

A

the administartion of analgesic drugs prior to the occurrence of tissue damage (during sx) . Reduces nociceptive input to the dorsal horn.

  1. This prevents or limits central sensitization.
  2. Post operative pain is easier to control
2
Q

What is preventative analgesia? Why do we use this strategy?

A

administration of analgesic drugs throughtout the peri operative period.

  1. to prevent or limit the develoment of sensitization induced by pre, intra, or post operative noxious stimulation .

It is good practice to give good analgesia before and continue it during surgery, because sensitization can develop at any time.

3
Q

What is multimodal analgesia? Why is the a good strategy to use?

A

the use of a combination of drugs that act at different points in the nociceptive pathway.

  1. Provides a more effective analgesia.
  2. Fewer adverse reactions because giving lower doses of drugs.
4
Q

What are adjunctive analgesics? what are some examples?

A

drugs not normally used to alleviate pain but have certain analgesic properties. They are used increasingly usually in the management of chronic pain.

  1. NMDA receptor antagonists (ketamine) decreases central desensitization.
  2. Anticonvulsants (gabapentin)
  3. tricyclic antidepressants.
5
Q

Clinical use of Local anesthetics:

What is the use of topical anasthesia?

A
  1. to desensitize mucous membranes (oral, ocular, nasal)
  2. to desnesitize intact skin (EMLA cream)
6
Q

Clinical use of Local anesthetics:

What is the use of local infiltration?

A

to desensitize dermal and subcutaneous tissues for minor surgery (flank blocks- L-shaped)

7
Q

Clinical use of Local anesthetics:

What is the use of the locally applied method, “instillation into a cavity or wound”?

A
  1. intrapleural anasthesia
  2. intra articular anasthesia
  3. wound soaker catheters.
8
Q

Clinical use of Local anesthetics:

What is the purpose/ use of intravenous regional anasthesia?

A

Bier’s Block. IV administration of lidocaine distal to a tourniquet used to desensitize distal limb i.e. digit amputation.

9
Q

Clinical use of Local anesthetics:

What is the purpose/ use of peripheral nerve blocks?

A
  1. Paravertebral
  2. Intercostal
  3. Bachial plexus
  4. Dental Nerve blocks
10
Q

Clinical use of Local anesthetics:

What is the use of an epidural (extradural) block?

A

To desensitize perineum, hindlimb & caudal abdomen. Given @ the site between the last sacal and 1st coccygeal bone.

11
Q

Clinical use of Local anesthetics:

What is the use/ purpose of systemic administration?

A
  1. IV infusion of lidocaine in very painful patients. (LIDOCAINE ONLY). Decreases overall nociception.
12
Q

What is the target site of action for local anesthetics?

A

Local anesthetics will inhibit the tranmission of the afferent nerve fiber which runs from the local nociceptor and synapses in the grey matter of the dorsal horn in the spinal cord.

13
Q

Pertaining to local anesthetics, what is the physiology involved in the transmission of noxious stimuli?

A

The resting membrane potential is -60 to -90mV.

Excitable cells will generate an action potential in response to the DEPOLARIZATION of the membrane which entails the opening of voltage gated Na+ channels.

REPOLARIZATION involves closing of the voltage gated Na+ channels and delayed opening of voltage gated K+ channels.

Na+/ K+ pump

14
Q

What are the mechanisms of action of Local anesthetics?

A
  1. Sodium Channel Blockers: sodium channels are blocked preventing initiation & conduction of action potentials.
  2. Local anesthetics are weak bases and block sodium channels: the charged form is active, however it is the unionized form that is able to pass through membranes. Must gain charge to become active once passes through the memrbane. The drug is too large to enter the sodium channel from the outside therefore it must enter through one of two pathways:
  • hydrophobic pathway: drug enters the cell membrane and enters sodium channel, then blocks it.
  • hydrophilic pathway: drug enters the cell membrane and travels to the intracellular interior and then acts on the sodium channel.

Sodium channels exists in three states:

  1. Open
  2. Inactivated
  3. Closed

LA have a higher affinity to bind to open/ inactivated channels.

15
Q

What is the chemical structure of Local anesthetics?

A

lipophilic aromatic group attached to hydrophilic amine side chain by ester or amide link.

16
Q

What are the physical properties of Local anesthetics…what kind of base, ionisation, where do they act?

A
  1. weak bases
  2. largely ionised at physiological pH.
  3. ionisiation increaes as pH falls.
  4. LA are pH dependent meaning that since they are weak bases they are unionised in an alkaline environment and therefore able to travel through membranes, etc… However, the drug is often used at the site of inflammation which is usually acidic therefore it becomes ionized and unable to move and penetrate through the membrane.
17
Q

Describe the pharmacokinetic aspects of Local anesthetics involving speed of onset, duration, and potency.

A

speed of onset is related to degree of ionization.

Duration is related to protein binding (increase protein binding, increase duration)

potency related to lipid solubility

18
Q

What effect would the addtion of bicarbonate and adrenaline have with Local anesthetic have?

A
  1. Bicarbonate will speed up onset (creates an alkaline environment, allowing drug to be unionised)
  2. Adrenaline will cause a local vasoconstriction therefore decreasing blood flow and decreasing the drug flow to the site of action.
19
Q

In regards to the elmination of Local anesthetics, what two structures influence the pharmokinetics?

A
  1. Ester linked drugs:
    - rapidly hydrolyzed by non specific cholinesterases
    - short half lives
  2. Amide-linked drugs
    - metabolised in the liver
    - longer half lives.
    - have to be transported to the liver away from site of action therefore they have a longer half life.
20
Q

What are the adverse effects of Local anesthetics?

A

Harmful effects are most likely to be seen following overdose or accidental intravenous administration. (ONLY LIDOCAINE GIVEN I.V.)

Adverse effects:

  1. CNS: initial stimulation leading to convulsions
    - later depression leading to coma and death.
  2. CVS: myocardial contractility & heart rate fall
    - peripheral vasodilation (decreased HR, contractility, and blood pressure)
  3. MiSC: allergic reactions are rare (more so with ester than amides)
21
Q

Describe the clinical pharmacology of Lidocaine.

What animals is it licensed for?

Chemical structure?

Onset?

Duration?

Metabolized?

Adverse effects?

A
  • Use in all types of local anasthetic technique.
  • Effective antidysrhythmic drug and GIT pro kinetic agent. (Good management of colic in horses)
  • Licensed for the use in dogs, cats, and horses.
  • The license preparation contains adrenaline.
  • Chemical structure: Amide linked (therefore metabolized in the liver)
  • Rapid onset (25% unionized at pH 7.4) (remember speed of onset related to degree of ionization)
  • Duration is 1-2 hours (70% protein bound)
  • Metabolized in the Liver.
  • Adverse effects: CNS toxicity & seizures.
22
Q

Describe the clinical pharmacology of Bupivacaine.

What is it used for?

What animals is it licensed for?

Chemical structure?

Onset?

Duration?

Metabolized?

Adverse effects?

A

Used mostly in SMALL ANIMALS for therapeutic nerve blocks & epidural techniques. **(NOT FOR I.V. USE) **

  • No veterinary license
  • Amide Linked
  • Slow onset (15% unionized at pH 7.4 -physiological pH)
  • Long duration 4-8 hours (95% protein bound)
  • Metabolized in the Liver (glucouronide conjugation)
  • Adverse effects: CVS toxicity & bradycardia (the L-isomer is less cardiotoxic) **(If given I.V. admin) **
23
Q

Describe the clinical pharmacology of Procaine.

What is it used for?

What animals is it licensed for?

Chemical structure?

Onset?

Duration?

Metabolized?

Adverse effects?

A

Used for peripheral nerve blocks & infiltration.

  • Licensed in cats, dogs, cattle, and horses.
  • Preparation contains adrenaline.
  • Ester linked ( have a higher incidence of sensitivity reaction because of ester linkage)
  • Slow onset (3% unionized at pH 7.4) not a very effective LA due to slow onset.
  • Short duration 45-60 min. (6% protein bound)
  • Hydrolysed by plasma cholinesterase enzymes
  • metabolite para amino benzoic acids (PABA) antagonizes sulphonamide antimicrobials.
  • Adverse effects: CNS toxicity & seizures
  • hypersensitivity.
24
Q

Describe the clinical pharmacology of Mepivacaine.

What is it used for?

What animals is it licensed for?

Chemical structure?

Onset?

Duration?

Metabolized?

Adverse effects?

A

Used for infiltration, nerve blocks, intra articular & epidural anasthesia in HORSES.

  • Licensed in horses.
  • Amide linked
  • Rapid onset ( 39% unionized at pH 7.4)
  • Duration 90-180 min (77% protein bound)
  • Adverse effects: CNS toxicity
25
Q

What is an opiod?

A

relates to any substance (endogenous or synthetic) that produces morphine like effects that can be blocked by naloxone.

26
Q

What is an opiate?

A

restricted to synthetic morphine like drugs with non peptidic structure.

27
Q

What are the 3 families of endogenous ligands?

A
  1. enkephalins
  2. endorphins
  3. dynorphins
28
Q

What are some examples of opiod agonists?

A
  • Morphine
  • Pethidine
  • methadone
  • fentanyl
  • alfentanil
  • loperamide
  • codeine
  • dextro-propoxyphene
  • etorphine
29
Q

What are some examples of opiod partial agonists?

A
  • Buprenorphine
  • butorphanol
  • nalbuphine
30
Q

What are some opiod antagonists?

A
  • Naloxone
  • diprenorphine
31
Q

What is the Opiod’s mechanism of action?

A
  • They bind to opiod receptors in the brian, spinal cord, periphery.
  • Receptor effector pathway:
  • G protein coupled receptors (cell surface receptors) 3 different pathways:
    i. inhibit adenylate cyclase –> ⇣ cAMP
    ii. promote openign of K+ channels to decrease neural excitability.
    iii. inhibit opening of voltage gated Ca 2+ channels.
  • Decrease neuronal excitability and transmitter release
  • Differential distribution in receptors results in varied response.
32
Q

What are opiod analgesic effects on the CNS?

A
  1. central and peripheral sites
  2. acute and chornic pain
  3. reduces affective component of pain (still aware of the pain but doesn’t bother them)
33
Q

What are opiod CNS effects on respiratory system?

A
  1. Respiratory depression (can occur with normal therapeutic dose)
  2. decreased sensitivity of the respiratory center to Pco2.
  3. increased arterial Pco2
  4. altered tidal volume.
34
Q

What are opiod CNS effects on coughing?

A

Depresses the coughing reflex.

Antitussive effect.

35
Q

What are opiods effects on the CNS?

A
  1. Nausea and vomiting and defecation via chemoreceptor trigger zone. Usually transient.
  2. Pupillary constriction: pin point pupils. Diagnostic feature in opiods
    - Cats: mydriasis
    - Dogs: miosis
  3. Respiratory Depression
  4. Depressed cough reflex
  5. Analgesia
  6. Euphoria
36
Q

What are opiods effects on the GIT?

A
  • increases tone, ⇣ motility
  • constipation
  • constriction of biliary sphincter
  • anal sphincter tone increased.

Opiod receptors are in the myenteric plexus. If these receptors are stimulated, we will see:

  • a decrease in Ach, and a decrease in peristalsis.
  • Increased tone, and decreased motility.
  • Therefore constipation.

This can also effect the absorption of other drugs being given at the same time due to decreased motility. (Gut stasis)

37
Q

What effects do opiods have in regards to:

  • histamine
  • CVS
  • smooth muscle
  • immune system
  • body temp
  • tolerance
  • dependance
A
  1. Histamine release from mast cells:
  2. No major effects on CVS unless large doses given in which case:
    - hypotension
    - bradycardia.
  3. Little effects on smooth muscle except
    - spasm of uterus/ bladder
  4. immunosuppression
  5. Small effects on body temp.
  6. Tolerance: An increase in dose required to produce a given pharmacological effect.
  7. Dependance: characterized by a clear cut abstinence syndrome causing irritability, body shakes, aggression. Piloerection (cold turkey) skin gets goosebump appearance.
38
Q

What are opiod pharmacokinetics?

A
  1. oral absorption is variable due to considerable first pass metabolism: losing a portion of the drug before its reaching circulation due to absorption through the GIT, HPV, Liver, systemic circ. Can Give thru buccal mucosa instead and absorbed directly into systemic circ.
  2. Half life: 3-6 hours.
  3. 33% plasma protein bound.
  4. Hepatic metabolism
    - usually conjugation by glucouronide
    - demethylation (pethidine)
    - hydrolysis (morphine)
  5. excreted in urine and bile
39
Q

What are opiod side effects?

A
  1. Resp. depression
  2. nausea/ emesis
  3. constipation
40
Q

What are the clinical uses of opiods in Veterinary Medicine?

A
  1. To relieve pain (moderate or severe)
  2. Provide sedation (sedative + opiod combo better than sedative alone)
    - Beneficial- less anesthetic required
    - less sedation required
  3. Reduce the dose of general anesthetic required.
  4. Treat diarrhea.
  5. Control coughing .
41
Q

What are the contrindications to Opiod use?

A

Opiods should be used in caution in some patients:

  1. Exisiting hypoventilation
  2. Head injuries: Many opiods increase intracranial pressure ( due to increase in Pco2)
  3. hypoventilation causes increase in Pco2 which causes an increase in intracranial pressure)
42
Q

What shoul we consider when choosing an opiod drug?

A
  1. Efficacy
  2. Adverse effects
  3. Duration
  4. Licensing
  5. Route of admin
  6. Potency
  7. Cost
  8. Controlled drug legislation
43
Q

When Choosing an opiod we must consider analgesic efficacy i.e. What level of anaglesia does this patient require to stop its pain?

A
  • For moderate/ severe pain we want to choose a HIGHLY efficacious opiod.
  • Full agonist are MORE efficacious than partial agonists.
  • Mu agonists are more efficacious than kappa agonists.
44
Q

When Choosing an opiod we must consider ADVERSE EFFECTS: are the side effects of the opiod of choice a concern in this patient?

A
  • Side effects are common to all opioids
  • they are usually dose dependent and less significant with partial agonists.
  • The are different side effects for different drugs.
45
Q

When Choosing an opiod we must consider LICENSING: What opiods are available for Veterinary Medicine i.e. full agonists, and partial agonists?

A

Full agonists:

  1. Methadone
  2. Pethidine
  3. Fentanyl

Partial agonists:

  1. Buprenorphine
  2. Butorphanol
46
Q

When Choosing an opiod we must consider CONTROLLED DRUGS:

What are Schedule 2 controlled drugs?

What are schedule 3 controlled drugs?

Which opiods aren’t controlled?

A

**Schedule 2: **
Includes all full agonists opioids i.e. mrophine, methadone, pethidine, fentanyl, etorphine.

These drugs must be stored in a fixed locker and recorded with usage.

**Schedule 3: **

Buprenorphine: still locked up but not recorded.

Not controlled:

  1. Butrophanol
  2. Tramadol
47
Q

When Choosing an opiod we must consider ROUTE OF ADMINISTRATION: The differences of routes of administration between drugs can affects drug choice in some patients.

A

Not all opiods can be given I.V. an Example being pethidine which causes histamine release if given I.V.

Few opiods have suffiicent oral bioavailability to be effective orally. The exception being TRAMADOL and CO CODAMINE.

48
Q

When Choosing an opiod we must consider POTENCY: the amount of drug required to produce a given effect.

Define Potency.

What is EC50?

A

Potency is a measure of the concentration of the drug requred to induce a given response.

EC 50: concentration of the drug that results in 50% of the maximum response.

Highly potent opioids (Etorphine)

49
Q

What is the definition of Efficacy?

A

The ability of a ligand once bounds to elicit changes which lead to its effects.

50
Q

When Choosing an opiod we must consider OPIOID ANTAGONISTS: When should we use an opioid antagonist?

A
  • To treat respiratory depression. (overdoses)
  • to treat excitement, dysphoria– emotional or mental discomfort (high doses)
  • To reverse effects of opioid analgesics in puppies delivered by Cesarean sections.
51
Q

Clinical Pharmacology of Methadone:

Usage?

Schedule?

Licensed?

Receptors?

Administration?

Duration?

Side effects?

A
  • Analgesic used for **moderate/ severe acute pain. **
  • Used in the management of heroin addiction.
  • Schedule 2 C.D.
  • Licensed for use in dogs and cats.
  • Mu-selective agonists (some Kappa & delta activity)
  • *-NMDA receptor antagonist so therefore would reduce central sensitization. **
  • Can be administered I.V, I.M, S.Q
  • Duration: 2-6 hours.
  • Side effects:
  • ->less sedation than morphine.
  • -> no vomiting
52
Q

Clinical Pharmacology of Fentanyl:

Usage?

Schedule?

Licensed?

Receptors?

Administration?

Duration?

Side effects?

A
  • INJECTIBLE SOLUTION: used for severe acute pain including itra-operative “rescue analgesia” & post op analgesia.
  • Schedule 2 C.D.
  • Liecnsed for I.V admin in dogs.
  • Potent pure Mu selective agonist.
  • I.V. admin
  • Rapid onset (1 min I. V) & short duration (5-20 min.)
  • Signifcant side effects:
  • -> Bradycardia
  • -> Respiratory Depression
53
Q

Clinical Pharmacology of Fentanyl: Transdermal Preparations:

Usage?

A
  • TRANSDERMAL PREPARATIONS:
  • Used for post-op or chronic pain.
  • Self-Adhesive Transdermal patch:
  • No vet license.
  • Delay in onset
  • Variable absorption
  • Transdermal spot on:
  • Licensed in dogs (onset 4 hours, duration 4 hours)
54
Q

Clinical Pharmacology of Buprenorphine:

Usage?

Schedule?

Licensed?

Receptors?

Administration?

Duration?

Side effects?

A
  • Analgesic used for mild/ moderate pain & sedation.
  • Schedule 3 C.D.
  • Licensed in dogs, cats, horses.
  • Partial agonist: Mu selective partial agonist.
  • -> has a high affinity for the Mu receptor therefore it is difficult to reverse with opiod antagonist however since its a partial agonist its less efficacious for analgesia but also has less side effects.
  • Admin I.V, I.M, SQ, Oral trans-mucosal route in cats.
* Slow onset (45 min)
 Long Duration ( up to 12 hours but normally 6-8 hours) 
  • Side effects:
  • -> Mild Sedation
55
Q

Clinical Pharmacology of Butorphanol:

Usage?

Schedule?

Licensed?

Receptors?

Administration?

Duration?

Side effects?

A
  • Used for mild pain (unreliable)
  • Effective sedative and anti-tussive.
  • Not a schedule C.D. (along with tramadol)
  • Licensed for use in dogs, cats, horses.
  • **Mixed agonist/ antagonist
  • -> Kappa partial agonist
  • -> Mu antagonist. **
  • Admin. IV, I.M, SQ or orally.
  • Short duration (2 hr post injection)
  • Side Effects:
  • -> Dysphoria with high doses.

In birds and reptiles the Kappa receptor is of major importance so this drug is preferable in these guys.

56
Q

What is Cox and how to NSAIDS maniuplate them?

A
  • COX- Cyclooxygenase is the enzyme responsibel for catalyzing the production of PROSTAGLANDINS and THROMBOXANES from arachidonic acid.
  • NSAIDS inhibit COX.
57
Q

What is the difference between COX 1 and COX 2?

A

**COX 1: **
A house-keeping enzyme responsible for physiological activites of prostaglandins.

COX 2:

induced under inflammatory conditions, responsible for pathological prostaglandins that produce pain and high temperature.

Have a better G.I. Safety profile however has CV & RENAL SIDE EFFECTS.

Both COX 1 and COX 2 have physiological and pathological roles.

58
Q

What are the functions of COX -1?

A
  • Constitutively expressed in most tissues.
  • Involved in normal homeostasis.
  • Has Many physiological functions **especially maintaining GI tract mucosa. **
  • Up-regulated under stress conditions i.e. nerve injury.
59
Q

What are the functions of COX-2?

A
  • Consitutively expressed in many tissues including kidney, testicular ovarian cells and in the CNS.
  • Induced in response to inflammatory stimulii which will then produce pathological prostaglandins that produce pain and high temperature.
  • **Physiological funtions: **
  1. Maintaining renal blood flow.
  2. Nerve function.
  3. Bone metabolism.
60
Q

Traditional NSAIDS and COX selective NSAIDS.

A

Traditional NSAIDS will block both COX 1 and COX 2 channels by binding to the non selective binding site and preventing the entrance of Arachadonic acid into its binding site therefore preventing the production of pathological prostaglandins and preventing pain and high temperature.

COX 2 SELECTIVE NSAIDS will enter the COX channel and bind to the non specific binding site as well as an additional site therefore preventing the entrance of arachadonic acid.

HOWEVER, the COX 2 channel is wider than the COX 1 channel, therefore the COX 2 selective NSAID is too large to enter the COX 1 channel and will not prevent the entrance and binding of Arachadonic acid into it.

61
Q

Why is Aspirin a significant NSAID?

A

It will permanently bind to the COX enzyme therefore there will be permanent inhibition and the cell will have to produce new COX to work again. The vast majority of NSAIDS don’t do this.

62
Q

What are the functions of COX 3?

A

Expressed predominately in the CNS.

It is an inducible enzyme linked analgesia and anti pyretic activity. (fever reducing)

Potential target for paracetamol (acetaminophen)

Paracetamol inhibits pain and fever and is one of the world most popular analgesic/ anti pyretic drugs. MOA is unknown however.

63
Q

What are two kinds of preferential COX 2 inhibitors?

A

Meloxicam

Diclofenac

They will effect COX 2 with greater efficacy but WILL AFFECT COX 1 somewhat.

64
Q

What are 3 kinds of SPECIFIC COX 2 inhibitors?

A
  1. Rofecoxib
  2. celecoxib
  3. firocoxib

only affects COX 2 and not COX 1

65
Q

What is the most commonly use COX inhibitors?

A

Non-selective COX inhibitors.

66
Q

What are the effects of NSAIDS?

A
  • Analgesic
    1. Central
    2. Peripheral
  • Anti-pyretic
  • Anti-inflammatory
  • Anti-endotoxic
  • Anti-thrombotic
67
Q

What are the analgesic effects of NSAIDS?

A
  1. Peripheral action:
    - NSAIDS decrease PG production at site of inflammation- Reduced sensitization of nociceptive nerve endings to inflammatory mediators.
    - PG is an inflammatory mediator produced from Arachadonic Acid with the use of the COX enzyme.
    - PG acts on the nociceptor, lowering its threshold, increasing the firing of AP causing a hypersensitivity.
  2. Central Action:
    - NSAIDS block PG release and neuronal excitation- reduced central sensitization.

**BOTH OF THESE ACTIONS OF NSAIDS THEREFORE REDUCE HYPERALGESIA AND PAIN. **

68
Q

NSAID anti pyretic effects:

A

The hypothalamus regulates the bodies normal temperature.

When inflammation occurs, cytokines (IL-1) are produced and act to increase production of PGE synthesis via COX enzymes.

PGE’s will act on the thermoregulatory centre in the hypothalamus to increase body temp ( remember PGE’s cause pain and high temp–inflammatory mediators) which will cause fever.

————-> When administering NSAID’s, they decrease production of PGE to prevent an increase in temp associated with fever. REMEMBER: NSAIDS have no effect on normal body temp, they will only act to decrease body temperature in association with fever in response to infection.

69
Q

NSAID anti- inflammatory effects:

A

NSAIDS inhibit COX induction and the release of prostanoids at the site of inflammation to:

  1. Reduce vasdolation effects of PGE to reduce edema.
  2. Reduce the inflammtory response by preventing peripheral sensitization.

PGE (prostanoids) cause an increase in peripheral sensitization by lowering the nociceptor threshold, causing increase firing of AP, causing increase hyperalgesia.

PGE is an inflammatory mediator which causes vasodilation and edema.

Both of these effects are reduced by NSAIDS.

70
Q

NSAID Anti- thrombotic Effects:

A

NSAIDS inhibit synthese of Thromboxanes (TXA2) therefore inhibiting platelet aggregation.

more effective as anti thromotic agents at low doses.

  • Platelets produce TXA2 which stimulate aggregation:

@ low doses of NSAID:
1. TXA2 will be inhibited
_2. Anti-thrombotic action. _

  • Endothelial cells produce PGI2 which inhibits aggregation:

@ high doses of NSAID:
1. PGI2 is inhibited.
_2. Pro-thrombotic action. _

71
Q

NSAID Anti-endotoxic action:

What are endotoxins?

A
  • Endotoxins are LPS produced from gram-negative bacteria.
  • Endotoxins damage WBC’s and vascular endothelium thus releasing vasoactive mediators.
  • NSAIDS prevent the generation of vasoactive mediators during endotoxemia.
72
Q

What are the Pharmacokinetics of NSAIDS?

A
  1. Most well absorbed following Oral admin.
  2. Small Vd- ECF
  3. High plasma protein bound: Good penetration into actue inflammatory exudate. At the site of inflammation there is an acidic environment, NSAID becomes unionized because they are weak acids, they can therefore penetrate the tissues since they are unionized and mobile and decrease inflammation.
  4. Metabolism: NSAIDS are metabolized by:
  5. conjugation in the Liver
  6. Renal elimination/ Biliary elimination

Because they are weak acids they are unionized readily in the GIT (acidic environment) therefore have GOOD absorption in the GIT. Careful of Ulcers!!

73
Q

NSAID Adverse effects?

A
  1. Dyspepsia (indigestion)
  2. nausea
  3. vomiting
  4. GI ulceration
  5. Renal toxicity
  6. Hepatic Toxicity
  7. Injury to cartilage
  8. Precipitate asthma.
74
Q

NSAID Adverse effects:

G.I.T ulceration

A

PGI2 and PGE2 in the gut protect the gastric mucosa by inhibiting the gastric secretion, inducing vasodilation, and increasing blood flow through the gastric mucosa.

COX 1- is primarily responsible for gastric mucosal PG production.

Inhibiton of COX-1/ reduction in PG’s causes ulceration:

  • mucosal ischemia.
  • impariment of protective barrier
  • exposing mucosa to damaging effects of acid.

NSAIDS should be given with food to help protect the GIT mucosa.
-the contact area of the tablet with the mucosa is very concentrated increasing the potential for ulcer formation.

COX 2- absent in normal gastric mucosa but induced rapidly in response to injury/ gastric erosions.

75
Q

NSAID Adverse effects:

Renal toxicity

A
  • PGE2 and PGI2 synthesized in renal medulla and glomerulus.
  • Involved in renal blood flow and excretion of salts and water via their vasodilatory actions.
  • Inhibition of PG’s impairs renal blood flow.
  • If volume depleted (dehydrated) significan renal toxicity can occur. Less likley in well hydrated animals.
76
Q

NSAID Adverse effects:

Hepatotoxicity

A

Uncommon in animals.

Possibly idiosyncratic.

Can occur in animals with renal insufficiency.

Aged horse receiving phylbutazone.

77
Q

NSAID Adverse effects:

Cartilage Damage

A

Chronic NSAID therapy may worsen cartilage degneration in animals with osteoarthritis.

78
Q

What are some examples of Clincal use of NSAIDs in Vet Med in regards to:

  1. Management of pain
  2. Management of inflammatory disorders
  3. Management of endotoxemia
  4. Management of prothrombotic states
  5. Management of tumors.
A
  1. Acute pain (traumatic/ surgical)
    Chronic pain- Cancer, osteoarthritis.
2. Inflammatory arthritis 
 Ophthalamic disorders (Keratitis, uveitis)
  1. Equine Colic
    Bovine toxic mastitis
  2. Feline Hypertrophic Cardiomyopthay
  3. Some tumors are dependent on COX 2 and since NSAIDS inhibit COX 2 they can be anti tumor like.
79
Q

Contraindication to NSAID use:

NSAIDs should not be administered to animals with:

A
  1. Acute/ chronic renal disease
  2. Hepatic insufficiency
  3. gastric ulcerations
  4. Coagulopathies (thrombocytopenia, Von Villebrands disease)
  5. Severe or poorly controlled asthma.
  6. Breeding/ pregnant/ lactating animals because NSAIDs are potentially teratogenic (causing birth defects)
  7. Animals with low effective circulating volume
    - Hypovolemic
    - Hypotensive
  8. Animals being treated with corticosteroids.
80
Q

What NSAID is the most effective anti thrombotic?

A

aspirin.

81
Q

What NSAID is the most effective analgesic?

A

NONE. no NSAID is consistently more effective then another with respect to analgesia but efficacy in respect to other actions are recognized.

82
Q

Considerations when Choosing an NSAID:

Adverse effects:
Cox 2 Selectivity

A
  • NSAIDs have a narrow safety margin therefore they must be specifically dosed for their patient:
  • ALL NSAIDs are capable of producing:

G.I. ulceration
Renal injury
Hepatic Injury

  • COX 2 selectivity can be used to predict GIT safety
    (COX 2 selectivity is preferred b/c less likely to produce GIT problems)
  • —> Described by the COX 1 IC50: COX 2 IC50.
  • The IC 50 is the inhibitory concentration. The concentration of NSAID needed to be given that inhibits 50% of COX activity.
  • We want a drug that doesn’t inhibit COX-1 since it maintains the PG in the GIT protecting the mucosa. Rather we want a drug thats highly selective for COX 2 giving us an overal ratio >1.
  • if the ratio is >1 that means we have COX 2 selectivity.
  • The risk of GIT toxicity decreases with increasing COX 2 selectivity.
83
Q

What is the clinical pharmacology of Paracetamol?

Licensed?

Usage?

Mechanism of Action ?

Metabolized?

A
  • Licensed in combination with codeine for use in DOGS.
  • Poor anti inflammatory, but good analgesic & anti pyretic.
  • Mechanism: Central COX inhibition
  • Metabolized by 3 pathways:
    1. Glucuronidation (most important)
    2. Sulphation
    3. Oxidation
84
Q

Comment on Hepatotoxicity caused by Paracetamol.

A
  1. Although glucuronidation is the main metabolic pathway for Paracetamol, it can also be metabolized via oxidation.
  2. In the case of oxidative metabolism, the Phase 1 metabolite, NABQ, will form which is normally conjugated with hepatic glutathione.
  3. However, in times of paracetamol overdose, hepatic glutathione is overwhelmed and not able to conjugate the NABQ metabolite, which will then proceed to bind to the hepatocytes causing hepatic necrosis.
85
Q

Comment on Paracetamol Toxicity in Cats.

A
  • There is a narrow safety margin in cats when using paracetamol.
  • This is due to the fact that cats have limited glucuronidation therefore they will use oxidative metabolism moreso, thereby increasing the amount of NABQ metabolites, overwhelming the glutathione in the liver, and inducing toxicity.
  • Symptoms of toxicity include
  • Facial Swelling
  • methemoglobin
  • Hemolytic Anemia
  • Icterus
86
Q

Firocoxib:

Mechanism?

Admin?

Licensed?

A
  • Specific COX 2 inhibitor therefore the Cox-1 IC 50: Cox-2 IC50 must be > 1.
  • Chewable tablet, oral paste, injectible solution.
  • Dogs & horses.
87
Q

Robenacoxib:

Mechanims?

Admin?

Licensed?

A
  • Specific Cox-2 inhibitor
  • tablet or injectible
  • Peri operative pain in dogs and cats.
88
Q

Cimicoxib:

Mechanims

Admin

Licensed

A

Highly selective Cox-2 inhibitor

Chewable tablet

Dog

89
Q

Mavacoxib:

Mechanism?

Usage?

Admin?

Licensed?

A
  • Preferential Cox-2 inhibitor
  • authorized for long term magament of osetoarthritis in dogs.
  • Chewable tablet. Repated after a fortnight and thereafter montly (max 7 tablet per treatment cycle)
  • Maintains a constant plasma concentration which provides better control of chronic pain.