Exam 1 Flashcards
M3 Agonists role in the eye
o accommodation (near vision) o miosis (pinpoint) o increased drainage (conventional route) ->
M3 Antagonists role in the eye
o profound mydriasis (dilated)
o may precipitate acute pressure
o increase dry eyes and loss of accommodation
Beta Agonist Vs Antagonist role in the eye
beta agonist
o increase ocular fluid
beta antagonist
o decrease ocular fluid formation
Alpha Agonists role in the eye
relatively weak mydriasis (a1) (dilation)
decrease fluid formation
• a2 - direct
• a1 - indirect (vascular)
Drugs to decrease ocular fluid formation
o Adrenergic agonists / NET inhibitors
o Beta antagonists (Timolol)
o Carbonic Anhydrase inhibitors
Drugs to Increase drainage of the eye through trabecular meshwork
o Muscarinic agonists / AChE inhibitors
o ROCK inhibitors (Netarsudil)
o Nitric Oxide
Drugs to pull ocular fluid out & reduce fluid formation
- Systemic Osmolites
- Mannitol or glycerin
- Reduces ultrafiltrate in ciliary blood vessels
- Emergency cases only
Drugs to Increase ocular drainage through uveoscleral route
o PGF2 analogs
o Latanoprost
o only useful in dogs
Topical Muscarinic Blocker; use, drugs, side effects
used to dilate pupil
Tropicamide
• Short acting
• Good for eye exam
atropine
• long acting
adverse effects
• paralysis of ciliary muscle
• acute glaucoma
• decreased tears
Topic alpha-adrenergic agonist use & drug
- used to dilate pupil
- Phenylephrine
- Not as effective as muscarinic blocker
- Useful as vasoconstrictor
Keratoconjuctivitis sicca (dry eye); what is it? what drugs to use? side effects of drug
o May be immune mediated
o Dogs
Drug to use
• Topical cyclosporine
Side Effects of Drug • Suppresses immune system • Increases tears • Dry eye returns after stopping med • Rare systemic toxicities
Drugs to use in eye inflammation
Topical corticosteroids
• prednisolone or dexamethasone
or NPDex
• used for conjunctiva, sclera, cornea, and anterior chamber
• deeper structures require systemic drug
• immunosuppressive and inhibit wound repair
• can worsen or cause corneal ulceration
• should not be used if viral infection present
Topical NSAID
Muscarinic antagonists
• Atropine or tropicamide
• Treat uveitis & prevent synechia and ciliary spasm pain
Drugs to use in eye infection
Topical tetracyclines
• conjunctivitis in cats
• Works against chlamydia & mycoplasma
Triple antibiotic ointment
• Conjunctivitis in dogs
• Bacitracin + polymixin B + neomycin
• Systemic toxicity
Drugs to use for viruses like feline herpes virus
Antivirals • Agent incorporated into viral DNA & breaks protein transcription • Nucleiside analogues = Trifluridine • Reduce signs but don’t sure virus • Need frequent dosing
Define Pain
o protective mechanism to make animal withdraw from damaging situation
o can have detrimental health impacts
Define Nociception & what are the fibers?
o Neural response to painful stimulus
A-delta fibers
• fast conducting
• sharp and acute pain
• easy to localize
C fibers
• slow conducting
• dull, aching, burning or throbbing pain
• hard to localize.
Hyperalgesia & Allodynia
Hyperalgesia
o Exaggerated response to painful stimuli
Allodynia
o Pain due to stimuli which does not normally provoke pain
Opioid Receptors
- 7 G-couple protein receptors
- Mu, delta, & kappa
- Mostly inhibitory
- Most drugs use Mu receptor
Opioid Receptor Signaling Pathway
- Activation of receptor ->
- Inhibit cAMP production ->
- Open K+ channels (hyperpolarization) ->
- Close voltage gated Ca2+ channels
Analgesic Effect of Opioids & Location Targeted
o Decrease chronic dull pain better than acute sharp pain
CNS
• Decrease pain perception
• Increase descending inhibitory path
Spinal Cord
• Decrease activation of spinothalamic tract by incoming nociceptor afferents
Pre-synaptic
• Inhibits glutamate release from nociceptor neurons
Post-synaptic
• Directly inhibits ascending neurons
Sedative Effects of Opioids
o sedation greater in dogs than cats
o Excitement occurs in some animals: cats, horses, and huskies, sheep, cattle, swine
o Need to distinguish between agitation due to pain or drug!
o Can be used for chemical restraint
Calming/euphoria & antitussive Effects of Opioids
Calming/euphoria Effects
o activate the reward centers of the brain
o how much euphoria occurs is unclear and is probably species dependent.
Antitussive Effects & Depression of Laryngeal Reflex
o Inhibition of cough center of medulla oblongata
o Dextromethorphan, Morphine, codeine, butorphanol
GI effects of Opioids
o Contraindicated in pancreatitis or biliary dz
Acute:
• vomiting and defecation
• Initial stimulation of medullary chemoreceptor trigger zone (CTZ), & delayed suppression of inhibition of medullary vomiting center
later:
• cause constipation
• increase spontaneous GI smooth muscle contraction but decrease coordinated peristalsis
Loperamide
o opioid that doesn’t cross the BBB at therapeutic concentrations
o used to treat diarrhea
o removed from the CNS by the efflux transporter P-glycoprotein
o can cause neurological toxicity in dogs w/ MDR1 mutation
Respiratory & Cardiovascular Effects of Opioids
Respiratory Effects
o decrease sensitivity of respiratory center in medulla oblongata to CO2
o Normally the cause of death in an overdose
o Less of a problem given alone
o cross the placenta and depress fetus respiratory
Cardiovascular Effects
o bradycardia more likely in animal not in pain
o can increase cardiac output in horses.
o can also cause hypotension due to vasodilation, particularly during surgery
Temperature Effects & Panting w/ Opioid Use
Temp Effects
o Can interfere with thermoregulation
o Most animals get hypothermic
o Cats may get hyperthermic
Panting
o may occur in some dogs, particularly after oxymorphone.
o due to resetting the thermoregulatory center in thalamus
Effects of Opioids on Urinary Tract & pupils
Urinary Retention
o Increase detrusor muscle and sphincter tone
o Especially common after epidural morphine
Effects on pupils
o Miosis – dogs, humans
o Mydriasis – cats, sheep, horses
Neuroendocrine Effects of Opioids
o Increase vasopressin (ADH) release -> oliguria
o Decrease gonadotropin release
o Increase prolactin release
Histamine & Opioids
o histamine release W/ IV administration of morphine.
o cause vasodliation and hypotension
Acute Symptoms & Antidote for Opioid Overdose
Acute
• Miosis
• Respiratory depression
• Coma
Antidotal Therapy
• Opioid antagonists: Naloxone, Naltrexone, Diprenorphine
• Supportive respiration
Long Term Opioid Treatment Results
Tolerance:
• Tolerance to all effects except Miosis & Constipation
• Cross tolerance to other opioid analgesics
Dependence:
• Psychological dependence
• Physiological dependence
Withdrawal or Abstinence Syndrome
o opioid is stopped precipitously following chronic treatment (5-7 days)
o restlessness (thought to be craving for drug)
o vocalization, hyperactivity and aggression
o Hyperthermia,
o tremors,
o salivation
o Retching,
o Vomiting & diarrhea
Absorption, Distribution, & Metabolism of Opioids
Absorption
• Well absorbed
• substantial 1st pass metabolism orally
Distribution
• Lipophilic
• Well distributed
• Can accumulate in fat
Metabolism
• Many opioids metabolized via hepatic cyp/p520 enzymes and conjugated via glucoronidation
• filtered and eliminated via the kidney
• cats have low glucoronidation -> longer effects of drug
2 Types of Opium Alkaloids
Morphine: • standard narcotic analgesic • used for severe pain • Fairly well tolerated in most species • can stimulate histamine release • Can stimulate emesis • lasts up to 4 hours • useful for traumas and surgeries
Codeine:
• Antitussive
• Weak analgesic
Hydromorphone
- 5-7X more potent than morphine
- greater lipophilicity = faster onset time
- used for mild to severe pain
- Less histamine release
- Reduced emesis and nausea
Fentanyl
- 100X potency of morphine
- well tolerated in dogs and cats
- can cause excitation in horses
- no histamine release
Etorphine
- 1000X potency of morphine
- tranquilizer
- Mainly in zoo/wildlife vet med
Oxymorphone
- 10X potency of morphine
* Less emesis, nausea, sedation and histamine release
Methadone
- Ocationally used in vetmed
* treatment programs for heroin
Meperidine
• 1/8 potency of morphine
Sufentanil
• 5-10X potency of fentanyl
Carfentanil
- 8000X potency of morphine
* Zoo tranquilizer
Buprenorphine
- Much safer than morphine
- partial agonist at mu receptors (ceiling effect)
- antagonist at k receptors
- high affinity but low efficacy
- longer duration of action than morphine
- used in mild to moderate pain
- can precipitate withdrawal if following long-term full agonist
- less highly scheduled (III) than morphine (II)
Butorphenol
- Antagonist at mu receptor,
- agonist at k receptor
- limited degree of analgesia
- mild to moderate pain only
- reduced side effects,
- less highly scheduled (IV),
- can precipitate withdrawal
- especially noted as better tolerated in horses (less excitement)
Tramadol
- Derivative of codeine
- 1/6000 the affinity of morphine for mu receptors
- Multimodal analgesia
- thought to inhibit NE and 5HT reuptake
- binds a2-adrenergic receptors
- has an active metabolite (M1) that has more potent opiate receptor binding, 200X more affinity, 6X more potent analgesia than tramadol (hepatic metabolism CYP2D6 (P450))
- better oral bioavailability than morphine
- controversial about how much pain relief it actually provides
Tapentadol
- mu opioid receptor agonist
- inhibits NE reuptake
- In humans thought to produce less GI side effects
- Most concerned about respiratory depression
Delta Opioids
o Analgesia generally equal to morphine
o may be more effective than morphine in relief of neuropathic pain
o less addiction liability than morphine
o less respiratory depression than morphine
o less gastrointestinal side effect than morphine
Local Anesthetics: Mechanism of Action & Order of Sensation Loss
Mechanism of action
o Reversible block of voltage-dependent Na channels that are required for action potentials
Order of loss o Small unmyelinated fibers are most sensitive o Pain -> o Temp -> o Touch -> o Joint -> o Deep pressure
Chemical Structure of Local Anesthetics
o Weak bases
o Lipohilic group +
o Intermediate chain w/ ester or amide link +
o Hydrophilic group capable of ionization
Amino Esters; basics, example drugs
o local anesthetic
o Hydrolyzed by plasma esterase
o Can form PABA
o Potential allergen
Drugs
• Benzocaine
• Procaine
• Proparacaine
Amino Amides; basics, example drugs
o local anesthetic o Biotransformedd by liver enzymes o Rarely allergen o Liver issues affect metabolism o Longer T1/2 than esters
Drugs
• Lidocaine
• Mepivacaine
• Bupivacaine
Bioavailability of Local Anesthetics
o Must be uncharged to cross cell membrane & get inside cell
o BUT must be charged to block Na channel
o Inflamed tissue is acid so local anesthetics less effective
Routes of Administration for Local Anesthetics
Surface
• Oral spray
• Eye drops
• Patches
Conduction
• Nerve block
Spinal
• Injection into subarachnoid space
• Epidural
Dose Related Drug Toxicity of Local Anesthetics
CNS
• Seizures, twitching, very high CNS depression
Cardiovascular
• Dysrhythmias
• Hypotension
Methoglobinemia
• High levels of hemoglobin that doesn’t bind O2
Respiratory
• Depression if drug affects C5-C7 or CNS
Order of Adverse Effects of Local Anesthetics
- Analgesia
- Altered consciousness
- Muscle twitching & hypotension
- Myocardial depression & seizures
- Unconsciousness & apnea
- Cardiovascular collapse & death
Unusual Effects of Local Anesthetics
- Hypersensitivity or allergic reaction
* Drug idiosyncrasy
Local Anesthetics Interactions w/ Vasoconstrictors
o Use w/ epinephrine, norepinephrine & phenylephrine
o Increase duration of anesthesia
o Decrease systemic toxicity
o Can cause problem w/ circulation
o Can increase risk of arrhythmias & V fib
Lidocaine
o Very versatile & widely used in vet medi o pKa = 7.9 o rapid onset of action(1-5minutes) o short duration(60- 120 minutes) o metabolized by the liver o also used IV as anti-arrhythmia
Bupivicaine
o Long acting (5-8 hrs) o Slow onset (up to 20-30 mins) o Risk of cardiac toxicity o Metabolized by liver o Not used IV or topical
Ropivicaine
o 5-10 min onset
o lasts 5-8 hrs
o lesk cardio & CNS risk than bupivacaine
Mepivicaine
o Structure similar to lidocaine
o pKa = 7.6
o onset 2-5 mins
o lasts 2-3 hrs
Procaine
o Non irritating
o Quick
o Lasts 45-60 mins
o Commonly used to reduce pain for IM injections
Proparacaine
o Used in eye
o Fast onset & short lasting
NSAIDs & Analgesia
- PGs sensitize pain fibers to other chemical mediators
- NSAIDs inhibit PGs -> reduce activation of pain fibers skeletomuscular and vascular pain responds better than visceral pain
NSAIDs & Inflammation
- COX-2 induced at sites of inflammation
- PGs increase vascular permeability & vasodilation
- NSAIDs inhibit PGs -> decrease inflammation
NSAIDs & Fever
- stimulated neutrophils release ‘endogenous pyrogens’ (IL-1 and TNF-a)
- endogenous pyrogens generate PGs in hypothalamus
- PGs in hypothalamus increase temperature ‘set point’,
- fever is induced
- NSAIDs inhibit PGs -> decrease fever
NSAIDs & Platelets
- NSAID targets COX-1 -> inhibits platelet aggregation
- NSAID targets COX2 -> platelets aggregate
- TXA generated by platelets causes aggregation
- PGI generated by endothelial cells inhibits aggregation
- aspirin has an irreversible action
NSAIDs & Gastric Ulcers
- Most common side effect of these drugs
- PGI and PGE inhibit acid secretion and stimulate cytoprotective mucous secretion
- can cause secondary anemia due to gastric bleeding
- not as much an issue with COX-2 selective agents
NSAIDs & Renal Blood Flow
- COX-1 maintains GFR
- COX-2 regulates Na+ reabsorption
- inhibition causes salt and water retention (reduced renal blood flow)
- prolonged use can lead to papillary necrosis and nephritis
NSAIDs & the Heart
- concern for all COX2 selective agents
* COX2 inhibition encourages thrombic events
Salicylates (Aspirin); basics, signs of acute overdose
o used in all species, but high tendency towards gastric ulceration
o can induce hepatic damage,
o detrimental to cartilage
o has been replaced by newer and safer NSAIDs
o irreversible inhibition of cyclooxygenase = anti-platelet compound
o metabolized via glucuronidation (slow in cats!)
acute overdose
• respiratory actions via CNS
• acid/base problems
Pyrazolone Derivatives (Phenylbutazone)
o very popular in equine
o used for bone, joint, & soft tissue pain
o problems associated with blood disorders
o certain pony breeds very sensitive to GI effects
o classic microsomal enzyme inducer (many drug interactions!)
o T1/2 cattle = 40 hr
o T1/2 horse = 6hr
o drug has tendency to accumulate
Proprionic Acid Derivatives
o Reversible inhibition of cyclooxygenases
Carprofen • approved in dogs for osteoarthritis • high selectivity for canine COX2 • high safety level in dogs • thought to inhibit PLA2 • liver metabolism • rare hepatotoxicity ( reversible if caught early)
Naproxen
• Use in horses
• Many adverse reactions in dogs
Ibuprofen
• Serious GI erosion in dogs
Nicotinc Acid Derivatives (Flunixin meglumine)
o Horses IV or IM to treat visceral pain (colic)
o Cows IV for pyrexia, endotoxemia, inflammation
o Dogs in septic shock
o Causes GI upset in dogs
o Use for only short duration
Oxicams (Meloxicam)
- COX2 selective
- in dogs osteoarthritis & post op pain
- in cats post-operative pain – one dose only (fatal kidney damage)
Coxibs (Robenacoxib)
o Highly COX2 selective
o One of few NSAIDs for cats
Piprants (Grapiprant)
o PG receptor antagonist
o recently approved for use in dogs (2016)
o Targets EP4 receptor
o Helps with pain and inflammation associated with osteoarthritis
o preserves PGE2 action at other EP receptors (e.g., GI tract)
o so far relatively mild toxicities have been seen
Aceteminophen (Tylenol)
o analgesic and antipyretic o only weakly anti- inflammatory o COX3 inhibitor o not effective on platelets o low incidence of GI side-effects o hepatic damage o not used in veterinary medicine o generation of toxic metabolite prevented by glucuronidation o TOXIC to CATS
elete
Delete
Control of Release of cortisol & ACTH
- ACTH released by stress & diurnal rhythm ->
- ACTH acts on fasiculata/reticularis to release cortisol ->
- cortisol feeds back to reduce ACTH release
Receptors for Glucocorticoids
- found on almost every cell in body
- Mostly glucocorticoid (GC) receptors
- Some mineralocorticoid (MC) receptors
Metabolic Effects of Glucocorticoids
o Decrease insulin sensitivity
o Release protein from muscle & lymph for glucose production
o Release fat from adipocytes & redistribute to central compartment
o Increase gluconeogenesis & glycogen storage in liver
Actions of Glucocorticoids on CNS
o sense of well being
o decrease sensory acuity
o other behavioral effects
Actions of Glucocorticoids on Cardiovascular
o decreases vascular permeability
o Maintain catecholamine effects on vasoconstriction
o Maintain cardiac contractility
o Excess can lead to hypertension
Actions of Glucocorticoids on Kidneys
o needed to concentrate or dilute urine
o excess interferes with ADH action
o excessive drinking/urination = early sign of overdose
Actions of Glucocorticoids on GI
o Increases gastric acid secretion (via decrease PGs)
o inhibits Ca2+ and PO4 absorption
Actions of Glucocorticoids on Bone
o decrease turnover
o increases reabsorption via indirect decreased absorption of Ca2+ from GI tract
Actions of Glucocorticoids on Connective Tissue
o excess causes decrease in collagen synthesis
Actions of Glucocorticoids on Hematopoietic System
o pharmacological doses decrease proliferation of B and T lymphocytes
o high doses kill lymphocytes
o reduced size of thymus, spleen, and lymph nodes
o increased neutrophils, platelets, & rbc’s
o decreased eosinophils
Anti-Inflammatory Actions of Glucocorticoids
o Decrease proliferation, differentiation, and survival of inflammatory cells (T lymphocytes and macrophages)
o Prevent release of histamine, serotonin, and lyzosomal enzymes
o Decrease generation of arachidonic acid metabolites (prostaglandins and leukotrienes)
o Prevent release and actions of IL-1, IL-2, TNF-a
o Inhibit release of cell adhesion molecules reducing recruitment of inflammatory cells
Uses for Glucocorticoids in Musculoskeletal, skin, renal, GI, Lungs
Musculoskeletal
• arthritis, bursitis, tendenitis, myositis
Skin
• allergic dermatitis, otitis externa
Renal
• glomerulonephritis
GI tract
• colitis, gastroenteritis
Lungs
• asthma
Adverse Reactions of Glucocorticoids
o PU/PD o Polyphagia o Muscle weakness o Osteoporosis o Fat mobilization o Pancreatitis o GI ulcers o Seizures o Diabetes o K+ loss & Na+ retention o Prone to infection o Slow wound healing o Corneal ulcers o Hypogonadism o Lethargy, depression, behavioral change o Hepatomegaly o Blunted HPA axis o GI issues o Laminitis o Drug interactions
Strategies to Reduce Side Effects of Glucocorticoids
o Use minimal dose for shortest time
o Intermittent dosing
o Supplementing protein, Vit D & A, & K+
T1/2 in Plasma & Time till Tissue Effect of Cortisol, Cortisone, Prednisone, Prednisolone, Fludrocortisone, & Dexmethasone
JUST REMEMBER WHICH DRUGS ACT LONGER THAN OTHER
Cortisol
• T1/2 Plasma = 90 min
• Tissue = 8-12 hr
Cortisone
• T1/2 Plasma = 30 min
• Tissue = 8-12hr
Prednisone
• T1/2 Plasma = 60 min
• Tissue = 12-36hr
Prednisolone
• T1/2 Plasma = 200 min
• Tissue = 12-36 hr
Fludrocortisone
• T1/2 Plasma = 200 min
• Tissue = 8-12hr
Dexmethasone
• T1/2 Plasma = 200 min
• Tissue = 36-54 (too long for alternate day therapy)
Relative GC & MC (kidney) Potency of Cortisol, Cortisone, Prednisone, Prednisolone, Fludrocortisone, & Dexmethasone
s AREN’T IMPORTANT JUST REMEMBER WHICH DRUGS HAVE MORE GC OR MC
Cortisol
• GC & MC = 1
Cortisone
• GC & MC = 0.8
Prednisone & Prednisolone
• GC = 4
• MC = 0.8
Fludrocortisone
• GC = 10
• MC = 125
Dexmethasone
• GC = 25
• MC = 0
Cortisol & Cortisone
- Cortisol is natural GC.
* Cortisone needs to be converted to cortisol
Prednisone & Prednisolone
- Widely used GC
- Prednisone is converted to prednisolone (active) in the liver
- If liver disease may not convert
- Cats have a limited ability to convert, therefore prefer prednisolone (& horses)
- Clinician preference
Dexmethasone
- Extremely strong GC
- very powerful to treat signs initially
- Longer term use = more side effects
- not useful for alternate day dosing
Fludrocortisone
- Used to treat hypoadrenocorticism in dogs and cats
- Has both MC and GC
- While GC is lower it is sufficient to restore GC activity
Nutraceuticals
o Symptomatic Slow-Acting Drug for Osteoarthritis
o oral
o effectiveness questionable
o sold as supplements
Hyaluronate
o Symptomatic Slow-Acting Drug for Osteoarthritis
o Restores synovial fluid viscocity
o Given intra-articular
o Works best when degeneration isn’t severe
Polysulfated Glycosaminoglycans
o Symptomatic Slow-Acting Drug for Osteoarthritis
o Isolated from bovine cartilage
o Use in horses & dogs
o inhibits proteolytic enzymes that degrade proteoglycans
o precursor for proteoglycan synthesis
o decreases PGE2 levels
o increases hyaluronic acid concentration in synovial fluid
o actions are slow
o prolonged use can help maintain joint cartilage
o intra-articular or IM
o interfere w/ platelet aggregation
Glucocorticoids for Osteoarthritis
o intra-articular injection
o long acting (3-4 weeks)
positive effects
• decreases release of lyzosomal enzymes
• inhibits PG synthesis
• relieves pain and inflammation
negative effects
• catabolic - will inhibit repair process
• decrease hyaluronate synthesis
• may obscure true degenerative process
NSAIDs used for Osteoarthritis
Carprofen
o Kidney & liver issues prevalent in older animals
Gapiprant
o EP4 receptor antagonist
o PGE2 interacts with EP1, EP2, EP3, and EP4
o EP4 receptors mediates PGE2 effects to cause pain and swelling
o preserves PGE2 functions at other sites
o newer agent with limited experience
Dimethylsulfoxide
o Free radical scavenger
o vasodilator
o analgesic action (inhibits PGs generation)
o Topical
o Rapidly absorbed
o Labeled for reduction of acute swelling and trauma
Timolol
o beta antagonist
o lower occular pressure
o decrease occular fluid
o use carefully w/ respiratory or heart dz
Demecarium
o Acetylcholinesterase inhibitor.
o Improves fluid drainage
Pilocarpine
o muscarinic agonist
o lowers intra ocular pressure
o improve fluid drainage
Epinephrine
o mixed α−β-adrenergic receptor agonist
o decrease occular pressure & fluid formation
Dorzolamide
o carbonic anhydrase inhibitor
o reduces occular fluid formation
