Exam 3 Flashcards
Nociception vs. pain
- Nociception – reception of primary afferent AP signals from activated nociceptors that detect tissue-damaging (noxious) stimuli
- Pain – conscious perception of a noxious stimulus
how do inflammatory products Bradykinin, cytokines, PG’s affect nociception/pain?
Active TRP’s peripherally to increase pain
How do glutamate agonists affect nocicpetion/pain
In CNS, dorsal horn: affects AMPA receptors first to stimulate pain, then stimulates windup via NMDA receptors
How does substance P affect nociception/pain
inflammatory mediator, affects G-prot linked receptors at synapse (CNS, dorsal horn)
How does BDNF affect nociception/pain
affects G-prot linked receptors at synapse
How do TRP receptors mediate nociception/pain
Transient receptor potentials (TRP’s) must be activated in to increase pain perception
How are TRP’s involved in nociception in periphery
TRP’s activate peripheral nociceptors or are activated by inflammation
PG’s, bradykinin, cytokines (TNFa, IL-1, IL-8), lipids –> activate TRPA1, TRPV1
How are TRP’s involved in nociception centrally
increase pain sensation by increasing the number of AP’s sent up to CNS via wind-up
How do NSAIDs act peripherally as analgesics?
NSAIDS ↓ prostaglandin synthesis and ↓ TRP activation via COX inhibition
How do local anesthetics act peripherally as analgesics?
Local anesthetics block APs
Work anywhere along pain pathways BUT limited use except on nerves, lower spinal cord
How does Capsacin act peripherally as analgesics?
topical analgesic from hot pepper oil - desensitizes TRPV1 (heat)
Where to opioids work to effect analgesia?
Dorsal horn, centrally
periaqueductal gray matter/raphe magnus
May inhibit or excite descending neurons
How does Tramodol work?
Serotonin/NE reuptake inhibitor
Weak mu opioid agonist
Acts in raphe magnus to inhibits dorsal horn neurons (secondary afferents) –> Fewer pain signals to brain
How do alpha 2 agonists act centrally as analgesics?
work post-synaptically at non-adreneric receptors, cause CNS inhibition & decrease pain signaling from post-synaptic neuron
How do NMDA antagonists act centrally as analgesics?
affect synapses by blocking NMDA receptors
e.g. Ketamine
2 major pools of histamine
Mast cells in connective tissue (and baso’s)
Non-mast cell tissue (lungs, skin, gastric mucosa)
What effect does a histamine receptor blockade have on degranulation
Only partially antagonizes histamine release by degranulation
Things that trigger histamine release
Immune-mediated (e.g. IGE hypersens)
Drug-induced (NMJ blockers, morphine
Plant & animal stings
Physical injury (trauma, heat, cold)
Class H1 histamine receptor
Relaxation of of vascular smooth m. –> vasodilation
Contraction of bronchial smooth m. (except cats, sheep)
Increase capillary permeability –>edema
Stims sensory nerves –> pain, itching
Classic sign of H1 receptor activation
reddening, swelling (wheal) & flare
typically due to allergy or inflammation
Class H2 histamine receptor
Histamine released from ECL (enterochromaffin-like cells) –> stim gastric acid secretion from parietal cells
How do H1 antagonists work
- prevent action of released histamine (doesn’t prevent histamine release)
- relax constricted bronchioles, decrease vasodilation & capillary permeability, antipruritic, pain relief
- also prevents motion sickness
First generation H1 antagonist
enter CNS, often cause sedation, anti-muscarinic mostly
e.g. Diphenhydramine (benadryl)
Adverse effects of H1 antagonists
- CNS depression, anti-muscarinic (anti-sludge) effects
- Contraindicated for glaucoma (increase intra-ocular P)
- Causes tolerance (decreases efficacy)
2nd generation H1 antagonist
enter CNS less, less sedation caused
E.g. Ioratadine (Claratin)
H2 antagonist
Used for ulcers, drug-induced gastritis, reflux
Inhibit gastric acid secretion by blocking H2 receptors
e.g. Famotidine (pepcid), anything ending in -tidine
Adverse effects of H2 antagonists
uncommon, usually well-tolerated
Cimetidine inhibits cytochome p450 - other drugs metabolized by this pathway can build up
What does serotonin regulate
gut motility, body temp, sleep, mood, behavior, pain
What are ergot alkaloids
serotonin agonists
Ergovaline - fungus in fsecue grass, SE US, causes neurotoxicity, gangrene in cattle
Blocked by ketanserin (serotonin receptor, H1 antaognist)
Uses of serotonin modifiers in GI
- Metaclop, Cisapride (receptor agonists) - Increase parasymp activity, increase gut motility
- Receptor antagonists - appetite stim, antiemetic, anti ergovaline-induced toxicity
SSRI’s (selective serotonin reuptake inhibitor)
- increase serotonin = positive behavior effects
- May involve desens or down regulation b/c 4-6 weeks before see effects
SSRI use in dogs
separation anxiety
compulsion behaviors
aggression
SSRI use in cats
inappropriate urination (spraying)
compulsive behaviors
aggression
psychogenic alopecia
When would you use NSIM’s
- when NSAID not effectively managing a condition
- when immunosuppression is desired
- AI systemic dz
Calcineurin inhibitors
Bind to certain proteins to inhibit cacineurin = no dephosphorlyation of NFAT –> no nulcear translocation, no gene exression –> no T cell activation or cell-mediated immunity
Cyclosporine & Tacrolimus
Difference between NSAIDs and NSIMs
NSAIDs don’t get immunosuppression
Calcineurin inhibitor uses
IMHA, IBD, IM-polyarthritis, atopic dermatitis, perianal fistulas in dogs, organ transplant regimens, dry eyes
Adverse effects of Calcineurin inhibitors
Vomiting (dogs), anorexia (cats), weight loss, depression, lethargy
Cytotoxic alkylating agents
- Suppress B, T cells & rapidly dividing cells (bone marrow)
- MOA - nitrogen mustard adds alkyl grp –> damages DNA of B, T cells (but T cells less susceptible to inhibition)
- Cyclophosphamide, Chlorambucil (slower acting, less toxic)
Uses for Cytotoxic alkylating agents
IMTP, SLE, rheumatoid arthritis, phemphigus, maybe IMHA
Cytotoxic alkylating agent toxicity
Bone marrow suppression
Nausea, vomiting, diarrhea, alopecia
Sterile hemorrhagic cystitis (just Cyclophosphamide)
Chlorambucil - phemphigus, IM skin dz in cats
Cytotoxic inhibitors of purine synth
Pro-drug - active metabolite disrupts purine synth = no B/T cell proliferation
MOA unclear, immunosuppression may take weeks
Azathioprine, Mycopheonlate mofetil (more $$)
Uses for Cytotoxic inhibitors of purine synth
Often used in combo w/ corticosteroids
IBD, IM skin dz, IMHA, etc.
Cytotoxic inhibitors of purine synth toxicity
Immunosuppression & bone marrow sup (esp. cats) - Myco may be better alternative
Less commonly causes GI distress, anorexia, pancreatitis, heptotoxicity
Oclacitinib (aka Apoquel)
Manages chronic itching, chronic/severe atopic dertmatitis
JAK-1/3 inhibitor - decreases inflammatory cytokines and cytokines that cause itch (IL-31)
Causes bone marrow suppression, but good alternative if dogs not tolerating other drugs
Cytopoint
Manages atopic dermatitis in dogs
Monoclonal Ab against IL-31 (itchy cytokine)
Minimal bone marrow suppression
Types of corticosteroids
glucocorticoids (cortisol)
Mineralocorticoids (aldosterone)
Glucocorticoids
- zona fasiculata
- stress –> hypothalamus releases CRG –> anterior pituitary releases ACTH –> adrenal cortex releases cortisol
- See changes in genetic expression (slow) or see more rapid increase in metabolism
Mineralocorticoids
- zona glomerulosa
- stimm’d by ACTH, Angiotensin II –> AIP cause salt, water retention
Metabolic changes from glucocorticoids
increased glu production, increased insulin secretion/resistance (can lead to diabetes)
Cardiovascular changes from glucocorticoids
vasoconstriction, cardiac contraction,
angiotensin release & salt/water retention –> plasma vol expansion
Can see hypertension (dogs), CHF (cats)
Other glucocorticoid effects in body
bronchodilation, skin probs, immune fx, digestive enz secretion (possibly ulceration), anti-inflammatory at higher doses
How do glucocorticoids cause anti-inflammatory effects
inhibit activity of phospholipase A2 (step before cox) = no PG’s, etc.
Also suppress WBC migration, fx
Cell mediate immunity suprpessed
How are glucocorticoids compared to eachother?
Everything compared against Hydrocortizone
Short duration (< 12 hrs)
Anti-inflamm potency: 1
Mineralocorticoid potency: 1
Fludrocortisone
Short duration (< 12 hrs)
Anti-inflamm potency: 10
Mineralocorticoid potency: 125
Can be used systemically for cortisol AND aldosterone replacement w/ Addison’s
Prednisone & methylprednisolone
Intermediate duration (12-36 hrs)
Anti-inflamm potency: 4 & 5
Mineralocorticoid potency: 0.8 & 0.5
Used systemically for long-term management of allergy, chronic inflammation (e.g. arthritis), and immunosuppression (e.g. AI dz)
Dexamethasone
long duration (36 - 72 hrs)
Anti-inflamm potency: 25
Mineralocorticoid potency: 0
Used systemically for immediate relief of hypersensitivity and septic shock, long term control of allergy and immunosuppression
Alternate-day therapy
Used to taper of GC’s & fix iatrogenic hypoadrenocorticism
Useful if GC’s being used for anti-inflam effects, not great if used for immunosupp effects
Generalized seizures
Can occur repeatedly or become continuous (+5 min Status epilepticus) Grand mal (majorly motor) or petit mal (lose touch, less motor)
MOA’s for anticonvulsants
Prevent initiation or spread of seizure focus
Raise seizure threshold
Inhibit excitatory neural activity
(suppress AP’s, agonize GABA)
Anticonvulsant vs. Anesthetic
Anticonvulsant - suppress seizure activity but don’t produce unconsciousness
Anesthetic - suppress seizure activity but do produce unconsciousness
Diazepam and seizures
commonly used, esp. for status epilepticus
rapidly distributes to CNS to inhibit neuronal activity
Increases efficacy of endogenous GABA (= neuronal inhibition)
Good for short-term stabilization tx - multiple administration methods, half life 3 hrs dogs
Adverse effects of Diazepam
Tolerance developed if used chronically
Sedation, behavioral changes
Hepatic toxicosis in cats w/ chronic oral treatments
Bromide
stabilization, maintenance tx if Diazepam or Pheno don’t work - or in combo
MOA unknown, hyperpolarizes activated Cl channels
Adverse - joint stiffness in rear limbs, CNS depression, coughing (cats)
Clonazepam (benzodiazepine)
- Like Diazepam but more potent
- maybe good alternative to cats (no hepatotoxicity)
- inhibition via GABA receptors
- eliminated by zero-order kinetics
Phenobarbital
Most widely used SA anticonvulsant for chronic maintenance tx (good 2nd line to Diazepam)
Doesn’t produce significant sedation
hepatic metabolism via cP450’s
Phenobarbital MOA
- increase seizure threshold
- decreases electrical activity of the seizure focus
- increases the efficacy of endogenous GABA on GABA(a) receptors
- Bind to specific sites on GABA(a) receptors – sites distinct from benzodiazepine sites
Phenobarbital adverse effects
sedation, polyphagia, PU/PD that subsides w/ tolerance, increased hepatic metab
Increased liver enz, heptocutaneous syndrome (necrolytic dermatitis)
Affects thyroid and corticosteroid metab
Gabapentin
- Structural analog of GABA but doesn’t interact with GABA receptors
- MOA unknown - inhibits Ca channels in neurons
- Use in combo w/ other drugs to treat refractory seizures, or when hepatic dz an issue
- Avoid human liquid product of it (has xylitol)
Levetiracetam
New, increasing use, $$
MOA unk, may influence Ca-dependent NT release, short half life
Binds exclusively in CNS
Dogs w/ refractory seizures
Drugs to use to stabilize/stop seziures
Diazepam
Phenobarbital
Bromide
Drugs used for seizure maintenance
Primary: Phenobarbital, Bromide
Secondary/add on: Gabapentin, Levetiracetam
