Exam 1 Flashcards
(164 cards)
1
Q
Lecture 1
A
-Important terminology: anesthesia, analgesia, sedation, tranquilization, neuroleptanalgesia.
-Review of Calculations: calculate anesthetic drug dosage, fluid drop rates, convert % solutions to mg/ml, and determine drug dilution amounts.
2
Q
Define the following terms
anesthesia, analgesia, sedation, tranquilization, neuroleptanalgesia.
A
Anesthesia: total loss of sensation in a body part or in the whole body, generally induced by drug (s) that depress the activity of nervous tissue either locally, regionally, or generally (central).
Analgesia: Loss of sensitivity to pain without loss of consciousness.
Sedation: CNS depression in which an animal is awake but calm and generally uninterested in its surroundings, often interchangeable with tranquilization. If given sufficient stimulation the animal will be arouse/awaken.
Tranquilization: similar to sedation. The animal may be awake or not. Potentially indifferent to minor pain.
Neuroleptanalgesia: Hypnosis and analgesia produced by the combination of a neuroleptic drug (e.g., tranquilazer) and an anelgesic drug.
Anelgesia = loss of feeling
Awareness = consciousness
Agonist: a drug that produces an effect by interacting with an specific receptor site ex: opioid agonist morphine.
Antagonist: a drug that cunteracts the effects of another drug ex: opioid antagonist naloxone.
3
Q
What are the five phases of anesthesia?
A
- Preanesthetic
- Induction
- Maintenance
- Recovery
- Postanesthetic period.
4
Q
What is the difference between dose and dosage?
A
Dose: quantity of drug to be delivered at a particular time. It is expressed in mg, ml and calculated from the dosage rate.
Dosage: the amount of drug per unit of body weight.
5
Q
Which is the only distinguishable microdrip set size after the bag has been opened?
A
The 60 drop.
6
Q
What are some useful formulas for IV drop calculations?
A
drip rate = ml required/time * drops/1ml
concentration in mg/ml = mg of drug/ml of IV fluids.
ml per hour = volume to be infused in ml/length of infusion in hr
ml per minute = volume to be infused in ml/ length of infusion in hr * 60 (min/hr).
7
Q
Lecture 2
What are the five W’s of performing a patient evaluation (pre-anesthetic)?
A
- Who should perform it: the veterinarian in charge of the patient should perform the evaluation
- What does it include: Start with the signalment. History (include previous anesthetic events)
-If patient is ill, find out what symptoms are present, the severity and how long it has been going on.
-What about recent medications, vaccinations?
-Physical exam (PE). Including BCS and BW
-Blood and urine samples
-Temperament/mentation, level of pain and stress
-Advanced diagnostics if indicated: ECG, BP, radiographs, and U/S, echo, endocrine testing, etc. - Where
- When
- Why
8
Q
Is ECG a routine screening?
A
-For Patients with a history of cardiovascular disease
-Geriatric patients
-Underlying disease that may lead to arrhythmias: Hypekalemia, GDV, Splenomegaly, traumatic myocarditis.
AliceCor Heart monitor is an FDA approved iPhone case that produces an ECG
-Telemedicine consults with boarded cardiologists.
9
Q
Physical exam, how do you use your stethoscope and fingers?
What do you evaluate with stethoscope?
Why should you palpate the trachea?
A
-Auscultate for murmur while palpating for femoral pulse simultaneously.
-Rate, quality, rythm
Respiratory rate: describe what you hear or don’t hear. “no presence of cracking, wheezing,..etc.
Mucus membranes, Capillary refill time. 2 seconds or less is normal. A CRT <1 sec is indicative of hyperdynamic state and vasodilation (bright red mucous membranes). It can be associated with systematic inflammation, heat stroke, distributive shocks, and hyperthermia.
10
Q
What are some of the physical findings in dehydration? by percentage
A
<5 not detectable
5-6% subtle loss os skin elasticity
6-8% Defined prolonged CRT, eyes possibly sunken, dry mm possilbe.
10-12% tented skin stands in place, definite prolongation of CRT, eyes sunken, signs of shock.
12-15% definite signs of shock (tachycardia, cool extremities, rapid and weak pulses). Death imminent.
11
Q
What are some other important part of PE and why?
A
-Integument: infection, tick, fleas
IV and epidurals should not be placed through infected skin. Surgery may be canceled.
Lymph nodes: maybe inflammation indication. FNA
GI tract, abdominal palpation, gut sounds. Pregnant, enlarged prostate,
Genitourinary tract: check for descended testicles
CNS: want to know about balance, seizures, aggression to select proper anesthetics.
12
Q
What kind of lab work should be done before surgery?
Does extensive labwork pre-sx improve the outcome? NO
A
Depends on the physical exam and history of the patient.
-Young (<5 years old) healthy patient having an elective surgery with no abnormal history = PVC/TS/GLUCOSE/BUN (Big 4 or QATS).
-Older patients elective or non-elective, history of recent illness, etc. = CBC/CHEMISTRY profile/UA (minimum database).
-If break in preventative =4Dx
-+/- T4, ECG, blood pressure, thoracic radiographs, liver function, coagulation profile, etc.
13
Q
Where is the pre-anesthetic evaluation performed?
When should it be performed?
Why should a pre-anesthetic evaluation be done in all patients?
A
-Clinic, but also done during farm calls
-Find a quiet area can better auscultate heart and lungs
-Within the day before the surgery or up to one week prior.
-Emergency cases done immediately
Questions to ask the owner:
-When was the patient last fed, pregnant, any drug or toxin exposure?
-Greater chance of safe anesthetic episode and/or more successful outcome.
-Formulate assessment of the patient’s overall organ function and preoperative risk.
-Provide client with valuable information for decision/risk.
Document the conversation prior to anesthesia
14
Q
What are the five categories of ASA Physical Status Scale?
Which categories are more likely to suffer complications?
A
- A normal healthy patient
- A patient with mild systemic disease
- Patient with severe systemic disease
- Patient with severe systemic disease that is a constant threat to life
- Moribund patient that is not expected to survive without operation.
3-5 categories 4 times > complications than 1-2
Add E for emergency
15
Q
What is the physical status of a patient?
When should the ASA be assigned?
How is an emergency defined?
A
-Presence or absence of disease
Determined by history, PE, laboratory and other diagnostics.
-Severity of pain present
-Levels of stress
-Overall efficiency and function of organs
-ASA after PE and labwork and diagnostics.
-Emergency: as existing when delay in treatment would lead to a significant increase in the threat to life or body part.
16
Q
Why is ASA Physical status important?
A
-Used to assess the anesthetic risk of a case and select appropriate drugs.
-Physical status effects the pharmacokinetics and pharmacodynamics and aids in the selection of drugs, techniques for the patient.
Organs/systems we’re concerned with? = cardiovascular, pulmonary.
-Can also be used from a legal standpoint, retrospective.
17
Q
What are often more important factors to considered in predict operative risk than increased ASA classification?
A
-Age, obesity
-Severity of operation
-anesthesia providers skill, staff
-Medicine, blood, implants
-Competence of surgical team, etc.
Increased cardiopulmonary emergencies during surgery*
18
Q
Is age a disease? obesity?
What are other considerations for dosing drugs selection?
A
-No but it is an important independent risk factor regarding morbidity and mortality. Predictor of preoperative outcome.
-Obesity decreases CV function, at risk for hypoventilation.
-SA vs. LA
-Species variation in PK & PD
-Size of patient: smaller animals require a higher dose per unit of BW
-Obesity: volume of distribution for drugs changes
-Poor body condition, starvation
-Age: how does it change metabolic rate?
19
Q
What are some of the effects of age when selecting anesthetic drug dosages?
How does fever affect metabolic rate?
A
-Neonate or pediatric: decrease dose
-Juvenile to early adulthood: Increase dose
-Geriatric: decrease dose
Fever: increases metabolic rate. 1 degree = 7% increase.
Hyperthyroidism: increases metabolic rate
Hypothyroidism: decreases MR.
Leukemia: can increase MR
Long-term pain: increases MR
Shock: lowers MR
20
Q
Conditions for specific breeds or species
A
- Pigs: Malignant hyperthermia. Stress triggered, genetic.
- Quater horses: Hyperkalemic Periodic Paralysis, which causes episodes of tremors, myotonia, weakness, or paralysis in association with elevated serum potassium
- Rabbits: Malignant hyperthermia?
- Herding breeds: ABCB1/MDR1 (multidrug resistent gene mutation)
- Doberman Pinschers: Von Willebrand’s disease. Bleeding disorder. Do a buccal mucosal bleeding before emergency surgery. Avoid Acepromazine tranquilizer.
- Miniature Schnauzers: Sick sinus syndrome. Heart rate and rhythm condition, abnormal. Careful with atropine bc it can induce initial sinus bradycardia. Glycopyrrolate safer.
- Boxers: Arrythmogenic Right Ventricular Cardiomyopathy. Adult onset cardiac muscle disease. Caution with Acepromazine
- Pugs: Brachycephalic syndrome
21
Q
What substances can either induce or inhibit microsomal enzymes?
A
Inducers
-Diazepam: maximal enzyme level after 5 days
-Diphenhydramine
-Hyperthyroidism
-Pentobarbital
-Phenobarbital
-Phenylbutazone
-Rifampin
-Progesterones
-Strogen
-Griseofulvin
-Prednisone
Inhibitors
-Chloramphenicol
-Cimetidine
-Cyclophosphamide
-Erythromycin
-Ketoconazole
-Morphine
-Organophasphates
-Quinidine
-Tetracycline
-Verapamil
22
Q
Why is it important to ask owner about any current medications, including natural supplements?
A
They could cause problems during pre-anesthesia
23
Q
What are the recommendations for the owner for patient preparation?
A
-Fasting and water: species and age dependent
Canine and feline: 6-12 hours. Water: access up to time of premed
Small ruminant: 12-18 hrs. Water: 8-12 hrs
Equine: 4-12 hrs. Up to premed
Cattle: 18-24 hrs. 12-18
Swine 12-24 hrs.
Rodents and rabbits: not necessary
Bird: 4-6 hrs
Birds <200g: not necessary
Neonate: not necessary.
Patients are fasted prior to anesthesia for the following reasons:
-Decrease food and fluid in stomach
-Decrease risk of aspiration
-Distended stomach or rumen impairs ventilation and could lead to hypoxemia and hypercapnia.
-In horses, a full stomach could rapture at induction
24
Q
Why is it nor necessary for neonates, small birds, and some mammals to be fastened?
What about water deprivation?
A
They are prone to hypoglycemia within a few hours of starvation
Increased metabolic rate in birds and small mammals.
Some animals can not vomit, horses and rabbits
Water
-Renal insufficiency
-Febrile
-Diabetes
-Hot environment
Gastroesophageal reflux incidence in dogs decreased with small amount of canned food 3hrs prior to surgery.
25
What are the 4 H's of Anesthetic concerns?
1. Hypotension
2. Hypoventilation
3. Hypothermia
4. Hypoxemia
26
Lecture 3
Premedication drugs for the anesthetic patient
-Explain why premedication drugs are beneficial for our veterinary patients
-Summarize the MOA and cardiorespiratory effects for drugs used for premedication
-Compare and list examples of neuroleptanalgesia and pre-emptive analgesia
-Estimate the cost and availability associated with different drug choices
-Associate meat and milk withdrawal times in food animals
-Identify the best resource a veterinarian can use to determine meat and milk withdrawal times in food animals.
27
-Explain why premedication drugs are beneficial for our veterinary patients
Should you ever induce an unsedated horse? NO
Pre and post anesthetic medications are essential to safe anesthetic management.
1. Minimize stress, cardiopulmonary depression, and deleterious effects of IV and inhalant anesthesia.
2. Ease of handling of patient
-Facilitates holding the patient, placing IV catheter, and further examination.
3. Lower dose of induction and maintenance drugs
-Minimum Alveolar Concentration (MAC) sparing effect for inhalant anesthetics.
4. Pre-emptive analgesia
5. Smoother recovery period
6. Synergistic effect form combining drugs produces better results than a single dose alone
28
What are the categories of preanesthetic medications? benefits? side effects?
1. Anticholinergics
-Atropine
-Glycopyrrolate
2. Phenothiazine tranquilizers
-Acepromazine
3. Alpha-2 agonists
-Xylazine
-Dexmedetomidine
4. Benzodiazepines
-Diazepam
-Midazolam
5. Opioids
-Morphine
-Butorphanol
Post Anesthetics
6. Analeptics
-Doxapram
7. Analgesics
-Alpha-2 agonists, opioid, non-opioid,
-Meloxicam
-Tramadol
Antagonists
-Benzodiazepine
-Naloxone
-Atipamazole
29
What is pre-emptive analgesia and why beneficial?
Analgesics given before surgery and continued intraoperative period.
Benefits:
-reduce pathophysiology associated with pain
30
Anticholinergics
-Inhibit bradycardia
What are they primarily used for?
When and what patients is preferred?
-Treatment of organophosphate toxicity
-Used primarily to limit salivary secretions, prevent bradycardia, or deliberately increase heart rate.
-Preferred when high vagal tone is currently suspected.
-Pediatric patient
-Prefer during anesthesia only
-Decrease cholinergic transmission
Negatives
-Atropine may induce sinus tachycardia (abnormally low sinus rhythms) or ventricular arrhythmias.
-Dry mouth, blurry vision, trouble urinating, constipation, hallucinations, confusion, decrease sweating (body temp can rise), flushing of the skin.
31
What is the MOA Anticholinergics Atropine and Glycopyrrolate?
Compare Atropine with glycopyrrolate
What are the side effects of these type of drugs?
MOA: inhibit acetycholine (and other cholinergic stimulators) at the postganglionic parasympathetic neuroeffector site.
Both: IV, IM, SQ.
Atropine
-60-90 mins
-crosses BBB and placenta
-Causes pupil dilation- impairs vision and may lead to poor recovery in cats.
-High doses inhibits urinary and GI tract motility
-Caution in horses and cattle
-Risk of colic, bloat.
-May produce drowsiness, disorientation, restlessness, in ruminants and elephants.
-ER endotracheal tube ok.
Glycopyrrolate
-Does not cross BBB nor placenta
-2-3 hrs
32
What are the physiological outputs mediated by muscarinic receptors? parasympathetic stimulation
Eyes: promotes miosis (pupillary constriction), relaxation of lens, focus on near objects possible.
Glandular secretion: stimulation of secretions except for sweat glands (inhibits).
Heart: reduced contractility, sinus rate, and AV nodal conduction. Reduce cardiac output and rate.
Lungs: bronchoconstriction, increased airflow resistance.
33
Recommendations for administering Atropine and Glycopyrrolate
Atropine
-Expect initial HR increase followed by a transient decrease (increase vagal tone).
*Half dose IV, Half IM or SQ*
34
Tranquilizers and sedatives
Phenothiazines
MOA: calming and neurologic effects are mediated by depression of the reticular activating system and antidopaminergic actions in the CNS
-Suppress sympathetic nervous system (depress mobilization of catecholamines centrally and peripherally)
-May lower seizure threshold in epilepsy, but INHIBIT KETAMINE.
**Inhibit dopamine interaction in the chemoreceptor trigger zone in the medulla**
Advantages
-Increase threshold for responding to external stimuli, though animal can be aroused by noxious stimuli.
-Reversible except Acepromazine
-ACEPROMAZINE most commonly used, not reversible
-Not analgesic but improves other drugs
35
Acepromazine
What breed of dog is a concern?
Phenothiazine tranquilizer
-Alpha-1 adrenergic blockade = vasodilation and HYPOTENSION
-Subsequent epinephrine drop due to B-2 effect
Reversal
-Alpha-adrenergic agonist ex: Phenylephrine
-Caution/Avoid Boxer dogs (spontaneous syncope due to sinoatrial block cause by excessive vagal tone) Atropine may help prevent this effect.
-Giant dog breeds caution, use minimum dose possible
-IV fluids for hypotension
Negatives
-Non reversible
-No analgesic effect
-Synergistic with analgesic drugs
-Antihistamine effects, careful when allergies present.
-Altered thermoregulation
Positives
-Muscle relaxer
-Long lasting 4-8 hours
-Ani-arrhythmic properties
Avoid/Caution
-Fractious or aggressive animals
-Liver disease or portocaval shunts. Primary organ of metabolism is liver.
-Valuable breeding stallions due to potential for praphimosis (inability to retract penis).
-Von Willebrand's disease or other clotting disorders. Doberman Pinschers.
-Acepromazine significantly decreases platelet numbers, however ok in normal/healthy animals.
**Acepromazine decreases platelet aggregation**
-Shock or cardiovascular disease
36
Alpha-2 Adrenoreceptor Agonists
Xylazine 20-40 mins
Detomidine 90-120 mins
Romifidine 45-90 mins
Medetomidine 45-90 mins
Dexmedetomidine 45-90 mins
MOA: Produce CNS depression by stimulating both presynaptic and postsynaptic Alpha-2 adrenoreceptors in the CNS and peripherally.
-Decrease norepinephrine release and reduces ascending nociceptive input = decrease circulating catecholamines.
-Polysynaptic reflexes are inhibited, but neuromuscular junction is not affected.
Caution/Avoid
-Horses may be startled, approach carefully. Aggression reported in horses after Xylazine and Detomidine.
-If patient anxious or excited be careful
-Hypoventilation or apnea
-Decrease sensitivity to increased PCO2 in respiratory center.
-Horses and brachycephalic animals are prone to stridor and dyspnea from upper respiratory airway obstruction.
-Decrease cardiac output (tissue perfusion)
-Increase peripheral vascular resistance
-Ileus and bloat in dogs
-Colic in horses
-Pale mucous membranes cause by vasoconstriction
-Ataxia
-Diuresis: increase urination bc inhibits antidiuretic hormone.
-Vomiting in dogs and cats
-Suppress insulin resistance - hyperglycemia and glucosuria
Desired effects
-Pronounced sedation, sleep-like state.
-Muscle relaxation
-Analgesia
-Anxiolysis
-Can be buccally or by epidural or subarachnoid administration
-Antagonized by Alpha-2 receptor antagonists: Yohimbine, Tolazoline, Atipamezole.
**Work synergistically with opioids to produce profound state of sedation**
Cardiopulmonary effects
-Decrease CNS sympathetic outflow and increase parasympathetic activity.
-Induce bradycharchia, may initiate sinus bradychardia Xylazine ( Miniature Scherzer)
-Increase systemic vascular resistance
37
Should you give an anticholinergic when giving and alpha-2 agonist?
NOT generally recommended
-Consider administering anticholinergic IM or SQ
-Lidocaine could be considered instead. Lidocaine bolus and CRI following dexmedetomidine IV.
-Reversal with atipamezole (but patient may start waking up during surgery)
38
Which drug is an excellent analgesic for treating GI pain but causes oxytocin-like in ruminants? How does it work on pigs?
Xylazine or Alpha-2 agonists.
-induce premature delivery in cattle
-Pigs metabolize it too fast
Xylazine inflammatory if SQ in horse or cattle
Xylazine has two different concentrations one for SA and other for LA
1-5 mins onset or 20-40 mins
39
How does Detomidine compare to Xylazine?
Detomidine IM or IV
-Onset of action is lightly longer than xylazine
-Sublingual formulation available for horses
-Effects 90-120 mins
**Horses 1ml IV per 1100 lbs**
40
Romifidine produces more or less ataxia than xylazine?
Produces less ataxia than xylazine
-Effects 45-90 mins
-Typically LA dentals
41
Dexmedetomidine onset after IV is how long?
- 1-3 mins IV
-Quick onset
-IM 5-10 mins
-90-120 mins effects last
-Reversed with Atipamezole
-Smaller patients
42
Medetomidine analgesic effects last how long and sedation?
-Onset in 10 mis IM, faster if IV
-30 mins analgesia
-2 hrs sedation
-Reversed with Atipamezole
43
Latest drug on the market
Zenalpha
Should it be used in cats?
-Mixture of medetomidine and vatinoxan (peripheral alpha2 agonist)
1. Procedural sedations
2. Short onset 5-15 mins
3. Short duration
4. CV stability maintained at more acceptable levels
5. Reversed with Atipamezole
NOT in cats as hypotension is seen
44
Alpha-2 Antagonists
-Yohimbine: reversal for Xylazine typically
-Tolazoline: reversal used in camelids
-Atipamezole: concentration was formulated to the volume of injectable dose of dexmedetomidine
Tolazoline Toxicosis in Llamas
45
Benzodiazepines
Synergistic with other drugs for general anesthesia
Diazepam
Midazolam
Zolazepam
MOA: -Enhance the activity of CNS inhibitory neurotransmitters: gamma-amminobutyric acid, glycine, combined with CNS benzodiapzepine receptors. hyperpolarize membranes by opening the chloride channels.
-Reduces sympathetic output, minimal sedation, muscle relaxation, and antiseizure effects
Reversal: Flumazenil
Desirable effects
-No anelgesia
-Relax muscles
-Antiseizures effects
-Minimal calming effects
-Diasepam Stimulate appetite and produce pica (abnormal craving).
-Midazolam and Zolazepam are water soluble.
-Antagonize by Flumazenil
46
Diazepam
Where is it metabolized?
How fast can it be administered?
How long is the effects?
Can you mix with other drugs for use in cats?
-Paradoxical excitement and aggression can occur.
-Water insoluble, NOT IM (poor absorption and painful)
-Must be formulated in propylene glycol to make drug soluble.
-SLOW administration to prevent bradycardia, hypotension, or apnea.
-1-4 hours
-DO NOT mix except Ketamine. Liver failure in cats
47
Midazolam
Where is it metabolized?
How long is the effects?
Do you get the desirable results in normal to excitable patients?
-Liver, but metabolites are inactive
-Shorter acting and less risk of accumulation
-Absorbed through mucosal membranes in the oral cavity and in the stomach (intranasal or rectal).
-Water Soluble can IV, IM
-Better choice for sick, debilitated or older animals.
-2hrs
-NO, it won't get them calmed down
48
Reversal of Benzodiazepines
Is it expensive?
Flumazenil
-Expensive
-Do not give to epileptic patient
49
Opioids
Where are they metabolized?
MOA: Act by reversible combination with one or more specific receptor (e.g., mu and kappa, delta) in the brain and spinal cord producing a variety of effects including analgesia, sedation, euphoria, dysphoria, and excitement.
Coupled to G-protein receptors that ultimately decrease conductance through calcium channels and open inward potassium channels, hyperpolarizing membranes and decreasing propagation of action potentials.
-Several senses are not significantly depressed by opioids: touch, vibration, vision, hearing, smell.
-Often administered before (preemptive), during (adjunctive), or after (rescue analgesia) surgery for analgesia.
-Metabolized in the liver
50
What are the CNS effects of opioids?
How do they especially affect cats and horses?
What are some of the negative effects?
-CNS effects include sedation, euphoria, dysphoria.
Cats and horses
-anxiety, restlessness, agitation, and dysphoria.
Negative effects
-Depression of respiratory center
-Bradycardia
-GI vomiting, defecation, salivation, decreased gastric emptying time, and ileus (absence of peristalsis, bowel obstruction).
-Miosis occurs in dogs
-Mydriasis occurs in cats
-Increased urethral sphincter tone and inhibition of voiding.
-Disruption of thermoregulation that is dose-related.
51
Morphine
-mu receptor high affinity
-Hydrophilic, longer duration of action than lipophilic opioids
- IM or SQ best
-Dose dependent, MAC sparing effect.
(Minimum alveolar concentration or MAC is the concentration of a vapour in the alveoli of the lungs that is needed to prevent movement (motor response) in 50% of subjects in response to surgical (pain) stimulus. MAC is used to compare the strengths, or potency, of anaesthetic vapours.).
-Duration 4-6hrs
52
Hydromorphone
What is a nice advantage that makes it preferable for horses?
-Semi-synthetic
-5-10 >potent than morphine
-IV, IM, SQ
-4-6 hrs (acute surgical pain 4hrs)
-Hyperthermia in cats
-Less likely to vomit if given IV
53
Fentanyl
-Synthetic
-100 >potent than morphine
-5-10mcg/kg
-IV bolus, followed by continuous rate infusion (CRI).
-Fast onset 1-2 mins
-Short duration 30 mins due to lipophilicity
-Transdermal fentanyl patches available
-Lollipops pediatric use in human anesthesia
54
Remifentanil
-Unique because metabolized by nonspecific esterases.
-Rapidly cleared not dependent on liver or kidney function
-Half as potent as fentanyl
-Requires CRI
-3-7 recovery after discontinuation
-Intense analgesia for a short time perfect
55
Methadone
Pure mu agonists
-Similar potency to morphine
-IV, IM dogs
-Least likely of mu agonist opioids to cause vomit
-NMDA receptor antagonist and serotonin reuptake inhibitor, which could improve analgesia and help prevent development of tolerance
-2-6 hrs.
-Very expensive.
56
Butorphanol
-Mixed agonist at kappa receptor and partial mu receptor agonist/antagonist
-Used for mild to moderate visceral pain, not effective for severe or orthopedic/dental pain
-IV, IM, SQ
-Duration 30 mins-2hrs
-Can be used to reverse sedative effects on respiratory mu agonists.
**Useful premed for bronchoscopy or airway exam, also upper GI scope because it does not prevent passage of scope through pyloric sphincter.**
57
Buprenorphine
-Partial mu agonist and an antagonist at kappa receptors
-Not adequate for severe pain
-Difficult to antagonize
-Long duration of action 4-8 hrs, maybe 12
-Slow onset 30 mins after IV
-IV, IM, SQ (not recommended), or transmucosal in cats
58
Simbadol
(buprenorphine injection)
-SQ use in cats for 24 hrs surgical pain control
-FDA approved for cats
-Up to 3 dose daily total 72 hours
-10 ml $200
59
Transdermal Buprenorphine (Zorbium)
-FDA approved in 2022
-Postop pain up to 4 days in cats
-Risk of accidental exposure for others
-Do NOT use in debilitated patients
-At least 4 mts of age and 2.6lbs
Adverse effects
-Hyperthermia, sedation, dysphoria, alterations in BP
60
Opioid Antagonists
Naloxone
-Reversal pure mu and mixed agonist/antagonist ex: butorphanol.
-High affinity for mu and kappa receptor
-Rapid onset 1-2 mins
-Lasts 30-60 mins
Nalmefene
Nalorphine
Diprenorphine
Naltrexone: longer duration twice as naloxone, wildlife reversal of carfentanil
61
Neuroleptanalgesia
A state of CNS depression and analgesia produced by the combination of a tranquilizer or sedative and analgesic drug.
-Hypnosis and analgesia
-May or may not remain conscious
-Useful in preanesthetic medication for a short time, simple operative procedure and cesarean section
-Horses become stuporous and attain a "saw-horse" stance.
-Bradycardia and respiratory depression can occur
-Synergism, so dose of each typically reduces
62
What are some examples of neuroleptanalgesia?
-Acepromazine + Opioid
-Benzodiazepine + Opioid
-Alpha2-agonist + Opioid
*Dexmedetomidine (20mcg/kg) + Butorphanol (0.2 mg/kg) + (5mg/kg) Ketamine IM* Kitty magic, castration procedure.
*Dental on a horse: Detomidine 40mcg/kg + Morphine 0.3 mg/kg all IV
63
Lecture 4 Induction of Anesthesia
Induction Drugs
Propofol
Dissociative Anesthetics
Alfaxalone
Etomidate
Barbiturates
Describe the following for the major categories of injectable drugs (listed to the right) covered in this lecture:
1. mechanism of action
2. effects of the drug on the body
3. time to onset and duration of action
4. species specific considerations
5. if contraindications to their use in a patient
6. common clinical usage
64
Propofol
-Abuse usually for its sedative and relaxing properties and induction of euphoric effects.
-It is nor a currently regulated substance that all veterinarians must track, depends on state.
-Milky white oil in water emulsion
**Dogs ONLY**
1. mechanism of action:
-Activates GABAa receptor, increases Cl- conduction and blocks sodium channel.
-Hyperpolarization
-CNS depression and loss of consciousness
-Lipophilic
-Rapid hepatic metabolism and excretion by kidneys Except Grey Hounds and Cats = longer recovery time.
2. effects of the drug on the body:
-Decreases intracranial pressure and cerebral metabolism of oxygen. Anticonvulsant effects.
-Head trauma good choice
-CV: decreases BP
-Pain on injection: can give a small dose of lidocaine IV prior
-Be ready to ventilate patient if needed
Analgesia:
Muscle Relaxation: YES, transient myoclonus
Small volume:
Wide Safety Index:
Short duration of action and non-cumulative: YES
Water soluble (IM):
Minimal CV and respiratory changes:
Readily metabolized and excreted: YES
Long shelf life once vial is opened:
Availability:
Abuse potential: YES
3. time to onset and duration of action
-20-30secs
-Recovery 2-12 mins
4. species specific considerations
-Greyhound and cats longer recovery time
-Horse: rarely used for induction excitation and volume cost, but can be use intra-op
-Swine: does not induce malignant hyperthermia
-Small ruminants and camelids: smooth rapid induction in good quality, but cost in food animals.
5. if contraindications to their use in a patient
-Hypovolemia, advanced age, or decreased left ventricular function.
6. common clinical usage
-Induction
-Constant Rate Infusion (CRI)
-C-section acceptable though crosses placenta barrier
-Can be use in patients with refractory seizures
65
Ketamine and Tiletamine
cats: Zolazepam + tiletamine
dogs: tiletamine + zolazepam
1. mechanism of action:
-Mainly via antagonist effects at NMDA receptor: blocks binding of glutamate receptor and passage of calcium and sodium into the nerve cells = unconscious and relaxed.
-AMPA, BNDF, opioid.
-Ketamine: intranasal, IV, IM. 1 ml per 10 kg in 50:50 ratio per body weight with benzodiazepine or alpha-2 agonist. 5kg = 0.5mg = 0.25 ketamine + 0.25 benzo
2. effects of the drug on the body:
-Dissociation from thalamocortical (consciousness) and limbic (emotion, memory loss).
-CNS: cataleptic effect (not asleep but no response to stimuli).
-Emergence deilrium: ataxia, hyper-reflexive, sensitivity to touch, increased motor activity.
-CV: direct negative cardiac inotropic effects, but usually overcome by sympathomimetic effects.
-Increased BP, HR, CO, myocardial oxygen requirements and cardiac work.
-Inhibition of NE reuptake: increased plasma catecholamines.
-No significant respiratory depression
-Muscle rigidity and even spontaneous movements (which can be diminished with benzodiazepines)
-Increased inter ocular pressure due to increased tone of extra ocular muscles.
-Highly lipophilic crosses BBB and placenta
Analgesia: YES
Muscle Relaxation:
Small volume: YES
Wide Safety Index: YES
Short duration of action and non-cumulative:
Water soluble (IM): YES, but may be painful
Minimal CV and respiratory changes:
Readily metabolized and excreted:
Long shelf life once vial is opened: YES
Availability: YES
Abuse potential: YES
3. time to onset and duration of action
-60 sec if IV or 10 min if IM
-Duration: 7-23 minutes
4. species specific considerations
-Cats form an active metabolite excreted unchanged in urine.
-Reports of fatal pulmonary edema in cats
-Dog: combine ketamine with benzodiazepine for induction, but can also use a alpha-2 agonist or opioid
-Cats: combine with ketamine, alpha-2 agonist, or benzodiazepine, and or acepromazine for IM
-Caution: dissociative seizures-like behavior can occur.
-Horses: adequately sedate before induction. Ketamine with benzo, or alpha-2 agonist, or guaifenesin
Telazol inductions are smooth, but recovery can be rough
-Ruminants: combine Ketamine with benzo, or guaifenesin
"ketamine stun" technique sub-anesthetic dose of ketamine (and xylazine) given to calves prior to castration
-Swine: does not induce malignant hyperthermia
Telazon reconstitute with 250mg xylazine and 250mg ketamine
Calm, slow recovery, not for pot belly pigs due to prolonged recovery
5. if contraindications to their use in a patient
-Not to be used in cats with renal insufficiency
-Contraindicated if pancreatic or severe CV or pulmonary disfunction
-Avoid critically ill patients with decrease reserve, decrease BP
-Avoid if severe CV disease, tachycardia or arrhythmiaa.
-Avoid in C-section due to fetal depression
-Caution if hepatic dysfunction or pancreatitis.
6. common clinical usage
-CRI at sub anesthetic to reduce inhalant requirements and provide analgesic effects. NOT as sole analgesic agent
-Oral, ocular, and swallowing reflexes remain intact; nystagmus is common. Eyes stay open, provide lubrication.
66
Telazol
1. mechanism of action:
2. effects of the drug on the body:
Analgesia: YES
Muscle Relaxation: YES
Small volume: YES
Wide Safety Index:
Water soluble (IM): YES
Minimal CV and respiratory changes:
Short duration of action and non-cumulative:
Readily metabolized and excreted:
Long shelf life once vial is opened: IF REFRIGERATED
INEXPENSIVE
Availability: YES
Abuse potential: YES
3. time to onset and duration of action
-60 sec IV or 10 if IM
-35-70 mins, can take up to 3-5 hours for full recovery (shorter in dogs than in cats).
4. species specific considerations
-Cats
-Not to be used if pancreatitis
5. if contraindications to their use in a patient
-Not to be used in cats with renal insufficiency
-Contraindicated if pancreatic or severe CV or pulmonary disfunction
6. common clinical usage
-shelter medicine combined with other drugs
67
Alfaxan (multi dose)
-Historically poorly water soluble. Combined with castor oil vehicle, dogs anaphylactic reaction
-Now, no longer reaction
-P450 hepatic metabolism and elimination via kidneys and feces.
-Shelf life = 56 days addition of preservative/
1. mechanism of action:
-Neuroactive steroid molecule binds to GABAa receptor to increase Cl- conduction into cell, hyper polarization of postsynaptic membrane = CNS depression
2. effects of the drug on the body:
-CNS: decreases Cerebral blood flow, Intracranial pressure, and Cerebral Metabolic Rate O2 consumption.
-CV: hemodynamic stability at clinically relevant doses, but can dose-dependent hypotension due to vasodilation.
-Muscle relaxation
-Neofetal crosses placenta barrier. Safe for C-section.
-Increase interocular pressure in dogs
-Transient excitement (cats), paddling, vocalization (dogs).
-Rough recovery reported in horses
-Recommended quiet room recovery
Analgesia: NO
Muscle Relaxation: YES, it is good
Small volume:
Wide Safety Index: YES
Water soluble (IM): YES, IV also
Minimal CV and respiratory changes: YES
Short duration of action and non-cumulative: YES
Readily metabolized and excreted: YES
Long shelf life once vial is opened: YES
Availability: YES
Abuse potential: ?
3. time to onset and duration of action
4. species specific considerations
-Horses rough recovery
-Dogs IOP
-Cats excitement
5. if contraindications to their use in a patient
6. common clinical usage
-Typically for induction
-CRI to maintain anesthesia
-C-section surgery
-Acceptable induction agent in dogs
-No pain on IV injection
-Scheduled IV substance controlled
68
Etomidate
What would make this induction drug desirable for use in patients with trauma to the head? ICP
1. mechanism of action: GABBAa
2. effects of the drug on the body:
-CNS depression
-Hypnosis
-Rapid penetration of brain, quick induction
-Metabolism by liver and plasma esterases; excreted in urine.
-Rapid redistribution
-Hyperosmolality can result in perivascular irritation (pain on injection) and intravascular hemolysis following prolonged administration.
-Endocrine: Adrenocortical suppression (5hrs in cats, 6hrs in dogs)
-Muscle tremors can occur
-Neonatal minimum effects
-CNS: decreases Cerebral blood flow, Intracranial pressure, and Cerebral Metabolic Rate O2 consumption.
-Decreases IOP
-Respiratory minimal effects
-Adequate benzo prior to etomidate decreases myoloclonus.
Analgesia: NO
Muscle Relaxation: YES
Small volume:
Wide Safety Index: YES
Water soluble (IM):
Minimal CV and respiratory changes: YES YES
Short duration of action and non-cumulative: YES
Readily metabolized and excreted:
Long shelf life once vial is opened:
Availability: YES
Abuse potential: No reports
3. time to onset and duration of action
-Quick
-5-12 min
4. species specific considerations
-Cats: drooling, salivation, concern for intravascular hemolysis.
5. if contraindications to their use in a patient
-Adrenocortical suppression problem if not healthy
-Caution with Addison's disease patients or highly stressed patients.
-No CRI due to adrenocortical suppression and RBC damage possible.
6. common clinical usage
-Preferred induction agent for patients with hemodynamic instability, increased ICP or cirrhosis
-Commonly seen in referral practice
69
Thiopental
-Generally IV
-short shelf life: 3 days at room temperature or 7 days in refrigeration
-Not commonly used in large animals
-Apnea induction
1. mechanism of action:
2. effects of the drug on the body:
Analgesia:
Muscle Relaxation: YES
Small volume:
Wide Safety Index:
Water soluble (IM):
Minimal CV and respiratory changes:
Short duration of action and non-cumulative:
Readily metabolized and excreted:
Long shelf life once vial is opened:
Availability:
Abuse potential: YES
3. time to onset and duration of action
-20-30 sec, 10-30 min
4. species specific considerations
5. if contraindications to their use in a patient
6. common clinical usage
70
Trick up your sleeve, Opioid induction.
-Fentanyl + benzodiazepine
-Ketamine + propofol (ketofol)
-Guaifenesin + ketamine (double drip)
-Guaifenesin + ketamine + xylazine (triple drip)
-Guaifenesin + thiopental
-Propofol + thiopental
-Ketamine + xylazine (or dexmedetomidine for SA; Detomidine for LA).
-Telazol + ketamine + xylazine or dexmedetomidine
-Ketamine + alfaxalone.
71
Lecture 5
Maintenance of anesthesia
Learn Objec
-Physical and chemical properties of inhalant anesthetics, determine their method of administration and determine their effect in the patient
-List and explain the factors that cause a rapid change in alveolar anesthetic tension
-Define minimum alveolar concentration (MAC), know the values for isoflurane and sevoflurane for main domestic species anesthetized and factors that affect MAC
-Describe the effect that inhalant anesthetic drugs have on the body
-Understand the different methods of general anesthesia: inhalation, anesthetics, total intravenous anesthesia (TIVA), and partial intravenous anesthesia (PIVA).
72
Currently Used Inhalants
Isoflurane
Sevoflurane
Desflurane
Nitric Oxide (N20)
Halothane: not in US.
73
Chemical and Physical Characteristics
Kinetics in the Patient
Determinants for method of administration
1. Solubility of gas
-Blood/gas partition coefficient
-Oil/gas partition coefficient
2. Method of administration depending on
-Boiling point
-Liquid density (specific gravity)
-Vapor pressure
Where does it want to go?
How does it get there?
Does it require a preservative?
74
What are properties that are altered to reduce by halogenation? (Fl, Cl, Br)
1. Reactivity
2. Potency
3. Flammability: ether was too flammable
75
Gas vs. Vapor
Vaporizer machines do not require an energy source/electricity to function. They take heat source from the environment, that's why they are cold to the touch.
1. Gas: agent that exits in gaseous form at room temperature and sea level. Ex: N20. Inhalant is the only proper term in anesthesia
2. Vapor: gaseous state of a substance that at ambient temperature and pressure is a liquid. Ex: Isoflurane, sevoflurane, halothane, desflurane.
3. Gas: gas laws describe predictable behavior of gases
-Boyle's law (volume vs. pressure)
-Charles law (volume vs. temperature)
-Gay-Lassuc's law of partial pressure. (temperature vs. pressure)
-Dalton's law of partial pressure
76
What is vaporization in anesthetics?
-Vapor pressure of an anesthetic is the measure of the ability to evaporate (enter gas phase)
-Saturated vapor pressure (SVP) = max concentration of molecules in vapor state.
Temperature dependent, unique for each anesthetic agent. Treat as if at sea level and then adjust for temp.
**Latent heat of vaporization** temperature remains constant as liquid turns into gas.
77
Saturated Vapor Pressure
-If temp of liquid decreases = lower vapor pressure/concentration
How much vapor is formed from 1ml of liquid isoflurane?
-Specific gravity = 1.52 g/ml
1 ml = 1.52 g
-Molecular weight = 185 g
1.52 g divided by 185g = 0.0081 mole
-Since one mole of gas = 22.4 L at 0 degrees Celcius then:
0.0081 mole x 22,400 ml/mole = 181.4 ml of isoflurane vapor at 0 celcius (273 K)
-181.4 ml x (293/273) = 197.1 ml at 20 celcius
78
Is the SVP of most anesthetics safe for clinical use?
No, it is not
-Must control amount delivered to patient
-Gas delivered by pass or vaporizing chamber
-Modern vaporizers are variable-bypass, concentration calibrated, agent-specific, and temperature compensated.
79
Blood- Gas Solubility Partition Coefficient, what is it?
What does a lower number mean?
What does the ratio affect?
What is FA/FI?
What anesthetic inhalant will have longer induction and recovery period according to B/G partition coefficient?
- Distribution of gas between blood and the alveolar gas.
-Lower the number the less soluble gas in blood
-Ratio of drug concentration at equilibrium
-Low B/G coefficient inhalant = short induction and recovery times. Partial pressure, we want it to stay in the gas phase. Need for the anesthetic to reach the CNS.
-FA/FI: Fraction of drug in Alveolar, Fraction of drug Inspired.
-Sevoflurane = 0.69 closest to 1/1 = 1 best
-Isoflurane = 1.41
-Nitrous Oxide = 0.42
80
What is the pressure flow and factors that rapidly change alveolar pressure (PA)?
1. P delivered
2. P circuit
3. P inspired
4. P alveolar
5. P expired
6. P arterial
7. P tissues
8. P venous
9. P alveolar
10. P expired
1. Change in alveolar delivery
-Altered inspired anesthetic concentration: Increase vaporization of agent, decreased vaporizer setting, increased fresh gas inflow, decrease gas volume of anesthetic circuit.
- Alter alveolar ventilation
-Minute ventilation
-Dead space ventilation
2. Change the removal from alveoli
-Blood solubility of anesthetic
-Cardiac Output
-Alveolar-venous anesthetic gradient
81
What factors rapidly Increase alveolar pressure? (PA)
A. 1. Altered inspired anesthetic concentration
-Pdelivered, Pcircuit, Pinspired, Palveolar.
a. increased vaporization of agent
b. increased vaporizer dial setting. Oxygen flow effects (needs to change in circuit).
c. Decreased gas volume of patient breathing circuit. Ex: from 10 L to 1 L bag.
A. 2. Increased alveolar ventilation
a. Increased minute ventilation
b. Decreased dead space ventilation (where there is no gas exchange).
B. 1. Decrease the removal from alveoli
-Palveolar, Parterial, Ptissues, Pvenous.
a. Decreased blood solubility of anesthetic
b. decreased cardiac output
c. decrease alveolar-venous anesthetic gradient
82
What are the effects of cardiac output on anesthetic inhalants?
Cardiac output
-carries the anesthetic away from the lungs
-Greater the CO the slower the rate of rise of alveolar concentration of anesthetic
-Excited, stressed animals have slow inductions
-Hypovolemia or heart failure with low cardiac output may have rapid induction
83
What are the time constants in Anesthetics?
-Dividing the capacity of the system by the flow through the system.
-Results in the time that it takes to achieve a percentage of total change in concentration
-Ex: to make a 98% change in concentration = 4 Time constants
-Initially the machine is full at room air temperature: 0% anesthetic, Room air is 20% oxygen and 80% nitrogen.
-Tc = volume of machine/gas flow
-has a volume of 6L, Fresh Gas Flow is set at 1 LPM.
-Tc= 6L/1LPM = 6 min (0%)
-So to change the isoflurane concentration from 0% to 2% it takes 4 Tc. So, 6min x 4 Tc = 24 minutes. But, I can change LPM (liter per minute) to 3 instead of 1, 6/3 = 2 min, 2x4= 8Tc.
84
What is the MAC?
Minimum alveolar concentration of inhaled anesthetic at 1 atmosphere that produces immobility in 50% of subjects exposed to a supramaximal noxious stimulus.
-Standard of measuring potency
-Inverse relationship
-Corresponds to ED50, want 95% effective dose
-95% usually 1.2 to 1.4 MAC
-1.5 MAC produces moderate anesthesia "Surgical MAC"
-2.0 deep anesthesia
85
What factors affect MAC?
Decrease
-BP <50mmHg
-Hypothermia
-Drugs CNS depression
-Smaller body size
-Age of animal (geriatric)
-Hyponatremia
-Pao2 < 40mmHg
-Pregnancy
-Disease State (severe anemia, hypovolemia, sepsis, hypothyroidism).
Increase
-Hyperthermia
-Drugs that cause CNS stimulation (ephedrine)
-Increased metabolic rate and/or stress
-Hyperthyroidism
No change
-Gender
-anticholinergic
-duration of anesthesia
-abnormal K+
-Metabolic alkalosis or acidosis
86
What are the advantages of Isoflurane?
-No preservative needed
-Low blood-gas solubility
-Great for short procedures
-More potent that sevoflurane
-Fairly rapid induction and recovery
-Good muscle relaxation
-Less cardiac depression but more respiratory depression: -hypotension due to vasodilation and decreased myocardial contractility.
-Hypoventilation is common
-<1% metabolized in body
-Mostly eliminated lungs
-Reasonable cost
-Mask induction, noxious odor may lead to breath holding and bronchoconstriction
-Produces carbon monoxide when exposed to disiccated CO2 absorbent
87
Sevoflurane
-Lower blood-gas partition coefficient than Isoflurane
-More rapid induction and recovery
-Lower potency, need higher vaporizer setting
-Similar cardio-respiratory depression to Isoflurane
-Good muscle relaxation
-Could trigger malignant hyperthermia
-Mask induction, less odor, smoother induction.
-3% metabolized in body eliminated in lungs the rest
-Can be degraded by CO2 absorbents to produce Compound A (no clinical significance).
88
Lecture 6 NSAIDs
Learning objectives
89
What do NSAIDs provide and what do they target?
do they provide immunosuppression?
-Provide anelgesia, anti-inflammatory, anti-pyretic (allaying fever) and target the source of the pain instead of masking perception.
-No immunosuppression, affordable, not controlled substance, convenient to administer.
90
What is the NSAIDs mechanism of action?
-Block cellular expression of COX enzymes.
-Flow:
1. Trauma or toxin
2. Cell membrane phospholipids
3. Phospholipase (target or Glucocorticoids, block)
4. Arachidonic acid cascade
5. a. Lipoxygenase = leukotrines and other inflammatory mediators
-Inflammation, hyperalgesia, bronchoconstriction, vasoconstriction, plasma leakage.
b. Cyclooxygenase (NSAIDs target, block here).
-Cox and Lox enzymes initiate a complex cascade that results in conversion of polyunsaturated acids to PGE2, thromboxane, and leukotrines = activate membrane receptors and produce many effects including pain and inflammation
-Prostaglandin PGE2: hyperalgesia, inflammation.
91
What are the first steps of arachidonic acid cascade?
What activates COX-2?
Where are COX 1 and COX2 expressed?
Cox has a bifunctional role depending on the isoform and target tissue.
1. Release of AA mediated by phospholipase A2 (PLA2) from injured cell membrane
2. AA is a substrate for generation of varios eicosanoids (PGs, TXA2, leukotrines)
3. Production of TXA2, PGs is mediated by COX.
4. Inflammatory mediators = increased vascular permeability, heat, decreased, nociceptor sensitivity increase.
Activation of COX2
-Bacterial LPS
-Inflammatory cytokines: IL-1, TNF-alpha
COX1 and COX2
-expressed in kidney
-COX1:
Constitutive Isoform of COX
control renal blood flow and GFR. Basal PG production = homeostasis "housekeeping function"
Stomach, kidney, platelets, repro-tract. Gestation and parturition
-COX2: sodium and water excretion
Induced isoform of COX
Neural tissue, repro and renal. Homeostatic function
**Continuously produced in certain areas of brain, pathologic in most tissues**
Also, In smooth muscle, endothelial cells, chondrocytes, fibroblasts, monocytes, macrophages, synovial cells.
92
Where do NSAIDs work?
COX2
PGs and pain
-CNS and peripheral tissue
-Inhibition of COX2 = peripherally blocked tissue. No PGs, no dilation of arterioles, nor sensitized nociceptors (pain) bc no histamine and bradykinin.
-COX2 produced in CNS, lowering threshold of neuronal depolarization.
PGs
-Release of PGs from activated tissue within the CNS and Spinal cord results in increased signaling molecules = promotes hyperalgesia and allodynia.
-Inflammatory response, vasodilation, mediators and cytokines (Histamine, Bradykinin)
-Mediated by COX2
-Can't solely target COX2 because Gastric Ulcers side effects.
93
Which Coxibs are approved for use in animals?
-Deracoxib
-Firoxib
-Mavacoxib
-Robenacoxib
94
Are NSAIDs water soluble? How long for action? Route of administration? Duration of effect? Protein binding? Metabolize where?
-Lipid-soluble
-Weak organic acids
-Oral administration
-30-60 mins onset of action
-Duration 24 hrs
-High degree of plasma protein binding
-High protein binding = consistent delivery to tissues
-Liver metabolism to inactive metabolites
95
Should you use systemic steroids while NSAIDs?
How many NSAIDs at a time?
What organs/systems function should be evaluated prior to administration? How many days should you wait prior to switching?
Is Aspirin, ibuprofen, naproxen, and meloxican approved/good for cats and dogs?
What are some contraindications?
-Not concurrent with systemic steroids
-One at a time
-Kidney, liver function
-Offer lowest effective dose for shortest duration possible
-5-7 washout period before swtiching
-naproxen, and meloxican NOT approved/good for cats and dogs
Contraindications
-Renal or hepatic insufficiency
-Active GI disease
-Pregnancy
-Decreased circulatory volume (dehydration, hypotention, shock, hypovolemia, heart failure, ascites, active hemorrhage or suspected blood loss)
-Known sensitivity
-Systemic steroid use
96
Nine ways to minimize risks
What step is critical when prescribing pets NSAIDs?
Pet owners need to be told what the possible side effects are and their clinical signs
-Carprofen 75 mg. Discontinue and alert DVM if inappetence, vomiting, diarrhea, dark stools occur.
-Usually happens within 48-72 hrs
97
Carprofen Features and Considerations
What is it approved for?
Routes of admin?
-COX2 Selective, COX1 sparing
-Platelet function alterations
-Chronic use should be avoided
-Possible liver dysfunction
-Major Side effect: GI upset
-Approved for dogs, osteoarthritis, soft tissue surgery, pain and inflammation.
-IV, chewables, SQ.
98
Deracoxib
Features and Considerations
What is it approved for?
Routes of admin?
-COX2 Selective, COX1 sparing
-Major Side effect: GI complication (perforation of ulcer).
-Approved for dogs, osteoarthritis, soft tissue surgery, pain and inflammation.
-Oral approved
99
Firocoxib
Features and Considerations
What is it approved for?
Routes of admin?
COX2 selective COX1 sparing
-Major Side effect: GI upset, but minimal
-Approved for dogs, osteoarthritis, soft tissue surgery, pain and inflammation.
-Injectable and Oral approved for equine also.
100
Meloxicam
COX2 selective COX1 sparing
-Major Side effect: GI upset mostly
-Approved for dogs, osteoarthritis, soft tissue surgery, pain and inflammation.
-Transmucosal oral mist, parenteral formulations approved
-Cats approved single dose orthopedic surgery, castration, OHE in USA.
**Warning renal failure and death associate with repeated use in cats**
101
Robenacoxib
COX2 selective COX1 sparing
-Major Side effect: GI upset, but minimal
-Approved for dogs, osteoarthritis, soft tissue surgery, pain and inflammation.
-Injectable SQ
-Cats approved >4mts of age
102
Grapiprant
-Prostaglandin Receptor antagonist (PRA)
-Dogs approved: OA pain, inflammation.
-Blocks EP4 receptor the primary mediator of canine OA pain
-No inhibition of homeostatic functions housekeeping prostanoids
103
Aspirin
Non selective COX inhibition
-Non use in VetMed much
-Mostly used for anti-thromboxane effects (antiplatelet plug).
-Washout period of 10 days in dogs
104
Acetaminophen NOT and NSAIDs
-Cats susceptible to toxicity, methemoglobinemia within a few hours followed by heinz vody formation.
-Cats >10-40mg/kg
-Dogs> 100mg/kg
105
Acetaminophen NOT and NSAIDs
-Cats susceptible to toxicity, methemoglobinemia within a few hours followed by heinz vody formation.
-Cats >10-40mg/kg
-Dogs> 100mg/kg
106
Piroxicam
Cox-2 selective in dogs
-Longer half-life in dogs
-every 24-48 hrs
-Neoplastic cells Tx
-GI upset
107
Flunixin meglumine
Non-selective NSAID
-FDA approved inflammation and fever in FOOD ANIMALS
-Colic and endotoxemia horses
-Oral paste, not IM
-Dogs: occasionally for ocular inflammation single dose.
108
Phenylbutazone
Non-selective NSAIDs
-musculoskeletal pain and inflammation in horses
-Prohibited in cattle
-GI ulceration, renal necrosis, anemia.
-Paste oral, injectible, tablets
109
Ketoprofen
Non-selective Cox1 inhibition
-Low dosage safe for OA in dogs long term
-Horses, birds, cats, not approved for food animals.
-Injectable
110
Diclofenac Sodium
-Topical anti-onflammatory cream Tx joint pain OA in horses
-Commonly used in humans
-Acts locally, safer than systemic NSAIDs
-Liposomal formulation for slow absorption and elimination
111
Etodolac-FYI
-Kerratoconjunctivitis historically interesting, not on market
112
GI side effects
Caused by PGs inhibition
COX1 mediates production of PGs that decrease hydrochloric acid secretion and increase bicarbonate and mucus production
-Inhibition of intestinal healing mechanism, gastric ulceration
-Inappetence
-Nausea, vomiting, diarrhea amy include blood
-GI ulcer
Lab results
-Decrease HTC and TP
-Increased BUN
-Elevated leukocyte count
FDA NSAIDs for pets, remember
-BEST FS
-Behavior, eating less, skin redness, scabs, tarry stools, diarrhea, STOP.
113
Renal Side Effects and Hepatic
Due to PGs inhibition
-Renal dysfunction
If dehydration: NO NSAIDs
pre-anesthetic screening
Limit use of NSAIDs after operation
-Hypovolemic: vasoconstriction of afferent arteriole loss of medullary perfusion
Hepatic
-Carprofen associated with idosyncratic hepatocellular necrosis in labrador retrievers
-Rare
-Monitor liver function while NSAIDs
114
Bone and Cartilage
Coagulation Effects
-PGs important in bone repair and bone homeostasis
-Altered bone healing after fracture or bone surgery.
-Ok to use post-op but not for weeks
Coagulation
-Aspirin is the only one drug of concern due to irreversible effect on platelet function that persists until platelets are replaced. Discontinue 7-10 days after surgery
115
Treatment NSAIDs Toxicity
1. Famotidine: H2-receptor blocker decrease dose in renal failure
2. Sucralfate: mucosal protectant. Separate from admin of abx and antiacids
3. Omeprazole: Proton pump imhibitor. Do not admin a partial tablet unless dissolved in HCO3
4. Pantoprazole and Misoprostol: Prostaglandin analog. Do not give if pregnant
5. Metoclopramide: Promotility agent. Do not admin if GI FB or other mechanical obstruction suspected.
116
Lecture 8 Adjunct Drugs and Interactions
Balanced anesthesia: simultaneous use of multiple drugs and techniques for calm pain free experience with few adverse effects as possible
Multimodal analgesia: using two or more different drugs or techniques to manage pain
117
Does Maropitant (Cerenia) prevent gastroesophageal reflux (GER)?
What is it used for?
What is its MOA?
What are the indications for use?
-No, it does not prevent GER
-Antinausea (antiemetics), vomiting that could lead to aspiration pneumonia.
-MOA: Neurokin-1 receptor antagonist used for motion sickness.
-Admin prior to premedication, before hydromorphone (nausea still present after)
-MAC lowering effects
-Give 1 hr prior or 2 hrs if oral prior to car ride.
118
Chemoreceptor Trigger Zone (CTZ)
-Neurotransmitters: Dopamine, adrenaline (epinephrine), 5-HT, Acetylcholine, histamine, encephalins, and substance P.
-Xylazine: alpha2-adrenergic agonist more potent emetic in cats than dogs.
-D2-dopamine receptor agonist potent in dogs but not cats.
119
Ondansetron (Zofran, human med)
What receptor?
Best for vomiting or nausea?
-MOA: 5-HT3 receptor
-Better for nausea than Maropitant
-Works at the level of the vomiting center in the brain, prevents vomiting due to chemo drugs or anasthetic
120
Metoclopramide
-Best bolus and continuous infusion
-MOA: blocks D2-dopamine receptor in CTZ. Blocks serotonin receptor.
-May increase CNS depressant effect
-STOP if GI obstruction or history of seizures
121
Histamine receptor antagonists
Diphenhydramine = Benadryl (H1)
Famotidine (H2)
Ranitidine (H2)
-MOA: histamine receptor antagonist. H2 or H1
-Decreases acid production in the stomach
122
Proton pump inhibitors
Pantoprazole
Omeprazole
-MOA: decrease gastric acid production by blocking H+/K+ ATPase pump.
-Long acting drugs
-Not recommended for routine use
-Omeprazole: effective at reducing incidence GER
-Omeprazole: can be use for Tx neoplasia, hepatic disease, inflammatory bowel disease, gastroduodenal ulcers with underlying cause such as NSAIDs.
123
NSAIDs MAC sparing effect
-Carprofan: decreased MAC of Sevo to 2.10% in digs
-Meloxicam: decreased MAC of Sevo to 2.06% in dogs.
-MAC of sevo in dogs typically 2.4%
124
Glucocorticoids
NEVER concurrent with NSAIDs
-anti-inflammatory, anelgesic, immunosuppressive, and for physiologic support of Addisonian patients.
-Exacerbates hyperglycemia
-Do not give if head trauma
125
Antibiotics
-Cefazolin: IV slowly 5 min(hypotension in anesthetized patients)
-Unasyn (ampicillin/sulbactam): IV slowly 15-30 min
-Gentamicin: IV slowly
-K-pen: IV slowly
-Naxcel: used in food animals
126
Aminocaproic Acid
Anti-fibrinolytic agent.
-Good for Greyhounds (higher rate of bleeding) post operative increase clot strength
-24-48hrs post op bruising typical in Greyhounds
-Slowly IV 30 min
-vWD
-Preoperative management of dogs with liver disease or dysfunction
127
Desmopressin
vWF
-Synthetic replacement for Vasopressing: hormone that reduces urine production
-Hormone that increases vWF temporarily, secretion from endothelium
-Nasal spray typically
128
Dantrolene
-Peripherally acting muscle relaxant
-MOA: Rynodine receptor antagonist = Reducing Ca++ release from SR into cytoplasm
-Pigs, humans, dogs, horses
-Tx malignant hyperthermia and exertional rhabdomylosis
129
Doxapram
CNS stimulant
-Arousal from sedation
-MOA: Not fully understood. Significant increase in minute ventilation through an increase in RR and tidal volume.
-Short-lived effects
-Cortical stimulation
-Avoid in epileptic patients
130
Guaifenesin (GG or glyceryl guaiacolate ether)
-Relaxant and sedative properties
-MOA: unknown
-Combine with Ketamine in horses and ruminants
-Induction and maintenance
-Risk of hemolysis
-Risk of thrombus
-Females rapidly eliminate
131
Continuous Rate Infusion drugs
Lidocaine
Ketamine
Opioid (Fentanyl, Remifentanil, Morphine, Hydromorphone, Butorphanol, Buprenorphine)
Lidocaine: Local anesthetic, Tx for ventricular arrhythmias.
-MAC sparing
-Anti-inflammatory
-Analgesic
-Stimulates GI motility
-NOT for CATS
-Equine OK: discontinue 30 minutes prior to end of anesthesia.
-Impactions, duodenitis-jejunitis, Ileus contractions.
-Often given for 1-3 days
**Preserves microvascular integrity, prevents neutrophil migration, inhibits cytokine production.
-May cause ataxia
Ketamine: NMDA receptor antagonist binds at CNS (stimulation of NMDA receptors in spinal cord = pain signals) receptors and prevents "wind up"
-Best for neuropathic pain when chronic
-Always combine with opioid
-Hyperalgesia, next allodynia, where more painful stimuli is perceived by spinal cord when chronic pain = amplification of signals. "wind up"
Opioid (Fentanyl, Remifentanil, Morphine, Hydromorphone, Butorphanol, Buprenorphine)
-Loading dose given first
-Recommended IV fluid pump over a free drip rate
132
Drug Incompatibillities
Diasepam: precipitation occurs in aqueous solutions and absorption in soft plastic bags
Epinephrine, dobutamine, dopamine: incompatible with alkaline solutions
Phenylbutazone: precipitates with aqueous solutions
Sodium bicarbonate: do not mix with solutions that contain calcium (LRS) precipitation will accour.
133
Morphine-Lidocaine-Ketamine (MLK) CRI
-Lowers Isoflurane MAC significantly
-In 500 ml bag of fluid at 5ml/kg/hr add:
a. 24 mg of morphine
b. 60 mg of Ketamine
c. 300 mg of Lidocaine
134
Additional Analgesic Adjuncts
-Gabapentin
-Pregabalin
-Tramadol
-Amantadine
-Amitriptyline
-Acetaminophen: CATS NEVER
-Locoregional anesthesia
-Dexmedetomidine CRI
135
Drug Interactions
Can be harmful or beneficial
Can be in vivo or in vitro
In vitro
-Drug precipitation
-Drug toxicity product
-Drug inactivity
-Acid-base reactions
-Chemical incompatabilities
In vivo
-Absorption
-ABCB1
-Hepatic clearance
-Drug protein binding
**Vets are compounding drugs when mixing in syringe**
136
MDR1 gene mutation (aka ABCB1 mutation)
Butorphanol
Acepromazine
-Some Herding breed dogs: limited ability for drug absorption and distribution, delayed excretion making them susceptible for toxicity
-Mutation in gene coding for P-glycoprotein
-Drstically affect drug
a. absorption
b. distribution
c. metabolism
d. excretion
-P-glycoprotein part of BBB, protects from toxicity accumulation
-Blood or swab test DNA test
-Three/four Collies have MDR1 a.k.a ABCB1 mutation
What can happen?
-These dogs may have more serious side effects, CNS depression, respiratory depression, recovery may take longer.
-Recommended to reduce dose by 25-50% in homozygous dogs
137
Terms to know
Adddition: additivity of fractional doses of two or more drugs
Synergism: response to fractional doses if greater than response to the sum of the fractional doses
Potentiation: enhancement of action of one drug by a second drug that has no detectable action on its own.
Antagonism: opposing action of one drug toward another. Can be competitive or noncompetitive
Isobologram
-If curve is concave = synergy
-If curve if convex = antagonism
-Additivity in the middle.
138
Lectures 8 & 9
Fluid therapy
Overview
-Almost all drugs used to produce anesthesia decrease the force of cardiac contraction and cause vasodilation
-Hypovolemia as result
-IV fluids and drugs help maintain adequate blood volume, improve tissue perfusion, and cardiac output.
-Fluids to treat acid-base imbalances, electrolytes.
Choices
a. Balanced electrolyte solution or Crystalloids
b. Colloids
c. Plasma
d. Cell-free blood substitutes
e. Blood
Common side effects of anesthesia
-Depress minute ventiation; respiratory acidosis may occur
-Decrease urine output and renal concentrating ability
-Predispose to hypothermia
-Hypotension
-Fluid loss leads to metabolic acidosis
Normal Body water Distribution
-60%, 40% intracellular, 15% interstitial, 5% plasma
-Extra cellular fluid = 20% (blood) Plasma 5%
-Interstitial fluid = 15%
-Intracellular = 40%
-Blood volume constitutes 8-10% of body weight.
Electrolyte Distribution
-Extracellular: Na, Cl. Plasma: albumin, glycoproteins, antibodies, glucose, etc.
-Plasma osmolarity: sodium chloride, potassium, glucose, urea, and others.
-Plasma osmolarity = 2(Na) + (glucose) divided by (Blood urea nitrogen)/2.8. Normally 280-300mOsm/kg
-Intracellular water contains K+ lots.
139
Principles of Fluid Administration
-Correct dehydration 24-48 hrs prior to surgery
-30-60 ml/kg/day normal daily fluid maintenance in animals
-6-8% dehydration: obvious delayed in return of tented skin, slightly increase CRT, Eyes sunken and dry mucous membrane.
-Monitor hemodynamics, pulmonary, and renal function when administering fluids rapidly
-Monitor blood pressure
-Improve renal function before anesthesia
-Mannitol IV induces urine production
-Overhydration can lead to pulmonary edema increasing respiratory effort
140
Fluid administration during anesthesia
-Usually polyionic isotonic crystalloid solutions ex:
Crystalloid: 0.9% NaCl, Lactated Ringer's solution. Need 4L or more to increase plasma volume by 1L
Hypertonic crystalloid: 7.5% Saline (NaCL). Need 300ml to increase plasma volume by 1L
-Colloid solutions ex:
Starch. Need 1L to increase plasma volume by 1L
Natural colloids: albumin
synthetic: gelatins, dextrans, starches.
Replacement Rates
-small animals: 3-10 ml/kg/hr
-Large animals: 3-5 ml/kg/hr
-Blood loss: 3 ml crystalloid or 1-1.5 ml colloid/1ml of blood
141
What is the approximate ratio of crystalloids to blood in replacement?
What are the typical guidelines for fluid replacement?
What do hypertonic fluid affect?
-Approx 3ml of crystalloid per 2 ml of blood (3:1 ratio) as high as 8:1 in traumatized patients
-If HCT >20% and TP >3.5 g/dl blood is replaced with crystalloids
-Crystalloids diffuse within 20 mins after completed administration
-Blood loss up to 15% normally tolerated. 20-30% moderate. 30-40% severe. 40-50% life threatening
Hypertonic fluids
-Increase vascular volumen by pulling water from interstitial fluid space into vascular space.
-Increase arterial pressure, cardiac output, renal perfusion and diuresis.
-7% use for hypotension and shock. Good for head trauma patients.
Overdose of HS
-Hypernatremia, hyperchloremia, and nonrespiratory acidosis, cardiac arrhythmias possible.
Colloids
-Compare to crystalloids produce acute and lasting increase in
-Intravascular volumen, Arterial BP, Cardiac Output, Tissue perfusion and oxygen delivery
-Maintain intravascullar osmotic pressure and prevent fluid extravasation.
-May prolong bleeding time.
Blood Substitutes
-Oxygen carrying but now always
-HBOCs (hemoglobin based oxygen carriers)
-Replace Hb in anemic patients
-Improve oxygen delivery
-Polymerized bovine hemoglobin in modified lactated Ringer's solution is a colloid solution that carries oxygen.
-2 years shelf life
142
Contraindications of fluid therapy and recommendations
-Fluid overload can result in heart failure and pulmonary edema.
-Crystalloids can be mixed with colloids to maintain vascular volume and systolic arterial BP.
-Restore blood volume and tissue perfusion: maintain systolic arterial BP 80-90 mmHg
-Maintain Hg >7 g/dl, PVC > 20%
143
Lectures 10-11
Pain Mechanisms I and II
What is pain?
-"unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage"
-An inability to communicate does not negate the possibility that a human or nonhuman animal experiences pain.
-Hierarchy of response
a. Homotopic withdrawl reflexes
b. Autonomic outflow changes, increased heart rate and pressure
c. Activation of hypothalamopituitary axis, yielding increased circulating concentrations of a variety of stress hormones (prolactin, adrenocorticotropic hormone ACTH, cortisol).
144
The Pain Phenotype
Pathways of Pain
-Peripheral nerves extension of the CNS
a. Sensory
b. Motor
c. Autonomic never fibers
-Action potentials are carried to the dorsal horn of CNS where they are encoded and relayed to the supraspinal sites within the brainstem (medulla, pons, mesencephalon, diencephalon, telencephalon).
-Brainstem: drives various somatic and autonomic responses (e.g., activation of parasympathetic (vagal) and preganglionic sympathetic outflow).
-Noxious stimuli
a. Mechanical
b. Chemical
c. Thermal
Pathways
Transduction
Transmission
Modulation
Projection
Perception
145
Acute Nociception
-physiological response generated by high-intensity stimuli
-Circuitry
a. Primary sensory afferents
b. Dorsal horn of the spinal cord.
c. Projection fibers to the brain
d. Central pain processing centers.
-The pain threshold is the point at which stimulus intensity is just strong enough to be perceived as painful e.g., a vocal report.
Primary Afferents and Dorsal Root Ganglia
-A-delta (myelinated) and C (unmyelinated) sensory afferent: pain, mechanical, thermal, and chemica (C).
-A-beta (rapidly conducting): tactile and physical stimuli, touch, pressure. Myelinated
-A-alpha: proprioception, fast conducting. Myelinated.
-The high threshold A-delta are called nociceptors. Skin, muscles, all inner organs. Mechanical forces, chemical such as inflammatory cytokines, pH, and temperature.
-The C fibers are called polymodal nociceptors. High intensity thermal, mechanical and chemical products.
-Noxious stimuli activates G-protein coupled receptor or the specialized transient receptor potential channel (TRP).
146
Pain Pathways
-AlphaBeta (Large myelinated) = Group II fastest: Low threshold mechanical (tactile or joint position)
-AlphaDelta = Group III less fast: Low threshold, mechanical or thermal. High threshold mechanical or thermal (specialized nerve endings).
-C (small myelinated) = Group IV slow: High threshold thermal, mechanical, chemical (polymodal nociceptors).
Dorsal Root Ganglia (DRG)
-Cell bodies of afferent axons provide main trophic support for the afferent nerve. Neurotransmitter synthesis.
-Large A and small B neurons: centrally nerve roots and peripherally nerves.
Terminal transduction and action Potential
-Peripheral terminal activation travels to peripheral terminal (antidromic conduction) and back to spinal cord (orthodromic conduction)
a. Low threshold transducers
b. High threshold transducers: activated by extreme changes of intensities.
147
Transmission at the first-order synapse
AMPA (Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
NMDA (N-Methyl-D-aspartate).
The primary afferent synapse shows several specific characteristics and properties
-Terminal depolarization: opening of voltage-gated calcium channels (CaV) to activate synaptic proteins (SNAREs). Results in EXOCYTOSIS of transmitter into the synaptic cleft.
-Release of transmitter initiates postsynaptic excitation. -GLUTAMATE = principal afferent transmitter. It affects postsynaptic ionotropic receptors.
-AMPA receptor: mediates acute membrane activation through massive increase in sodium conductance
-NMDA receptor: when activated leads to a large increase in Ca++ conductance, mediates more persistent input.
148
Spinal Cord Dorsal Horn
Second order neurons
-Gray matter: sensory input
-White matter: projection fibers link spinal cord with brain
-Dorsal horn: receives input from AlphaBeta, AlphaDelta, and C fibers.
-Ventral horn: motor neurons, skeletal muscle.
Rexed laminae: gray matter of spinal cord division
Marginal Layer (Lamina I)
-Neurons that respond to nociceptive and thermal input from AlphaDelta and C fibers.
-Project to thalamus, periaqueductual gray matter (PAG), lateral parabrachial area, nucleus of the solitary tract, and medullary reticular formation (RF).
Substantia Gelatinosa (Lamina II)
-Receives noxious or thermal stimuli from AlphaDelta and non-peptide C fibers
-IIi (inner subdivision)
-IIo (outer subdivision)
Nucleus Propius (Laminae III-IV)
-Receive low threshold sensory information (touch, innocuous temp) AlphaBeta fibers.High threshold from AlphaDelta and C fibers (viscera, skin, muscle).
-Lamina V neurons are wide dynamic range (WDR) because they receive convergent input.
149
Ascending spinal tracts
-Studies demonstrate that unilateral injury of the ventrolateral quadrant will yield contralateral thermal or mechanical analgesia below that spinal section.
150
Central Pain Processing Centers
-Perception: recognition and processing of sensory information occurs in multiple specific areas of the brain, which communicates via interneurons to produce an integrated response, arousal, somatosensory input and autonomic and motor output.
-Several neural pathways (redundancy) parallel processing for ensuring adequate input to CNS.
-Cortex: Perception
-Thalamus: Integration
-Limbic Cortex-Cingulate gyrus: Behavior, emotion
-Periaqueductal gray: Modulation
-Locus ceruleus: Arousal, vigilance. NE (inhibitory)
-Reticular formation: Antinociception
-Hippocampus: Memory
-Hypothalamus: Autonomic, Homeostasis, synaptic modulation
-Amygdala: Fear, anxiety
The reticular activation system (RAS): in the brain stem and critical, mediates motor, autonomic, and endocrine responses.
151
Tissue Injury and Inflammatory Pain States
Factors leading to altered peripheral afferent response properties: changes in local chemical milieu
Peripheral Sensitization
"Sensitizing Soup" = algogenic products = Hyperalgesia
-Damaged tissue: products K+, H+, NE
-Local inflammation: histamine, peptidases, PGs, TNF-alpha, Leukotrines
-Blood products: 5-HT = serotonin, Bradykinin
-Transmitters released from local C fibers primary afferents (Substance P, CGRP).
Central Sensitization
-Allodynia
-Strong (high-instensity) persistent stimuli activates C fibers.
-Release of transmitters, Glutamate, Substance P, BNDF (Brain derived neurotrophic factor)
-Activation of AMPA, NMDA, Neurokinin-1, and Tyrosine receptor kinase B(Trk B).
-Gene expression and change.
152
"Wind up" phenomena
-WDR neurons exhibit a dependent response to C-fiber stimuli. Rapid repetitive electrical stimulation of C fibers results in "wind up"
-Increase in pain intensity over time
-Non-noxious afferent input from dermatomal areas adjacent to the un-injured region yields discomfor (ALLODYNIA).
153
Acute Onset Postsynaptic Events
1. Glutamate release from primary afferents
2. Receptor-linked ionophores
a. AMPA: fast depolarization, sodium
b. NMDA: Magnesium block in resting state. Remove during activation and allows Glutamate activation = influx of Ca++
= Central Sensitization
**Blocking spinal AMPA receptor = virtual anesthetic-like state
**Blocking NMDA (ex: ketamine) = reduces "wind up" but NO EFFECT on NOCICEPTION
154
Delayed-Onset, Intermediate-Duration Postsynaptic Events
Persistent C-fibers activity = more enduring intracellular biochemical cascades
-Ca++ activation of phospholipase A2 (PLA2).
-Arachidonic acid is released from plasma membrane, available as substrate for COX1 and COX2
-Production of PGs, NO, etc.
-Normally local inhibitory circuits control and regulate excitation.
-GABA-ergic and glycinergic neurons changes or reductions in regulation leads to an enhanced response of the second order neurons evoked by large afferent nerve fibers.
155
Slow-Onset, Long-Duration Postsynaptic Events
-Increased intracellular calcium
-Activation of a variety of transcription factors, activate protein synthesis and expression of COX1 and COX2 and NO
156
Activation of Silent Nociceptors
-Silent nociceptors, skin deep tissues contain additional nociceptors called "silent or sleep" nociceptors
-Normally unresponsive to noxious mechanical stimulation, but become active (responsive) to mechanical stimulation during inflammation and tissue injury
-Transient Receptor Potential
Vanilloid type 1: molecular integrator for a broad variety of unrelated noxious stimuli.
Targets
TRPV1
TRPV3
TRPV4
TRPV8
157
Pain and Stress
Hypothalamo-pituitary adrenal axis
-Behavioral changes: flight or fight, freezing, panting, facial expressions
-Autonomic nervous system:
Sympathetic: tachypnea, tachycardia, hypertension, salt and water retention, sweating, piloerection, pupil dilation
Parasympathetic: urination, defecation, bradycardia, gastric ulcers.
-Neuroendocrine activation: Increased cortisol, hyperglacemia, epinephrine, norepinephrine.
158
Sickness syndrome
Glial Cell Neuroinflammation
-Occurs when animals are semi-continuously or continuously exposed to factors that activate the immune-inflammatory response (ex: endotoxins, chronic disease, CNS trauma, reperfusion injury)
-Cytokines: IL-6, TNF-alpha: activate glial cells in the CNS contributing to Centralized Sensitization State.
-Chemokines
-Trophic factors (NGF)
-Endothelins
-Hyperalgesic state
-Malaise, fever, depression, inappetence, somnolence, anxiety, relentlessness, inability to sleep/rest.
-Manage: shelter, food, warmth, bedding.
Allostasis: the protective, coordinated, adaptive body response/reactions that ensure the process of sustaining homeostasis stay within the normal range.
NSAIDs and specialized pro-resolution mediators (SPMs): lipoxins, resolvins, protectins, and maresins polyunsaturated fatty acids (fish oil).
159
Stress
"surgical stress" is produced by procedure and anesthesia.
-C-reactive protein and heptoglobin are correlated with the severity
-Inhalant anesthetics, opioids, and alpha-1 agonists modify and depress the surgical stress response.
-Stressor
-Defense response
-Distress: biological cost o stress negatively affects homeostasis, pain and suffering.
-Stress alters the CNS microenvironment and disinhibits the immunoregulatory mechanisms that constrain microglial and neuroinflammatory processs producing a primed state of activation.
-Alarmins (danger signals)
-DAMPSs damage-associated molecular patterns
-HMBG1 a stress protein; a cytokine mediator of inflammation
-Modulation
160
Neuroendocrine Axis
What is the most important component (release) of stress?
CRF from brain
Humoral communication between CNS and the peripheral glands or organs
Acute surgical stimulation initiates the release of cytokines (IL-1, IL-6, TNF-alpha) into the bloodstream and activation of the hypothalamic-pituitary-adrenal (HPA) system axis and the sympathetic nervous system. Adrenocorticotropic hormone is released (ACTH), vasopressin or ADH, GH, and thyroid stimulating hormone (TSH). Sympathetic release of Epinephrine, norepinephrine, cortisol, aldosterone, and renin.
Together these changes an alter hemodynamics, elevate heart rate, increase blood coagulability predisposition to thrombosis, increase metabolic rate, caloric requirement, and when exaggerated, depress immune function.
***Release of Corticotropin-Releasing Factor in the Brain is the most important component of Stress***
161
ACTH
Cortisol
Catecholamines
Glucagon and Insulin
Other hormones
-ACTH: from pituitary, increases during anesthesia.
-Cortisol: stimulates gluconeogenesis, increases proteolysis and lipolysis, facilitates catecholamines effects and produces anti-inflammatory effects.
-Catecholamines: inhibition of insulin release, peripheral insulin resistance, lipolysis. Elevated heart rate, RR, and BP.
-Glucagon and Insulin: surgery increases glucagon, decreases insulin secretion.
-Other hormones: GH, TSH, vasopressin, act together to protect cellular function and restore homeostasis.
-GH: spares glucose for use by CNS.
-TSH: carbohydrate metabolism, heat production, enhances catecholamines
-Vasopressin: ADH same
Protein supplementation: fewer infections and better recovery after surgery, help maintain body temperature.
Hematologic and Immune response to stress
-Cytokine production
-Acute-phase response
-Neutrophil leukocytosis
-Lymphopenia
-Immune system depression
162
Endogenous Opioids
Endocannabinoids
Leukocytes secrete endogenous opioids:
-Beta-endorphin
-Enkephalin
-Dynorphin
They suppress peripheral C-terminal excitability and inflammatory mediator release.
-Anti-inflammatory effects in peripheral nociceptor
Endocannabinoids
-CB1 receptor in the brain, immune system and other peripheral tissues
-CB2 primary immune cells
They produce anxiolytic, neuroprotective, anti-inflammatory immune-suppressing effects.
-Involved in Pain sensation, appetite, memory.
-TRPV1 vanilloid receptor present in C terminals and in the endings of primary sensory neurons, produced in response to tissue trauma.
-Anandamide modulates peripheral pain mechanisms, agonist effects on TRPV1 and cannabinoid receptors.
163
Assessing Pain
Pain States
1. Nociceptive: Evidence of noxious (mechanical) insult
-Pain localized
2. Inflammatory: evidence sterile or infectious inflammation: redness, warmth, swelling, loss of function.
3. Neuropathic: evidence of sensory nerve damage
-Burning, tingling, shock-like, spontaneous pain, parenthesias or dysthesias.
4. Dysfunctional/Centralized: pain in the absence of detectable pathology.
164
Pain scoring system
1. Behavior
-Visual analogue scales
0: none
1-3: mild
4-6: moderate
7-10: severe
-Demeanor: anxious, depressed, distressed, quiet
-Response to people: aggressive, fearful, indifferent
-Posture: curled, hunched, rigid, tense
-Response to food: disinterested, eating hungrily, picking
-Mobility: lame, slow, reluctant, stiff, unwilling to rise
-Activity: restless, still, sleeping
-Response to touch: crying, flinching, growling, guarding
-Attention to painful area: chewing, licking, looking
-Vocalization: crying, groaning, howling, screaming.
2. Severity of pain
3. Duration of pain
4. Mechanism of pain
