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254 Cards in this Set
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- 3rd side (hint)
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What are the five characteristics of general anesthesia?
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1. amnesia; 2. analgesia; 3. unconsciousness (may or may not); 4. inhibition of sensory and autonomic reflexes; 5. skeletal muscle relaxation
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What is balanced anesthesia?
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preoperative administration of drugs for sedation and analgesia and interoperative use of neuromuscular blocking drugs and/or regional anesthetics with the general anesthetics
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What are the four signs and stages of anesthesia?
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I. Analgesia and Amnesia (amnesia prior to loss of consciousness; pain sense lost, but motor activity and reflexes are normal); II. Excitement (delirium); III. Surgical Anesthesia (rhythmical respirations); IV. Cardiorespiratory Collapse (requires ventilatory and circulatory support, never used/required)
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What is the theorized mechanism of action for Inhaled Anesthetics?
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GABAa receptor chloride channel, facilitating GABA inhibition, ultimately increases threshold for firing CNS neurons
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Are highly lipid soluble anesthetics more or less potent?
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more potent (have very low ED50)
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What is used for the measure of potency of inhaled agents?
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MAC (minimum alveolar concentration), or the minimum concentration at 1 atm that prevents movement during a noxious stimulus in 50% of people
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What factor is the MAC of an inhaled drug multiplied by to achieve near 100% (95%) clinical efficacy?
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1.3
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What factors change the MAC of an inhaled drug? What factors don't change the MAC?
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Do change: body temperature, age, and other drugs (opiods, benzodiazepines)
Do Not change: sex, species, state of oxygenation, acid-base changes, and arterial blood pressure |
None
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What three factors determine the tension of anesthetic gas in the brain?
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inspired concentration; transfer of the gas to the arterial blood; and transfer of the agent to the brain
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What four factors determine how rapidly anesthetic gases pass from the inspired gas to the brain?
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the solubility of the anesthetic in blood; rate and depth of ventilation; rate of blood flow through the lungs; the partial pressure of the anesthetic in arterial and mixed venous blood
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What are the direct cardiovascular effects of inhaled anesthetics?
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All are myocardial depressants (by ↓ intracellular Ca2+); all volatile gases are negative chronotropes; there is variation in the baroreceptor function and sympathetic tone
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What is analgesia?
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a state of decreased awareness of pain, sometimes amnesia
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What are the clinical circulatory effects at normal anesthetic doses of Halothane?
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myocardial depression; ↓venous tone and inhibition of baroreceptor reflex (bradycardia) →↓CO and BP & ↑intracranial pressure (due to ↓cerebral vascular resistance)
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What are the clinical circulatory effects at normal anesthetic doses of Isoflurane, desflurane, and sevoflurane?
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myocardial depression; ↓venous tone with active baroreceptor reflex (tachycardia) → ↑/↔CO and ↓BP
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What are the clinical circulatory effects at normal anesthetic doses of Nitrous Oxide?
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myocardial depression; ↑venous/arterial tone tachycardia → ↑CO and ↑BP (acts like a sympathetic stimulant)
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How does an inhaled anesthetic's blood/gas coefficient relate to the speed of anesthetic induction?
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drugs with low b/g coefficient (ie. nitrous oxide) are not very soluble in blood so equilibrate quickly with the alveoli and are quick to induce their effect, while drugs with high b/g coefficient take more time to reach higher blood tensions
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How does an increase in the minute ventilation affect the anesthetic gas tension in arterial blood? Does this more greatly affect drugs with a low or high blood/gas partition coefficient?
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as minute ventilation increases the gas tension in the arterial blood also increase (direct relation) this more significantly affects drugs with a high blood/gas coefficient
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How does pulmonary blood flow (cardiac output) affect the rate at which anesthetics pass from the alveoli to the arterial blood?
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an increase in pulmonary blood flow slows the initial rise in arterial tension, (overall there is little change in total time); however a low CO preferentially feeds the brain and speed anesthetic induction
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How does the tissue/blood partition coefficient vary between lean and fatty tissues?
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the coefficeint is low for lean tissues because the drug usually has similar solubility with blood and lean tissue; however it is high for fatty tissues because they are highly fat soluble
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Do drugs with a low or high blood/gas solubility coefficients wash out more quickly?
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low
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If the administration of an inhaled anesthetic lasts longer than 45 minutes will the elimination be delayed? Why or why not?
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it will be delayed if it has a high fat solubility regardless of the drug's blood/gas coefficient because a significant amt of drug has been delivered to fat tissue
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What are the volatile halogenated hydrocarbon inhaled general anesthetics?
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Halothane, Isoflurane, Sevoflurane, Desflurane
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What are the gaseous general anesthetics?
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Nitrous Oxide
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What are the ultrashort-acting barbiturate general anesthetics?
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Thiopental, Methohexital
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What are the sedative-hypnotic general anesthetics?
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Ketamine, Etomidate, Propofol
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What are the opioid general anesthetics?
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Morphine, Fentanyl
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What are the benzodiazepine general anesthetics?
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Midazolam
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Do all general anesthetics increase or decrease cerebral and global oxygen consumption?
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decrease, in healthy individuals the decrease in O2 consumption always exceeds the reduction in CO
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Do all general anesthetics increase or decrease CO2 responsiveness? Increase or decrease ventilation in a dose-dependent manner?
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decrease and decrease
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What do inhaled anesthetics do to ventilation?
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decrease tidal volume and increase rate (except isoflurane); produce an apneic threshold (4-5 mmHg below resting CO2)
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What do inhaled anesthetics do to renal function and urine output?
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decrease
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What is Fa/Fi?
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fraction of [alveolar anesthetic]/ fraction of [inspired anesthetic]; how long to saturate the brain
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Where are all anesthetics metabolized to some degree?
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the liver
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What determines the onset of action of an anesthesia?
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blood flow to receptor organs or tissues; solubility in that organ
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What two factors play a role in the termination of an anesthetic?
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elimination and redistribution; follows zero order kinetics
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What are the aminoester local anesthetics?
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procaine, cocaine, tetracaine, benzocaine
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What are the aminoamide local anesthetics?
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lidocaine, mepivacaine, bupivacaine, L-Bupivacaine, ropivacaine
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What is the definition of local anesthetics?
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they produce a loss of sensation and attenuate muscle activity in circumscribed areas of the body by reversibly blocking nerve conduction
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What local anesthetic is used as a cardiac antiarrhythmic?
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lidocaine
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What nerve fiber class is unmyelinated? Myelinated?
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unmyelinated: C fibers; myelinated: A and B fibers
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What is the structural similarity between aminoamide and aminoester local anesthetics?
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both involve the joining of a hydrophobic aromatic group to a hydrophilic base (tertiary amine) via their respective bond
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What state of a local anesthetic is the most active form at a receptor site?
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the cationic, ionized state
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What state of a local anesthetic is important for penetration of biological membranes?
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uncharged state
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What does the hydrophobicity (lipophilicity) of the aromatic group of a local anesthetic determine?
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is directly related to the potency and duration of the block, bc of the tendency of the compound to associate with membrane lipids
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Where do local anesthetics work?
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block open sodium channels on the cytosolic side of a cell, they are most effective on small nerves, myelinated nerves, and those that fire at high frequencies (ie fast firing pain-conducting neurons)
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Are local anesthetics more or less effective in acidotic, inflamed tissue?
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less effective, bc they are in their ionized state and unable to enter the nerve cells and provide their function in blocking pain signaling, yet need to be ionized in a more acidic state within the cell to be in its active state
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Why is epinephrine added to most local anesthetics?
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bc it produces local vasoconstriction and slows the removal of the drug from the site of injection and provides for a longer duration and less bleeding; does not effect onset or intensity of the drug
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What are contraindications for using epinephrine with local anesthetics?
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cardiac tachyarrhythmias, ischemic heart disease, hypertension, uteroplacental insufficiency, block in an area of poor collateral circulation (digit, penis); intravenous regional anesthesia
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How are aminoester local anesthetics metabolized? Aminoamide local anesthetics?
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aminoester: by circulating plasma cholinesterases to PABA (therefore no toxicity); aminoamide: in liver by microsomal enzymes and excreted in bile/urine
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What local anesthetic is used as a topical anesthetic to provide skin anesthesia?
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prilocaine and lidocaine cream mixture
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What class of local anesthetics are not toxic?
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Esters because they are metabolized in the blood
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Why can amide local anesthetics cause toxicity?
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because with sufficient absorbtion into circulation they can produce CNS activation (excitation, lightheaded, dizzy, tinnitus, blurred vision, seizures) and CV toxicity (negative inotropy and chronotropy) (CNS is more sensitive than the heart)
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What class of local anesthetics causes an allergy?
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esters because when they are metabolized they produce PABA which is an allergen for some people
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What class of local anesthetics does not cause an allergy?
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amides, although the preservative that some are stored with, methylparaben, can lead to hypersensitivity
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Which amide local anesthetics preferentially block the sensory over motor systems? Why is that beneficial?
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Bupivacaine, L-bupivacaine, Ropivacaine; beneficial in labor epidurals so the mother can still push
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Can the dose of an anesthetic be more or less when administered with a vasoconstrictor?
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more, because less of a concern that it will effect the central vacular system
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What does the degree of toxicity of a local anesthetic depend upon?
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dose administered, local vascularity, inclusion of a vasoconstrictor for amides; or plasma cholinesterase deficiency for esters
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What are the uses of local anesthesia in surgery?
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local infiltration, field block, intravenous regional anesthesia, nerve block, centro-neuroaxial block (subarachnoid aka spinal or epidural)
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Where is the anesthetic placed for a spinal?
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in the CSF of the subarachnoid space, blocking all nerves at or below the site of injection, resulting in the drug concentration to move and dilute as it moves away
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What is the sensitivity of a spinal block on different neurons?
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sympathetics are most sensitive followed by sensory and motor are the least sensitive
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What are the cardiovascular effects of centro-neuraxial blocks?
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arterial dilation and venodilation → ↓CO and BP; if a high block (T1-T4) can cause bradycardia due to unopposed vagal stimulation but below T4 will result in tachycardia to compensate for drop in CO and BP
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What are the respiratory effects of centro-neuraxial blocks?
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thoracic level: reduced vital capacity due to abdominal m. paralysis, but tidal volume is normal; high spinal does not result in respiratory arrest because cannot block phrenic nerve but can be a result of hypoperfusion of respiratory center of brain
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What are the GI effects of centro-neuraxial blocks?
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hyperperistalsis due to unopposed vagal activity, ideal for intra-abdominal surgery but not good for bowel obstructions; cause nausea and vomiting (Rx atropine)
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What are the renal effects of centro-neuraxial blocks?
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minimal effect on renal perfusion/function; postoperative urinary retention
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What factors increase the incidence of postdural puncture headache?
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younger age, females>males; larger needle, > when pregnant, standing
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What is given to treat hypotension resulting from centro-neuraxial blocks?
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ephedrine
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What are side effects of both spinals and epidurals?
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postdural puncture headache or diplopia, hypotension (nausea, vomiting, respiratory arrest); bradycardia (if above T4, treat with atropine or ephedrine); backache
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What are side effects of just spinals?
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failed; neurologic injury (transient radicular irritation treated with lidocaine)
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What are side effects of just epidurals?
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accidental dural puncture, total spinal anesthesia, intravascular injection with acute toxicity, systemic absorption, failed
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What is a secondary headache?
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severe pain in the head unassociated with the musculature of the head of vascular disturbances, a sign of severe pathology or benign issue: tumor, trauma, HTN, LP, inflammation, metabolic changes, drug intox, caffeine withdrawl
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What is a primary headache?
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headache is both the symptom and the disease, tension headache, migraine headache, cluster headache
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What are the warning signs and signals of a secondary headache?
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singular, sudden onset, onset after 50 years of age, systemic signs (fever, myalgia, weight loss), systemic dz (malignancy, AIDS), change in headache patterns (frequency, severity), neurologic symptoms or abn physical findings
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What is the general treatment of primary headaches?
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symptomatic treatment via analgesia, or treat underlying syndrome to control the symptoms
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What is the general treatment of secondary headaches?
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treat the underlying process independently from analgesia treatments
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What is the pain medication ladder?
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the slow progression from weaker analgesics to stronger analgesics in the management of pain, start with OTC meds and work up if needed to control the pain
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What two drug classes are specific for the treatment of primary headaches?
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triptans and ergot alkaloids (both treat migraines, there are no dz specific treatments for cluster or tension headaches)
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What is classical vs. common migraines?
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classical: have prodrome aura; common: lack prodrome aura
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What are characteristics of a tension-type headache?
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duration of 30min-7days, bilateral, non-pulsatile pressure pain that is not aggravated by physical activity, no vomiting, occasionally associated with nausea, photophobia or phonophobia, has musculoskeletal component
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What are characteristics of a migraine headache?
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duration of 4-72hrs, unilateral, pulsatile severe pain, aggravated by physical activity, associated with nausea/vomiting, photophobia, phonophobia, timing of menstrual cycle, triggers, awaken from sleep, but sleep abates pain, familial history, dizziness, vertigo
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What are characteristics of cluster headaches?
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more common in men age 20-30, severe unilateral orbital pain with ipsilateral autonomic (horner's) symptoms, duration of 15-180 min triggered by alcohol, genetic predisposition, repeated occurrence of attacks with periods of remission, often begin in REM sleep
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What effects are mediated by the 5-HT 1A, 1B, 1D receptor?
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neuronal inhibition of CNS neurons, smooth m. relaxation, contraction of some vascular smooth muscle
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What effects are mediated by the 5-HT 2 receptor?
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neuronal depolarization, vasoconstriction of most blood vessels, bronchoconstriction, contraction of GI smooth m., platelet aggregation
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What effects are mediated by the 5-HT 3 receptor?
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neuronal depolarization leading to activation of autonomic reflexes, neuronal excitation in the CNS
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What effects are mediated by the 5-HT 4 receptor?
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gastrokinetic action, myocardial stimulation, esophageal relaxation
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What is the role of serotonin in the treatment of migraine?
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serotonin stimulation of 5-HT 1D receptors causes neuronal inhibition of CNS neurons, and 5-HT 1B receptors relaxes smooth muscles, this selective drug binding is critical to the therapeutic efficacy
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What medications used in the treatment of migraines have established a statistical and clinical benefit (class A evidence)?
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triptans, DHE, acetaminophen/aspirin + caffeine, aspirin/ibuprophen/naproxen sodium
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What do the three different classes/grades of evidence mean?
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A: multiple well-designed randomized clinical trials, relaengt to the recommendation with consistent pattern of findings
B: some evidence from randomized clinical trials support the recommendation, but not optimal C: consensus on the recommendation in the absence of relevant trials |
None
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What are the indications for using preventative treatment of migraines?
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recurring migraine that is disabling despite acute treatment, frequent attacks (>2/week) which increases the risk of overdose of symptomatic medicines, pt has problems with acute medications (ineffective, contraindicated, side effects); pt. preference; presence of uncommon migraine conditions (hemiplegic migraine, prolonged aura, basilar migraine, migrainous infarct)
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What are the goals of preventive migraine treatment?
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reduce attack frequency, severity, duration; improve response to acute treatment; improve function and reduce disability; possibly treat co-morbid conditions
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What are the medicines which can be used to preventatively treat migraines?
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Topiramate, valproic acid, Propranolol, Methysergide, Amitriptyline, Calcium channel blockers (verapamil, nifeipine, flunarizine, and nimodipine)
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How does Topiramate act as a migraine prophylaxis?
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is a broad spectrum anticonvulsant which prevents migraines, has side effects: cognitive disfunction, kidney stones, and weight loss
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How does Propranolol act as a migraine prophylaxis?
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decreases the frequency and severity of attacks, dose not abolish attacks, is the first choice, other β blockers are also used (nadolol, atenolol); contraindicated in PV dz, ischemic heart dz, cardiac failure, bradycardia, depression, DM type I, and asthmatics
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How does Methysergide act as a migraine prophylaxis?
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is an ergot derivative and serotonin antagonist, also used with cluster headaches, doesn't provide symptomatic relief, effect takes 1-2 days to develop, has side effects: hair loss, weight gain, liver dz; contraindicated in pregnancy (causes spina bifida)
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How does Amitriptyline act as a migraine prophylaxis?
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5-HT 2 antagonist, used for tension headaches as well
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What are some alternative (not pharmaceutical) means of preventing migraines?
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regular exercise, biofeedback, relaxation techniques, dietary changes
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What are some symptomatic treatments for migraines?
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salicylates and acetaminophen, triptans, ergotamine (non-analgesic often potentiated with caffeine), narcotic analgesics (codeine, meperidine, hydromorphone, and non-narcotic phenylpiperidine)
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What are some alternative (not pharmaceutical) means of treating acute migraine symptoms?
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manual or cold compression of carotid arteries
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What medicines can be used to preventatively treat cluster headaches?
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lithium carbonate, methysergide, β-adrenoceptor antagonists (propranolol), amitriptyline, calcium channel blockers (nimodipine, flunarizine), corticosteroids
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What medicines can be used to treat cluster headache symptoms?
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inhaled oxygen, injectable sumatriptan, intranasal lidocaine, intranasal DHE
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What are treatments of a lumbar puncture headache?
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intrathecal injection of sterile saline, lower head below the level of the legs, salicylates for mild pain
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What drugs are part of the triptan class of drugs?
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sumatriptan, zolmitriptan, rizatriptan
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What are some ways to prophylatically treat tension headaches?
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assess psychological co-morbidity, stress, address underlying musculoskeletal problems, assess caffeine use, abuse, and withdrawl; pharm: tricyclic antidepressants (amitriptyline, nortriptyline), anticonvulsants (gabapentin, topiramate); muscle relaxants (baclofen, tizanidine)
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What is a seizure?
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finite episode of brain disfunction resulting from abnormal dischard of the cerebral neurons
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What is epilepsy?
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a tendency toward recurrent unprovoked seizures
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What is epileptogenesis?
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sequence of events that converts a normal neuronal network into a hyperexcitable network
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What is a simple partial seizure?
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consciousness is preserved, manifested variously as convulsive jerking, paresthesia, psychic symptoms (altered sensory perception, illusions, hallucinations, affect changes), and autonomic dysfunction. A seizure aura is a simple partial seizure
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What is a complex partial seizure?
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impaired consciousness that is preceded, accompanied or followed by psychological symptoms: zoning out, presence of aura, automatisms, often from temporal lobe epilepsy
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What are secondarily generalized seizures?
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begins focally and spreads with variable symmetry, intensity, and duration of tonic and clonic phases, usually last 1-2 min, postictal confusion, somnolence or transient focal deficit
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What is a tonic-clonic seizure?
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tonic phase (<1min) involves abrupt loss of consciousness, muscle rigidity, and respiration arrest; clonic phase (2-3min) involves jerking of body, with lip or tongue biting, fecal/urinary incontinence
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What is an absence seizure?
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impaired consicousness with sudden onset and cessation, duration 10-45sec, sometimes associated with automatisms, loss of postural tone, enuresis; begin in childhood and grow out; characteristic 2.5-3.5 Hz spike-wave pattern
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What are myoclonic seizures?
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single or multiple myoclonic muscle jerking
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What is status epilepticus?
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a series of seizures (usually tonic-clonic) without recovery of consciousness btw attacks, is a life threatening emergency
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How does epilepsy develop?
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Acquired epilepsy: physical insult, brain tumor, CNS infection, febrile seizures; Genetic epilepsy: genetic mutation, cortical dysplasia, benign familial neonatal convulsions
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What is the general definition of an anticonvulsant?
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a drug which decreases the frequency and/or severity of seizures in people with epilepsy; treats the symptoms of seizures not the underlying epileptic condition
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What percentage of epileptic patients become seizure free with drug therapy? Remain refractory?
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65%; 30%
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What factors are taken into consideration when choosing an antiepileptic drug?
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age, gender, seizure type, epilepsy syndrome, pharmacokinetic profile (pt compliance); interactions, co-morbidity, efficacy, adverse effects, cost
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What are two cellular mechanisms of seizure generation?
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excessive excitation (inward Na and Ca currents; glutamate and aspartate); too little inhibition (inward Cl, outward K currents; GABA)
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What are some extrinsic factors which modify neuronal excitability?
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changes in extracellular ion conc.; remodeling of synapse location or configuration by afferent input; modulation of transmitter metabolism or uptake by glial cells
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What are the targets of anticonvulsant drugs?
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↑ inhibitory NTs (GABA); ↓excitatory NTs (glutamate); block voltage gated inward positive currents (Na or Ca); ↑ outward positive current (K)
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What are the two types of GABA receptors?
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GABAa: post synaptic, specific, linked to Cl channel; GABAb: presynaptic, autoreceptors, mediated by K currents
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Which anticonvulsant drugs act primarily on GABA?
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Benzodiazepines (diazapam/clonazapam; ↑frequency of Cl channel openings); Barbituates (phenobarbital/primidone; increase the duration of Cl channel openings); Gabapentin (may interfere with GABA reuptake); Tiagabine (interferes with GABA reuptake); Vigabatrin
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Which anticonvulsant drug acts by increasing the frequency of GABA-mediated chloride channel openings and which increases the duration?
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frequency: benzodiazepines (diazapam/clonazapam) makes it difficult to overdose on this drug alone; duration: barbituates (phenobarbital/primidone) makes it easy to overdose
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Which anticonvulsant drugs act primarily on Na channels?
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Phenytoin, Carbamazepine (block voltage dependent Na channels at high firing frequencies); Oxcarbazepine (block voltage dependent Na channels at high firing frequencies; also affects K channels); Zonisamide (block voltage dependent Na channels and T-type Ca channels)
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Which anticonvulsant drugs act primarily on Ca channels?
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Ethosuximide (blocks low threshold T-type Ca channels)
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Which anticonvulsant drugs act primarily on K channels?
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Valproate (K channel agonist to decrease hyperexcitability)
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What are the pleiotropic (broad spectrum) anticonvulsant drugs?
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Felbamate (blocks voltage dependent Na channels and modulate NMDA receptor); Lamotrigine (blocks voltage dependent Na channels and interfere with glutamate release); Topiramate (blocks voltage dependent Na channels, increases GABA Cl channel opening frequency); Valproate (enhance GABA transmission, block voltage dependent Na channels, augment K channels)
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What anticonvulsant drugs are inducers of the cytochrome P-450 enzyme system?
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phenobarbital; primidone; phenytoin; carbamazepine; felbamate (CYP3A)
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What anticonvulsant drugs are inhibitors of the cytochrome P-450 enzyme system?
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valproate, topiramate (CYP2C19); oxcarbazepine (CYP2C19; CYP3A); felbamate (CYP2C19)
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What anticonvulsant drugs do not appear to be inhibitors or inducers of the cytochrome P-450 enzyme system?
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Gabapentin; Lamotrigine; Tiagabine; Levetiracetam; Zonisamide
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What are some non-pharmalogical treatments for unresponsive epilepsy?
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surgery (focus region is removed, usually non-dominant temporal lobe); diet (ketogenic diet); implants (vagus nerve stimulation)
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What are the older anticonvulsants?
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phenobarbital; primidone; phenytoin; ethosuxamide; carbamazepine; valproate
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What are the new anticonvulsants?
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felbamate; gabapentin; lamotrigine; topiramate; tiagabine; zonisamide; oxcarbazepine; levetiracetam
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What are the drugs of choice in treating Partial seizures with or without secondary generalized tonic-clonic seizures?
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carbamazepine, phenytoin, valproate, phenobarbital
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What are the drugs of choice in treating primary generalized tonic-clonic seizures?
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valproate, phenytoin, phenobarbital
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What are the drugs of choice in treating absence seizures?
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ethosuximide, valproate
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What are the drugs of choice in treating atypical absence, myoclonic, or atonic seizures?
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valproate
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|
What anticonvulsant drugs also can be used to treat neuropathic pain?
|
Gabapentin, carbamazepine
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|
|
What anticonvulsant drugs also can be used to treat bipolar disorder?
|
lamotrogine, carbamazepine
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What anticonvulsant drugs also can be used to treat migraine?
|
valproate, topiramate, gabapentin
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What are the three uses of NSAIDs?
|
inflammation, fever, pain
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|
|
|
What are prostaglandins?
|
lipid mediators that act in an autocrine/paracrine fashion to promote inflammation, pain, and fever, as well as control a variety of housekeeping functions (cytoprotection of the stomach)
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What are the three distinct classes of NSAIDs?
|
1. aspirin and salicylates; 2. traditional NSAIDs; 3. specific COX-2 inhibitors
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What are some of the therapeutic applications of NSAIDs?
|
mild to moderate pain associated with inflammation; chronic inflammatory dz (rheumatoid arthritis, osteoarthritis, gout); localized musculoskeletal syndrome; pain relief; fever reduction; dysmenorrhea; prophylactic treatment of colon cancer
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What is an aspirin specific therapeutic application?
|
low dose prophylactic treatment to reduce the risk of myocardial infarction and stroke by inhibiting platelet aggregation
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What is the cause of inflammation?
|
non-specific response to tissue damage/infection; due to release of mediators (cytokines, prostaglandins); results in pain, heat, swelling, and redness; intended to attenuate infection to prepare for tissue repair
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How are prostaglandins synthesized?
|
dependent upon cyclooxygenases (COX) enzymes for the rate limiting step; prior phospholipase A2 forms arachidonic acid from plasma membrane phospholipids; the products of the Cox enzymes (prostacyclin and thronboxane etc) cause the response
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What is the mechanism of action that is common to all NSAIDs?
|
inhibition of the COX enzymes activity
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What are the characteristics of COX-1?
|
constitutively expressed; in all tissues; located in endoplasmic reticulum; functions in general housekeeping by the protection/maintenance of different tissues; not induced; inhibited by aspirin and NSAIDs but not celecoxib
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What are the characteristics of COX-2?
|
induced by inflammatory stimuli in macrophages, monocytes, chondrocytes, fibroblasts, osteoblasts and endothelial cells; contitutively expressed at low levels in kidney, endothelium, brain, ovaries, uterus, and small intestine; located in endoplasmic reticulm; functions in the signaling and mitogenesis in pro-inflammatory responses; aspirin, NSAIDs and COX-2 inhibitors effect
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In what three ways do prostaglandins affect pain response?
|
peripheral sensitization of primary afferent neurons by lowering their activation threshold to pain; centrally in dorsal horn neurons enhance the depolarization of the secondary sensory neurons; recruit leukocytes to the site of inflammation leading to more inflammatory mediators
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How do prostaglandins mediate fever production?
|
PGE2 released in the endothelium of the hypothalamus in response to mediators (IL1/TNF) act on the median preoptic nucleus of the hypothalamus and change the temperature set point
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What are the housekeeping functions of prostaglandins produced in the GI system (via COX-1)?
|
PGE2/PGI2 are cytoprotective and limit the damage to the stomach lining from gastric acid and enzymes; ↓gastric acid secretion; ↑gastric bicarbonate production, mucous production, vasodilation to increase gastric blood flow
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What are the housekeeping functions of prostaglandins produced in the cardiovascular system?
|
platelets only express COX-1 and produce TXA2 (thromboxane) for vasoconstriction and platelet aggregation and activation; endothelial cells oppose platelets, express COX1 and 2 and produce PGI2 (prostacyclin) which is a vasodilator and inhibits platelet aggregation; this balance regulates blood pressure/thrombogenesis
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What results from a TXA2/PGI2 imbalance?
|
↑vasoconstriction/platelet aggregation→↑HTN, ischemia, thrombosis, MI, and stroke
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What are the housekeeping functions of prostaglandins produced in the kidney?
|
both COX-1 and COX-2 are constitutively expressed; PGs ↑GFR and water and sodium excretion; promote vasodilation to prevent renal ischemia (important with diseases such as HF and renal dz to counteract vasoconstrictors of the dz state)
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What are the housekeeping functions of prostaglandins produced in the female reproductive system?
|
PGs stimulate uterine contraction and play a role in birth, overproduction during menstruation can cause dysmenorrhea; NSAIDs can delay labor
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What are the housekeeping functions of prostaglandins on the ductus arteriosus?
|
PGs maintain the patency of the ductus during fetal life; NSAID treatment during pregnancy may close the ductus prematurely; NSAIDs can be used in newborns to promote closure of a patent ductus
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What is the mechanism of low dose aspirin in the treatment of CV disease?
|
permanently inhibits COX-1 of platelets since they cannot regenerate it (long lasting)→↓TXA2→↓pro-thrombolytic effects; doesn't affect endothelial cells much bc they can regenerate COX-1 and form PGI2 at low dose but at high doses they can't
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What is the most common adverse effect of all NSAIDs?
|
GI toxicity: epigastric distress, nausea, vomiting, GI bleed, aggravates ulcers; damage due to ion trapping of aspirin; inhibition of PGs to protect the stomach (not caused by Celecoxib due to lack of COX-1 inhibition)
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What can be given to ameliorate the effects of GI toxicity with NSAIDs?
|
misprostol (PGE1 analog); Omeprazole (proton pump inhibitor)
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What kind of adverse reactions can occur in the kidney in response to aspirin and salicylates?
|
hemodynamically-mediated acute renal failure usually in pts with underlying kidney dz or volume depletion (heart failure or cirrhosis) esp in elderly; due to depletion of vasodilatory PGs which counteract the high levels of vasoconstrictors
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What are the six primary adverse reactions to aspirin and salicylates?
|
GI toxicity; acute kidney failure; increased bleeding; exacerbation of HTN/heart failure; Reye's syndrome; hypersensitivity
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What is Reye's syndrome?
|
a unique aspirin side effect which is a rare and often fatal liver degenerative disease with associated encephalitis; is caused when aspirin is given to children with a febrile viral infection
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What is the cause of aspirin's ability to exacerbate hypertension and heart failure?
|
at high doses aspirin promotes vasoconstriction which increases blood pressure and increases the afterload on the heart and decreases cardiac output esp in pts with pre existing HTN or heart failure
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What are the early and later symptoms of aspirin intoxication?
|
early: nausea/vomiting, abdominal pain, lethargy, tinnitus, and vertigo; Later: hyperthermia, hyperventilation, resp. alkalosis; metabolic acidosis; hypoglycemia; agitation; hallucinations; tremors; seizure; cerebral edema, coma, death
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What is the mechanism for aspirin intoxication?
|
salicylates increase respiration causing resp. alkalosis followed by metabolic acidosis; acidified blood promotes salicylate transport into CNS and direct toxicity with cerebral edema, coma, and death
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How does one treat a salicylate intoxication?
|
symptomatic treatment, sodium bicarbonate to counteract metabolic acidosis; if severe: gastric lavage, IV fluids, and dialysis
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|
What characterisitics are common to all NSAIDs?
|
competitive inhibition of COX enzymes, inhibit prostaglandin synthesis; non-selective inhibitors of COX-1 and COX-2 (for the most part); exhibit anti-inflammatory, anti-pyretic and analgesic effects
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What are three ways in which NSAIDs can have an adverse effect on the renal system?
|
NSAID induced vasoconstriction (most common) due to ↓vasodilatory PGs can lead to renal failure in pts taking ACE inhibitors and diuretics; NSAID-induced acute interstital nephritis (Nephrotic syndrome - rare) after several months of exposure inflammatory cells infiltrate; NSAID-induced chronic interstital nephritis (analgesic nephropathy) due to chronic daily overuse
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What adveres effects can NSAIDs have on the cardiovascular system?
|
worsen underlying HTN; interfere with beneficial anti-platelet effect of aspirin (take hrs apart); can worsen pre-existing heart dz by ↑afterload
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What 10 systems can NSAIDs adversely effect?
|
GI; Renal; cardiovascular; liver; anti-platelet effect; hypersensitivity; CNS; skin rxns; pseudoporphyria/photosensitivity; pregnancy
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|
What are general contraindications for all types of NSAIDs?
|
GI ulcers (not celecoxib); bleeding disorders or anti-coagulants(not celecoxib); renal disorders; hypersensitivity; pregnancy; elderly; salicylates for pts with gout; aspirin for children with febrile viral infection
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What is the interaction btw low dose aspirin and all NSAIDs except celecoxib?
|
antagonize beneficial effects of low-dose aspirin (prevents binding of aspirin to COX-1) give at distinct times
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What is the interaction btw oral anti-coagulants (warfarin) and all NSAIDs except celecoxib?
|
increased anti-coagulant effect/ increased risk of bleeding due to platelet COX-1 inhibition and protein displacement
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What is the interaction btw anti-hypertensives (ACE inhibitors and β-blockers) and all NSAIDs?
|
decreased anti-hypertensive effect (NSAIDs promote renal vasoconstriction)
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|
What is the interaction btw diuretic agents (eg. Furosemide) and all NSAIDs?
|
↓diuretic effect - NSAIDs promote water and Na retention (increasing risk of HTN)
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|
What is the interaction btw oral hypoglycemics (sulfonylureas) and salicylates?
|
potentiate hypoglycemic effects (salicylates displace protein-bound sulfonylureas and independently enhance glucose utilization)
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|
|
How does an acupunture needle effect the body's physiology?
|
functions electrically on the body surface; electro-ionically in the interstitial milieu; perineural conduction along the myelin sheaths; nerve and neurohumoral functions; blood input via effects of neurohumoral, cellular, and blood chemistry changes; immunologically
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|
In the JAMA study, what issues was acupuncture shown to be efficacious in treating?
|
adult postoperative and chemotherapy nausea and vomiting, and postoperative dental pain?
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In the JAMA study, what issues was acupuncture shown to be efficacious as an adjunct treatment?
|
addiction, stroke rehab, headache, menstrual cramps, tennis elbow, fibromyalgia, myofascial pain, osteoarthritis, low back pain, carpal tunnel, and asthma
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What endogenous opiod peptide families are implicated in acupuncture analgesia?
|
beta-endorphin, enkephalin (met-enkephalin and leu-enkephalin); dynorphin
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|
What major neurotransmitters are implicated in acupuncture analgesia?
|
serotonin, norepinephrine, substance P, GABA, dopamine, ACTH
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What nerve fibers are important in acupuncture?
|
A-δ and C fibers
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What are the neurochemical effects of low frequency/high intensity electroacupuncture?
|
via stimulation of a small afferent neuron it stimulates a endorphinergic cell to release enkephalin/dynorphin to presynaptically inhibit primary pain fibers in the spinal cord; also ascends in midbrain to excite PAG cells to release enkephalin to disinhibit to dorsolateral tract which will postsynaptically inhibit the secondary afferent pain fiber; activates pituitary release of β-endorphin and ACTH into blood
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|
What inhibits the low frequency/ high intensity electoacupuncture?
|
naloxone because this system involves the use of so many endogenous opioids to elicit its actions
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What are the neurochemical effects of high frequency/low intensity electroacupuncture?
|
stimulates only the spinal cord and midbrain without endorphin synapses (effects not blocked by naloxone); in spinal cord uses GABA to presynaptically inhibit the primary afferent pain fibers
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|
What are the three centers activated by electroacupuncture to cause analgesia?
|
spinal site; midbrain; pituitary (spinal site only activated when needle is placed close to the site of pain; midbrain and pituitary sites are activated regardless of whether the needle is proximal or distal to the site of pain)
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|
What are the characteristics of the analgesia produced by low frequency electroacupuncture?
|
slower onset, long duration; effects are cumulative in repeat sessions, possibly due to increase in mRNA for endorphins seen for 48 hrs after stimulation
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What are the characteristics of the analgesia produced by high frequency electroacupuncture?
|
rapid onset, short duration and no cumulative effects
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|
How does the nature of an acupuncture needle benefit its purpose?
|
the stainless steel shaft with spiral handle creates a temperature gradient when put into the skin which produces conductive properties causing electrons to move up the needle, this current is reinforced by the electromagnetic effect created by the spiral metal creating a capacitor; the needle removes heat and electrons
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|
How does moving an acupuncture needle change its properties?
|
causes electrons to be put back into the body with manipulation, induces lamellar flow along the fascial planes
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|
What FDA class of medical device is an acupuncture needle?
|
Class 2b
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|
What is analgesia?
|
absence of pain without the loss of consciousness
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|
|
|
What narcotic has greater efficacy than morphine?
|
None, there is no substantial evidence that supports that any other narcotic has greater efficacy or fewer side effect than morphine
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|
What is the upper limit dosage of morphine?
|
there is no upper limit to the dosage and achievable pain relief as long as the dose is increased gradually to allow tolerance to develop to adverse effects (esp resp. depression)
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|
Where is the opioids' site of greatest action (ie sites of most opiod receptors)?
|
central dorsal horn cells (esp μ receptors on primary afferent neurons) and in limbic cortex and PAG
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|
Where do endogenous opioids act on the descending control of pain?
|
enkephalins act in the PAG and in the dorsal horn
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|
|
What are the three types of opiate receptors?
|
μ, κ, and δ; all are inhibitory G protein coupled receptors which inhibit adenylate cyclase and the production of cAMP and primarily block presynaptic Ca uptake and NT release; also cause postsynaptic hyperpolarization by increasing K current
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|
Where are there μ opiate receptors?
|
PAG and dorsal horn of spinal cord; external plexiform of olfactory bulb; nucleus accumbens; limbic cortex; nuclei of amygdala; nearly all leukocytes (inhibit immune response); primary sensory neurons
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|
What are the effects of the kappa opiate receptor?
|
modest analgesia, little to no respiratory depression; little to no dependence; dysphoric effects
|
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|
What are the effects of the deltal opiate receptor?
|
poor analgesia, little addictive potential, may regulate the μ receptor
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|
What are the direct effects of opioids on neuronal transmission?
|
reduce the release of inflammatory transmitters esp from Ad and C fibers at their nerve terminals by reducing Ca influx; reduction of neuronal activity of the secondary neurons in the dorsal horn which express MOR and are hyperpolarized by opiates; both methods reduce the reception and perception of pain
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|
|
What do opiate analgesics do to the perception of pain?
|
they are the only clinically available drug used that can attenuate the subjective component of pain due to their ability to activate MOR and suppress neuronal firing in the limbic cortex
|
|
|
|
What are the three sources of opioids?
|
juice of the opium poppy (morphine and codeine); endogenous endorphins; semi-synthesized from morphine (heroin) or synthesized from precursor compounds (fentanyl)
|
|
|
|
What is POMC?
|
a precursor polypeptide necessary for β-endorphin and met-enkephalin; synthesized by a variety of brain regions ie. anterior pituitary, arcuate nucleus, dorsomedial hypothalamus, and brainstem
|
|
|
|
What are some reasons for the undertreatment of pain?
|
lack of understanding of pain mechanisms and management principles; over estimation of the risk of addiction; poor communication btw pt and medical personnel
|
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|
|
What is the goal of pain therapy?
|
to eliminate or reduce the pain to a tolerable intensity and prevent it from recurring; it is easier to treat acutely then when it is chronic
|
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|
|
What is a contradictory side effect of opioid therapy?
|
while opioids are used to alleviate pain they may render patients more sensitive to pain and potentially may aggravate their pre-existing pain and produce opioid induced hyperalgesia
|
|
|
|
What are some advantages of fully synthetic opioid analgesics?
|
greatly enhanced analgesic efficacy; decreased abuse liability; increased oral bioavailability and/or prolonged duration of action
|
|
|
|
If you are changing an opioid analgesic with another in treatment what should be the new dose?
|
an equivalent dose to the prior opioid analgesic
|
|
|
|
At what receptor does the analgesic potency of most opioid largely reside?
|
MOR
|
|
|
|
What is the physiological response of the opioid receptors Mu/delta?
|
analgesia at supraspinal and spinal levels, euphoria, drowsiness, resp. depression, dependence, endocrine effects, nausea, constipation and miosis
|
|
|
|
What is the physiological response of the opioid receptor kappa?
|
analgesia largely at the spinal level only, dysphoria
|
|
|
|
What are some common pharmacokinetic features of opioid analgesics?
|
lipophilic, so readily absorbed from the GI tract; effect of oral dose is less than parenteral administration due to 1st pass effect
|
|
|
|
What is tolerance?
|
decreased effectiveness of a drug resulting from neuroadaptive processes that occur during chronic use
|
|
|
|
What is physical dependency?
|
only seen when the opioid is stopped abruptly or the dose is markedly decreased; it does not indicate addiction
|
|
|
|
What is addiction?
|
characterized by a dysfunctional pattern of use for purposes other than alleviating pain (ie euphoria)
|
|
|
|
What is pseudoaddiction?
|
behaviors seen in patients with severe unrelieved pain. These patients may become preoccupied with obtaining opioids, however their underlying focus is on finding relief for their pain
|
|
|
|
What are the strong opioid analgesics?
|
morphine; hydromorphine; methadone; merperidine; fentanyl
|
|
|
|
What causes the respiratory depression seen with morphine?
|
diminished medullary response to increases in blood CO2 tension
|
|
|
|
What causes the pupillary constriction seen with morphine?
|
edinger-westphal nucleus of the oculomotor nerve
|
|
|
|
What are the triad of signs of a narcotic overdose?
|
pinpoint pupils, marked respiratory depression, and coma
|
|
|
|
What are the moderately strong opioid analgesics?
|
codeine; oxycodone, hydrocodone; propoxyphene
|
|
|
|
What are the mixed receptor agonist-antagonists opioid analgesics?
|
pentazocine, buprenorphine, butophanol, nalbuphine
|
|
|
|
What are analgesic adjunctive agents with opioid analgesics?
|
corticosteroids; benzodiazepines; selective serotonin reuptake inhibitors; adrenergic agonist; NMDA antagonist; aspirin; acetaminophen
|
|
|
|
What are the reversible forms of dementia?
|
alcoholic dementia (korsakoff syndrome); normal pressure hydrocephalus; drug toxicity; pseudodementia (depression, schizophrenia); hypo/hyperthyroidism; encephalitis; hypoxia; pernicious anemia; pellegra (niacin); cushing syndrome; neurosyphilis; brain tumor
|
|
|
|
What is dementia?
|
progressive memory loss, disorientation, inability to perform abstract thinking
|
|
|
|
What are three general types of drug treatment for dementia?
|
drugs to treat symptoms; drugs to modify the progress; drugs to prevent the disease
|
|
|
|
What are some symptomatic treatment strategies for Alzheimer's disease?
|
cholinomimetics: degradation inhibitors (tacrine, donepezil, rivastigmine), direct cholinergic agonists (cevimeline, nicotine agonists), NMDA antagonist (memantine); Monoaminergics: SSRIs; Neuroleptics for agitation (haloperidol)
|
|
|
|
What variant of Alzheimer's disease is often successful with cholinesterase inhibitor treatments?
|
ApoE4 negative; lewy body variant
|
|
|
|
What are some preventative treatments for Alzheimer's?
|
genetic role (id and counteract mutation); estrogen prior to dz; NSAIDs (decreases the age of onset if used prior to dz); Antioxidants (vitamin E?), Abeta 1-42 vaccine (Ab against Abeta); statins (used prior to dz onset); herbal treatments (ginko biloba)
|
|
|
|
What neurochemical changes are associated with the degeneration of the caudate and putamen seen in huntington's dz?
|
met-enkaphalin, GABA, substance P neurons; NOT dopamine, serotonin, or glutamate cells
|
|
|
|
What are some treatment strategies for Huntington's disease?
|
ciliary neurotrophic factor (stimulate growth of GABA and substance P cells, doesn't work); glutamate antagonists (memantine); creatine (not successful); neuroleptic drugs for symptomatic agitation (haloperidol); understand function of huntingtin protein
|
|
|
|
What are some treatment strategies for ALS?
|
riluzole (Na channel blocker inhibits glutamate release, prolongs life without improving quality); Neurotrophins, human recombinant insulin-like growth factor I; role of superoxide dismutase mutations
|
|
|
|
What are some treatment strategies for dementia due to large vessel artherosclerosis?
|
diet (prevent diabetes and high glucose level); anti-hyperlipoproteinemia drugs (clofibrate, atrovastatin)
|
|
|
|
What are some treatment strategies for dementia due to small vessel artherosclerosis?
|
anti-hypertensive drugs (captopril)
|
|
|
|
What are some treatment strategies for dementia due to embolism?
|
anticoagulants for post MI ar atrial fibrillation (warfarin, heparin); anti-bacterials for infectious endocarditis
|
|
|
|
What are some acute treatment strategies for dementia due to non-hemorrhagic strokes?
|
recombinant tissue plasminogen activator (rt-PA); streptokinase/urokinase; experimental (glutamate antagonist, free radical scavengers, anti-inflammatory agents)
|
|
|
|
What is the general mechanism of pharmacotherapy of Parkinson's disease?
|
compensation for the loss of DA input to the caudate and putamen via replacing dopamine or modulating NT systems regulated by dopaminergic input
|
|
|
|
What percentage of the nigral dopaminergic cell bodies and fibers are usually lost in PD when symptoms appear?
|
60-80%; the symptoms may begin unilaterally
|
|
|
|
Why is L-Dopa usually not used as a first line treatment for Parkinson's disease?
|
L-Dopa potentially can lead to more loss of dopamine neurons so it is usually saved until the later stages of the disease so as not to exaccerbate the progression
|
|
|
|
What are the 4 dopaminergic systems in the brain?
|
mesostriatal (nigrostriatal system); mesolimbocortical system; hypothalamo-hypophyseal (tuberoinfundibular system); chemoreceptor trigger zone
|
|
|
|
What dopamine system is first affected in parkinson's disease?
|
mesostriatal (nigrostriatal system)
|
|
|
|
What is the mesostriatal (nigrostriatal system)?
|
dopamine projection from lateral substantia nigra to the neostriatum (caudate and putamen); involved in the intiation and maintenance of motor behaviors
|
|
|
|
What dopamine systems are affected by parkinson's disease?
|
mesostriatal (nigrostriatal system); mesolimbocortical system
|
|
|
|
What dopamine systems are Not affected by parkinson's disease?
|
hypothalamo-hypophyseal (tuberoinfundibular system); chemoreceptor trigger zone
|
|
|
|
What is the mesolimbocortical system?
|
dopamine projection from the medial substantial nigra of the midbrain to the limbic and cortical structures. Degenerates in some cases of PD and can lead to parkinson's disease with dementia. Mediates euphorigenic properties of cocaine and hypersensitivity/hyperreactivity can lead to psychotic states
|
|
|
|
What is the hypothalamo-hypophyseal (tuberoinfundibular) dopinergic system?
|
hypothalamic dopamine neurons release DA into portal system to anterior pituitary. DA inhibits prolactin secretion. Is not affected in PD
|
|
|
|
What is the chemoreceptor trigger zone?
|
dopamine receptor activation area in the area postrema which induces nausea and vomiting. Is not affected in PD.
|
|
|
|
What is the timeline of pharmacotherapy interventions for PD?
|
early: MAO inhibitor (selegiline); DA releaser (amantidine); Dopamine agonists (bromocryptine, ropinerole); Later in Dz: DA precursor (levodopa/carbidopa); COMT inhibitors(talcapone, entacapone)
|
|
|
|
What is the "on-off" phenomenoa seen with L-Dopa/Carbidopa?
|
not an end dose akinesia, occurs in 30-40% of pts after 1 year of treatment; is a sudden period of "lock-up" during treatment, drug holidays may help to reduce these episodes
|
|
|
|
What is the burnout fuctuation in response seen with L-Dopa/Carbidopa treatment of PD?
|
desensitization or major down regulation of DA receptors and additional loss of DA neurons in 5-8 years causing loss of drug efficacy
|
|
|
|
What is the interaction btw MAO inhibitors and L-Dopa/Carbidopa?
|
can lead to hypertensive crisis if the MAO inhibitor is a MAO-A and B inhibitor (phenelzine) but not of it is just a MAO-B inhibitor (selegilene)
|
|
|
|
What are some alternative/ non-pharmacological treatments of Parkinson's disease?
|
transplants (fetal DA cell body tissue, may cause increased uncontrolled dyskinesias); stem cells (to differentiate into DA producing cells); Deep brain stimulation (in STN to treat tremor); Pallidotomy (unilateral globus pallidus lesion to relieve symptoms short term)
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