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41 Cards in this Set

  • Front
  • Back
What is pain perception?
Process whereby the brain integrates both sensory and emotional components of nociceptive or neuropathic input.
What is analgesia? How do we achieve this?
Relief of pain
-- remove painful stimulus
-- block generation of nerve impulses at sensory nerve endings
-- reduce signal strength in pain pathways
What is anesthesia? How do we achieve this?
Loss of all sensation w/ or w/o the loss of consciousness and is achieved by local application of agents or systemic administration
-- block the generation of nerve impulses at sensory nerve endings
-- reducing signal strength in pain pathways
Describe nociception.
1. specialized sensory receptors (nociceptors) in nerve endings are activated by noxious insults (injury, inflammation) to both central and peripheral tissues

2. activation of these receptors transmits signals
-- first via primary sensory neurons
-- then via both spinal and supraspinal nociceptive pathways resulting in the perception of pain

3. primary sensory (afferent) component of dorsal root ganglion cells terminate in the dorsal horn of the spinal cord by forming synapses w/ neurons projecting to supraspinal structures involved in processing and integrating nociceptive signals
What occurs w/ the nociceptors during inflamm and injury?
Inflamm and injury results from release of diverse array of chemicals including K+, prostaglandins, leukotrienes, bradykinin, ATP, histamine, ACh, substance P, norepi, and serotonin
-- substances either directly or indirectly lower the threshold for activation of nociceptors on primary afferent neurons
Released from primary sensory terminals activates both
-- NMDA and
-- non-NMDA subtypes of receptors
Substance P and calcitonin gene-related peptide (CGRP)…
Are colocalized and presumably co-released from terminals of primary afferents
Adenosine and protein kinase C…
Also appear to play a modulatory role in nociceptive signaling
Endogenous opiate peptides…
Modulate both ascending (pain perception) and descending (pain control) signaling in nociceptive relay circuits
Norepi and serotonin…
Mediate one component of descending control of nociceptive relay circuits
Is responsible for excitatory conduction in brain pathways mediating nociception and awareness
Decreases neuronal signal strength by increasing inhibitory conduction in pathways which in part mediate awareness
Voltage-dependent ion (Ca++, Na+, K+) channels…
Mediate axonal as well as synaptic conduction in nociceptive pathways resulting in both excitatory and inhibitory transmission
Analgesic/Anesthetics sites of action (continued)?
K+, Ca++, Na+ channels and GABA-A receptor Cl- channel system
-- general anesthetics
-- sevoflurane

GABA-A system
-- injectable anesthetics
-- propofol, thiopental

NMDA receptors
-- ketamine

Opiate and NMDA receptors
-- methadone
Analgesics/Anesthetics and their sites of action?
Central and Peripheral prostaglandin synthesis:
-- non-narcotic analgesics
-- aspirin, ibuprofen

Central prostaglandin synthesis
-- acetaminophen

Opiate receptors
-- narcotic analgesics
-- morphine

Na+ Channels
-- local anesthetics
-- lidocaine
What is local anesthesia?
Reversible depression of both central and peripheral nerve conduction in a circumscribed area of the body
Routes of administration of anesthesia?
1. IV anesthesia
2. surface (topical) anesthesia
3. infiltration local anesthesia
4. nerve block anesthesia
5. spinal (subarachnoid) anesthesia
6. epidural and caudal anesthesia
How are local anesthetic agents classified?
Based on their structure
What are the three structural components of anesthetic agents and what properties do they confer?
1. lipophilic group (aromatic ring)
-- confers lipophilic properties
-- essential for anesthetic activity

2. hydrophilic group (amine group)
-- confers hydrophilic properties

3. intermediate hydrocarbon chain commonly including an ester or amide
-- joins the two groups
How are anesthetics classified?
-- hydrolyzed by plasma cholinesterase (pseudocholinesterase) to water soluble metabolites which are eliminated by the kidney
-- EX: procaine HCl

-- metabolized largely by the liver to water-soluble metabolites which are excreted in the urine
-- EX: lidocaine HCl
What features are common to most local anesthetics?
1. They are weak bases
-- pKa in the range of 8.0-9.0
-- available as salts as this confers both solubility and stability

2. Solutions are an equilibrium mixture
-- unionized, lipid soluble (free base) form and ionized water soluble (cationic or conjugate acid) form
-- relative proportion of these two forms is governed by their pKa and pH of the body fluids

3. Uncharged (lipophilic) base penetrates across the nerve sheath
-- pH dependent re-equilibration occurs in the interior of nerve to water soluble (charged) form
-- water soluble (charged) form binds to the active site in the nerve mbrn
How are local anesthetic agents administered?
Adjacent to the nerve fibers to be nlocked (by injection or direct application)
What factors influence the onset, potency (density of block) and duration of local anesthetic action?
1. dosage and volume of injectate or applied amount

2. site of injection or application

3. local blood flow

4. local anesthetic formulation

5. physicochemical and pharmacological properties of the agent

6. protein and tissue binding
Explain how diffusion away from the application site and metabolism account for the duration of action of local anesthetic agents.
1. Ester local anesthetic agents are metabolized by pseudocholinesterase in the blood thus accounting for very short plasma half-lives of PROCAINE

2. Amides are metabolized in the liver by cytochrome P450 resulting in hydrolysis of amide linkage
-- metabolism depends on hepatic blood flow
-- liver disease can decrease metabolism and therefore sustain blood levels and increase toxicity
-- competition by other drugs for cytochrome P450 isozymes can occur and delay elimination

3. Blood flow and hence diffusion away from the injection site significantly affects the duration of action of both ester and amide local anesthetic agents
-- reducing local blood flow increases duration of block
Give a general overview of the MOA for local anesthetic agents (locals).
Locals bind to and block voltage-gated Na+ channels thereby altering the ability of nerve fibers to conduct action potentials

Bind to receptor sites near the intracellular end of the Na+ channel and block the channel in a time- and voltage-dependent fashion
Describe how the locals block Na+ channels in a time- and voltage-dependent fashion
1. Na+ channels exist in the activated-open, inactivated-closed, and rested-closed states

2. local anesthetics selectively bind to Na+ channels in the inactivated-closed state to prevent their change to activated-open

3. Effect of a local is greater in rapidly firing axons compared to resting fibers since theses fibers are more rapidly converted to the inactivated-closed or high affinity state (state-dependent blockade)
Describe the sequence of events for a blockade.
1. bind to receptor site in voltage-gated Na+ channel

2. block Na+ channel and decrease Na+ conductance

3. depress rated of electrical depolarization

4. fails to achieve threshold potential for firing

5. failure to propagate action potential results in conduction blockade
What are the electrical changes in a nerve local following anesthetic binding?
1. increased threshold for electrical excitability

2. decreased rate of rise of depol phase of action potential

3. lengthened refractory period w/ fewer impulses conducted

4. resting mbrn potential is NOT significantly affected

5. electrical changes are progressive w/ increasing number Na+ channels blocked due to absorption of local
Compare the nerve fiber classes and their order of blockade by a local.
Nerve fibers differ in their susceptibility to local based on
-- size
-- myelination

A(d), B, C fibers are smallest and least myelinated, thus are blocked first, indicating pain sensation is reduced before motor fxn blocked

Locals preferentially block small fibers b/c the distance over which such fibers can passively propagate an impulse is shorter
Local toxicity?
Although locals exert their effects largely on a limited anatomical area and are relatively safe (1 death per 45million admin), absorption into systemic circulation can occur

Clinical efficacy and toxic effects are related to binding to neuronal voltage-gated Na+ channels

Toxicity is directly related to BLOOD LEVELS of anesthetic
Toxicity and blood levels – describe further.
1. greater lipid solubility means longer duration of action and also greater potential for toxicity

2. certain admin routes produce greater potential for toxicity

3. decreasing blood flow at the injection site reduces absorption into the systemic circulation

4. plasma proteins serve as a “sink” to which locals bind, thereby decreasing “free” drug and potential for toxicity

5. Toxicity not limited to neuronal voltage-gated Na+ channels (see neurotoxicity)
What are the general CNS signs of toxicity to a local?
1. initial stimulation reflected by apprehension, salivation and tremor

2. convulsions may occur w/ increasing blood concentrations

3. CNS mediated HTN and tachycardia followed by HYPOtension
What are the general CV signs of toxicity to a local?
1. DIRECT effects upon cardiac and smooth muscle; INDIRECT effects on autonomic nerves

2. cardiac voltage-gated Na+ channels are blocked, leading to alterations in pacemaker activity, and conduction blockade

3. w/ high doses, CV collapse may occur due to combined effects on cardiac and CNS voltage-gated Na+ channels
How do we treat local toxicity?
Symptomatic: restore normal ventilation and circulation

Benzodiazepines used to treat seizures
-- midazolam
-- diazepam
How can neurotoxicity occur?
Occurs w/ placement of local in the epidural or subarachnoid space (direct contact w/ spinal nerves)
Symptoms of neurotoxicity?
Transient numbness
Radicular irritation of lumbosacral nerves or myotomal weakness have been reported

Permanent neuro injury after regional anesthesia is rare
Allergic rxns to locals?
Ester-type locals
-- bronchospasm and anaphylaxis have been reported
Local reaction/interaction with existing disease or drug therapies?
1. CV disease may lower threshold for cardiac toxicity of locals

2. Therapy w/ drugs that inhibit myocardial impulse propagation (B-blockers, digitalis, Ca channel blockers) may also lower threshold for cardiac toxicity

3. Hepatic metabolism of amide agents can be decreased by reduced liver blood flow and concomitant admin of drugs which are substrates for cytochrome P450
What are the individual locals that you need to know?

Procaine HCl?
1. first synthetic local – an ESTER

2. hydrolyzed by pseudocholinesterase which provides very short duration of action
Lidocaine HCl?
1. First AMIDE local synthesized

2. metabolized in liver via oxidative dealkylation

3. hepatic disease or decreased hepatic blood flow decreases metabolism

4. effective topically and also orally as antiarrhythmic agent

5. intrinsic vasodilator properties