Title: CNS Pharma / Lecture 1

Q: What is the function of local anesthetics: (3)
A: 1. They reversibly block impulse conductions along nerve axons that utilize sodium channels as the primary means of action potential generation
2. They are used to block pain sensation from specific areas of the body
3. They also block sympathetic vasoconstrictor impulses to specific areas of the body

Q: The ionotropic glutamate receptors for local anesthetics: (3)
A: 1. α-amino-3-hydroxy-5-methylisoxazole-4-
proprionic acid (AMPA) receptors
2. Kainic acid (KA) receptors
3. N-methyl-D aspartate (NMDA) receptors

Q: α-amino-3-hydroxy-5-methylisoxazole-4-
proprionic acid (AMPA) receptors: (2)
A: 1. Present in all neurons
2. The majority of these receptors are permeable to Na+ and K+, but not to Ca++

Q: Kainic acid receptors: (2)
A: 1. They are expressed at high levels in the hippocampus, cerebllum, and the spinal cord.
2. Kainate receptors are permeable to Na+ and K+ and some can be permeable to Ca++

Q: N-methyl-D-aspartate (NMDA) receptors: (2)
A: 1. They are rpesent on essentially all neurons in the CNS (just like AMPA receptors)
2. All NMDA receptors are highly permeable to Ca++ as well as to Na+ and K+

Q: Substances that are released from a neuron to transmit pain: (2)
A: 1. Substance P is contained in and released from small unmyelinated primary sensory neurons in the spinal cord and brain stem and causes slow EPSP in target neurons --> transmit noxious (harmful) stimuli
2. Glutamate, which is released with substance P from these synapses plays an important role in transmitting pain stimuli

Q: History of anesthetics: (3)
A: 1. Cocaine: the first local anesthetic introduced into clinical practice (for ophthalmic use, 1884)
Its chronic use was associated with psychological dependence
2. Procaine: synthesized to improve upon the clinical properties of cocaine (1905) and became the dominant local anesthetic for another 50 years
3. Lidocaine (1943) the most widely used local anesthetic.

Q: Chemical composition of anesthetics: (2)
A: 1. Most agents consist of a lipophilic group (aromatic) connected via an ester or amide linkage to an ionizable group (tertiary amine)
2. They are weak bases, and exist in the body either uncharged base or a cation

Q: Chemical form of anesthetic and its activity: (4)
A: 1. The cationic form is the most active form at the receptor because it can not exit from the closed channels
2. The uncharged form is important for rapid penetration of the biologic membranes, since the receptor is not accessibke form the external side of the cell membrane
3. They are much less effective when injected into the infected tissue, because low pH cause ionization of the drug
4. Esters usually have a shorter suration of action because they are more prone to hydrolysis than amides

Q: Classification of local anesthetics: (2)
A: 1. Amides: Lidocaine, Bupivicaine, Ropivacaine
2. Esters: Cocaine

Q: MOA of local anesthetics: (2)
A: 1. The primary MOA is the blockade of voltage-gated sodium channels
2. Local anesthetics bind to recpetors near the intracellular end of the sodium channel and block the channel in a time- and voltage- dependent fashion.

Q: The effects of a local anesthetic on a nerve fiber: (5)
A: When there is increasing concentration:
1. The threshold for excitation increases
2. Impulse conduction slows
3. The rate of rise of the action potential declines
4. the action potential amplitude decreases
5. The ability to generate an action potential is completely abolished.

Q: In what order are different nerve fibers blocked by local anesthetics?
A: The smaller B and C fibers are blocked first, followed by other sensations, and the motor function is the last to be affected.

Q: Other actions of local anesthetics: (3)
A: 1. Motor neurons are also affected and cause motor paralysis (which can be desirable during surgery), it can limit the ability of the patient to cooperate during obstetric delivery and may impair respiratory activity
2. Autonomic nerve block can result in hypotension and interfere with bladder function leading to urinary retention
3. Some local anesthetics (lidocaine) have antiarrythmic effects in the heart at aoncentrations lower than those needed to produce nerve block.
OTHERS (bupivacaine, ropivacaine) can cause lethal arrythmias in high concentrations

Q: Pharmacokinetics of local anesthetics: (3)
A: 1. Ester- based local anesthetics are rapidly broken down in the plasma (t_1/2 < 1 minute)
2. Absorption of the local anesthetic to the systemic circulation from the site of application depends on many factors including local blood flow
3. Application to  highly vascular area results in high blood levels of the local anesthetic

Q: What is the purpose of adding vasoconstrictor substances with the local anesthetics injection? (2)
A: Vasoconstrictor substances such as epinephrine reduce the systemic absorption of the local anesthetic from the injection site:
1. by decreasing blood flow, and prolong its local effect
2. and the systemic toxic effexts of the local anesthetic is reduced

Q: How does epinephrine function with local anesthetics?
A: When used in spinal anesthesia, it stimulates alpha2-adrenoreceptors which inhibit release of substance P (neurokinin-1) and reduce sensory neuron firing
This enhances and prolongs local anesthesia

Q: How do α2-agonists function with local anesthetics?
A: Clonidine and Dexmedetomidine have been used to augment local anesthetic effect in the subarachnoid space and peripheral nerves

Q: Metabolism of amide agents: (4)
A: 1. The amide agents are metabolized in the liver by microsomal cytochrome P450 isozymes.
2. Toxicity may result in patients with hepatic dieasease (lidocaines half life increases from 1.6 to 6 hours.
3. Reduction in hepatic blood flow also decreases elimination of the amide agents
4. There is also a possibility of drug interactions with agents metabolized by the same isozyme resulting in reduced elimination of the local anesthetic

Q: Therapeutic use of local anesthetics:
A: To produce highly effective nalgesia in well defined regions of the body

Q: Administration of local anesthetics: (5)
A: 1. Topical application: nasal, mucosa, wpund margins
2. Infiltration: injection in the vinicity of the peripheral nerve endings
3. Nerve block: injection in the vinicity of major nerve trunks
4. Injection into the epidural or subarachnoid spaces surrounding the spinal cord
5. Intravenous regional anesthesia for short surgical procedures involving the upper and lower limbs

Q: Other uses of local anesthetics: (2)
A: 1. Neuropathic pain syndromes
2. Cardiac arrythmias

Q: Why do local anesthetics cause adverse effects: (2)
A: 1. They can cause systemic effects following absorption of the agent from the site of administration
2. They can cause direct neurotoxicity from the local effects when administered in close proximity to the spinal cord and major trunks

Q: Adverse effects in the CNS at low concentrations: (5)
A: 1. Sleepiness
2. Dizziness
3. Visual and auditory distrubances
4. Restlessness
5. An early symptom of local anesthetic toxicity is circumoral and tongue numbness and a metallic taste

Q: Adverse effects of the CNS at higher concentrations: (3)
A: 1. Nystagmus and muscular twitching can occur
2. Followed by overt tonic-clonic convulsions --> they apparently cause the depression of cortical inhibitory pathways
3. The stage of unbalanced excitation is followed by generalized CNS depression

Q: Adverse effects of cocaine:
A: 1. All the adverse effects of local anesthetics in addittion to:
2. Severe cardiovascular toxicity:
3. Hypertension
4. Arrythmias
5. Myocardial failure

Q: Tyoes of adverse effects of local anesthetics:
A: 1. CNS toxicity
2. Direct local neural toxicity (transient neuropathic symptoms)
3. Cardiovascular toxicity
4. Hematologic effects
5. Allergic reactions

Q: How do local anesthetics cause cardiovascular toxicity? (3)
A: 1. Results from effects on the cardiac and smooth muscle membranes and indirect effects on the ANS
2. Block cardiac sodium channels (antiarrythmic)
3. At extremely high concentration, they can block sodium channels

Q: Cardiovascular toxicity of local anesthetics:
A: 1. They depress cardiac contraction and produce arteriolar dilation (except cocaine) leading to systemic hypotension
2. Large doses of bupivacaine and ropivacaine have produced cardiac collapse
3. Cocaine produces vasoconstriction and hypertension as well as cardiac arrythmias
It can ALSO lead to local ischemia and ulceration of mucosal membranes in chronic abusers who use the nasal route.

Q: Hematologic effects of local anesthetics:
A: Administration of large doses of prilocaine during regional anesthesia may lead to accumulation of the metabolite o-toluidine, an oxidizing agent capable of converting hemoglobin to methemoglobin

Q: Allergic reations of local anesthetics:
A: 1. Ester-type agents are metabolized to p-aminobenzoic acid derivatives which seem to produce allergic reactions
2. Amide-type agents are extremely unlikely to produce allergic reactions