Local Anesthetics- Pharmacology- Exam 2

Ester Local Anesthetics Drugs

Procaine

Benzocaine

Cocaine

Amide Local Anesthetics

Articaine

Lidocaine

Bupivacaine

Ropivacaine

What are drugs that produce transient and reversible loss of sensation of feeling in a limited area of the body without loss of consciousness

Local Anesthetics

-Delivered directly to the target tissue

Are Local Anesthetics vasoconstrictors or vasodilaots

Some have additional vasoconstrictor activity (Cocaine)

Others cause vasodilation and get combined with a vasoconstrictor to keep it localized

What only diminishes or terminates the effect of the anesthetic

Systemic circulation

Recovery is spontaneous with few side effects compared to general anesthetics

LA MOA

Prevent the generation and conduction of nerve impulses by blocking NA channels

-Blocks Voltage-gated NA channels from the Inside of nerve cell

Action Potential Mechanism

1) Resting membrane potentiaal ~ -70mV

2) Excitation causes Na INflux in a depolarizing current till AP threshold is reached

3) Maximal depolarization

4) Na conductance decreases & K Increases

5) Movement of K+ out of cell repolarizes the cell

Charge of LA

Exist as both nonionized base (high pKA) and cationic form

Injected as a charged hydrochloride salt (water-soluble ionized form)

- non-ionized base crosses sheath/membrane

Re-equilibration at the internal pH of the axon results in the cationic form being quantitatively the principal form of anesthetic on the internal surface of the membrane

Cationic form enters NA+ channel from internal surface to block NA movement

What form of the LA enters the NA+ channel from the internal surface to block NA+ movement

Cationic form

LA binds to the inner domain of Na channel to prolong _____________ state

Inactive state

Works better on nerves that fire rapidly (pain fibers)

Slows recovery time of 10-100X

How LA changes nerve impulses

1) Threshold gradually increases (requires more Na+ conduction)

2) The rate of depolarization decreases

3) Membrane does not depolarize sufficiently to reach the firing threshold- NO AP

Becomes a complete block as more Na channels are inhibited

Variable Affecting LA action

Differential Sensitivity of nerve fibers

Physiochemical properties of drug

pH

Biotransformation (drug metabolism)

Effect of Vasoconstrictors

Differential Sensitivity of Nerve Fibers

Preferential block of small diameter fibers- usually propagate a signal over short distance

Myelinated nerves take 2-3 nodes of Ranvier to block

Rapid-firing pain fibers are blocked early

Preganglionic B fibers are blocked before the smaller un-myelinated C fibers that transmit pain signals, but together these are blocked earlier than other nerve fibers

Do myelinated of non-myelinated nerves block earlier

Myelinated nerves blocked early

How nodes of Ranvier does a LA need to bind to cause LA

2-3 nodes of Ranvier to block

-thinner nerve fibers have more nodes per unit length -> LA have more access -> more effective

The smaller ___ and __ fibers are blocked before other fibers

B & C

A-delta and C fibers have a high frequency of firing and are blocked before A-a fibers

Pain>Temp>Touch>Pressure>Motor

The lipid solubility of LA correlates with what physiochemical property

Potency

-Greater lipid solubility enhances diffusion through neural coverings and cell membrane, allowing a lower mg dose

pKA/Dissociation Constant of LA correlates with what physiochemical property

Time of onset

-Determines dose that exists in lipid-soluble, tertiary molecule state at given pH

-Agents with lower pKA have greater proportion in the tertiary, diffusible state, and hastens onset

Chemical Linkage of LA correlates with what physiochemical property

Metabolism

-Esters are hydrolyzed by cholinesterases; amines biotransformed in liver

The protein binding of LA correlates with the physiochemical property

Duration

-Plasma Protein affinity corresponds with receptor site affinity within Na channels

General Structure of LA

Aromatic Portion

Intermediate chain

Amine Portion

How doses the Aromatic portion of LA affect drug activity

Provides lipophilicity

How does Intermediate linkage of LA affect drug activity

Determines route of metabolism and allergy potential

How are Esters metabolized (What reaction)

Hydrolysis

-shorter half life than amindes

How does the Amine portion of LA affect drug action

Provides water solubility

Compounds lacking amine portion= water-insoluble (topical use)

When administered, usually in the ionized state to increase the aqueous solubility

Is Procaine an ester or amine

Ester

What LA is a natural alkaloid that can be classified as an ester and is used for ENT surgery

Cocaine

What LA ester lacks hydrophilic component (insoluble) and is used topically

Benzocaine

-used to numb gum before anesthetic injection with swab held between cheek and gum)

Easy way to tell if a LA is an ester

Rule of i

Lidocaine

ArtiIcaine

BupiIvacaine

LA are weak base or acid

Weak Base (depending upon pH)

Describe a LA when pH is higher than pKa and with pH is lower than pKA

pH> pKa:

Uncharged free base (unionized- crosses membrane)

pH

When pH is lowered how does LA become more ionized or nonionized

Ionized (Weak base protonated -> BH+)

Inflammation drops pH-> harder to anesthetize

How does the concentration of LA necessary for nerve block change when pH decreases

Will need to Increase LA concentration

-Higher amount of ionized drug

What can be added to LA to raise pH and shorten the onset of drug action

Bicarbonate

-pKa affects onset: closer to physiological pH, faster onset

The biotransformation of LA depends on what

Dosage

Delivery method

Local blood flow- vasoconstrictors

Systemic absorption terminates the effect

- potential to be toxic

LA like any drug undergoes what type of metabolism

Biphasic

Phase I: Formation of Reactive Intermediate

Phase I: Formation of Water soluble metabolite

Phase I reactions

Functionalization Reaction

Oxidation, Reduction, Hydrolysis

CP450, Esterases

Phase II Reaction

Conjugation with a polar group

Glucuronidation, GSH Conjugation, Acetylation

transferases

Ester LA are hydrolyzed in plasma by what enzyme

Pseudocholinesterase

Patients with atypical enzyme can experience prolonged effects or toxicity

What type of LA is associated with Allergic phenomena

Ester type

Attributable to formation of p-aminobenzoic acid

Amide LA is metabolized primarily where and how

Liver by cytochrome P450

Depends on

-Enzyme activity

-Hepatic blood flow

-Plasma protein level

Variability in Biotransformation

Enzyme differences (CYP450)

Age (elderly heterogeneous due to different rates of deterioration of enzyme and elimination systems)

Gender

Pathology

Enzyme inhibition

Severe liver disease can make it harder to metabolize what kind of LA

Amides

Effect of Vasoconstrictors in LA

Adding vasoconstrictor can prolong/retain and increase depth of anesthesia

-Epinephrine

Duration of LA action is proportional to what

Time of contact with nerve fiber

LA has Vasodilation properties which can limite duration

Clinical use of Topical Anesthesia

Direct application of aqueous solutions of local anesthetic salts to mucous membrane of nose, mouth, tracheobronchial tree, genitourinary tract

Does not exend to submucosal structures

Infiltration Anesthesia

Injection of LA directly into tissue to be incised (may have epi)

Nerve block anesthesia

an injection made into a nerve to block the conduction of impulses between the nerve and the CNS

Intravenous regional anesthesia

insertion of IV cannula into the extremity on which the procedure is to be performed and a tourniquet applied to interrupt blood circulation; then a large volume of local anesthetic injected into a peripheral vein, anesthetizing the extremity.

Spinal Anesthesia

regional anesthesia produced by injecting medication into the subarachnoid space

Epidural Anesthesia

regional anesthesia produced by injecting medication into the epidural space of the lumbar or sacral region of the spine

What is the choice of short-acting LA

Procaine

Cholorprocaine

What is the choice of LA for intermediate use

Lidocaine

Articaine

Mepivacaine

Prilocaine

What is the choice of Long-acting LA

Bupivacaine

Ropivacaine

Tetracaine

Levobupivacaine

What LA has a fast onset and an intermediate duration-suitable for use in dental procedures

Articaine

Undesired effects of LA

Local Anesthetic Systemic Toxicity

-Unintentional IV injections

Effects from Local Anesthetic Systemic Toxicity

Restlessness and tremors, Sensory Disturbances -> Unconsciousness -> Convulsions-> Respiratory Failure-> CVS Depression

Treated with

Benzodiazepines, O2, Supportive care

Excess systemic absorption can lead to what affects on BP

Decrease in BP (LA are Vasodilators)

Effects on Myocardium from LA

Decreases in:

Excitability

Conduction rate

Contraction force

Lidocaine and procainamide can be used as

Antiarrhythmic

Highly lipid soluble, highly protein-bound LA have greater _________toxicity

Cardiotoxicity

Bupivacaine

Etidocaine

LA Brain Toxicities

CNS toxicity linked to Twik-related acid-sensitive K+ channel (TASK)

Induces membrane depolarization (increased excitability)

Initial: agitation, confusion, dizziness, drowsiness, perioral numbness

Progressing to seizures, Respiratory arrest, coma

Caring for LA Brin Toxicity

Airway management

Cardia-epi

Seizures: benzodiazepines

Lipid emulsion therapy- lipids soak up lipid-soluble LA

Allergic Reaction to LA

Likely due to preservatives (Methylparaben or antioxidants)

Ask about epi or PABA sensitivity

Rarely due to LA

Allergic dermatitis/bronchospasms

More common with esters