Exam #01a (Local Anesthetics) Flashcards
These agents prevent the generation and conduction of nerve impulse via actions on Na+ channels?
Local anesthetics (LA’s)
What was the earliest LA?
cocaine (1884)
LA’s can be structurally classified into what two categories? Give the prototype LA for each category?
- Amino-esters (Procaine)
2. Amino-amides (Lidocaine)
How do LA’s MOA of blocking conduction of action potentials (AP) in excitable membranes work? How does the ionization affect LA’s MOA?
LA’s block the increase in permeability of excitable membranes to Na+ normally produced by depolarization by interacting with 1 or more binding sites on Na+ channels on the INTRACELLULAR side of cell membranes. Neutral form of LA required to cross membrane and ionized form of LA required to bind to Na+ channel and have activity
True or False - at higher concentrations, LA’s can bind to other ion channels like Ca2+ and K+?
True
In what state do LA’s exist at physiological pH?
uncharged base and as a cation (+ charged)
True or False - since pKa of most LA’s is 7.5-9.5, at physiological pH a > fraction will be charged in cationic form?
True
LA onset of action dependent on?
LA duration of action dependent on?
Onset - pKa (the larger the difference between pKa and pH means drug will be more ionized and will take LONGER to cross the membrane)
Duration - lipophilicity
Why are LA’s less effective when injected into infected tissue?
Infected tissue has a lower extracellular pH and therefore > amount of ionized LA exists. Since unionized LA is required to cross the membrane, you’ll see a decrease in effectiveness of the LA
True or False - highly non-ionized (lipophilic or high partition coefficient) results in poor penetration, but high activity?
False - highly non-ionized results in good penetration but low activity…meaning a high partition coefficient allows the LA to cross the membrane but will be difficult to ionize and have activity
What effect would an ortho-substituent have on an amino-ester LA activity?
It would increase duration of action by hindering hydrolysis
In general, what effect does adding alkoxy and NH2 substituents to the meta position on aromatic rings of amino-esters have on lipophilicity (DOA)?
meta alkoxy groups increase lipophilicity
meta amino groups decrease lipophilicity (charged compounds increase polarity/decrease lipophilicity
Why must amino-amide (lidocaine) LA’s aromatic ring be ortho substituted?
Ortho substitution hinders hydrolysis and contributes to resonance forms that lead to more effective binding and therefore activity
True or False - LA ester functional group MUST be in conjugation with aromatic ring for activity?
True - reverse esters are inactive (double bond O is not directly adjacent to aromatic ring)
What effect does branching of the intermediate chain (btwn int. chain and hydrophilic group) in both categories of LA’s have on activity?
Branching increases DOA, but has NO EFFECT on activity
What effect does methylene insertion between the carbonyl and aromatic have on activity and SE?
Results in poor activity and anticholinergic effects (dry mouth, hypotension, tachycardia)
What is the most common type of amine at the hyrophilic region of a LA?
tertiary amine
Comment on the size of the N substituent at the hyrophilic region of a LA? What is the optimal range of #’s C’s?
the > C’s, the > potency and toxicity
optimal range is 3-4 C’s (any more would be too lipophilic)
What effect would the addition of polar (OH) groups to the N at the hydrophilic region of a LA have on activity?
Decreases activity
Fill in the blanks:
A LA with a pKa close to physiologic pH and high partition coefficient will have a BLANK onset and BLANK duration of action?
rapid onset of action (more drug will be in neutral form and able to cross membrane)
long duration of action (high lipophilicity means better penetration and distribution)
In general, what onset and DOA do amino-ester LA’s have? Name (3) amino-ester LA (generic and brand)? Indicate which one is considered long acting?
Slow onset and short to intermediate DOA
- Procaine (Novocain)
- Chloroprocain (Nesacaine)
- Tetracaine (Pontocaine) - LONG ACTING
In general, what onset and DOA do amino-amide LA’s have? Name (6) amino-amide LA (generic)? Indicate which ones are considered long acting?
Rapid onset and intermediate to long DOA
- Lidocaine
- Prilocaine
- Mepivacaine
- Bupivacaine - LONG ACTING
- Articaine
- Ropivacaine - LONG ACTING
RAMP BL
What effect does Epi have on LA DOA (Hiint 2 effects)?
- Increases DOA
2. decreases probability of CNS toxicity b/c restricts removal from injection site decreasing blood levels
What (4) factors influence onset and DOA?
- pKa of drug
- pH of environment
- Lipophilicity of drug
- rate of drug metabolism
True or False - when applied at high concentrations, all LA’s can be toxic to nerve tissue?
True
Which (2) LA’s may be more neurotoxic when used for spinal anesthesia?
- chloroprocaine
2. lidocaine
True or False - spinal neurotoxicity of LA’s results from LA MOA?
False - it is NOT the result of excessive Na channel blockade
CNS effects from LA’s is dose dependent. What are (2) early symptoms of CNS toxicity from low doses of LA? At higher concentrations, what (2) effects are seen in patients? What are the final stages of high concentration CNS toxicity from LA?
LOW CONCENTRATION EARLY SYMPTOMS
- tongue numbness
- metallic taste
HIGH CONCENTRATION SIGNS
- nystagmus (invol eye movement)
- muscular twitching
FINAL STAGES
tonic clonic convulsions (excitation) followed by CNS depression/death (excitation b/c of depression of cortical inhibitory pathways allowing unopposed excitatory activity)
Which LA is also effective for ventricular arrhythmias and only active parenterally? CNS toxicity of this LA has been attributed to the formation of which metabolite?
Lidocaine
monoethylglycine xylidide metabolite
True or False - LA toxicity resulting in CV effects is a result from direct effects on smooth muscle membranes and indirect effects on autonomic nerves?
True
Which LA is more cardiotoxic than other LAs?
Bupivacaine
The (S)-isomer of which LA has a LOWER propensity for CV toxicity than its racemic mixture?
Levobupivacaine
What toxic metabolite of prilocaine can cause cyanosis in which the skin appears blue b/c tissues near skin surface do not have enough oxygen
o-toluidine
What metabolite are ester type LAs metabolized to that are responsible for allergic reactions in a small % of population?
PABA
True or False - Amide type LAs are metabolized to PABA?
False - therefore allergic reactions are rare
Which LA is the only useful TOPICAL agent we discussed in class, but is a weak LA, and doesn’t fit the SAR discussed?
Benzocaine
Where are the amide type LAs hydrolyzed?
At the carbonyl (C=O)
