Test 2 Flashcards
Local anesthetic structure
Aromatic group Linker region (either amide or ester) Amino group (can accept a proton) Non ionized = traverse cell membrane Ionized/protonated = aqueous soluble (higher affinity for binding site in Na channel) - responsible for most of the blockade
Local anesthetics: Amides
all amides have an “i” before the “caine
Local anesthetics: molecular target
All local anesthetics bind/block within the pore of voltage-gated Na+ channels, thereby decreasing conduction velocity and increase threshold for APs (block APs, but do not affect K, so do not change membrane resting potential).
Little selectivity for subtypes of Na+ channels
Can affect neurons generally (CNS, PNS) and some cardiac cells
Lack of selectivity contributes to adverse effects
Physiological pH: LA
Most LAs are weak bases, with pKa = 7.5-9 - so most are protonated at physio pH. The remaining base that is membrane-permeable.
Two routes to the local anesthetic binding site in the channel:
The major route under most conditions is intracellular: Drug in the cytoplasm can enter the open channel and block it.
A quantitatively minor route is membrane-delimited: Drug diffuses from within the lipid bilayer to channel pore.
Other barriers for LAs besides axon cell membrane
In the nerve, LA must pass through a series of lipid and aqueous phases: Epineurium, perineurium, endoneurium, cell membrane.
Takes the longest to get to the center - more proximal regions are blocked first
LA Potency
correlates with hydrophobicity of the base - Highly hydrophobic base accumulates in the lipid bilayer.
Creates a reservoir of drug molecules that can be protonated at the cytoplasmic surface and enter the open channel
LA Sensitivity
The most sensitive are small-caliber C-type fibers.
Sensory are nociceptors for mediate 2nd pain (slow)
Motor confer sympathetic tone (a receptors, vasoconstriction)
Ad fibers also are quite sensitive (these carry 1st pain).
Larger fibers are relatively spared.
Factors affecting sensitivity to LA
Size: small are more sensitive (eg C pain fibers)
Firing rate
Location within nerve
Mylinated more sensitive than unmylinated
LA: vasoconstrictors
due to inhibition of sympathetic postganglionic fibers to the vasculature - increases blood flow and permeability carrying the drug away from the tissue into systemic circulation.
Epinephrine is often administered with LA to increase duration and reduce systemic adverse effects
LA: esters
Hydrolyzed by plasma pseudocholinesterases
Metabolized to PABA, which triggers a local hypersensitivity (allergic) reaction in some patients
Local metabolism reduces the risk of systemic effects, especially if the drug is administered with a vasoconstrictor
LA: Amides
metabolized by the liver, in part by cytochrome P-450 enzymes
The local anesthetic effect of an amide is terminated by systemic distribution.
Greater risk of systemic adverse effects than esters, esp in those with severe hepatic disease
Can bind to a1-acid glycoprotein and cant be metabolized in that form - affecting the rate of elimination
LA Adverse effects - CNS
At relatively low toxic levels, mainly sedation
At higher levels: seizures, loss of consciousness
May reflect blockade of inhibitory neurons
Typical progression with increasing dose:
drowsiness to sensory disturbances to dizziness to twitching to seizures to coma
LA Adverse - Cardiac
Generally occur at higher toxic levels than CNS symptoms
Cells specialized for conduction (eg Purkinjee) are most sensitive.
Arrhythmias include A-V block, ventricular arrest.
Mediated mainly by block of cardiac Na+ channels
Very high toxic doses can directly inhibit Ca2+ conductance and reduce cardiac contractility. Except Cocaine and prilocane, which are vasoconstrictors.
Cocaine
Ester. The only naturally occurring local anesthetic in clinical use
Introduced into practice by Koller (1884) for corneal anesthesia.
Notable for its vasoconstrictory activity – do not need epi
Inhibits monoamine uptake, including norepinephrine from sympathetic postganglionics
Subject to hepatic metabolism if systemically distributed, even though it is an ester
Approved for topical use on mucous membranes
Mainly used in eye, nose, and throat procedures
Procaine
Ester. developed as a replacement for cocaine; devoid of abuse potential, novocaine.
Low potency, slow onset, short duration
Not effective topically: too rapidly metabolized
Use is now confined largely to infiltration anesthesia
Tetracaine
Ester. Relatively slow onset of effect, but more potent and longer acting than procaine.
Used mainly for spinal block, and in topical preparations
Benzocaine
Ester. Unique structure: Lacks an ionizable group, so poor aqueous solubility – cant be protonated. Accesses Na channel binding site by diffusion in the bilayer.
Strictly for surface anesthesia
Lidocaine
Prototypical amide; the most commonly used local anesthetic
Rapid onset
Base is moderately hydrophobic
Relatively low pKa (7.9), so substantial fraction is in base form
High extraction drug
Elimination is flow-limited - avidly broken down by liver; extra caution in patients with liver disease
Used systemically to treat cardiac arrhythmias
Prilocaine
Amide. Weak vasodilator, so Epi not generally required
Has large volume of distribution (Vd): ~300 liters (in fat)
In regional block, this property reduces systemic concentration
Rapid systemic elimination (hepatic + renal)
Adverse effect: methemoglobinemia
Fe3+ (ferric) heme rather than normal Fe2+ (ferrous)
This effect can occur with benzocaine, but less likely
Bupivacaine
Amide. Blocks sensory > motor neurons; especially useful in labor
More cardiotoxic than equieffective anesthetic doses of lidocaine; due mainly to the S(+)-enantiomer (racemic drug)
Potentially serious ventricular arrhythmias, myocardial depression
Slowly dissociates from cardiac Na+ channel, retained during diastole, cumulative blockade; recovery hastened by intravenous lipid emulsion
Sustained-released liposomal formulation (24 h duration) for management of post-operative pain
Ropivacaine
Amide. Derivative of the R(-)-enantiomer of bupivacaine
Less cardiotoxic than racemic bupivacaine
Levo-bupivacaine, which contains only the R(-)-enantiomer of bupivacaine, has been withdrawn from US market.
Local ocular distribution
Most eye drugs are topical.
Transcorneal/transconjuctival route: Aqueous humor to intraocular structures including trabecular meshwork (which can allow systemic absorption)
Also systemic circ via nasal mucosa
Ocular metabolism
Determined by Tear and tissue proteins and Diffusion across cornea and conjunctiva
Metabolized by traditional hepatic metabolism after systemic absorption
Ocular elimination
Nasolacrimal drainage
Topical eye drugs can be systemically absorbed
First pass liver metabolism is avoided through absorption by nasal mucosa
Ocular sympathetic response (fight or flight, need more light)
Mydriasis (dilation) via stimulation of outer radial muscle of iris
βreceptors on ciliary epithelium promotes secretion of aqueous humor.
Blocking βreceptors will decrease intraocular pressure by reducing aqueous humor.
In the eye, the predominant βreceptor is β2.
Ocular parasympathetic response (rest and digest)
Miosis (constriction) via stimulation of inner circular muscle of iris
Ciliary muscle contraction (causing relaxation of the zonules and tension on trabexular meshwork), resulting in accomodation (lens is more convex and shifted forward)
Accommodation can be blocked by muscarinic cholinergic antagonists–cycloplegia
Intraocular pressure is decreased with increased aqueous humor outflow via outflow into the Canal of Schlemm & trabecular meshwork.
Tension is produced on trabecular meshwork by ciliary muscle contraction, opening pores and facilitating aqueous humor outflow into the Canal of Schlemm & trabecular meshwork.
Glaucoma
Second leading cause of blindness worldwide
Characterized traditionally by elevated intraocular pressure
Causes optic neuropathy
Cauess Damage of optic nerve causes progressive retinal ganglion cell axon loss
Can cause loss of visual field and irreversible blindness
Glaucoma is classified as either:
Open-angle glaucoma – some can drain by trabecular meshwork
Closed-angle (Angle-closure) glaucoma = emergency: requires surgical intervention – trabecular meshwork blocked
Open angle glaucoma
Rarely present with symptoms
Found on comprehensive ophthalmic exam
Central vision loss is a late manifestation
Increase uveoscleral outflow
Increase trabecular meshwork & Canal of Schlemm outflow
Decrease aqueous humor production – beta blocker
Closed angle glaucoma
Emergency - treat with lazer iridotomy Visual acuity loss Pain Conjunctival erythema Corneal edema
Glaucoma diagnosis
Fundoscopic exam
Cupping is a hollowed-out appearance of the optic nerve.
Glaucoma is associated with a cup’s diameter > 50% of vertical optic disc diameter.
Visual Field Testing
Intraocular Pressure
Treatment for glaucoma
Increase uveoscleral outflow
Increase trabecular meshwork & Canal of Schlemm outflow
Decrease aqueous humor production – beta blocker
Latanoprost
Prostaglandin Agonist.
Analog of PGF 2α
1st line medical therapy for glaucoma
Once a day dosing
Mechanism of action: Increased aqueous humor outflow via uveoscleral pathway. Unclear how.
Side effects: Blurred vision, Burning sensation in eye, Conjunctival hyperemia, Eye irritation, Foreign body sensation, Iris color change, Itching of eye , Punctate keratopathy or keratitis (white specs)-
