3. LA pharmacology and pharmacokinetics Flashcards
Describe neuronal physiology action potential at rest, initiation, conduction and propagation
- At rest, distribution and Na+ and K+ is predominantly extracelullar and intracellular respectively. Axolemma is relatively leakier to K+ than Na+. The chemical gradient enables K+ to passively diffuse through the membrane thus creating a slightly negative environment intracellularly. Thus resting membrane potential is ~-70mV.
- Initiation of action potential may start as a rise in membrane potential to -50mV. Voltage-gated Na+ channels open at this threshold, influx of Na+ causes depolarisation. K+ channels then open after Na+ channels close, efflux of K+ causes repolarisation follwoed by K+ channel closes.
- Intracellular environment are now slightly excessive of Na+ while extracellularly K+. The neuron is now hyperpolarised. Na/K-ATPase now actively pumping 3Na+ out and 2K+ to restore initial concentration.
- During this absolute refractive period, Na+ channels cannot open, and another action potential cannot be initiated. This ensures the unidirectional flow of APs.
Describe saltatoy conduction
- Myelinated neurons can conduct APs 10-100 times faster than unmyelinated neurons (1.2m/s vs 14.8-120m/s)
- intracellular and extracellular fluids are conductants thus may dilute the density of current
- myelin sheath provides the insulation to maintain current density, thus faster conductions
- this appears to be of jumping impulses at the Nodes of Ranvier
- LA needs to cover ~3 Nodes to function
The mechanism of LA is to produces a ______ ______ of ______ at peripheral nerves without a loss of ________
The mechanism of LA is to produces a reversible inhibition of neurontransmission at peripheral nerves without a loss of consciousness
Describe the molecular structure of LA
- All consist of a lipophilic part, intermediate chain and hydrophilic part
- intermediate chain can be classed in to easter (procain) and amides (lignocain, priolocain, bupivacain, mepivacain)
Describe the mechanism of action of LA and where on the neurons does it take place
- LA exist as a base (RN) and a cation (RNH+)
- it exist as equilibriums
- RN diffuses through the membrane, re-equilibriates to RNH+ which binds to speicific Na+ receptors on the channels
- this only occurs at the node of ranvier since other places are barriered by myelin sheath
- blockage of Na permeability result in the failure to reach threshold and failure to propagate
True/False
the mechanism of LA alters the resting membrane potential
False
LA does not alter resting memrbane potential
What is the difference between pharmacology and pharmacokinetics
Pharmacology is the properties of durgs and effects on body
Pharmacokinetics is the handling of drug in the body, which includes its absorption, distribution, metabolis and excretion
Why is salt added to LA solutaion
LA by itself is unstable and poorly soluble in water, salt can assist with that (usually HCl)
What is the percentage of base extracellularly in a healthy tissue of a LA with pKa of 8.3 theoretically according to the H-H equation
pH of healthy tissue = 7.4
pKa = 8.3
pH-pKa = -0.9
10^(-0.9) = 0.125
base:acid = 1:8
percentation = 1/(8+1) = 11%
Infiltration of inflammed tissue may present with which problems?
- much painful
- highly vascularised (risk of overdose and high turnover, decreased local concentration)
- low pH, low permeability into neuron (low dissociation)
- risk of infection
Speed of onset
Potency
Duration of Action
depends on which properties of LA
Speed of onset: pKa, dissociation and penetration into cell
Potency: lipid solubility, effective conduction blockade at lower concentration
Protein binding: protein affinity influence on how tightly/duration of drug binds to channels
Preservatives are added to LA for what reasons?
Preservatives are antioxidants that lengthens the shelf life of LA.
Since vasoconstrictors oxidates quickly
Commonly Sodium bisulfite
note allergies towards preservatives
Systemic toxicity of LA are significantly higher in what types of organs.
In highly perfused organs as they will have higher plasma levels and thus significant bearing on the potential toxicity of the drug (heart, lung, liver, kidney and brain) (fast equilibrium space)
muscles and fat may act as buffers due to their lipophilic properties (slow equilibrium space)
Rate of absorption and elimination depends on..?
site of adminitration (some more vascular than other)
dosage
how fast it is metabolised and excreted (depends on health and age of patients)
describe the metabolism of each class of LA in the body
amide: primary biotransformation in liver, can be secondary in lungs
pt with low hepatic blood flow (hypotention, congestive heart failure), poor liver function (cirrhosis) are unable to metabolise amide LA at a normal rate, increases potential for toxicity
ester: hydrolyzed in plasma by enzyme pseudocholinesterase into PABA
pt with atypical enszyme leads to prolongation of higher levels of LA in blood
PABA may cause allergic reaction
