clinical theraputics

why are smaller fibes more susceptible to local anaesthetics

because for any given volume of local

why are ester linkages not heat stable

as they are more easily broken so less stable in solution

what are local anaesthetics used clinically in the form of

salts

what two forms do local anaesthetics exist in

unionised (B) and ionised (BH+)

what form do local anaesthetics exist in

uncharged molecules and cations

in what order do local anaesthetics block conduction

small myelinated axons non myelinated axons large myelinated axons

what is the mechanism of action of local anaesthetics

LA's block initiation and propagation of action potentials

how do LAs block initiation and propagation

by preventing voltahe dependent increase in Na+ conductance

what do you lose in progression of local anesthesia

pain cold warmth touch deep pressure motor function

why does local anesthesia result in loss of pain first

pain fibres are more sensitive than those carrying pressure and proprioception

How do ions move during the action potential

Na + channels open, Na + begin to enter cell K+ channels open, K+ begins to leave cell Na + channels become refractory, no more Na+ enters cell K+ continues to leave cell, causes membrane potential to return to resting level K+ channels close, Na+ channels reset extra K+ outside diffuses away

what does a local anesthetic do

eliminates sensation in a limited region of the body and interferes with impulse transmission in perpherial or spinal cord nerves

how do local anaesthetics interrupt neural conduction

by inhibiting the influx of sodium ions through Na+ channels.

is there loss of conciousness with local anesthetics

no

what does depolarisation of the membrane result in?

conformational shape changes of channel proteins and the Na+ channel inactivates.

what is a local anaesthetic

a drug which reversibly precents transmission of the nerve impulse in the region to which it is applied

what is the molecular structure of all local anaesthetics

lipophilic aromatic ring intermediate ester of amide linkage tertiary amine

what is the lipid-soluble base (B) essential for

penetration of the neuronal membrane

why don't local anaesthetics work in infected tissue

As

what physiochemical features determines the lipid solubility of a local anaesthetic

aromatic ring and hydrocarbon chain length

what does a pKa of a local anaesthetic determine?

the amount which exists in an ionised form at any given ph

how do ester type anaesthetics and amide tyoe anaesthetics differ in their metabolism

esters posess short half lifes while amide type have longer half lives

how are esters broken down

rapidly by plasma esterases to inactive compounds

esters are broken down by plasma esterases. What ester is not, and where and how is it broken down.

Cocaine, it's hydrolysed in the liver

how are amides metabolised

by amidases (hepatically)

how may duration of action be increased (2)

by increasing dose adding a vasconstrictor agent

example of vasoconstrictor agent

adrenaline

what are the types of local anaesthesia (5)

• topical infiltration peripheral nerve block spinal epidural

what consists in topical local anesthesia

skin, mucous membranes

example of infiltration in LAs

subcutaneous injection

why can amide anaesthetics be autoclaved but esters cannot

amide anaesthetics are heat stable

what does an injected local anaesthetic exists in equilibrium ?

a quaternary salt (BH+) and tertiary base (B)

what is a lipid soluble base essensial for

penetration of the neuronal membrane

what is a local anaesthetic.

a drug which reversibly prevents

explain the structural classification of local anaesthetics

Local anaesthetics generally have a lipid-soluble hydrophobic aromatic

what bond do local anaesthetics omit

amide or esters

what are significant differences between esters and amides

The ester linkage is more easily broken than the amide bond so the

antagonise these effects.

Bradycardia and salivation occur due to increased activation of cholinergic

recommended?

These drugs activate/stimulate pathways that enhance GABAergic

vulnerable to ionisation in the body

Local anaesthetics are weak bases. These drugs have a pKa that is greater

what is the mechanism of action in local anaesthetics

Local anaesthetics disrupt ion channel function within the neurone cell

What is the pKa for local anaesthetics?

Varies and those with a lower pKa will have a faster onset of action

specifically block.

Voltage gated Na+ channels

the action of non-depolarising muscle relaxants.

Indirect parasympathomimetics affect metabolism of AcH, increasing its

what is the importance of the pka of a local anaesthetic drug

All local anaesthetic agents are weak bases, meaning that they exist in

indirect parasympathomimetic drugs.

increased GI motility, decreased heart rate

how could the physicochemical characteristics of a local anaesthetic affect its function

Physicochemical features such as the aromatic ring structure and

what happens after drug administration

1. absorption 2. distribution 3. metabolism 4. elimination

what is absorption

the movement of a drug from the site of administration across membranes into the bloodstream

what factors affect the rate of absorption (4)

• route of administration - dose - lipid solubility - weak organic acid/ base drugs

what are the routes of drug delivery (6)

• parenteral - inhaled - oral - transdermal -topical

what mechanisms allow drugs to cross membranes

passive and facilitated diffusion active transport

what are the requirements for passive diffusion

• water solubility - lipid solubility

what is facilitated diffusion

Selective

what is bioavaliability (F)

the fraction of a dose that reaches the systemic circulation in a chemically unaltered form

what is incomplete oral avaliability

1. failure of disintegration or dissolution 2. chemical, enzymatic or bacterial attac 3. failure of absorption 4. first pass metabolism in gut wall or liver

why might failure of absorption happen (3)

• binding to other molecules in the gut contents - too polar to undergo passive diffusion - efflux due to p-glycoprotiens

what is distribution

the process of reversible transfer of the drug from the blood stream ro other areas of the body

what is the rate and extent of distribution determined by (3)

how well perfused the organs / tissues are binding of the drug to plasma proteins and tissue components permeability of tissue membranes to the drug

if the drug doesnt return to the blood whats happened

has been eliminated

name 3 patient characteristics which affect drug distribution

gender ethnicity age

what is the distribution in relation to blood flow in brain,kidneys,fat,muscle and liver

kidneys - 22% brain - 15% fat - around 10% muscle - 15% liver - 27% 6% from systemic and 21% from gi

what does binding balance depend on in blood and tissues

relaive binding affinity

where do basic drugs accumulate

acidic environments

where do acidic drugs accumlate

basic environments

what is a compartment

the sum of all those tissues into which a drug distributes at approximately the same rate

what is a single compartment

all tissues penerated either rapidly or not at all

how fast do drugs spread in a single compartment

instantly

what happens to the drugs penetration in two compartments

some tissues penetrates rapidly and others slowly

how fast does the drug spread in the second compartment

instantly

what are two compartments made up of

blood and rapid tissues (t1 and t2) from first compartment and slow tissues (t3 and t4) as the second compartment

what is the volume of distribution

the apparent volume of distribution is the amount of fluid that would be required to contaim the drug in the body at the same concentration sd in the blood or plasma

what compartments can drugs distribute into

• plasma - interstitial fluid - intracellular fluid

volume of distribution calculation

C = D/Vd Vd = D/C

what are some changes underlying parkinsons disease

progressive neurodegenrative loss of dopamine

for levodopa to work what must there be

dopa decarboxuylase in remaining striatal neurones

side effects of levodopa (3)

nausea and vomiting red urine gi bleeding

how can you reduce effects of levodopa

a peripheral dopa decaboxylase inhibitor (DDCI)

what side effects do dopamine agonists have

• excessive daytime sleepiness hallucinations and confusion

what is dopamine dysregulation syndrome

an uncommon disorder in whcih dopaminergic medication is associated with behaviours like hyper sexuality

what are some anti muscarnic side effects (peripheral)

• dry mouth blurred vision constipation

what are some anti muscarinic side effects (central)

• confusion - hallucinations

how could you reduce the side effects of levodopa

se levodopa with a peripheral dopa decaboxylase inhibitor (DDCI)

what do monoamine oxidase B inhibitors do?

reduce breakdown of dopamine

what are side effects of monoamine oxidase B (MAO-B) inhibitors

hallucinations, confusion and insomnia

what are symptoms of parkinsonism

tremor rigidity slowness of movement (bradykinesia) - short shuffling steps

causes of parkinsonian

parkinsons disease stroke infection

what happens to neurons within the substantia nigra when you have parkinsons disease

you lose 70-80%

what happens to dopamine in the striatum when you have parkinsons

loss of dopamine

what are the three main dopaminergic pathways

• motor control - behaviour/emotion -endocrine/secretion

what is the nigrostriatal dopaminergic pathway

under motor control

what is the mesocortical dopaminergic pathway

controls behaviour and emotion

what is the tuberohypophyseal dopaminergic pathway

controls endocrine / secretion function

seizures are divided into groups depending on what (3)

where they start whether or not a persons awareness is affected whether or not seizures involve other symptoms such as movement

what are the 3 types of onset seizures

focal generalised unknown

what is a eeg used for

to meausre the cns electrical activity

what does having a normal eeg mean

epileptic

what do focal seizures affect

a part of the brain

what does drug treatmment of parkinsons disease aim to do (4)

treat symptoms not cause of neurodegeneration improve quality of life minimize deterioration minimize side effects

what do generalised seizures affect

both hemispheres