PHYSICOCHEMICAL
GROUPINGS OF DRUGS
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• It is the physicochemical properties, rather
than pharmacological actions of drugs, that
determine how they are handled in the
body.
• Five characteristic patterns of drug disposition
will be described corresponding with five
physicochemical groups.
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GROUPING OF DRUGS BY
PHYSICOCHEMICAL
PROPERTIES
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GROUPS
1.Water-soluble drugs
EXAMPLES
• Gentamicin
Digoxin.
2. Intermediate drugs
3. Lipid soluble drugs
4.Acidic drugs [ pKa 28]
5. Basic drugs [ pKa 612 ]
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Thiopentone; Phenytoin
Inhalatational anaesthesia.
Salicylic acid.
•Lignocaine.
4
•
There are two major properties of a drug
which determines how it is handled by
the body:a) THE DEGREE OF IONIZATION OF THE
DRUG MOLECULES IN SOLUTION
b) THE LIPID SOLUBILITY OF THE
UNIONIZED DRUG MOLECULE-
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a)THE DEGREE OF IONIZATION OF THE
DRUG MOLECULES IN SOLUTION• This is dependent on the pKa of the drug and
the pH of the fluid in which the drug is
dissolved.
• i.e. Many drugs can be ionized in aqueous solution. However,
only the non-ionized species of such drugs is lipid soluble. The
proportions of ionized and non-ionized species are determined
by the pH of the medium and the ionization constant of the drug
(the pKa = acid dissociation constant= the pH at which one half
of the drug molecules are ionized).
• This relationship is expressed in the Henderson-Hasselbach
equation
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b)THE LIPID SOLUBILITY OF THE UNIONIZED
DRUG MOLECULE• This is often expressed as the partition
coefficient between organic solvents and
water.
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1.WATER SOLUBLE DRUGS
EXAMPLES:
1) Highly ionized [ strong ] acids [ pKa less
than 2 ] which are almost 100% ionized
in all biological fluids. Drug conjugates
e.g. sulphates, glucuronides, glycine
conjugates; Sodium Cromoglycate.
2) Drugs with multiple polar groups-:
– Polyhydric alcohols- Mannitol, Sorbitol.
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– Aminoglycoside antibiotics- Gentamicin,
Streptomycin, Neomycin.
– Mucopolysaccharides- Heparin.
– Polypeptide antibiotics- Colistin
3) Highly ionized [ strong ] bases [ pKa more
than 12 ] which are almost 100% ionized
in all biological fluids. Quartenary
Ammonium derivatives [R4N+ OH ]– Mono-onium compounds- Choline,
Tubocurarine, Neostigmine, Pyridostigmine,
Cetrimide.
– Bis-onium compounds- Pancuronium,
Suxamethoniun.
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CHARACTERISTIC FEATURES
• All Water soluble drugs are handled by the
body essentially alike, that is : 1. Absorption from the G.I.T. is negligible and
injection is usually necessary for systemic
effects.
2. Distribution is restricted to the ECF.
3. The drugs do not penetrate into CSF or
brain.
4. Binding to plasma proteins is not important,
except
for some strong acids.
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5. Elimination is mainly by excretion of the unchanged
drug in the urine.
• The drug usually enters the urine by ultra filtration but
many anions and cations are also actively secreted
into the urine and the bile.
• Non renal excretion is relatively unimportant for these
drugs unless they have a high MW [ greater than 400
Da], when biliary excretion become important.
• THE DISPOSITION OF THE AMINOGLYCOSIDE
ANTIBIOTIC GENTAMICIN; is representative of the
group.
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1.1 GENTAMICIN
•
A widely used antibiotic which is effective
against Gram-negative bacteria, including
E.coli and Klebsiella pneumoniae.
•
It is important to understand how it is handled
in the body because it has toxic effects on
the inner ear (vestibular and auditory
function) and on the kidney;
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• Note
The vestibular ( middle part of inner ear )
function is more impaired than auditory
• the amount of drug required to produce
damage is only a little greater than the amount
required to treat infection [ i.e. the drug has a
low therapeutic index ].
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CHEMISTRY
•
Gentamycin is a variable mixture of three
very similar components giving an
average MW of about 480 Da.
• Each component consists of two
substituted aminosugar molecules linked
through an aminocyclitol.
• There are several polar groups on the
molecules [ chiefly –OH ] which make
them readily soluble in water and
insoluble in lipid or organic solvents. 14
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ABSORPTION
(a) The drug is not absorbed from the gut
and must be given by injection if a
systemic effect is required.
(b) As with other drugs the rate of absorption
from the site of injection is proportional to
the local blood flow.
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DISTRIBUTION
•
•
•
The water soluble antibiotic molecules
cannot generally penetrate into
mammalian cells. They are restricted to
ECF.
The distribution volume is about 15 Litres
in adult.
Penetration across tissue barriers (lipid
membranes) into brain, CSF, inner ear
fluid, fetal circulation and sputum is
slow.
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ELIMINATION
(a) Excretion by the kidney is the major
route and clearance (CL) closely
approximates to the GFR or creatinine
clearance (CLcr).
(b) Since, in general, cells are not
penetrated there is little opportunity for
contact with intracellular enzymes and
consequent biotransformation.
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PERSISTENCE AND
ACCUMULATION
• The average plasma half-life is about 2
hours…
• Thus 8 hours after a dose more than 90%
[ 50 + 25 + 12.5 + 6.25 ] of that dose has
been eliminated, the dose can therefore
be repeated without accumulation.
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PERSISTENCE AND
ACCUMULATION Cont….
• Severe renal disease produces a very
different state however. A reduction in CL
causes a proportionate prolongation of
plasma half-life. It is then essential to
scale down dosage in order to avoid
accumulation and toxicity.
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PLASMA CONCENTRATION AND
PATIENT RESPONSE
(a) Concentration [C] of gentamicin 1 hour after
dosage must exceed 5 mg/L, for
therapeutic effect in septicaemia but can be
as high as 12 mg/L without causing
toxicity.
(b) Trough concentration [just before the next
dosage ] are more relevant to toxicity.
However, with less than 2mg/L there is little
risk, but with more than 4mg/L the risk is large.
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PLASMA CONCENTRATION AND
PATIENT RESPONSE (continue)
If the trough concentration is large the tiny
but slowly penetrated compartment of the
inner ear fluid gradually fills up with the
drug.
(c) A mean concentration [ Css,av ] of 3 to 4
Mg/L represents a compromise that avoids
inadequate peaks and excessive troughs.
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DOSAGE REQUIREMENTS
IN RENAL DISEASE:
• The daily dosage rate to maintain a desired Cssav
is linear function of creatinine clearance (CLcr).
• It varies from about 20 mg/day [ 40 mg every 48
hours] in anuric patients (which allows estimation
of non-renal clearance) to about 480 mg/day [ 160
every 8 hours ] in patients with normal kidney
function.
• Thus the daily dosage rate required to produce a
given Cssav varies over a 24- fold range.
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SUMMARY
1. Water soluble drugs either possess
multiple polar groups or are strong acids
or bases.
2. The disposition of gentamicin is typical
of the group. It is not absorbed orally and
must be given by injection. Its distribution
is restricted to the ECF. It is eliminated
by renal excretion.
3. Dosage of gentamicin must be reduced
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in renal failure and in children
2. DRUGS WITH INTERMEDIATE
SOLUBILITY
• Not all drugs have extreme physical
properties. Many are intermediate
between highly water soluble
aminoglycoside antibiotic agents and
the highly lipid soluble i/v anaesthetic
agents.
• Tetracycline is included but Digoxin has
been selected as an important example.
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CHARACTERISTIC FEATURES
1. Absorption from the gut is adequate for
clinical use but is often not complete.
2. Distribution is not restricted to ECF; the
drugs penetrates through cell
membranes and into the intracellular
water.
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CHARACTERISTIC FEATURES
(continue)
3.Protein binding has an influence on the
distribution and elimination of the drug.
4. Elimination is predominantly by excretion
of the unchanged drug in the urine,
although a proportion of the drug suffers
biotransformation
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2.1 DIGOXIN
•
This drug has the invaluable effect of
slowing ventricular rate in patients with
atrial fibrillation and increasing the force
of contraction in heart failure.
•
The toxic dose [ heart block; ectopic
ventricular activity ] is very close to the
therapeutic dose, so there is little safety
margin.
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CHEMISTRY
•
The relatively lipid soluble steroid nucleus
carrying two OH groups is linked to a
highly water-soluble trisaccharide [ threedigitoxose units] by a glycosidic bond.
•
This structure probably favours concentration
at cell surfaces where the drug acts on Na+/K+
ATPase. (inhibits the Na+/K+-ATPase pump)
The glycoside (Mw 781 Da) dissolves more
readily in Ethanol than in water or other
organic solvents.
•
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ABSORPTION
• Digoxin is usually administered by mouth
in tablet form.
• The dissolution standard that tablets are
expected to meet is 75% in solution within
1 hour.
• It is absorbed quickly but not completely.
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Absorption…
• The fraction (F) absorbed or bioavailability is
approximately 0.6 (mean) and rather variable
(0.4-1.0)
• Reduction in particle size in the formulation
increases the rate of dissolution and improves
bioavailability
• A solution for i/m or i/v injection is available for a
more rapid response but at the cost of increased
liability of acute toxicity.
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DISTRIBUTION
•
Digoxin is distributed throughout body
water.
•
It is bound to protein in plasma [ fb=
about 0.3 ] and probably in tissues.
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• When distribution is complete most of the dose
is located in skeletal muscle.
• Digoxin does not enter fat.
• V is much greater than body weight [ about
5L/Kg ] because of the high binding capacity of
skeletal muscle.
• The distribution is best described by a twocompartment model.
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ELIMINATION
• The total CL is greater than for the
aminoglycosides but the t1/2 is much
longer (1-2 days) because of the large
volume.
EXCRETION
• The renal CL is approximately equal to
CLcr: both glomerular filtration and tubular
secretion contribute. 70% of the drug is
excreted unchanged in the urine
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ELIMINATION (continue)
METABOLISM
• The non-renal CL is about one-half of the
renal CL in normal subjects.
• -Sugar molecules are spilt off and the
steroid nucleus is further hydroxylated in
the liver.
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PERSISTENCE AND
ACCUMULATION
– about one-third of the dose is excreted per
day.
– Digoxin therefore accumulates until the
total amount of the drug in the body is
about 3 times the single daily dose.
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PERSISTENCE AND
ACCUMULATION (continue)
– This process is 90 % complete in about one
week [ 3- 4 x t1/2 ].
– Once the steady state has been attained the
total amount of digoxin in the body fluctuates
relatively little during the dosage interval.
(contrast to gentamicin)
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PLASMA CONCENTRATION AND
PATIENT RESPONSE
•
•
The concentration/ time curve is biphasic
because absorption is more rapid than
distribution.
The brief high peak may be associated
with nausea via an action on the
CTZ(Chemosensitive trigger zone) but
not with cardiac toxicity.
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• The cardiac response parallels the
hypothetically concentration in a deeper tissue
comparment.
• Css,av is probably the most relevant
concentration, which is approximated by C at
6 hours.
• A concentration of 1-2 g/L is usually
adequate to control the ventricular rate in atrial
fibrillation. However a concentration above 2
g/L is associated with an increased
frequency of ventricular ectopic beats.
• The
therapeutic index approaches unity
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DOSAGE REQUIREMENTS IN
DISEASE
– The rapid attainment of a high therapeutic
concentration (~2g/L) would require i/v
injection of 2 x V g or 10 g/Kg.
– V is approximately halved, however in the
elderly and in those with severe renal
impairment. Both these states are
associated with a relatively low skeletal
muscle mass.
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DOSAGE REQUIREMENTS IN
DISEASE (continue)
– Daily dosage requirement for Css,av of
1-2 g/L in the adult varies from 62.5 g
in the anuric (one paediatric/geriatric
tablet) to 500g in patients with normal
kidney function.
– Dosage requirement approximately
parallels CLcr
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SUMMARY
1. Digoxin is typical of a drug with
intermediate solubility. It is partially
absorbed from the gut. Its distribution
volume is large. Its elimination is by renal
and hepatic mechanisms.
2. Digoxin has a long half-life due to a very
large distribution volume, consequent on
extensive binding in skeletal muscle
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3. LIPID SOLUBLE DRUGS
• A large group of drugs including many
drugs that act on the CNS.
• They have in common a high lipid ( or
organic solvent) /water partition coefficient.
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• The group includes:
1. Weakly acidic drugs ( pKa greater than 8)Phenytoin and other anticonvulsants.
2. Virtually neutral drugs -Thiopentone and other i/v
anaesthetic agents, many sedatives and
inhalational anaesthetics, glycerly trinitrate,
steroids ( Ethinyloestradiol, Norethisterone,
Dexamethasone).
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CHARACTERISTIC FEATURES
1. Absorption from the gut is usually rapid
and complete unless chemical
inactivation occurs.
2. Initial distribution of the drug is very
rapid. Characteristically the drugs
enter tissues, including the brain, at a
rate that is limited by the flow of
blood, not by the rate of diffusion
through the cell membranes.
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CHARACTERISTIC FEATURES
(continue)
3. A large proportion of the drug is
bound to plasma proteins and to
intracellular proteins and lipids. The
concentration of drug molecules free in
the body water may be very small
indeed.
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4. The concentration of drug in the
glomerular filtrate is also very small and
the drug molecules are so lipid soluble
that they are re-absorbed from the renal
tubule as quickly as the filtered water.
Thus the unchanged drug is not effectively
excreted in the urine
5. Some of the drugs in this group, that have a
high vapour pressure, are excreted
unchanged in the expired air.
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6. Drugs of this group are oxidized in the liver,
and to a lesser extent in other tissues, to
more polar metabolites; which may be
alcohols or phenols. (phase I)
7. Water-soluble metabolites resembles
Gentamicin in their elimination. Many are
conjugated with sulphate, glycine or
glucuronic acid prior to excretion. (phase II)
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3.1 THIOPENTONE
• Is a short acting barbiturate administered
i/v for production of complete general
anaesthesia of short duration of action or
for induction of sustained anaesthesia.
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CHEMISTRY
• Thiopentone (MW 242 Da) is a highly
lipid-soluble compound due the
presence of barbituric acid and an alkyl
chain.
• Although it has a pKa of 7.6 and is
therefore a very weak acid ( it is used as
the sodium salt), its predominant
physicochemical property is its lipid
solubility.
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DISTRIBUTION
• Is approximately 70% bound to serum
albumin by ‘hydrophobic bonds’.
• The binding of barbiturates increases with
lipid solubility
• A single i/v dose of thiopentone can
produce almost instantaneous
anaesthesia that only lasts for
approximately 5 minutes.
• Large doses cause respiratory arrest.
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• An intermediate-acting barbiturate has a similar
potency to thiopentone (approx. the same
concentration in the brain is needed to produce
anaesthesia)
• However, no dose of it can mimic the very short
duration of action seen with thipentone
• The short duration of action is not due to rapid
metabolism but to rapid distribution into skeletal
muscle.
• Only after several hours is a substantial fraction
of a single dose located in fatty tissue.
• Consciousness returns whilst a large proportion of
the original dose is still in the body. Repeated doses
are
cumulative.
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TWO-COMPARTMENT
DISPOSITIONAL MODEL
The bi-exponential decay in plasma
thiopentone suggests that-:
• Its pharmacokinetic properties should be
considered in terms of a two compartment
model.
• Entry into various tissues (brain & liver) is
so rapid that it appears to be limited solely
by the rate of blood flow
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Two-Compartment Dispositional
Model (continue)
• Multicompartment ‘physiological models’
have been devised for thiopentone, which
employ known blood flow rates to principal
anatomical regions.
• One relatively simple model of this kind
comprises:
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1. A highly perfused central compartment or
vessel-rich group of organs including
brain; liver; myocardium; adrenal glands;
kidneys and receiving approximately
4L/min.
2. A lean tissue compartment (mainly skeletal
muscle ) and receiving approximately
1L/minute at rest.
•
Adipose tissue receives approximately
0.3L/minute.
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METABOLISM
• Thiopentone is cleared exclusively by
metabolism from the central vessel-rich
compartment; here the clearance concept
is applicable in the same way as it is to the
renal excretion of gentamicin and digoxin
• Less than 1 % is excreted unchanged in
the urine over 48 hours.
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• Some short-acting thiopentone is metabolized
to the intermediate-acting Pentobarbitone. (i.e.
the S is replaced by O)
• Both thiopentone and its pentobarbitone
product are further metabolized by the addition
of an OH group to the longer hydrocarbon
side-chain.
• The MFO system is responsible for this
metabolism.
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3.2 PHENYTOIN
• Anti-epileptic drug.
• It lacks the pronounced hypnotic action
seen with barbiturates
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CHEMISTRY
• Phenytoin is mainly used as the sodium
salt-MW (acid) = 252 Da; pKa= 8.3
• It is poorly soluble in aqueous solutions
(14 mg/L ) at pH less than 7.
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DISTRIBUTION
• The larger solubility in serum ( 75mg/L ) is
due mainly to extensive protein binding;
approximately 90% being bound to serum
proteins in vivo.
• Concentrations in saliva and CSF are
approximately 10% of the serum
concentration.
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METABOLISM
• Phenytoin is extensively metabolized by
MFO in the liver; less than 5% appearing
in the urine as unchanged drug.
• The glucuronide conjugate of the parahydroxylated product is the main
metabolite in the urine-phenytoin
exhibits both phase I and phase II
metabolism
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NON-LINEAR KINETICS
• Generally, a phenytoin serum Css,av less
than 10 Mg/L is only partially effective,
whereas a Css,av more than 30 Mg/L is
associated with toxic symptoms (
ataxia, dysarthria; nystagmus ).
• Monitoring of Css,av is essential. Since
the relationship between Css,av and daily
dose is non-linear.
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NON-LINEAR KINETICS
(continue)
• There is a disproportionate increase in
Css,av with increase in dose rate as a
consequence of distinctive dosedependent pharmacokinetics of this drug.
• There is an apparent increase in plasma
half-life with dose or C because the
pharmacokinetics are not first order.
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NON-LINEAR KINETICS
(continue)
• The elimination of phenytoin from the body is
best described in terms of MichaelisMenten/enzyme/ non-linear kinetics ( ethanol
and Asprin are eliminated similarly).
• The C/t curve appears to be biphasic,
approximating to zero order at larger C ( more
than 30 mg/L of phenytoin ) and becoming first
order (exponential) at small C ( less than 10
mg/L)
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CLINICAL APPLICATIONS
• A progressive but slow ( increment every 2
to 4 weeks ) increase in dose rate is
appropriate until control of seizures is
obtained or further increase is prevented
by toxicity. (refer table on next slide)
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INCREMENTS IN DOSE RATE PRODUCING
EQUAL INCREAMENTS IN Css,av VARY
INVERSELY WITH Css,av
Css,av (Mg/L)
• <5
• 5 to 10
• > 10
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INCREAMENT IN DOSE RATE (MG/DAY)
100
50
25
65
• Reduction in dosage necessitated by mild
intoxication require similar adjustments.
• Renal functional impairment reduces the
clearance of phenytoin metabolites but does not
reduce the rate of metabolism of unchanged
drug.
• Protein binding is reduced in severe kidney
disease and as a result the drug is metabolized
more rapidly.
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3.3 ETHANOL
CHEMISTRY
• In a dispositional sense ethanol (ethyl alcohol,
CH3CH2OH) belong to group 3; i.e. lipid soluble
group. BUT it is not a highly lipid soluble drug.
• Ethanol is highly water soluble, but its small
MW ( 46 Da ) enables it to pass rapidly
through the water-filled pores of cell
membranes and behaves as if it were a lipid
soluble drug.
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ABSORPTION
• Ethanol is rapidly and completely
absorbed through the mucosae of
stomach and jejunum.
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DISTRIBUTION
• Rapidly distributed throughout all aqueous
regions of the body.
• The Distribution Volume (Vd) is the total
body water.
• It equilibrates rapidly across the
blood/brain barrier.
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PLASMA CONCENTRATION AND
EFFECT
• Progressive increments of plasma
concentration (C) produce progressive
general CNS depression varying from
mild sedation to general anaesthesia
and fatal respiratory depression.
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ELIMINATION
METABOLISM
• Hepatic parenchymal cells oxidize
ethanol to acetaldehyde then to acetate
( by aldehyde dehydrogenase ).
• The main enzyme responsible for the first
stage is the cytoplasmic alcohol
dehyrogenase, although a microsomal
ethanol-oxidising system is a minor
contributor.
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ELIMINATION-Metabolism
(continue)
• Above a certain plasma concentration (
Km~ 100g/mL), elimination of ethanol
approximates to zero order i.e. is
independent of C.
• In most people, this saturating
concentration is reached after drinking a
single unit of alcohol.
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• The average maximum rate (Vmax) equals
8g/h or 10ml/h i.e 200 ml beer or 20 ml
whisky/ h .
• As elimination is constant irrespective of
concentration the time it takes for the
concentration to decrease to half-life is not
constant, so a meaningful plasma half-life
cannot be calculated.
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ELIMINATION (continues)
EXCRETION
• Ethanol is re-absorbed from the renal
tubule so that the urine concentration is
only slightly greater than the concentration
in the blood.
• Thus renal plasma Clearance
approximately equals the rate of urine flow
( 1 to 2 mL/ minute ).
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ELIMINATION (continues)
EXCRETION
• After small or moderate doses, less than
10% of the dose is eliminated in the urine.
• Excretion in expired air occurs but
represents less than 1% of the dose
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3.4 INHALATIONAL
ANAESTHETIC AGENTS
• These are gases or volatile liquids that
have a large solubility in lipid at normal
atmospheric pressure.
• The differences in physicochemical
properties between individual anaesthetic
agents influence the rate of onset of and
recovery from anaesthesia and partial
pressures necessary to induce
anaesthesia.
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PARTIAL PRESSURE
• In general the response to a drug is a function of
the concentration in the biophase (fluid in
intimate contact with receptors)
• The concentration of inhalational anaesthetics is
more conveniently expressed in terms of
partial pressure rather than mass of gas per
unit volume of liquid.
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• This is because diffusion of a gas between
phases occurs down a gradient of partial
pressure; at a speed proportional to the
gradient, until differences in partial pressure
are eliminated.
• Partial pressure is defined as the individual
pressure exerted by a gas in a mixture of
gases.
• In the gas phase the partial pressure of the
anaesthetic agent can also be expressed as
a proportion of the total pressure (normally
78
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atmosphere)
SOLUBILITY IN BLOOD AND
TISSUES
• Some anaesthetic agents have a greater
affinity for blood than for the gas phase.
• This affinity is expressed as their solubility
in blood.
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Henry’s law states that:
• Mass of gas dissolved by unit volume
of liquid=
Solubility X partial pressure of gas at a
constant temperature.
• Consequently the amount of
anaesthetic agent that must be
dissolved (and therefore the time it
takes ) to achieve a particular partial
pressure in the blood is proportional to
the solubility.
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POTENCY
• An anaesthetic agent is potent if it
produces a given depth of anaesthesia
at a low partial pressure in the inspired
air.
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• This is expressed as Minimal Alveolar
Concentration (MAC) for anaesthesia; which is
proportion ( percentage V/V ) of anaesthetic
agent in the inspired air that, at equilibrium,
prevents the reflex response to skin incision in
50% of subjects.
• Halothane (MAC=0.8) is potent whilst nitrous
oxide (MAC > 80 ) is of small potency.
• The potency of inhalational anaesthetic agents
is3/23/2016
positively correlated with lipid solubility. 82
INDUCTION OF ANAESTHESIA
•
The time to induction of anaesthesia is
dependent upon the rate of increase
of partial pressure of anaesthetic
agent in the brain.
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INDUCTION OF ANAESTHESIA
(continue)
• This time is reduced when:1. Inspired partial pressure is high.
2. Alveolar ventilation is large-this
increases transfer of anaesthetic agent
from external air to alveoli
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INDUCTION OF ANAESTHESIA
(continue)
3. Body weight is small-gas equivalent
volume is reduce
4. Anaesthetic agent is of small solubilitytime taken for equilibrium to be reached
is directly proportional to solubility e.g.
diethyl ether has a large solubility and
induction is slow while nitrous oxide has
a small solubility and induction is fast
•
Read on Maintenance of anaesthesia & Recovery
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SUMMARY
1. Lipid-soluble drugs are well absorbed
from the gut, distributed widely and
eliminated by metabolism
2. The decay of plasma concentration of
thiopentone, after i/v injection, is due to
distribution to a peripheral compartment,
and this process terminates its effect.
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SUMMARY (continue)
3. Ethanol has a small MW and behaves as
if it was lipid soluble
4. Phenytoin and ethanol exhibit saturation
kinetics
5. Inhalational anaesthetics are gases or
volatile liquids and are lipid soluble
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SUMMARY (continue)
6. The time to induction of anaesthesia is
reduced when inspired partial pressure is
high, ventilation is large, body weight is
small and blood/gas solubility is small
7. Potency is correlated with lipid solubility
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4. ACIDIC DRUGS
• Acidic drugs [ pKa 2 to 8 ] have similar
modes of absorption; distribution and
elimination but widely diverse
pharmacological action.
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EXAMPLES OF ACIDIC DRUGS
1. NSAIDs-Aspirin, Indomethacin and
Naproxen.
2. Oral anticoagulants- Warfarin.
3. Penicillin antibiotic agentsBenzylypenicillin;
Phenoxymethylpenicillin; Ampicillin and
Flucloxacillin.
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EXAMPLES OF ACIDIC DRUGS
4. Sulphonamide antibacterial drugs--Sulphamethoxazole and Sulphadiazine.
5. Oral hypoglycaemic drugs--Tolbutamide; Chlorpropamide and
Glibenclamide.
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EXAMPLES OF ACIDIC DRUGS
6. Diuretics—Bendrofluazide, Frusemide;
Ethacrynic acid.
7. Phenobarbitone is the only common
barbiturate with a pKa significantly less
than 8
8. Uricosuric agents--- Probenecid and
Sulphinpyrazone.
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EXAMPLES OF ACIDIC DRUGS
9. Diagnostic radio-opaque compounds are
usually acidic--- They are used, for
example in pyelography [ x-ray
examination of upper urinary tract ]
and cholangiography [ of the gallbladder and bile ducts].
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CHARACTERISTIC FEATURES
1. Most acidic drugs are present mainly as
the uncharged acid [ HA] at pH 3.
•
The undissociated acid [HA ] is the more
lipid soluble than the dissociated or
ionized form (A-,anion); thus, conditions
in the stomach are favourable to
absorption but surface area is small.
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2. In the plasma; acidic drugs are present to a
large extent as the charged anions [ A- ].
• The anions of different acidic drugs compete
for a common binding site on plasma albumin
and for active secretion into bile and urine.
3. The plasma clearance [ CL ] varies inversely
with the extent of reabsorption from the renal
tubule.
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CHARACTERISTIC FEATURES
(CONTINUE)
•
If the urine pH is high; the drug in the
urine is present mainly as the anion [ A]; non- diffusional reabsorption is
discouraged and CL is high.
•
Increase in CL causes a corresponding
reduction in plasma half-life
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96
• NOTE:
• Urine pH should be controlled when
measuring excretion rates of acidic
compounds
• The usefulness of alkaline diuresis in
acute poisoning by salicylates or
phenobarbitone
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97
4.1 SALICYLIC ACID
•
•
Aspirin( Acetylsalicylic acid) is used
for its analgesic; anti-inflammatory and
antipyretic properties.
There are 2 main use situations: -occasional, low dose utilizing the
antipyretic and analgesic properties;
-chronic high dose, utilizing the analgesic
and anti-inflammatory properties of
Aspirin.
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SALICYLIC ACID (continue)
• It is usually administered in the form of Aspirin [
Acetylsalicylic acid] but this is rapidly
hydrolyzed within the body [ plasma half-life~ 15
minutes ] to give acetate and Salicylic acid.
• Most of the pharmacological properties of aspirin
is due to the metabolite, Salicylic acid.
• Aspirin is therefore a pro-drug although it
may exert some therapeutic actions itself
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PHYSICAL CHEMICAL
PROPERTIES
• Aspirin is a weak acid (pKa 3) and is
soluble in water and organic solvents
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DOSAGE FORM AND
ABSORPTION
•
•
•
Drug in solution is rapidly absorbed
primarily from the small intestine.
Salicylates are poorly soluble at low pH.
Dissolution of Aspirin in intestinal fluids is
the rate-limiting step in absorption.
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DOSAGE FORM AND
ABSORPTION (cont.)
• Simple Aspirin tablets or dispersible
formulations; with consequent rapid dissolution
and absorption are appropriate when rapid onset
of effect is required ( e.g. to treat headache ).
• For treatment of chronic disease [ e.g. joint
inflammation ] where rapid onset of effect is not
required, enteric coated or other slow release
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DOSAGE FORM AND
ABSORPTION (cont.)
preparations may be preferred as they
minimize the local erosive action on
gastric mucosa (epigastric discomfort).
• Enteric coated tablets can give erratic and
incomplete absorption.
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DISTRIBUTION
• Salicylic acid enters cells by diffusion
through the lipid membrane (non-ionic
diffusion).
• It is distributed throughout total body water
and binds to sites on plasma albumin and
tissue protein.
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DISTRIBUTION (cont.)
• At high Salicylate doses its plasma
concentration approaches that of albumin
[0.6 Mmol/ Litre ], and albumin binding
sites become saturated with the drug.
Consequently, there is a disproportionate
rise in the fraction of free drug
concentration for any further increase in
dose.
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PLASMA SALICYLATE AND
PATIENT RESPONSE
•
Below 100 Mg/L therapeutic effect achieved
are analgesia and anti-pyretic effects.
-Side effects include bleeding from gastric
erosions [ reduced platelet stickiness and
hypoprothrombinaemia i.e.‘ deficiency of
prothrombin’ may contribute ] and
bronchospasm (an idiosyncrasy that is not due
to allergy but to cyclo-oxygenase inhibition)
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PLASMA SALICYLATE AND
PATIENT RESPONSE (cont.)
• 150 to 300 Mg/Litre: therapeutic effect
achieved is the anti-inflammatory action
-Side effects include tinnitus and deafness
at maximum therapeutic concentrations ].
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• 300 to 750 Mg/L -----Mild to moderate
intoxication is manifested as hyperventilation;
respiratory alkalosis, sweating; tachycardia,
salt and water depletion. Toxicity increases
with time.
500mg/L at 48h after overdose may represent
severe intoxication.
Treatment is by correction of salt and water
depletion and by alkaline diuresis.
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PLASMA SALICYLATE AND
PATIENT RESPONSE (cont.)
• Above 750 Mg/L: severe intoxication is
manifested as impaired utilization of
pyruvate and lactate; metabolic acidosis;
convulsions; circulatory arrest and renal
failure.
Haemodialysis may be required
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METABOLISM AND
DISPOSITION KINETICS
• Hepatic metabolism is the major
mechanism of elimination at small and
moderate plasma concentrations (Refer next slide)
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110
METABOLIC FATE OF ASPIRIN
FATE
Conjugated
[Phase II]
with :
Hydoxylated
[Phase 1 ]
Excreted
unchanged
[low
dose ]
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Glycine
Glucuronic acid
Glucuronic acid
METABOLITE
URINE %
Salicyluric acid
Acylglucuronide
Phenolic
glucuronide
45 to 55
7 to 12
Gentisic
acid
<3
15 to 25
5 to 25
111
ZERO ORDER SALICYLIC ACID KINETICSDEPENDENCE OF PLASMA-HALF LIFE ON
DOSE
DOSE ( GM )
APPARENT PLASMA
HALF-LIFE IN HOURS
0.3
2.3
1
6
10
19
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• Salicylic acid displays the same non-linear
elimination kinetics as Phenytoin and
Ethanol
• The process of conjugation to form
Salicyluric acid and Phenolic
glucucoronide becomes saturated in
therapeutic dose range. There is;
therefore; an apparent rise in plasma halflife with dose.
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•
RENAL CLEARANCE-Increases with pH
and urine flow
•
Renal excretion is a minor pathway at low
concentration but a major pathway at high
concentration [ intoxication ] due to
saturation of metabolic elimination.
•
Clearance increases about four-fold with
each unit rise unit rise in urine pH. This
explains the effective use of alkaline diuresis
in Salicylate intoxication.
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SUMMARY
1. Acidic Drugs can be absorbed from the
stomach, mainly exist as the anion in bodily
fluids, and their renal excretion is enhanced
when tubular pH is high.
2. Aspirin is rapidly metabolized to salicylic acid.
Hepatic metabolism is the major route of
elimination at low plasma concentrations but
exhibits saturation. Renal excretion is
important at high concentrations.
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5. BASIC DRUGS
• Basic drugs [ pKa 6 to 12 ] have similar
modes of absorption; distribution and
elimination but widely diverse
pharmacological actions.
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EXAMPLES
•
Opioid analgesics----Morphine;
Pethidine; Dextropropoxyphene;
Pentazocine [ and the antagonist
Naloxone ].
•
Local anaesthetics----Lignocaine
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•
Antidysrhythmic drugs---Lignocaine;
Quinidine
•
•
Ganglionic stimulants…..Nicotine.
Antagonist at muscarinic
cholinoceptors….Atropine and Hyoscine.
•
Acetylycholinesterase
inhibitors……..Physostigmine.
•
Adrenergic neurone blocking
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agents….Guanethidine
118
•
Sympathomimetic amines: direct
acting….Noradrenaline; Adrenaline;
Isoprenaline….
Indirect acting----Amphetamine.
•
Antagonists at adrenoceptors----Phenoxybenzamine; Phenolamine; Prazosin;
Labetalol; Propranolol.
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• Antipsychotics---Phenothiazine--Chlorpromazine; Promethazine.
• Anxiolytics---Diazepam.
• Tricylic anti-depressants---Imipramine;
Amitriptilyne.
• Antagonist at histamine receptors--Chlorpheniramine; Cimetidine.
• Antiparasitic drugs---Chloroquine and
Piperazine.
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• Smooth muscle relaxants: Theophylline;
Vasodilators—Hydralazine;
calcium channel blockers (L type)--Verapamil and Nifedipine.
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121
CHARACTERISTIC FEATURES
•
•
Basic drugs exist almost entirely as the
non-diffusible cation at pH 3; conditions
do not favour absorption from the
stomach.
Generally in plasma the fraction of bases
bound to protein is less than the fraction
of acidic drug bound; and 1- acid
glycoprotein is involved rather than
albumin.
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•
The concentration of total drug [ cation plus base ]
in urine is greatly increased when the urine pH is
reduced from 8 to 5.
•
When excretion is a major factor in elimination [ e.g
Amphetamine ] the plasma concentration half-life is
shortened if the urine is made acidic.
NOTE:
1. Urine pH should be controlled when measuring
excretion rates of basic compounds
2. The basic usefulness of acid diuresis in poisoning
by amphetamine
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123
5.1 LIGNOCAINE
• Used as antidysrhythmic drug and a local
anaesthetic agent.
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124
CHEMISTRY
• Lignocaine is a weak base (pKa 8) with
limited solubility in water (7mg/L) but very
soluble in organic solvents
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125
ABSORPTION
• Rapid and complete from all sites except
the gut. plasma half-life ~ 15 minutes.
• Absorption is more rapid from an alkaline
environment and greatest from highly
perfused tissues.
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DISTRIBUTION
•
•
50% of lignocaine in the plasma is bound
NOT to albumin, but to alpha acid
glycoprotein. Displacement is an unlikely
phenomenon
It is so lipophilic that cell membranes are
no barrier to its penetration.
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DISTRIBUTION (CONTINUE)
• The rate of tissue uptake is a function of
organ perfusion. This explains the rapid
onset ( about 1 min ) and termination
(about 20 minutes ) of CNS and cardiac
effects of lignocaine following a
therapeutic bolus dose (1 Mg/Kg ).
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DISTRIBUTION (CONTINUE)
•
The lipophilicity also explains the size of
the ‘resevoir’ in muscle after prolonged
administration.
•
Volume of distribution in a 70kg
individual is about 120 L, as the drug
lies mainly outside plasma in lung;
kidney; brain; muscle and adipose
tissue
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DISTRIBUTION (CONTINUE)
• The arterial plasma decay curve of
lignocaine after an i/v bolus dose is biexponential, as with thiopentone.
• Distribution is slow into fat (because it is
so poorly perfused) and quantitatively less
important
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PLASMA CONCENTRATION AND
EFFECT
• Lignocaine is generally ineffective at
plasma concentrations below 1.5 Mg/L;
the frequency and severity of adverse
effects ( convulsions ) increases with
plasma concentrations above 6Mg/L
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METABOLISM AND
DISPOSITION KINETICS
• The hepatic MFO removes one or both
ethyl groups ( N-deakylation ).
• Both products are biologically active
• Aromatic C-hydroxylation and hydrolysis of
side-chain at the amide position also
occur.
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CLEARANCE, BIOAVAILABILITY
AND PLASMA HALF-LIFE
• Elimination of lignocaine is almost
exclusively by hepatic metabolism and is
very high(1L/ min in a 70 Kg individual),
approaching liver blood flow (1.5 L/min/70
Kg ).
• High hepatic extraction ( 70%) explains
the low bioavailability ( 30% ) with oral
dosage of lignocaine
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CLEARANCE, BIOAVAILABILITY
AND PLASMA HALF-LIFE (cont)
• Metabolites are active so the oral dose is
more effective than the low bioavailability
suggests.
• Lignocaine has a high hepatic extraction
ratio so changes in liver perfusion affect
clearance.
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CLEARANCE, BIOAVAILABILITY
AND PLASMA HALF-LIFE (cont)
• Consequently dosage requirements are
diminished in disease depressing circulatory
function ( cardiogenic shock; congestive heart
failure ) or hepatic metabolism ( cirrhosis )
where shunting of blood away from damaged
areas can occur.
• Propranolol by reduces cardiac output and
hepatic blood flow and thus reduces the CL of
lignocaine.
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CLEARANCE, BIOAVAILABILITY
AND PLASMA HALF-LIFE (cont)
• Although CL is high; plasma half-life is not
excessively short ( 1 to 2 H ) because V is
large .
• There is long delay ( 3-5 x t1/2 ) between
initiation of an infusion and attainment of
the plateau concentration. Therefore, a
bolus dose is given by an infusion to
match metabolism.
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CLEARANCE, BIOAVAILABILITY
AND PLASMA HALF-LIFE (cont)
• Renal excretion is a minor pathway of
elimination of lignocaine due to extensive
re-absorption, so urine acidification has no
significant influence on its elimination
kinetics.
• This is in marked contrast with
amphetamine, the plasma half-life of which
is reduced from 16 h to 5 h by acidification
of the urine from pH 7 to pH 5
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SUMMARY
• Basic drugs are absorbed fro the small intestine,
exist at the cation in bodily fluids, and their renal
excretion is enhanced when tubular pH is low
• Lignocaine is a lipid soluble base whose
handling can be described a two compartment
model when given by i/v injection
• To attain and maintain therapeutic plasma
concentrations it is given by a bolus dose
followed by an infusion
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