Pharmacokinetics /prosthodontic courses

PHARMACOKINETICS
 Pharmacokinetics is a quantitave study of drug movement
in,through and out of the body
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Pharmocokinetics include
 Transport of the across the membrane
 Absorpiton of the drug
 Distribution of drug
 Biotranformation or metabolism of drug
 Excretion of the drug

MEMBRANE TRANSPORT
Biologic membrane is a bilayer of phospholipids and
cholestrol molecules

DRUGS ARE TRANSPORTED ACROSS THE MEMBRANES BY
 Passive diffusion and filtration
 Specilized transport
 Passive diffusion :
The drug Diffuses across the membrane in the direction
of its conc. gradient, the membrane playing no active role
in the process.
It is the most important mechanism for majority of the drugs
 Lipid soluble drugs diffuse by dissolving in the
Lipoidal matrix of the membrane, the rate of transport
 Being proportional to the lipid: water partition coefficient of the drug
A lipid soluble drug attains higher conc. in the membrane and diffuses quickly
 Also , greater the difference in the conc. of the drug on the two sides of the
membrane, faster is the diffusion.

INFLUENCE OF PH
 Weakly acidic drugs, which forms salts with cations
ionize more at alkaline ph
 Eg: sodium phenobarbitone,pottasium pencillin v
Weakly basic drugs,which forms salts with anions
ionize more at acidic ph
Eg: atrophine sulphate

FILTRATION
 Filtration is the passage of drugs through the
acqueous pores in the membrane or through
paracellular spaces
 This can be accelerated if hydrodynamic flow of the
solvent is occuring under hydrostatic or osmotic
pressure gradient

SPECIALIZED TRANSPORT

 CARRIER TRANSPORT : all cell membranes express a
host of transmembrane proteins which serve as carrier
or transporters for physiologically important ions ,
neutrients , metabolitestransmitters etc across the
membrane
 Carrier transport is specific for substrate ,saturable,
competitively inhibited, analogues which utilizes the
same transporter, and is much slower than flux through
channels
 Depending on requirement of energy ,carrier transport
is two types
 Facilitated diffusion
 Active transport

FACILITATED DIFFUSION
 The transporter belonging to the super family of solute
carreier(slc) transporters, operates passively without
needing energy and translocates the substrates in the
direction of its electrochemical gradient that is from
higher to lower concenteration
 It mearly facilitates permeation of a poorly diffusable
substrate
 Eg: the entry of glucose into the muscle and fat cells by
Gut

ACTIVE TRANSPORT
 It requires energy , is inhibited by metabolic poisons, and
transport the solute against its electrochemical gradient i.e low
to higher conc , resulting in selective accumulation of the
substance on one side of the membrane
 Active transport can be primary or secondary depending on
the sourse of the driving force
 Primary active transport: energry is obtained diretcly by the
hydrolosis of atp
 The transportrs belong to the super family of atp binding
cassete (abc) transpoters whose intracelluar loops have atpase
activity they mediate only afflux of the solute from the
cytoplasm eighter to ecf or into an intracellular organelle

 Secondary active transport: In this type of active
transport effected by another set of SLC
transporters, the energy to pump one solute is
derived from the down hill movement of another
solute (mostly NA) .

ABSORPTION
 It is the movement of drug from its site of
administration into the circulation
 Not only the fraction of administered dose that gets
absorbed,but also the rate of absorption is also
important
 Except when given i.v ,the drug has to cross bilogical
membrane ;absorption is governed by the above
described principles.other factors affecting absorption
are acqueos solubility , the concentration.area of
absorbing surface ,vascularity of the absorbing surface
,route of administration

BIOAVAILABILITY
 Bioavailabilty refers to the rate and extent of absorption of
drug from a dosage form as determined by its conc –time
curve in blood or by its excretion in urine.

 It is a measure of the fraction F of administered dose of a
drug that reaches the systemic cirulation in the unchanged
form
 Bioavailability of drug injected Iv is 100%, but is frequently
lowered as per oral injesion because
a) The drug may be incompletely absorbed
b) the absorbed drug may undergo first pass metabolism , in
the intestinal wall or liver or the excreted in bile.
 Incomplete bioavaiability after sc or im injection is less
common ,but may occur due to local binding of the drug
 Differences in bioavailability may arise due to variations in
disintegration and dissolution rate .
 Differences in bioavalabilty are mostly seen with poorly
soluble and slowly absorbed drug .

DISTRIBUTION
 Once a drug has gained access to the blood stream , its gets
distributed to other tissues that initially had no drug ,
concentration gradient is in the direction of plasma-tissues
 The extent of distibution of a drug depends on its lipid
solubility , ionisation at physiologic ph( a function of its pka ),
extend of binding to plasama and tissue proteins, presence of
tissue specific transporters and differences in the region of
blood flow
 Movement of a drug proceeds untill an equilibrium is
established between unbound drug in plasma and tissue fluids
subsequently, there is parallel decline in both due to
elimination

APPARENT VOLUME OF DISTRIBUTION
The volume that would accommodate all the drug in the body ,is
the conc through out was the same ,as in plasma.
Thus it describes the maount of drug present in the body as a
multiple of that contained in a unit volume of plasma.

REDISTRIBUTION
 Highly lipid soluble drugs gets intilayy distributed to
organs with high bolld flow i.e brain heart kidney
etc.;later, less vascular but more bulky tissues
(muscle,fat) take up the drug –plasma conc falls and the
drug is withdrawn from these sites
 If the site of action of the drug was in one of the highly
perfused organs, redistribution results in termination of
drug action.
 Greater the lipid solubility of the drug , faster is its
redistribuiton
 Anastetic action of thiopentene sodium injected I.V
isdominated in few minutes due to redistribution

PENETRATION INTO BRAIN AND CSF

PLASMA PROTEIN BINDING
Most drugs posesses physicochemical affinity for plasma proteins
Acidic drugs generally bind to plasma albumin
Basic drugs to alpha 1 acid glycoprotein.
Binding to albumin is quantitaively importanat
 Higly plasmaprotein bound drugs are largely restricted to the vascular
compartment because the protein bound drug doesnot cross the membrane
they tend to have smaller volumes of distribution

 The bound fraction is not available for action however ,it is a
equlibrium with a fee drug in plasma and dissociates when
the conc of the late r is reduced due to elimination plasma
protein binding thus tantamounts to the temporary storage of
the drug .
 HIGH DEGREE OF PROTEIN BINDING generally makes the
drug long acting because bound fraction is not available for
metabolism or excretion, unless it is actvely extracted in the
liver or kidney tubules
 Generally expressed plasma concentration of the drug refer to
ound as well as free drug
 One drug can bind to may sites on the albumin molecule.
Conversly, more than one drug can bind to same site this can
give rise to displacement interactions among drugs bound to
the same site.
Eg: salicylates displace sulfonyl urea

BIOTRANSFORMATION
 Biotranspformation means chemical alteration of the
drug in the body
 It is needed to render nonpolar(lipid soluble)
compounds polar(lipid insoluble) so that there are not
reabsorbed in the renal tubules and are excreted .
 Most hydrophillic drugs eg: strptomycin are little
biotransformed they are largely excreted unchanged
 Mechanisms which metabolise drugs( essentially
foregin substances ) have developed to protect body
from injested toxins
 Primary site for drug metabolism is liver others are
kidneys,intestines,plasma

 Biotransformation of drugs leads to following :
A) Inactivation
B) Active metabolite from inactive drug
C) Activation of inactive drug
Inactivation: most drugs ad their active metabolite are rendered
inactive or less active eg: ibuprofen,PCT,lidocaine
Active metabolite form inactive drug:many drugs have been
found to be partially converted to one or more active
metabolite

 Activation of inactive drug: few drugs are inactive
as such and need conversion in the body in one or
more active metabolites such a drug is called
prodrug .prodrug may offer advantages over the
active form in being more stable , having better
bioavailability less side effects and toxicity

 Biotransoformation reaction can be classified into
non synthetic or phase 1 or function alization
reactions
 Metabolite may be actve or inactive .
Oxidation
Reduction
Hydrolysis
Cyclization
Decyclization

 Synthetic or phase 2 reaction :
Metabolite is mostly inactive
Glucuronide conjugation
Acetylation
Methylation
Sulfate conjugation
Glycine conjugation
Glutathione conjugation
Libonucleoside or nulceotide snthesis

INHIBITION OF DRUG METABOLISM
 one drug can competetively inhibit metabolism of
another if it utilizes the same enzyme or cofactor

CON SEQUENCES MICROSOMAL ENZYME INDUCTION
 Decreased intensity and or duration of action of drugs
that are inactivated by metabolism
Eg: failure of contraception with oral contraceptives
 Increased intensity of action of drugs that are activated
by metabolism acute PCT toxicity is due to one of its
metabolites –toxicity occurs at lower dosage in patients
receing enzyme inducers
 Intermittent use of an inducer may interfere with the
adjustment of those of another drug prescribed on
regular bases eg: oral anticoagulants ,oral
hypoglycemics ,anti epileptics and anti hypertensives

POSSIBLE USES OF ENZYME INDUCTION
 Congenital non hemolytic jaundice it is due to deficinet
glucoridation of bilurubin ; phenobarbitone hastens
cleareance of jaundice
 Cushings syndrome phenatoin may reduce the
manifestation sof enhancing the degradation of
adrenosteroids
 Chronic poisoinings by faster metabolism of the
accumulated poisonous substance
 Liver disease

FIRST PASS (PRESYSTAMIC) METABOLISM
 This refers to metabolism of a drug during its passage from
the site of absortion into the systemic circulation
 All orally administerd drugs are exposed to drug
metabolizing enzymes in the intestina wall and liver( where
they first reach through portal vein)
 The extent of first pass metabolism differs for different drus
and is important for determinant of oral bioavailabilty

 Attributes of drugs with hisg first pass metabolism
 A) oral dosage cosiderably higher than sub lingual or
parenteral dose
 B) there is marked individual varation in the oral dose
due to differences in the xtents of first pass metabolism
 C)oral bioavailabiltity is apparently increased in
patients with severe liver diseases
 D) oral bioavailability of a drug is increased if another
drug competeing with it in first pass metabolism is
given concurrently
 Eg: chlorpromazine and propanalol

EXCRETION
 Excretion is the passage out of systemically absorbed
drugs
 Drugs and their metabolites are excreted in
 Urine
 Feaces
 Exhaled air
 Saliva and sweat
 Milk

RENAL EXCRETION
 Net renal excretion = (glomerular filtration +tubular
secretion)- tubular reabsorption
 Weak bases ionise more and are less reabsorbed in acidic urine
 Weak acids ionise more and less reabsorbed in alkaline urine
 Drugs utilizing the same active transport comete with each
other
Eg: probencid an organic acid which has high affinity for the
tubular oatp it blocks the active transport of both pencillin and
uric acid
Many dug interaction occur due to competetion ofr tubular
secretion
Salicylates block uricosuric action of probencid
And sulfinperazone and decrease tubular secretion of
methotrexate

KINETICS OF ELIMINATION
 They are 3 fundamental formacokinetics parameters namely
 Bioavailability(F)
 Volume of distribution(v)
 Cleareance (Cl)
 Drug elimiation is the sumtotal of metabolic inactivation and
excretion
 Drug is eliminated only from the central compartment (blood)
which is in equlibrium with perepheral compartments
including the site of action

 Depending upon the ability of the body to elimianate a
drug, is again the fraction of the central compartment
may be considered to be totally “cleared” of that drug in
a given period of time to account for elimination over
that period

CLEREANCE
 Clereance of a drug in the theoritical volume of plasma from
which the drug is ocmpletey removed in a unit time
 It can be caluclated as cl=rate of elimiation /C
WHERE C IS THE PLASMA CONC.
FOR MAJORITY OF DRUGS THE PREOCESS INVOLVED IN
ELIMINIATION ARE NOT SATURATED OVER THE
CLINICALLY OBTAINED CONCENTRATIONS

 First order (exponential )kinetics: The rate of elimitation is
directly proportional to drug concentraton,CL remains
constant
 Zero order kinetics:The rate of elimination remains constant
irrespective of drug concentration ,CL decreases with increase
in concentration
 plasma half-life: The plasma half life (t1/2) of a drug is the
time taken for its plasma concentration to be reduced to half
of its original value

PHARMOCOCKINETICS OF NSAID
 Aspirin: it is absorbed from stomach and small intestine its
poor water solubility is a limiting factor in absoorption .
 Microfining the drug particles and inclusion of an alkali
enhances absorption
 Aspirin is readily deacytylated in gut wall ,liver plasma,and
other tiuuses to release salycylic acid which is a major
circulating and active form
 It is 80% bound to plasma protein and has a volume of
distribution 0.17 lit/kg
 It slowly enters the brain but freely crosses plaacenta

ASPIRIN CONT’D
 Both aspirin and salycylic acid are conjugated in liver
by glycine to give salicyluric acid (major part) and with
glucorinic acid.
 Few other metabolites are also formed
Excretion : the metabolites are excreted by GF as well as
tubular secretion normally only 1/10th is excreted as
free salycylic acid ,it can be increased by alkalysation
Plasma half life of aspirin as such is 50-20min , but taken
together with that of released salycylic acid it is 3- 5 hrs

IBUPROFEN
 It is absorbed orally
 Higly bound to plasma proteins ( 90-99%), but
displacement interactions are not clinically significant-
dose of anticoagulants and oral hypoglycemics need not
to be altered becoz they inhibit platelet function , use
with anticoagulants should, neverthless, be avoided.
 All propionic acid derivitives enters brain ,synovial fluid
and cross placenta
 They are largely metabolized in liver by hydroxylation
and glucuronide conjugation and excreted in urine as
well as bile

DICLOFENAC SODIUM
 It is well absorbed orally ,99% protein bound,
metabolised and excreted both in urine and bile
 Plasma life is approximately 2hrs however, it had good
tissue penetrability and conc in synovial fluid is
maintaianed for 3 times longer period than in plasma,
exerting extended herpatic action in joints

KETOROLAC
 It is rapidly absorbed oral & im administration
 It is higly plasma protein bound and 60% excreted
unchanged in urine.
 Major metabolic pathway is glucorodination
 Plasma half life 5- 7hrs

NIMUSULIDE
 It is almost completely absorbed orally
 99% plasma protein bound
 Extensively metabolised and excreted mainly in urine
 2-5 hrs plasma half life

PARACETMOL
 Dethylated active metaboite of phenacetin
 It is well absorbed orally, only about ¼th is proein
bound in plasma and it is uniforamly distributed in the
body
 Metabolism occurs mainly by conjugation with
glucuronic acid and sulphate
 Conjugates are rapidly excreted in urine
 Plasma half is 2-3 hrs
 Effect after an oral dose lasts for 3- 5 hrs

INSULIN
 Insulin is distributed only extracellularly
 It is a peptide, gets degraded in git given orally
 In injected insulin or that released from pancrease is
metabolised primarly in liver and to a smaller extent in kidney
and muscles
 Nearly half of the insulin entering portal vein from pancrease
is inactivated in the first passage through liver
 thus normally liver is exposed to much higher conc of insulin
than other tissues

 During biotransformation the disulphide bonds are
reduced – A n B chains are seperated.these are further
broken down to the constituent amino acids
 Plasma half life 5- 9 mins

PHENATOIN
 Absoprtion of phenotoin by oral route is slow mainly
because of its poorly acqueous solubility
 80-90% bound to plasma protein
 Widely distribute in the body
 Metabolised in liver by glucoridination conjugation
 only 5% unchanged pheotoin is excreted in urine
 Plasma life is 12- 24 hrs

CARBAMAZEPINE
 Oral absorption of c is slow and variable because of
poor water solubility
 It is 75 % bound to plasma protein
 It is meabolised in liver by oxidation to an active
metabolite (10-11 ipoxycarbazepine) as well as by
hydroxylation and conjugation to inactive ones
 It s a substrate as well as inducer of CYP3A4 and other
drug metabolizing enzyme
 Initially its plasma half life is 20 -40 hrs , but, decreases
to 10 to 20 hrs on chronic medication due to
autoinduction of metabolism

PHARMOCOKINETICS OF ANTIBIOTICS
 Ciprofloxacin: it is rapidly absorbed orally but food delays
absorption and first pass metabolism occurs
 The most prominent featue of ciprofloxacin is high tissue
pennetrability ,conc in lung ,sputum,muscle , bone, prostrate
and phagocytes
Exceeds that of plasma, csf and acqueous levels are lowered .
It is excreted primarly in urine both by glomerular filtration and
tubular secretion
Urinary and biliary conc are 10-50 fold higher than plasma

OFLOXACIN
 It is relatively lipid soluble
 Oral bioavailability is high
 Attains high plasma conc.
 Food doesnot interfere with its absorption
 It is excreted largely unchanged in urine
 Dose needs to be reduced in renal failure

PENCILLIN G
 PENCILLIN G IS acid labile destroyed by gastric acid as such
less than 1/3rd of an oral dose is absorbed in the active form
 Absorption of sod.P.g from im site is rapid and complete
 Peak plasma level is attained in 30 min
 It is distributed mainly extracellularly
 Reaches most body fluids, but penetration in serous cavities
and csf is poor
 60% plasma protein bound
 It is little metabolised due to rapid excretion
 The pharmacokinetics of PmG is dominated by very rapid
renal excretion; about 105 by glomerular filteration and the
rest by tubular secretion

 Plasma half life of pencillin g is 30min in healthy
adults
 Neonates have slower tubular secretion – plasma
half life is longer ;but appraches adult value by
3months and its even shorter in childhood
 Aged and those with renal failure excrete pencillin
slowly
 Tubular secretion of penG CAN be blocked by
probencid – higher and longer lasting plasma conc
are achieved
 Probencid also decreases the volume of distribution
of pencillins

AMPICILLIN
 Ampicillin is not degraded by gastric acid
 Oral absorption is incompete but adequate
 Food interferes with absorption
 It is parly exctreted in bile and reabsorbed-
enterohepatic cirulation occurs
 However,primary zone of excretion is kidney. But
tubular secretion is slower than png
 Plasma half life 1hr

AMOXCILIN
 It is a close congener of ampicillin (but not a
prodrug);similar to it in all respects except oral
absorption is better
 Food doesnot interfere with absorption
 High but sustain blood levels are obtained

CLAVULONIC ACID
 It has rapid oral absorption and bioavailabilty of 60%
,can also be injected
 Plasma half 1hr and tissue distribution matches
amoxcillin with which it is used ( 3rd coamoxiclav).
 However,it is eliminated mainly by glomerular
filteration and its excretion is not effetced by pobenicid.
 Also. It is largely hydrolysed and decarboxylated before
excretion, while amox is primarly excreted unchanged
by tubular secretion

TETRACYCLINE
 older tetracyclines are incompletely absorbed from git
 Absorption is better if taken in empty stomach
 Dox & mino are compltely absorbed irrespective of food
 Tetracycline have celating propertie-insoluble and
unabsorbable complexes with calcium and other metals
.
 Milk,iron preparation, nonsystemic antacids and
sucrolfate reduce their absorption

 The csf conc of most tetracyclines is about one half of the
plasma conc ,whether meninges are inflamed or not
 Most tetracyclines are excreted in urine by glomerular
filteration
 Dose has to be reduced in renal failure;dox is an exception to
this
 They are partly metabolized and significant amounts enter
bile –some degree of enterohepatic circulation occurs
 They are secreted in milk I amounts sufficient to effect the
suckling infant
 Interaction: Enzyme inducers like phenobarbitone and
phenatoin enhance metabolism and reduces the half life of
dox

ACYCLOVIR
 Only about 20% of an oral dose of acyclovir is absorbed
 It is plasma protein bound and is widely distributed
attaining csf concentration that is 50% of plasma
concentration
 Excreted unchanged in urine
 T1/2: 2-3 hrs
 Renal impairment necessitates dose reduction

CORTICOSTEROIDS
 All natural & synthetic steroids are absorbed by
oral mucosa
 Hydrocortisone undergoes high first pass
metabolism ,,90% bound to plasma
 Steroids are metabolised by hepatic microsomal
enzymes
 Metabolites are excreted in urine
 T1/2 life is 1.5 hrs
Interaction: phenobarbitone and phenytoin induce
metabolism of hydrocortisone and prednisolone

MUSCLE RELAXANTS
 All neuromusculr blockers are not absorbed orally
 They are always given iv
 Atracurium is inactivated in plasma by spontaneous
noenzymal degradation
 Excreted in urine n bile
 Interaction : thiopentone sodium & SCH should be
mixed in the same syringe-react chemically

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