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pharmacokinetics Flashcards

1
Q

define pharmacokinetics PK

A

it is the mathematical description, prediction and understanding of the time course of the drug (and its metabolites) in the body
it is what the body does to the drug
just mathematical calculations

the study and characterisation of the time course of drug’s absorption, distribution, metabolism and elimination and the RELATIONSHIP of these processes to the time course of the therapeutic and toxicological effects of the drug.

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2
Q

define pharmacodynamics PD

A

is the study of the biochemical and physiological effects of the drug and their mechanism of action in the body
is the study of what the drugs do to the body

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3
Q

ADME

A

(lliberation) of a drug from its formulation eg. tablet
absorption
distribution
metabolism
excretion
describes the disposition of pharmaceutical compounds in the body
processes that determines the onset, intensity and duration of a drug

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4
Q

PK models

A

observation-simulation-prediction
empirical- uses eqns
physiological- prediction of in vivo PK from in vitro data
compartmental- no. of compartments defined by concentration over time data…one compartment assumes a drug is fully distributed throughout the body…two compartments assumes a simple model of absorption and elimination

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5
Q

compartmental

A

one compartment: IV bolus
all drugs initially distribute into a central compartment (Vc) before distributing into the peripheral compartment (Vt)
if a drug rapidly equilibrates with the tissue compartment, then for practical purposes, a one-compartment model is used which uses only one volume term: apparent volume of distribution, Vd

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6
Q

example of a one compartment model

A

distribution phase for aminoglycosides is onyl 15-30 minutes

shows drug is widely distributed around the body in a central compartment

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7
Q

example of a two compartment model

A

vancomycin
distribution phase is only 1 to 2 hours
initial distribution to major tissues
end with distribution ot the rest of the body

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8
Q 
PO
SI
IM
SC
IV
A 
oral
sublingual (applied under tongue)
intramuscular
subcutaneous
intravenous
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9
Q

what is distribution affected by?

A

affected by plasma protein binding/ may have free drugs binding to receptors
only free drugs (not bound to protein) that are able to travel to site of administration can bring about a pharmacological effect

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10
Q

why is ADME and PK important?

A

to prevent negative patient outcomes
ignorance leads to drug disasters
primary cause of withdrawal of drugs
a prominent component of marketing strategy

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11
Q

benoxaprofen

A

non-steroidal anti-inflammatory drug
marketed under name oraflex for arthiritis
cholestatic jaundice was an unreported side effect

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12
Q

PNPO- preventable negative patient outcomes

A

unecessary drug therapy (drug without indication)
improper drug selection (wrong medication)
sub-therapeutic dosage
over-dosage
adverse drug reaction
failure to take/ recieve drug (inappropriate compliance)
cost

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13
Q

examples of drugs on the market with serious side effects

A

zocor (simvastatin): a cholesterol- lowering drug that has been linked to rhabdomyolysis (breakdown of muscles) and myopathy (muscle injuries) and other serious side effects…kidney failure, liver problems, intersititial lung disease
Multaq (dronedarone): treats abnormal heart rhythm
serious side effects- liver failure, 2-fold inc in death and stroke

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14
Q

usefulness of PK for drug development

A

is the drug effective by mouth?
which organs is the drug exposed too?
how long does it stay in the body?
how is the drug removed from the body?
what factors influences its handling?
what is the appropriate route of administration?
what are appropriate doses (animals, volunteers, patients)?
how should the drug be formulated?
what drug interaction are likely to be important?

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15
Q

reasons fro withdrawal in drug development in UK

A 
pharmacokinetics
efficacy
animal toxicity
ADRs
other
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16
Q

the 4 main drug actions at receptors

A

stimulation through direct receptor action (agonist)
depression through direct receptor action (inverse agonist)
blocking/ anatgonist drugs bings to receptor but does not activate
partial agonist drugs bonds to receptor and has some activity, depending on dose and recipient

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17
Q

a drug must move from the site of administration to the site of action

A

simultaneously the drug distributes to all other tissues including those organs (liver or kidney) that eliminate it from the body
drug dose (D)
concentration (C)
effect (E)
time relationships defined by PK and PD
in vitro and in vivo studies shows that the magnitude of the response is a function of the concentration of drug at the site of action (receptor)

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18
Q

how is therapeutic success achieved

A

by maintaining an adequate concentration of the drug at the site of action for duration of therapy
yet most drugs are rarely placed at the site of action

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19
Q

general mechanisms of drug action

A

block the action of specific enzymes
inhibit cell transport mechanisms
exchange/replace susbtance or accumulating them to form a reserve
directly beneficial chemical reaction as in free radical scavenging
directly harmful chemical reaction to damage or destroy cells (act on cell wall proteins of bacteria- lysis)

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20
Q

drugs that inhibit enzymes

A

disulfiram: antabuse
responsible for oxidaiton of aldehydes to carboxylic acids which leaves the liver
3 diff types: ALDH1, 2, 3
used to treat chronic alcoholism
• ALDH2 plays a crucial role in maintaining low blood levels of acetaldehyde during alcohol oxidation
• Intermediate structures in this pathway can be toxic and can damage health if not eliminated
• High blood levels acetaldehyde can cause facial flushing, headache, palpitations, light headedness and general symptoms hangover
• ALDH2 inhibited by disulfiram
• Prescribed to abstinent alcohol dependent people
• If you drink during treatment, you get high levels of acetaldehyde: become violently ill
• Several drugs (antibiotic metronidazole) cause a similar ‘dislufiram-like reaction’
ASIAN FLUSH

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21
Q

psychoactive drug activity that is stimulative

A
  • Speed up body mechanisms
  • Increase heart rate, blood flow
  • Respiratory rate increased
  • BP raised
  • Increase attention span
  • Increase ability to focus
  • Increase ability to concentrate
  • Alertness increases

eg. caffeine, nicotine

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22
Q

psychoactive drug activity that is depressive

A
  • Slow down body
  • Decreased heart rate, blood flow
  • Respiratory rate depressed
  • Analgesia
  • Sedation
  • Peacefulness
  • Alertness decreases

benzoyhdyazapines: misused substances

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23
Q

a common cause of overdose

A

combining common drugs at the same time

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24
Q

PK and PD in drug addiction

A
  • Important as addicts tend to use drug doses much higher than the safe recommended levels
  • No quality control of material- so purity an issue
  • Monitor and publish adverse events
  • Poly drug use and interactions
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25
Q

TDM- therapeutic drug monitoring

A

the way in which we use PK and PD to optimise drug therapy for individuals
‘the use of drug concentrations, pharmacokinetic principles and pharmacodynamics factors to optimise drug therapy in individual patients’

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26
Q

conc vs time graph

A

administer drug
take blood samples at various times
measure [drug] in blood
plot data

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27
Q

time curve after single oral administration

A

tmax- time at which peak plasma conc occurs

cmax- concn max point

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28
Q

drugs that require therapeutic drug monitoring

A

possess a narrow therapeutic index
poor correlation between dose and effect
good correlation between serum concentration and effect

wide inter-patient variation in clearance of drug
influenced by range of diseases
management: report a plasma conc within an appropriate time period to be clinically useful

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29
Q

Css

A

steady state plasma conc
the goal of drug therapy is to ensure that Css falls within the therapeutic range
want therapeutic range to be maintained in a steady state- may take a few doses

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30
Q

TG- aminoglycosides

A

antibiotic

gentamicin

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31
Q

cardiac glycoside

A

atrial fibrillation

digoxin

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32
Q

phosphodiesterase inhibitor

A

asthma

theophylline

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33
Q

anticonvulsants

A

epilepsy

carbamazepine phenytoin

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34
Q

antipsychotic

A

mania, biopolar disorder

lithium

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35
Q

digoxin

A

0.8 to 2.0 ng/mL

nausea, anorexia, bradycardia, ventricular arrhythmias

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36
Q

theophylline

A

10 to 20 mcg/mL

link to degree of accumulation

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37
Q

phenytoin

A

10 to 20 mcg/mL

ataxia, nystagmus, lethargy, osteomalacia

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38
Q

lithium

A

0.4 to 1.0 mmol/L

vomitting, diarrhoea, anorexia, muscle weakness, ataxia, drowsiness

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39
Q

carbamazepine

A

4 to 12 mg/L
GI distress
dizziness, hepatitis, diplopia

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40
Q

association between theophylline serum conc and toxicity

A

(mg/L)
>10 nausea, insomnia, headahe, minor mainy transient
>20 nausea, vomiting, diarrhoea, insomnia, irritability, headaches, tremor, potentially serious
>35 cardiac arrhythmias, cardio-respiratory arrest , seizures, death, life- threatening

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41
Q 
M.bio
DD
DFORM
PVIG
PGEN
A 
molecular biology
drug development
drug formulation
pharmacovigilant/ patient vigilance
pharmcogenetics
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42
Q

parameters?

A 
bioavailability
volume of distribution
protein binding
steady state plasma conc
clearance
elimination half-life
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43
Q

bioavailiabililty

A

the amount of drug that gets into the systemic circulation
intravenous injection of a drug has a bioavailability of 1
digoxin is 63%

44
Q

distribution

A

refers to teh reversible transfer of a drug from one location to another within the body
-requires measurements in various tissues-difficult in humans
rate and extent of distribution can be derived from blood or plasma

45
Q

factors that determine distribution

A

ability of drug to cross tissue membranes
extent of binding in blood/tissues
partitioning into lipid/adipose tissues

46
Q

what does tissue conc depend on

A

physico-chemical properties of a drug - lipid solubility, crossing blood/brain barrier- prevents foreign substances from entering the brain
blood flow

47
Q

distribution follwing an intravenous bolus

A

injections- bioavailability of 1
• Rapidly places drug in blood- speeds up time to target site
• Distribution phase- time period in which drug in all tissues comes into equilibrium with that in plasma
• Characterised by volume of distribution- V

48
Q

high and low volume of distribution

A

digoxin takes 6 hours in the distribution phase
low volume of distribution- drug stays in the blood
high volume of distribution- wants to reach tissues
digoxin has a high volume of distribution- dialysis wouldnt work

49
Q

the assumptions of a one compartment model

A
  • The drug in blood is in rapid equilibrium with drug in extra vascular tissues
  • Drug concentration may not be equal in each tissue or fluid however we will assume they are proportional to the concentration of drug in the blood at all times
  • Not an exact representation- but useful for a number of drugs to a reasonable approximation
50
Q

rapid mixing?

A

• Assume that the drug is mixed instantaneously in blood or plasma
• Actual time taken for mixing is usually very short, within a few minutes
• In comparison with normal sampling times it is insignificant.
o Don’t usually sample fast enough to see drug mixing in the blood

51
Q

linear model

assume follows first order kinetics

A

rate of chnage of drug conc by an process is directly proportional to the drug conc remaining to undertake that process
first order kinetics is an assumption of a linear model not a one compartment model
if linear: if we double the dose, the conc will double at each point in time

52
Q

diff types of diffusion

A

passive diffusion
carrier mediated system
passive facilitated diffusion
active transport

53
Q

passive diffusion

A

molecules move down a concentration gradient with movement as a result of the KE of the drug molecules

54
Q

carrier mediated system

A

characterised by saturability, specifcity and competition inhibition

55
Q

passive facilitated diffusion

A

eg. glucose transport
glucose moves down conc gradient as a passive process
at high plasma glucose conc, rate of transport glucose reaches a maximum

56
Q

activde transport

A

distinguishing feature is the net movemet of a drug against a conc gradient which can be large
maintenance of this graidnet requires metabolic energy

57
Q

perfusion

distribution can be rate-limited by perfusion or permeability

A

passage of fluid through the circulatory system or lymphatic system to an organ or tissue
o Some tissue membrane presents no barrier to distribution (lipophilic drugs)
o Perfusion varies from 10mL/min/mL for lungs to 0.025mL/min/mL resting muscle or fat
o Well perfused tissues take up a drug much more rapidly than poorly perfused ones
o Tissue uptake of a drug is known as extravasation

58
Q

permeability limitation

A

rate limitation arises for polar drugs diffusing across tightly knit lipoidal membranes
differences in ease of entry are a function of both
-lipid to water partition coefficient
-degree of ionisation

59
Q

degree of ionisation

A

most drugs are weak acids and bases and exist in solution as an eqm between unionised and ionised drugs
pH partition hypothesis
o only unionised non-polar (lipophilic) drugs penetrates the tissue cell membrane
o increased accumulation of drug on side of membrane where pH favours ionised form
o at equilibrium concentration of the unionised species is equal on both sides

60
Q

lipid to water partition coeficient

A

• pH
o pH of gastric fluid varies 1.5-7
o urinary pH varies 4.5-7.5
o pH blood 7.5
• unionised form is assumed to be lipophilic enough to transverse membranes- if not no transfer occurs irrespective of pH
• fraction unionised is controlled by pH and the pKa of the drug according to the Henderson- hsaelbalch equation
• for acids: pH= pka +log10 (ionised conc/ unionised conc)

61
Q

warfarin

henderson-hasslebach

A
  • warfarin is an acid with pka 4.8 that has equimolar concentration of unionised and ionised forms at ph 4.8
  • …50% drug is unionised at pH 4.8
  • Only unionised drugs can traverse membranes
  • At pH 5.8 the ratio is 10:1 in favour of the ionised drug (91% ionised)
  • At pH 3.8 ionised 9% and unionised are 91%
62
Q

distribution of acidic drugs

A

• Very weak acids such as phenytoin (pka>7.5) are essentially ionised at all pH values
o Here drug distribution (transport) is rapid
• Acids with pka 3-7.5 are subject to dramatic changes in rate of transport with change in pH
• Acids pka <2.5 has v lowun-ionised fraction and transport across even gut membrane is very slow

63
Q

distribution of basic drugs

A
  • A base must be very weak pka< 5 for transport to be independent of pH e.g caffeine pka0.8
  • Bases pH 5-11 will be transported dependent upon Ph (amphetamine)
  • At low ph of gastric fluids strong bases are in ionised form and transport is slow.
64
Q

protein binding

A

• Many drugs are bound to plasma and tissue proteins
• Most important plasma protein is albumin
• Dynamic process which affects the ‘free’ drug concentration
• Only free (non-bound) drug is pharmacologically active
• Examples of drugs which are highly protein bound are
o Phenytoin (90%) and warfarin (99%)
o Small concentration free drug in plasma

65
Q

plasma protein binding

A 
•	Only unbound drug fraction is able to bind to target site (active)
•	Examples
o	100% unbound = lithium
o	20% unbound= quinidine
o	3-10%= methadone
o	2% unbound= oxazepam
o	0.5% unbound= warfarin
66
Q

conditions of altered binding

A 
•	Albumin decreased in
o	Liver cirrhosis
o	Serious burns to body
o	Pregnancy
•	a1- acid glycoprotein increased in
o	myocardial infarction
o	surgery
o	crohn’s disease
o	trauma to body
o	rheumatoid arthritis
67
Q

tissue binding

A
  • the fraction of the drug in body located in the plasma depends on binding to both plasma and tissue
  • a drug may have great affinity for plasma proteins but may still be located primarily in tissue if the tissue has an even greater affinity than that of plasma eg. methadone
  • distribution of plasma-protein bound drugs (warfarin) restricted to plasma and extracellular fluid, whereas alcohol distributes equally into the total body water
68
Q

multiple equibliria

A
  • multiple equilibria occur in plasma where drugs can bind to various proteins
  • acidic drugs commonly bind to albumin
  • basic drugs bind to a1- acid glycoprotein
  • within tissue binding can also occur
  • there may be partition into adipose tissue (fat)
69
Q

factors affecting distribution of drug into tissue

A
  • blood flow to tissues
  • partition co-efficient of the drug between blood and the tissue
  • degree ionisation of the drug at plasma pH
  • molecular size of drug
  • extent binding to plasma, tissue proteins
70
Q

PK parameters

A

volume of distribution
o Proportionality constant that relates the amount in the body to the drug concentration in blod/plasma
o Mathematical ‘fudge’ factor where amount ‘A’ of drug in body is related to ‘C’ concentration drug in plasma
o V is not a physiological volume
o Never

71
Q

body water compartments

A
  • Drug administered intravenously distributed immediately into the TBW= 42L
  • Tissues/fluids outside blood stream comprise main water compartment =37L
  • Initial plasma concentration= dose/4L
72
Q

apparent volume of distribution, Vd

A

• Vd is a reflection of the amount of drug left in the blood after all the drug has been absorbed
• That is, the concentration in plasma after distribution of dose administered is complete and indicates the extent of tissue distribution
• Magnitude Vd provides the extent of drug distribution but not the location of drug
o If drug is held in the blood stream it will have a small volume of distribution
o If very little drug remains in blood stream has a large volume distribution
• Vd expressed in litres or litre/kg

73
Q

equation for Vd

A
  • Simple eqn
  • Vd=Ab/Cp
  • Where Vd is the apparent volume of distribution
  • Ab= amount of drug present in the body
  • Cp= plasma concentration of the drug
  • Apparent Vd is a function of lipid vs. water solubilitys and the plasma and tissue binding properties of the drug
74
Q

plasma protein binding eqn

A

• Plasma protein binding is variable within and between patients
• Degree binding expressed as a ratio bound-to-total drug concentration
o Ratio limit= 0-1 (0.9 highly bound)
o Fraction drug unbound in plasma= fu
o Fu= Cu/C
o Where Cu= drug unbound in plasma
o Concentration drug in plasma = Cp
• Binding is a function of the affinity of the protein for the drug

75
Q

net rate of presentation

A

• The rate of presentation to the tissue is the product of blood flow = Q and arterial blood conc = CA
 Rate of presentation = QCA

76
Q

net rate of extravasation

A

• The net rate of extravasation is the difference between rates of presentation and leaving where CV is the emergent venous concentration
 Net rate of uptake= Q(CA- CV)
• Blood and tissue can viewed as one compartment (if no impediment to movement into tissue)
• Then: Cv is in equilibrium with that in tissue CT

77
Q

fraction of drug in body

A

• Can estimate the fraction of drug in and outside systemic circulation if know plasma volume (Vp) and volume distribution (Vd)
o Amount in plasma= Vp * concentration (Cp)
o Amount in body= V*C
o Fraction drug in plasma = Vp/Vd
• Vd larger than plasma compartment (>4L) only indicates that drug is present in tissues or fluids outside the department; actual sites cannot be determined from this value

78
Q

apparent volume of distribution, Vd for intravenous bolus dose

units for volume of distribution

A
  • Definition Vd= amount drug body/ conc meas blood
  • Immediately after the intravenous dose is administered the amount of drug is equal to the dose
  • Vd= D/C(0)
  • Vd- volume distribution
  • Dose= dose assuming absorption complete
  • C (O) initial conc drug in blood
  • Drug administration: amount (dose) of drug (mg, µg)
  • Drug analysis: concentration of drug (mg/L, µg/mL)
  • Need to know the volume Vd- which volume do we use?
79
Q

define absorption

A

The process by which unchanged drug proceeds from the site of administration to the general circulation (site of measurement).

80
Q

route and sites of administration

A 
•	Route of administration is the key factor in determining the rate and extent of absorption 
Site of administration
•	Intravascular- placement of a drug directly into the bloody stream
•	IV or inter-arterially
•	Extra vascular 
•	Oral
•	Sublingual
•	Buccal
•	Rectal
•	Conjunctival
•	Dermal
•	Intramuscular
•	Auricular
•	Subcutaneous
81
Q

absoprtion from other sites

A
  • Lungs- when substances are smoked or inhaled (cannabis, salbutamol)- absorption is almost complete as for IV use
  • Mucous membranes (nasal insufflation- snorting cocaine)
  • Sublingual and buccal (buprenorphine, nitroglycerine like vasolidators)
  • Skin patches (oestrogens, fentanyl, nicotine)
  • Rectally (suppositories morphine
82
Q

biopharmaceutics

A
  • Influence of dosage form on the therapeutic activity of a drug
  • Study of the relationship between the physical and chemical properties of a drug and its dosage form
  • Study of the biological effects observed following administration

…is concerned with onset, intensity (amount) and duration (length of time) of a drug at its site (s) of action.

Onset, intensity and duration are all influenced by the rate at which a drug enters the body.

83
Q

therapeutic response

A

of a drug is dependent upon an adequate concentration of the drug being first achieved and then maintained at the site(s) of action.

84
Q

mechanisms of absorption

A

• Absorption from formulation
Solid drug – drug in solution – absorbed drug
• Permeability rate limited- when absorption drug if mostly dissolved before absorption complete
• Drug release rate limited- when absorption will be very little drug at absorption site: absorption delayed until dissolution occurs

• Drugs must be in solution to be absorbed
• Transcellular permeation occurs by
 Passive diffusion
 Active transport
 Facilitated transport
o Vascular absorption predominates as blood flow is much greater than lymph flow
o Paracellular absorption- always passive

85
Q

passive diffusion

A

• Rate of absorption dependent upon
Conc gradient across membrane – surface area – permeability constant
• Rate limiting steps
o Perfusion rate= v small molecules, membrane not barrier (passage depend on blood flow)
o Permeability factor= polar hydrophobic compounds (some antibiotics) insensitive to blood flow dependent on membrane

86
Q

permeability constant

A

determined by…
• Physicochemical properties of the molecule
• Nature of membrane (thickness membrane varies from tissue to tissue) that is distance between surface of absorption and blood capillary
• Partition coefficient of the compound

87
Q

oral absorption

A
  • Most drugs are administered orally yet act systemically
  • A drug must be in solution to be absorbed
  • Sometimes a drug is intended to act locally (eye, lungs etc) so systemic absorption becomes a safety issue
88
Q

small intestine

A
  • Absorption works best here on all accounts
  • Large surface area (microvilli 200M2)
  • Good bloody supply (1L blood/min compared to 150mL/min stomach)
  • Permeability to drugs greater
  • Thus gastric emptying is important

• Absorption of acids much quicker from the less acidic small intestine

89
Q

gastric emptying and intestinal transit

A
  • Food especially fat slows down gastric emptying
  • Hastening gastric emptying quickens absorption
  • About 30 mins drug to dissolve in stomach
  • Anticholinergics- slow gastric emptying
  • Metroclopromide- hastens emptying
90
Q

pH partition hypothesis

A
  • Weak acids absorbed more rapidly from the stomach at pH 1.0 than at pH 8.0
  • Weak bases are absorbed more rapidly from the stomach at pH 8.0 than at pH 1.0
91
Q

first pass metabolism

A

 A drug must pass sequentially through the gut wall, through the liver, before entering the general circulation (bioavailability)
 Drugs may be destroyed by the acid in the stomach
 Enzymes in GI tract

92
Q

proteins as drugs (biologics)

A

• Absorption proteins (eg monoclonal antibody) given orally minimal
 Due to extensive degradation
 Poor intestinal permeability
• Most often given IV or IM
• Absorption large proteins drugs (>20000 Daltons) slow and via lymph
• Half-life rate limited by absorption

93
Q

bioavailability (F)

A

Is the proportion of drug that reaches the systemic circulation after oral compared to IV administration
• IV administration: bioavailability= 1 (100%) – instantenous for bolus intravenous administration
• Other routes of administration = <1

94
Q

absolute bioavailability

A

• Assessed with ref to IV dose
• F is measured by comparing the area under the curve (AUC) for oral against IV doses from zero to the time point for which elimination is complete
• F= Dose / AUC (iv) * AUC/Dose (oral)
When comparing routes of administration we try to determine amount of drug remaining to be absorbed (non-disintegrated/ dissolved dose)
That is calculate amount absorbed relative to amount released.

95
Q

if administered compounds is a produrg

A
  • F measured on active metabolite
  • IV ref is to active metabolite
  • Ester prodrug- drug gut wall- absorbed drug
96
Q

relative bioavailability

A
  • Used when no IV data available

* Used to compare F between formulations of drug given by route (tablet vs intramuscular solution)

97
Q

uses

A
  • Bioequivalence studies (for quality ass)
  • Clinical trials (batch testing before marketing drug)
  • Generic substitution when product comes off patent (calculation is usually innovators product and new preparation should be <20% different)
98
Q

A drug must pass sequentially through the gut wall, through the liver, before entering the general circulation (bioavailability)

A

A drug must pass sequentially through the gut wall, through the liver, before entering the general circulation (bioavailability)
• Drugs absorbed after oral ingestion pass through mesenteric circulation into the liver
• In this ‘first-pass’ drugs can be substantially metabolised

99
Q

first pass effect

A
  • Drugs readily metabolised by liver enzymes usually have lower F
  • First pass metabolism reduces the pharmacological action of the parent drug
  • First pass metabolism can metabolise a drug to its active form (Pro drug)

F= the fraction of dose reaching the systemic circulation as intact drug
F= FGFH
FG= fraction reaching splanchnic circulation intact
FH= fraction avoiding ‘first-pass’ hepatic extraction (=1-EH)

100
Q

ER- extraction ratio

A

magnitude of first pas hepatic effect
• ER= CLH/Q
• Where Q is hepatic blood flow (usually about 90L per hour [1500ml/min]
• Systemic drug bioavailability (F) may be determined from the extent of absorption (f) and the extraction ratio (ER)
• F= f* (1-ER)

101
Q

absorption rate Ka

A
  • Dependent on site of administration and drug formulation
  • 0 order: drug absorption rate is independent of amount remaining in the gut
  • First order: drug absorption rate is proportional to the drug concentration dissolved in the gastrointestinal tract
102
Q

absorption factor: first order

A
  • Rate of absorption = ka. Aa
  • Where Ka is the drug absorption rate constant which reflects drug permeability
  • Aa is amount remaining to be absorbed
  • The drug absorption half-life t1/2a= 0.693/Ka
  • Aa = F.De-ka.t
  • Where F is the fraction of the administered dose that is available to be absorbed
103
Q

reduced oral bioavailability

A
  • A drug must pass sequentially through the gut wall, through the liver, before entering the general circulation (bioavailability)
  • This may be affected by
  • Formulation: time taken for absorption
  • Poor intestinal permeability (generally polar drugs like H2 antagonist ranitidine; IV excreted unchanged: oral 66% absorbed 3-4hr after admin)
  • Molecular w’t > 400g/mole (Gentamycin)
  • Competing reaction (acid hydrolysis or enzymes)
104
Q

factors reducing bioavailability

A

o Hepatic extraction (first pass effect) that is drugs may be metabolised in the liver before reaching the circulation
o Examples of such drugs include: desipramine, dextropropoxyphene, ketamine, lidocaine, morphine, nicotine, papaverine

105
Q

improving absorption

A

• Three strategies for getting drugs into the body
• Alter physicochemical properties of the molecule
 Absorption weak acids and bases inc, if use a salt form
• Change formulation
• Administer by different route

106
Q

pharmaceutical formulation

A

• Aspirin (acetylsalicyclic acid) one of the first synthetic prodrugs
 Produced to overcome taste and GI irritation of parent drug salicyclic acid
 Was designed to be rapidly hydrolysed in body
 Dissolution time (surface area, solubility , PH and stirring)
• Coat tablets (erythromycin) so resistant to stomach acid (enteric coated products) but not intestinal fluids
• Retention in stomach of poorly soluble drugs (grisefulvin- antifungal agent) eat with fatty food
• Rapid release or controlled release forms

107
Q

older patients

A
  • Drug absorption is theoretically reduced in the older patient
  • Due to loss of mucosal intestinal blood flow
  • Decrease in gastrointestinal blood flow
  • Reduced gastric acidity

PPC (2 decks)

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