drug absorption and factors affecting absorption l1

8/7/2019 Drug Absorption and Factors Affecting Absorption L1

http://slidepdf.com/reader/full/drug-absorption-and-factors-affecting-absorption-l1 1/42

SK 081

Drug Absorption and Factors

Affecting Absorption



SK 082

Overview Routes of Drug administration

Transport process (absorption)

Factors affecting absorption

Membrane factors

Drug property factors

Formulation Factors



SK 083

Routes of Drug Administration

Enteral Parenteral Others

to do with not through Topical

alimentary canal alimentary canalRectal

eg Oral eg Injections

Buccal

Inhalation

Except for IV, at least one membrane must becrossed to reach systemic circulation, thus

an absorption process is involved



SK 084

Oral Most common route of Administration

(ROA)

Drug must be in solution form beforeabsorption can occur

Maybe absorbed from different sites in the

GIT Subject to variability

Students to cover this in tutorial



SK 085

Buccal Tablets which are held in the mouth -

Buccal

or under the tongue ± sublingual

Buccal tablets are harder ± 4 hrsdisintergration time, eg Nicotine

containing chewing gum S/L softer ± 2 mins disintergration time

eg.



SK 086

Rectal Mostly enemas or suppositories

Maybe used for local effect (drugs that are

not absorbed)

Eg.



SK 087

Intravenous

skin

subcut

tissue

muscle



SK 088

Inhalation Local effect ± eg

Systemic effect eg«.. (Large SA, good bld

supply)

Absorption of gases is efficient

Solids & liquids are excluded if > 20

micron even then only 10% is absorbed.

> 20microns ± impact in mouth and throat.



SK 089

Topical Applied to

Skin

Mucus membranes

Nasal

Eyes

Vaginal GIT ± mouth, oesophagus, intestine, rectal



SK 0810

Skin Usually used for local effect

Ideal - skin penetration, ¶ systemic

absorption Large variation in absorption due to

Blood supply

No of hair follicles

Skin damage Hydration

Properties of drug

vehicle



SK 0811

Transdermal For systemic effects ± delivery of drug

to bloodstream via skin

Small lipi soluble drugs more readilyabsorbed

Eg



SK 0812

Nasal Usually used for local effects; drops, oint/

cream

Eg

Drugs are well absorbed from nasal

mucosa into systemic circulation



SK 0813

Eyes

Used for local effects, usually in the form of

drops, ointments

Drug crosses cornea and enters aqueoushumour ´ distributes to other parts of the eye

Prolonged effect ± with gels, ointments

Ye can only hold 10QL (normal eye dropper 50-75 QL )

eg



SK 0814

Vaginal

Used for local effect ± systemic absorption

may occur

Pessaries, creams, gels, douches

eg



SK 0815

GIT

Local effects maybe required, absorption

may occur

Eg.



SK 0816

Physiological Factors

Affecting Oral Absorption



SK 0817

ADME Process

Ultimate goal if to have the drug reach the site of action in a conc which producespharmacological effect.



SK 0818

Membrane Physiology

In 1900 Overton measured

permeability of different

compounds across the

membranes of a frog muscle.He found that lipid molecules

could cross this membrane,

larger lipid insoluble molecules

couldn¶t and smaller polar

compd could slowly cross the

membrane.

There is also a layer of protein

on the membrane



SK 0819

Simplified model

The membrane then acts as a lipid barrier with

small holes through it. This is the generalstructure. Membranes in different parts havedifferent characteristics ± pore size



SK 0820

Examples of Membranes

Blood/ Brain Lipid membrane For lipohilic drugs onlyBlood kidney

(Bowman¶s )

Lipid membrane

with large pores

For both lipophilic and

hydrophilic drugs

Blood/Kidney

(Tubuli)

Lipid membrane For lipophilic drugs only

Lung Lipid membrane

with pores

For both lipohilic and

hydrophilic drugs

Stomach Lipid membrane

with few pores

For lipophilic, non

ionised acidic drugsSmall intestine Lipid membrane

with few pores

For lipophilic drugs

(acidic & Basic), less for

hydrophilic drugs



SK 0821

Transport Across Membranes

Carrier mediated

Active

Facilitated

Passive

Pinocytosis

Ion Pair transport



SK 0822

Active Transport

Active transportrequires a carrier molecule and a form

of energy. Eg aa,glucose

the process can besaturated

transport canproceed against aconcentrationgradient

competitive inhibitionis possible



SK 0823

Facilitated

A drug carrier is required but no energy is

necessary. e.g. vitamin B12 transport

saturable if not enough carrier

no transport against a concentration gradient,

downhill but faster



SK 0824

Passive

Diffusion occurs when the drug concentration on

one side of the membrane is higher than that on

the other side. Drug diffuses across the membrane in an

attempt to equalize the drug concentration on

both sides of the membrane.

The rate of transport can be described by FricksLaw of Diffusion



SK 0825



SK 0826

Frick¶s Law of Diffusion = D x A x (Ch ± Cl)

X

The parameters of this equation are:- D: diffusion coefficient - related to the size and lipid solubility

of the drug, the viscosity of the diffusion medium, the

membrane.

A: surface area. As the surface area increases the rate of diffusion also increases. Absorption is generally faster from

the intestine compared with absorption from the stomach.

x: membrane thickness. The smaller the membrane

thickness the quicker the diffusion process. As one

example, the membrane in the lung is quite thin thus

inhalation absorption can be quite rapid.

(Ch -Cl): concentration difference. Drug conc. in bld or

plasma will be quite q c/f the conc in the GIT. It is this conc

gradient which allows the rapid complete absorption of



SK 0827

GI Physiology

pH Membran

e

Bld

Supply

SA Transit

Time

By pass

liver

Buccal } 7 Thin Good,fast abs

with low

dose

Small Short Yes

Oesophag

us

5-6 Very

thick, no

abs

- Small Short -

Stomach 1-3 Normal Good Small 30-40mins No

Duodenu

m

6-6.5 Normal Good Very large Very short No

Small Int 7-8 Normal Good Very large10-14 ft

About 3 hrs No

Large Int 5.5-7 - Good Not very

large 4-5ft

Long, upto

24 hrs

Lower

colon,

rectum

yes



SK 0828

Gastric Emptying & Motility

Generally drugs are better absorbed in the SI (> SA)than in the stomach, @ u

stomach emptying will u drugabsp. Eg, a good correlation

has been shown betweenstomach emptying time andpeak plasma conc for Paracetamol. The quicker the stomach emptying the u

the plasma conc. Also vstomach emptying can

cause u degradation of drugsin the stomach's lower pH;e.g. l-dopa.



SK 0829

Factors Affecting Gastric Emptying

Volume of ingestion

Fatty meal (CHO ± few hrs) < protein < fat)

Carbohydrate

Temperature of food

Body Position

Anticholinergics

NarcoticsAnalgesics



SK 0830

Physical-Chemical Factors

Affecting Oral absorption pH ± Partition Theory

For drugs which are weak acids or bases the pKa of the drug, the pH of the GI tract fluid and the pH of the blood stream will control the solubility of thedrug and thereby the rate of absorption through themembranes lining the GI tract.

The pH - partition theory explains the influence of GIpH and drug pKa on the extent of drug transfer or

drug absorption. When a drug is ionized it will notbe able to get through the lipid membrane, but onlywhen it is non ionized and therefore has a higher lipid solubility.



SK 0831

Ionisation



SK 0832

Weak Acid- log I/U = pH ± pK a



SK 0833



SK 0834

Ionisation ± Weak base

Log I/U = pK a- pH

Consider ionisation

Calculate weak base pKa ± 5.0

Gastric fluid pH ± 1.2

Blood pH ± 7.4



SK 0835

Drug Dissolution

Dissolution Absorption

SOLID SOLUTION BLOOD

G-I Tract

Absorption rate limiting if absorption slower than dissolution

Dissolution rate limiting if dissolution slower than absorption



SK 0836

The diffusion layer

each particle of drug

formulation is surrounded

by a stagnant layer of

solution

There are number of

factors which affect drug

dissolution and we canlook at this process as

diffusion controlled.



SK 0837

Relationship describing dissolution

dm = D A (Cs ± C)

dt h

Where dm/dt = rate of dissolution

D = diffusion coefficient of the drug (affected by size of the molecule and the viscosity of the

dissolution medium) SR preps have > molecules

A = surface area of the dissolving drug



SK 0838

Cs= the solubility of the drug in diffusionlayer

C = solubility of the drug in bulk GI fluid(affected by vol of fluid available, rate of removal of

dissolved drug by absorption)

h = thickness of the diffusion layer (affected by agitation, u by u motility)



SK 0839

Changing Drug Solubility - Cs

Salts of weak acids andweak bases generallyhave much higher

aqueous solubility thanthe free acid or base,therefore if the drug canbe given as a salt thesolubility can be

increased and we shouldhave improveddissolution. One exampleis Penicillin V.



SK 0840

Influence of food on drug

absorption



SK 0841

Effect of volume on absorption



SK 0842

Formulation Factors

it is possible to alter drug bioavailability

considerably by formulation modification

Since a drug must be in solution to beabsorbed from the G-I tract, one may

expect the bioavailability of a drug to

decrease in the order solution >suspension > capsule > tablet > coated

tablet

drug absorption and factors affecting absorption l1

Documents