drug solubility absorption

8/12/2019 Drug Solubility Absorption

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Drug Solubility and Absorption

Goal of drug administration: get an adequate (but not

toxic) concentration of drug to the necessary site of

action as quickly as possible and to maintain that

concentration as continuously and evenly as

possible.

Route of drug administration determines how quickly a

drug reaches its sites of action.



Routes of Drug Administration

1. Topical. From the Greek topos which means “a place”. The

simplest route of drug administration, most often to anaccessible body surface. Examples include creams or

ointments to skin, eye or nose drops, solutions or sprays for

mouth, throat, rectum, vagina and urethra. Drugs applied to

mucous membranes are quickly absorbed (eg. cocaine) and

may have systemic effects; topical use refers to the applicationof small volumes and low enough concentrations to ensure the

drug only acts at the desired site.

Drugs may also be injected directly into body cavities for

localized actions at those sites (eg. corticosteroids into joints or

antibiotics into abcesses). Intrathecal injections into the

cerebrospinal fluid (CSF) bypass the blood-brain barrier and the

blood-CSF barrier, yielding high local concentrations, without

producing significant blood levels.

http://en.wikipedia.org/wiki/Intrathecal

http://en.wikipedia.org/wiki/Intrathecal



2. Percutaneous: Drug absorption through the skin, for the

purpose of a systemic effect. Absorption is proportional to

lipid solubility and can be enhanced by suspending drug in

an oily vehicle. Not generally an efficient method of

systemic drug delivery. Examples of compounds

administered by this route include nitroglycerin (angina),

scopolamine (motion sickness) and nicotine (smoking

cessation). Poisonings (eg. insecticides) often occur bythis route.

3. Gastrointestinal (GI) Tract:

A. Oral mucosa (sublingual) – eg. nitroglycerin tablets.

Very rapid absorption and drugs are not subject to gastricand intestinal digestive juices and also not subject to

immediate passage through the liver (the first pass effect)

before entering the systemic circulation.

Routes of drug administration continued…

http://en.wikipedia.org/wiki/Angina

http://en.wikipedia.org/wiki/Sublingual

http://en.wikipedia.org/wiki/First_pass_effect

http://en.wikipedia.org/wiki/First_pass_effect

http://en.wikipedia.org/wiki/Sublingual

http://en.wikipedia.org/wiki/Angina




B. Stomach & Intestine (oral; per os, p.o., PO): Absorption from

the upper GI tract depends on pH, gastric emptying rate,

intestinal motility, solubility of solid drugs, concentration of drugsolutions, stability of drugs in GI fluids.

Large surface area in g.i. tract,

prolonged contact of drug and

extensive blood supply aid in drugabsorption. Duration of time

substance spends in stomach is

greatest variable governing

gastric absorption. Factors

governing rate of gastricemptying: volume, viscosity &

composition of contents, physical

activity and the drug ingested.




C. Rectal mucosa (suppositories): Useful for unconscious or

nauseous patients or when drug has an objectionable taste or would

be degraded by acid or digestive enzymes. No first pass effect.

4. Pulmonary epithelium: Inhalation of gases, vapours & aerosols

(eg. volatile anaesthetics, antiasthmatic medications). Fast onset of

action.

5. Injections: advantages (more rapid & predictable absorption),

disadvantages (strict asepsis, pain, expense, psychological difficulty

in self-injecting?)

http://en.wikipedia.org/wiki/Suppositories

http://en.wikipedia.org/wiki/Volatile_anesthetic

http://en.wikipedia.org/wiki/Volatile_anesthetic

http://en.wikipedia.org/wiki/Suppositories



Types of injections

1. Subcutaneous (s.c.): Can only be used for non-irritating drugs in small

volumes. Provides for slow and even drug absorption, yielding sustained drug

effects.

2. Intramuscular (i.m.): Aqueous solutions are rapidly absorbed; slow and even

absorption occurs if drugs are suspended or dissolved in oil (forms a depot in

muscle).

3. Intravenous (i.v.): Rapid Infusion - desired blood concentration of drug can

be obtained accurately and immediately; no first-pass effect. However, onceinjected, rapid removal of drug is impossible. Slow Infusion (>20 min) - blood

levels can be titrated by adjusting flow rate and drug concentration. Used to

maintain constant blood concentrations of drug over time (decreased risk of

overdose).

4. Intra-arterial (i.a.): used to target small volumes of drug solutions to specifictarget tissues or organs (eg. anti-tumour drugs).

5. Injection into body cavities: The peritoneum provides are large absorption

surface and intraperitoneal (i.p.) injections are commonly used in laboratory

animals. Risk of infection, intestinal or vascular injury and adhaesions, make it

seldom used clinically.



How long does it take for a drug to get into the body,

act, and then be eliminated?

The choice of route dependson therapeutic objectives.

Rapid i.v. injection produces a

rapid, intense but short-lived

effect, compared to oral

administration.

Choice of route is also influenced by the physical properties of thedrug. Examples: EDTA, a chelator used in heavy metal poisoning is

poorly absorbed from the g.i. tract, and penicillin G is inactivated by

gastric HCl.



Once a drug has been administered, its uptake and

distribution largely depend on its physical properties.

The drug must cross across capillary walls into the circulation,and back out to reach its final site of action.

Factors influencing

a drug’s ability to

cross capillary

walls:1. Aqueous solubility

2. Lipid solubility

3. Molecular size &

shape



Drug Solubility

To be pharmacologically active a drug must have at least some

solubility in body fluids.

The water molecule acts as a partial dipole, with O being more

negative and the two H atoms positive. This helps the solubility of

charged molecules. Molecules readily associating with water are

termed hydrophilic.

Drugs that show greater affinity for the lipid (fatty) portions of cellmembranes are called lipophilic or hydrophobic.

Absolute solubility of a drug is less important than its relative

solubility in lipid and water phases in the body. Olive oil is the

experimental substitute for lipid. The relative solubility of a drug in oil

to water is termed the partition coefficient.

Poil/water = Coil /Cwater

How would you determine the partition coefficient of a drug?

http://en.wikipedia.org/wiki/Partition_coefficient

http://en.wikipedia.org/wiki/Partition_coefficient



Poil/water is an estimate of Pm/b = Cmembrane / Cbuffer Any chemical substituent group when attached to a drug molecule willaffect that molecule’s partition coefficient.

Pm/b

for Iso-butanol (CH3)2CHCH

2OH

Pm/b (methane) = 0.6, CH2-3 = 3, OH = .07,

Branch in C chain= 0.63

0.6 x 33 x 0.63 x .07 = 0.71



Drugs can vary greatly in size (nitrous oxide, 44 Da; d-Tubocurarine, 700

Da), but are still small compared to proteins (botulinum toxin, >1 Mda).

Pathways of drug permeation across cell membranes



Passive diffusion of water-soluble drugs

Depends on molecular size of drug that travels through aqueous

channels (aquaporins) that transverse cell membranes. These are

0.8-1 nm in diameter); therefore 150-200 Da size limit.



Passive diffusion of lipid-soluble drugs

• Most lipid-soluble drugs permeate cell membranes by passively

diffusing between lipids in cell membranes.

• The permeation rate depends on: (1) drug concentration or dose;

(2) drug Pm/b; (3) pH; and (4) surface area of the absorbing

membrane.

• Permeation rates do not vary systematically with drug molecule

size, however extremely large molecules do not readily diffuse.



An optimal Pm/b for absorption in the small intestine: an

exception to every rule

Deviation from linearity of absorption rate vs. Pm/b is due to an

unstirred water layer acting as a hydrophilic barrier around microvilli.

Drugs must have at least some appreciable water solubility to pass.

drug solubility absorption

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