Pharmacokinetics I: drug absorption and distribution

Question 1

sites of drug reabsorption

Answer 1

renal duct of the kidneys

cilliary action of the colon

Question 2

bioavailability

Answer 2

the fraction of the drug administered that gets absorbed and reached systemic circulation

1 = 100% bioavailability

Question 3

oral drug absorption

Answer 3

2 means:
1. passive diffusion which is the major form of drug absorption for most drugs across membranes

depends on lipid solubility and ionisation

non ionised&raquo_space;> ionised (less membrane penetrating availability)

2. Active transport which is far more selective as the drug requires a selective transporter

Question 4

drug using active transport

Answer 4

drugs must be structurally similar to endogenous molecules.

requires:
a specific receptor, ATP, against concentration gradient, saturation at high concentration (receptor sites become saturated)

1. levodopa
   for PD and uses an amino acid transporter in small intestine
2. 5 - fluorouracil (5 - FU) is an anti cancer drug and uses a pyrimidine transporter
3. Amphetamine structurally similar to dopamine and NE. Activates receptor sites blocking the reuptake of dopamine and NE and results in an accumulation of these neurotransmitters in the synaptic cleft.

Question 5

factors affecting oral drug absorption

Answer 5

1. Low GI motility i.e. gastric stasis or too fast GI motility
   in the case of muscarinic receptor antagonists which can slow down the absoprtion of other drugs. Brownian motion means that drugs are initially absorbed into GI tract but as there is low GI motility they will reach equilibrium and re-diffuse back across the membrane where it has a chance to be rapidly metabolised.

drug: metoclopramide can be used as pro kinetic to increase gastric emptying rate. migraine patients can take a combination of metoclopramide with an analgesic (paracetamol).

2. food intake
   decreasing drug absorption: after a meal where there is reduced stomach emptying but increased GI motility

increasing drug absorption: increased splanchnic blood flow can promote accelerated drug absorption

3. formulation of a drug
particle size (too large slower absorption)

and coating on tablets/capsules (acid resistance in stomach and delayed release in GI tract)

4. physiochemical factors
   e.g. complexation
   drug = tetracycline can form complexes with calcium and this reduces its level of absorption

Question 6

drug absorption at the mouth

Answer 6

2 sites:
sublingual (under the tongue)
buccal (lining of the check)

advantage of mouth absorption vs taking drug orally is that it is absorbed into blood system directly in the mouth and it by passes first pass metabolism

Question 7

examples of drugs absorbed at the mouth

Answer 7

glyceryl trinitrate (for angina)
benzodiazepines (during epileptic seizures)

Question 8

rectal absorption of drugs

Answer 8

NSAIDS

local use: treatment of ulcerative colitis

systemic use: to provide systemic relief where patient is vomiting or for post operative pain

Question 9

topical routes of administration

Answer 9

epicutaneous: onto the skin
percutaneous: through the skin i.e. transdermal patch

ophthalmic drugs: eye drops

otic drugs: ear drops

intranasal

inhalation: this is still considered topical as inhaled drugs are making direct contact with smooth muscle of the bronchioles.

Question 10

parenteral routes of administration

Answer 10

intravenous injection:
directly into systemic circulation and fastest route of administration

subcutaneous and intramuscular:
absorption depends on blood flow. by passes first pass metabolism. adrenaline is added with local anaesthetics to reduce blood flow and prolong local effects rather than systemic effects.

Question 11

drugs using facilitated diffusion to enter cells

Answer 11

Fludeoxyglucose (FDG) used in PET imaging of malignant tumours

Question 12

ion trapping

Answer 12

artificially changing the pH of bodily compartments so that ionisation of a drug may change.

e.g. Amphetamine is a weak base so ingesting sodium bicarbonate to slightly increase the pH of the stomach will have favourable absorption on amphetamine

Question 13

drug plasma protein binding

Answer 13

once drug is in plasma the drug molecule can move in bidirectional way i.e. between blood and tissues

plasma proteins are utilised to bind to free drugs and keep them in the plasma so that they cannot move across the enter the tissues.

main proteins involved:
albumin (binds both acidic and basic)
beta globulin and acid glycoprotein (binds basic)

some drugs can occupy half of all plasma binding sites at therapeutic doses so caution needs to be taken if second drug is then administered that will result in an increased concentration in the plasma (as most plasma binding sites have been occupied)

Question 14

drugs bound to albumin

Answer 14

albumin accounts for 50 - 65% of plasma protein

acidic drugs:
warfarin and NSAIDs

basic drugs:
TCA’s and chlorpromazine

Question 15

Drug displacement from plasma membranes

Answer 15

In cases where drug displacement can occur (i.e. another drug is administered that has a higher affinity for plasma binding sites then the drug initially taken) then this could lead to an increase in the free drug concentration of both drugs.

generally not a major concern as free drug is quickly metabolised.

major concern in drugs that have a narrow therapeutic index e.g. warfarin where if plasma concentration doubled would lead to haemorrhaging

Question 16

volume of distribution (Vd)

Answer 16

is the distribution of the drug from the plasma to other regions of the body.

(Vd) = total amount of drug in the body (dose) divided by drug plasma concentration

Vd < 3.5L i.e. remains in the plasma e.g. Heparin
Vd < 13.5 i.e. remains in the ECF with small distribution to ICF e.g. Gentamycin
Vd > 13.5 i.e. high volume of distribution through total body water or concentrated in certain tissues where it can act on receptors.

Question 17

Drug accumulation in body fat

Answer 17

is slow because fat is poorly vascularised but can occur in drugs such as thiopental (anaesthetic) and some antidepressants (benzodiazepine).

happens with chronic administration.