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1
Q

What factors influence drug

absorption?

A

Drug absorption describes the passage of a drug into the bloodstream from its route of administration.

Factors influencing this are as follows:

1 > Route of administration

2 > Particle size

3 > pKa and ionisation:
Unionised drugs cross membranes more readily
(see below).

4 > Lipid solubility:
The more lipid soluble a drug, the more readily it can cross the phospholipid bilayer of cells, and the faster it is absorbed.

5 > Concentration gradient:
The higher the concentration gradient between the lumen containing the ‘drug load’ and the cells into which it is diffusing, the faster it will be absorbed.

6 > Other factors:
Bacterial overgrowth will reduce drug absorption and
some drugs will be affected by intake of other substances, e.g. milk chelates tetracycline antibiotics and so decreases their availability for absorption

2
Q

How can manufacturers alter rate of drug absorption?

A

Most drugs are taken orally and pass from the mouth into the aqueous and acidic environment of the stomach. Here they may dissolve and cross into
the cells lining the stomach. Dissolution and absorption can be altered by the manufacturers in several ways:

1 > Particle size:
The larger the particle size (molecular weight) of the drug, the more slowly it will dissolve.

2 > Compounds used:
Different compounds dissolve at different rates.
Modified-release or slow-release drugs can improve the drug profile, minimising peaks and troughs in plasma concentration. Patient compliance improves with less frequent dosing.

3 > Coating the tablet: Enteric coating does not dissolve in acid conditions and therefore the drug will pass to the basic intestine before dissolving.

3
Q

What are the available routes for
drug administration?

X 11

A

> Enteral (variable availability: formulation of drug, pKa, gastric pH, GI
transit time, etc.)

>

 Intravenous (bioavailability is taken as 1.0 or 100%)

> Transdermal (suitable for small, potent, lipophilic drugs)

> Intranasal (rich blood supply, avoids first-pass metabolism, variable absorption: mucus flow etc.)

> Sublingual (rich blood supply, avoids first-pass metabolism, variable absorption: saliva flow, swallowing etc.)

> Intrapulmonary (conduit for volatile agents to lungs: large surface area, rich blood supply)

> Intramuscular (variable absorption: regional blood flow, injections can be formulated for slow release)

> Epidural (reduced systemic absorption in general, localised effect though
beware, opioids may still cause respiratory depression)

> Subarachnoid (as above)

> Rectal (avoids first-pass metabolism, useful when nausea and vomiting problematic)

> Vaginal (avoids first-pass metabolism, limited systemic absorption, primarily used to administer drugs whose action is on vagina/nearby structures)

4
Q

What is pKa and how does this influence drug absorption?

bassic conectps

acid

base

weak acid base

stronge acid base

A

Before answering this question, a reminder of some basic concepts:

> An acid is a proton (H+ ion) donor.

> A base is a proton acceptor (OH–).

> A weak acid/base is one that dissociates in water to form an equilibrium with its ions,
e.g. H2CO3 ⇌ H+ ⇌ HCO3

> A strong acid/base is one that dissociates very readily and does not form an equilibrium,
e.g. HCl → H+ + Cl

5
Q

What is pKa and how does this influence drug absorption?

What’s an amphoteric compound

what is the ka

How is it written

what does a high Ka mean

How is Ka expressed
and why

What is the pKa

Larger value of pKa means what

Can we tell form pKa wherther its an acid or base?

A

> An amphoteric compound has the ability to behave as an acid or a base, e.g. water

> The Ka is the dissociation constant and it describes how readily an acid in solution gives up its hydrogen ions.

> It describes the ratio of the products of the reaction, to the concentration of the initial reactants.

> It is written:

Ka = [A- ][H+ ] / [HA]

where HA is the acid, A− is its conjugate base
(i.e. the product that is now able to accept protons

and H+ its proton.

The higher the value of Ka, the more readily the acid gives up its proton and dissociates.

> Ka can be expressed in its logarithmic form giving us the pKa.

> pKa is the negative log of the acid dissociation constant, and is defined as –log10 Ka.

> pKa is used because it yields more convenient units that are easier to use for practical purposes.

> The pKa of a drug is the pH at which it is exactly half dissociated, i.e. the drug is 50% ionised and 50% unionised.

> The larger the value of pKa, the less readily the acid dissociates to donate its H+ ion at a given pH,
i.e. the weaker the acid.
Conversely, the smaller the value of pKa, the more readily the acid donates its proton and the stronger the acid.

> Most drugs are either weak acids or weak bases. Unfortunately, you cannot tell from the pKa of a drug whether it is basic or acidic; this is a
property of each drug you just have to learn.

6
Q

Some common Bases and the pKa

A

Bases from weak to strong

Diazepam 3.7

Etomidate 4.1

Midazolam 6.15

Alfentanil 6.5

Ketamine 7.5

Lignocaine 7.8

Bupivacaine 8.2

Fentanyl 8.4

Morphine 8.6

7
Q

Acids and their pKas

A

Salicylic Acid 3

Frusemide 3.9

Thiopentone 7.6

Methohexitone 7.9

Atropine 8.9

Paracetamol 9.5

Propofol 11

8
Q

What is pKa and how does this
influence drug absorption?

At pH less than pKa what does acidic drugs do

At pH < pkA what do basic drugs do

How is this relevant?
how do you get an acidic drug absorbed fast

A

At pH < pKa, acidic drugs become less ionised:

HA ⇌ H+ + A–

Putting the acidic drug in a more acidic environment raises H+ concentration and so drives the equation to the left.

At pH < pKa, basic drugs become more ionised as they accept protons:

B + H+ ⇌ BH+

Putting a basic drug in an acidic environment drives the equation to the right as the base (B) ‘accepts’ the protons.

Drugs cross membranes in the un-ionised state and so their pKa and the pH of the surrounding environment affect their rate of absorption.

Hence, acidic
drugs will be more readily absorbed in the highly acidic stomach, whereas basic drugs are better absorbed in the intestine where pH is higher.

Relationship between pH and the percentage of drug in the un-ionised form,
for (a) a weak acid (thiopentone: pKa 7.6) and (b) a weak base (fentanyl: pKa 8.4)
Fig. 4.2 pH vs. degree of ionisation for thiopentone and fentanyl

9
Q

What is the Henderson– Hasselbalch equation and how

is it useful in predicting drug absorption?

A

> The Henderson–Hasselbalch equation describes the derivation of pH as a measure of acidity. pH is calculated using the pKa and the equation
can be expressed in two ways:

page 12 of book 2

Where pKa is –log (Ka).
> Using the non-specific acid–base reaction: HA + H2O ⇌ A– + H3O+
pKa can be substituted into the equation, to give the Henderson–
Hasselbalch equation:

Page 12

> This is used to calculate:
• pH of a solution
• pH at which the equation is in equilibrium and the drug exists as 50%
ionised and unionised, i.e. the pKa of the drug, proportions of ionised
and un-ionised drug in a solution at a given pH.

10
Q

Define bioavailability.

A

> Bioavailability describes the fraction of the drug administered that reaches the bloodstream.

> If a drug is given intravenously it is introduced straight into the bloodstream and is said to have a bioavailability of 1 or 100%.

> For drugs given orally, the bioavailability is calculated by comparing the plasma concentration of the drug when administered orally to the plasma concentration when it is administered intravenously.

This is achieved by comparing the area under the curve (AUC) of the two conditions:

11
Q

What is first-pass metabolism?

A

> This refers to the process by which

drugs absorbed from the gastrointestinal tract

enter the hepatic portal circulation

and are carried to the liver.

The liver then metabolises the drug
such that only a fraction of the
original dose is returned
to the systemic circulation.

> Drugs that undergo extensive first-pass metabolism have low oral bioavailability and it may be necessary to find an alternative route of administration that allows the drug to enter the systemic circulation
directly.

12
Q

Can you give examples of drugs that undergo first-pass

metabolism?

A
>	 Aspirin (70%)
>	 Codeine (60%)
>	 Morphine (40%)
>	 Diltiazem (40%)
>	 Propranolol (30%)
>	 Verapamil (20%)
>	 Hydralazine (15–30%)