drug absorption L4

Question 1

what is pharmacodynamics and what 2 features make it up

Answer 1

The effects of a drug on the body

Drug interactions with molecules (e.g. receptors) to exert its effects

Influence of drug concentration on the magnitude of response

Question 2

what is pharmacokinetics and what features make it up

Answer 2

The effects of the body on the drug
ADME

Question 3

Describe ADME

Answer 3

A: The movement of the drug is dependent on its absorption into the blood stream From site of administration
D: Drug can reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids of tissues
M: Body inactivates the drug through enzymatic modification
E: Drug is eliminated from the body in urine, bile or faeces

Question 4

what are the two ways an administered drug can move around the body

Answer 4

1. Bulk flow (bloodstream, lymphatics, cerebrospinal fluid) – chemical nature of drug has no effect
   In blood, many drugs exist bound to plasma proteins e.g. albumin, β-globulin (> 1% could be free)
2. Diffusion across barriers (gastrointestinal mucosa, blood-brain barrier etc) – chemical nature has big effect

Question 5

what are the 3 ways a drug can cross membrane

Answer 5

1. simple diffusion
   - unionised, lipid soluble drugs
2. through aqueous pores
   - proximal renal tube has many but stomach has none
3. carrier proteins

Question 6

what are the two types of carrier proteins

Answer 6

1.Solute carrier transporters
- passive movement down electrochemical gradient

2. ATP-binding cassettes
   - use active pumps fuelled by ATP

Question 7

give 6 routes of administration

Answer 7

1. oral or rectal
   - gut
2. percutaneous
   - skin
3. intravenous
   - bloodstream
4. intramuscular
5. intrathecal
   - brain
   6.inhaliation
   - lung
   all end up in plasma
   The faster a substance reaches the plasma, the faster its delivery to the target

Question 8

when would an IV be used

Answer 8

A rapid onset of action is needed
High dose control is required
Drug is poorly absorbed

Question 9

what factors determine the best administration route for drug

Answer 9

Pharmacokinetic properties
Physicochemical properties
Patient preference
Therapeutic aims

Question 10

give 2 methods of administration

Answer 10

1. injection
2. orally

Question 11

when would an injection method be used

Answer 11

Drug is poorly absorbed
Drug is unstable or metabolised in GI tract (insulin)
A rapid onset of action is needed
High dose control is required

Question 12

give 3 kinds of injections

Answer 12

1. IV
   - Bolus or Infusion
2. Intramuscular
   - depot’ injections
3. Subcutaneous- under skin
   - Bolus or Infusion

Question 13

what are depot’ injections

Answer 13

drugs manufactured using an oil base which retards the movement of the formulation out of the muscle and into the bloodstream. The injected does is stored in the muscle and diffuses over time. Some antipsychotics and progynon are delivered in this way.

Question 14

what two factors effect rate of absorption

Answer 14

Diffusion through tissue
Removal by local blood flow

Question 15

what is the main administration method

Answer 15

oral
- GI tract route

Question 16

where is the main site of absorption in Gi tract route and why

Answer 16

small intestines
Large, highly permeable surface area
Excellent blood supply (‘vascularised’)
pH from 6 to 7.4- less likely to be ionised
Enterocytes of epithelium contain metabolic enzymes & transporters

Question 17

why is the stomach not main site of adsorption for GI tract route

Answer 17

pH partitioning
acidic pH causing most drugs to become ionised
these don’t pass through membrane easily so they get trapped

Question 18

what are the two types of transporters found on enterocytes of epithelium

Answer 18

uptake
- pumps drug into cell
efflux
- pumps drug out of cell

Question 19

give examples of efflux transporters

Answer 19

1. ABC transporter (ATP binding cassette)
   - They hydrolyse ATP to provide energy to transport molecules against the electrochemical gradient
2. MRP transporters (multidrug resistance proteins)
   - member of the ABC family
   - Really important as they eject cytotoxic drugs out of cells.
   MRP 1,2,3 and 4
3. P-gp transporters (P-glycoprotein)
   - MRP1
   -pumps xenobiotics drugs back into intestinal lumen
4. Solute carrier proteins
5. MCT1 (Monocarboxylate transporter 1)
   - passive
6. ENT1 (equilibrative nucleoside transporter)

Question 20

give examples of uptake transporters

Answer 20

1. ASBT (Apical sodium–bile acid transporter)
   - transports bile salts
2. Apical sodium–bile acid transporter
3. organic cation transporter (OCT)
4. organic anion transporter (OAT)

Question 21

what types of enzymes are found in enterocytes
what is a negative of them

Answer 21

CYPs / UGTs (Uridine glucoronosyltransferase)
- responsible for the process of glucuronidation, a major part of phase II metabolism
- drug could be broken down by these enzymes before they enter blood stream

Question 22

first pass metabolism is a neg of oral administration
- what is it

Answer 22

orally taken drug enters hepatic vein then goes to liver where it is metabolised before it enters blood stream

Question 23

what is the part of the drug that is not metabolised and enters systematic circulation referred to

Answer 23

bioavailable drug

Question 24

what is Enterohepatic recirculation (EHR)
give examples of drugs which can do this

Answer 24

when a drug is recycled
drug is given
Moves through gut, Absorption into blood, Enters hepatic portal vein, Transported to liver, Transferred to gall bladder
Secreted in bile to small intestine, small intestine reabsorbs it
- morphine, erythromycin, oral contraceptives, lorazepam

Question 25

what are two GI tract routes

Answer 25

1. sublingual 2. rectal

Question 26

describe sublingual

Answer 26

Films and sprays Taste important Excellent network of capillaries under the tongue – drug delivered directly into bloodstream = Bypasses first pass metabolism = Rapid action e.g. Glyceryl trinitrate for angina

Question 27

describe rectal

Answer 27

Suppositories & enemas Useful for local effects e.g. ulcerative colitis Avoids 2/3 first pass metabolism Absorption unreliable but useful if vomiting or no IV access e.g. managing opioid withdrawal / travel sickness / children in status epilepticus

Question 28

what is the circulation system from rectal

Answer 28

Circulation from rectum: Middle and inferior rectal veins = systemic circulation Superior rectal vein = Portal (to liver)

Question 29

what are the 6 parenteral routes of administration

Answer 29

1. inhilation 2. topical drugs 3. cornea 4. nasal mucossa 5. vaginal 6. transdermal

Question 30

describe inhilation

Answer 30

Powders, gases & suspensions Excellent network of capillaries = Bypasses first pass metabolism = Rapid Action e.g. anaesthetics, Entonox used during childbirth Local lung effects achieved e.g. Bronchodilators (may still get some systemic effects)

Question 31

describe topical drugs

Answer 31

administered to site needed reduce systemic absorption = reduce side effects they do not need to cross barriers to get to where needed, so higher concentration of drug at the site

Question 32

describe cornea

Answer 32

Local eye effects achieved without systemic effects e.g. Dorzolamide to lower ocular pressure

Question 33

describe nasal mucosa

Answer 33

Nasal spray e.g. gonadotrophin releasing hormone to stimulate ovulation

Question 34

describe vaginal what effects absorbance rate

Answer 34

gels, pessaries & rings Avoids first pass metabolism Useful for local drug effects with reduced systemic side effects (hormonal or antifungal pessaries) pH variance may affect absorption Normal premenopausal pH: 3.5-4.5 May be elevated during menstruation, after menopause, after intercourse, with use of hygiene products

Question 35

describe transdermal

Answer 35

Stick on patches Steady rate of drug delivery bypassing first pass metabolism Even highly lipid soluble drugs slow to enter bloodstream through the skin

Question 36

what factors effect absorbtion transdermally

Answer 36

Size of drug molecule Membrane permeability of drug delivery system Skin hydration pKa of drug – acid dissociation Drug metabolism by skin flora Lipid solubility Stratum corneum reservoir of drug e.g. hormone replacement

Question 37

what factors affect drug crossing membrane - pharmokinetics

Answer 37

1. pH 2. solubility and permeability 3. gastric motility

Question 38

how does pH affect crossing membrane

Answer 38

most drugs are either weak acids or weak bases in alkaline conditions, acids become ionised and are not lipid soluble and vise versa- traps ion in this compartment in acid conditions, acids are unionised and are lipid soluble

Question 39

when is ion trapping/ pH partitioning a good thing

Answer 39

aspirin – weak acid, so more ionised and accumulate in renal tube (urine), than in stomach, so theoretically higher levels in urine. In overdose, we went aspirin to be excreted from the body quickly. Therefore if aspirin is in the renal tube we don not want it to be ionised as it will be absorbed back into the body. Sodium bicarbonate can be given to make urine more alkaline and therefore the aspirin ionised and not reabsorbed.

Question 40

how does solubility effect drug crossing membrane

Answer 40

Solubility is property of a substance to dissolve Increased water solubility = increased dissolution in GI = concentration in GI Dissolution is the process where a solute in gaseous, liquid, or solid phase dissolves in a solvent to form a solution.

Question 41

how does membrane permeability effect drug crossing membrane

Answer 41

Many drugs are weak bases or acids and exist as Ionised – not lipid soluble Unionised – lipid soluble Unionised lipid soluble drugs can diffuse readily through lipid bilayers ionised have to go through carrier proteins

Question 42

what factors affect absorption of drugs taken orally

Answer 42

Gastric motility – may be altered by disorder e.g. migraine, diabetic neuropathy, or by drug treatment e.g. muscarinic receptor antagonists, or diarrhoea - Flow of drug through the gut With food – splanchnic blood flow Particle size e.g. digoxin (NY – same dose) - even though same does given, particle size effected absorbtions Capsules / coatings delay absorption

Question 43

define the three pharmacokinetics parameters

Answer 43

1. Cmax: Maximum concentration (Cp) of compound after dosing 2. Tmax: Time taken to reach maximum drug concentration 3. area under the curve 4. rate of absorption (Ka)

Question 44

How do we quantify total drug exposure over time?

Answer 44

area under the curve A measure of total systemic exposure Calculated by measuring the area under the concentration-time curve (linear trapezoidal) Units are concentration x time (i.e. mg*hr/L)

Question 45

How is area under the curve worked out

Answer 45

1. split in to trapezoid AUC of trapezoid = Average concentration Cp x time interval Total AUC = sum of all smaller AUCs

Question 46

what can area under the curve be used for

Answer 46

to measure bioavailability (f) The fraction of the drug administered that is absorbed and therefore available to have an effect in the body Compare against IV dosing Oral administration = some drug lost to first pass metabolism, lower overall exposure (observed as lower AUC)

Question 47

what factors are needed to know to work out bioavailability give formula

Answer 47

How much exposure using IV route How much exposure using oral route IV dose administered Oral dose administered

Question 48

give bioavailability formula

Answer 48

F= (area under curve for oral dose/ AUC for IV dose) X (does of IV/ dose of oral)

Question 49

define rate of absorption Ka

Answer 49

rate it takes to reach Cmax - all other factors stay the same, Route of admin / bioavailable dose / rate of excretion but and absorption occurs at a different rate higher Ka, faster Tmax