drug absorption L4 Flashcards
what is pharmacodynamics and what 2 features make it up
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
what is pharmacokinetics and what features make it up
The effects of the body on the drug
ADME
Describe ADME
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
what are the two ways an administered drug can move around the body
- 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) - Diffusion across barriers (gastrointestinal mucosa, blood-brain barrier etc) – chemical nature has big effect
what are the 3 ways a drug can cross membrane
- simple diffusion
- unionised, lipid soluble drugs - through aqueous pores
- proximal renal tube has many but stomach has none - carrier proteins
what are the two types of carrier proteins
1.Solute carrier transporters
- passive movement down electrochemical gradient
- ATP-binding cassettes
- use active pumps fuelled by ATP
give 6 routes of administration
- oral or rectal
- gut - percutaneous
- skin - intravenous
- bloodstream - intramuscular
- intrathecal
- brain
6.inhaliation
- lung
all end up in plasma
The faster a substance reaches the plasma, the faster its delivery to the target
when would an IV be used
A rapid onset of action is needed
High dose control is required
Drug is poorly absorbed
what factors determine the best administration route for drug
Pharmacokinetic properties
Physicochemical properties
Patient preference
Therapeutic aims
give 2 methods of administration
- injection
- orally
when would an injection method be used
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
give 3 kinds of injections
- IV
- Bolus or Infusion - Intramuscular
- depot’ injections - Subcutaneous- under skin
- Bolus or Infusion
what are depot’ injections
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.
what two factors effect rate of absorption
Diffusion through tissue
Removal by local blood flow
what is the main administration method
oral
- GI tract route
where is the main site of absorption in Gi tract route and why
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
why is the stomach not main site of adsorption for GI tract route
pH partitioning
acidic pH causing most drugs to become ionised
these don’t pass through membrane easily so they get trapped
what are the two types of transporters found on enterocytes of epithelium
uptake
- pumps drug into cell
efflux
- pumps drug out of cell
give examples of efflux transporters
- ABC transporter (ATP binding cassette)
- They hydrolyse ATP to provide energy to transport molecules against the electrochemical gradient - 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 - P-gp transporters (P-glycoprotein)
- MRP1
-pumps xenobiotics drugs back into intestinal lumen - Solute carrier proteins
- MCT1 (Monocarboxylate transporter 1)
- passive - ENT1 (equilibrative nucleoside transporter)
give examples of uptake transporters
- ASBT (Apical sodium–bile acid transporter)
- transports bile salts - Apical sodium–bile acid transporter
- organic cation transporter (OCT)
- organic anion transporter (OAT)
what types of enzymes are found in enterocytes
what is a negative of them
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
first pass metabolism is a neg of oral administration
- what is it
orally taken drug enters hepatic vein then goes to liver where it is metabolised before it enters blood stream
what is the part of the drug that is not metabolised and enters systematic circulation referred to
bioavailable drug
what is Enterohepatic recirculation (EHR)
give examples of drugs which can do this
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
what are two GI tract routes
- sublingual
- rectal
describe sublingual
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
describe rectal
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
what is the circulation system from rectal
Circulation from rectum:
Middle and inferior rectal veins
= systemic circulation
Superior rectal vein = Portal (to liver)
what are the 6 parenteral routes of administration
- inhilation
- topical drugs
- cornea
- nasal mucossa
- vaginal
- transdermal
describe inhilation
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)
describe topical drugs
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
describe cornea
Local eye effects achieved without systemic effects
e.g. Dorzolamide to lower ocular pressure
describe nasal mucosa
Nasal spray
e.g. gonadotrophin releasing hormone to stimulate ovulation
describe vaginal
what effects absorbance rate
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
describe transdermal
Stick on patches
Steady rate of drug delivery bypassing first pass metabolism
Even highly lipid soluble drugs slow to enter bloodstream through the skin
what factors effect absorbtion transdermally
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
what factors affect drug crossing membrane
- pharmokinetics
- pH
- solubility and permeability
- gastric motility
how does pH affect crossing membrane
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
when is ion trapping/ pH partitioning a good thing
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.
how does solubility effect drug crossing membrane
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.
how does membrane permeability effect drug crossing membrane
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
what factors affect absorption of drugs taken orally
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
define the three pharmacokinetics parameters
- Cmax: Maximum concentration (Cp) of compound after dosing
- Tmax: Time taken to reach maximum drug concentration
- area under the curve
- rate of absorption (Ka)
How do we quantify total drug exposure over time?
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)
How is area under the curve worked out
- split in to trapezoid
AUC of trapezoid =
Average concentration Cp x time interval
Total AUC =
sum of all smaller AUCs
what can area under the curve be used for
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)
what factors are needed to know to work out bioavailability
give formula
How much exposure using IV route
How much exposure using oral route
IV dose administered
Oral dose administered
give bioavailability formula
F= (area under curve for oral dose/ AUC for IV dose) X (does of IV/ dose of oral)
define rate of absorption Ka
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
