mark (L1-3) Flashcards
routes of administration of drugs
Absorption
Distribution
Metabolism
Elimination
therapeutic window (or index) equation
maximum non-toxic dose / minimum effective dose
bioavailability
Proportion of dose of unchanged drug
that reaches the site of action (which is the systemic circulation
pros/cons of intravenous injection
PROS
100% bioavailability
Rapid action
CONS sterile equipment trained personnel expensive potentially painful
pros/cons of oral route
PROS
Safest
most convenient most economical route
CONS
Nearly always less than 100% bioavailability
Destruction by enzymes, pH and/or bacteria
Drug can complex with food
Absorption depends on rates of passage
Irritation may cause vomiting
fick’s law of passive diffusion
rate = ( permeability x surface area x concentration difference ) / thickness of membrane
methods of absorption
passive diffusion active transport ion-pair absorption pinocytosis (membrane engulfs the wanted material) solvent drag
define ion-pair absorption
ion pair absorption allows a positive ion and a negative ion in the gut to bind to form a neutral complex that can then move into the bloodstream
define solvent drag
drugs that are highly lipid soluble, difficult to dissolve in the acqueous fluid of the lumen. but it can instead be dissolved in a solvent to be drunk
sites of drug absorption
- small intestine (very large area, alkaline pH, nlood flow at 1L/min)
- stomach (small SA, blood flow 150mL/min, quick to empty, acid pH, ion trapping)
- colon (lumen filled with bacteria, extensive metabolism, slow release formulations absorbed)
tablets’ absorption rates
as a tabelt, minimum dissolution.
it disintegrates into granules. medium dissolution.
it deaggregation into fine particles. maximum dissolution
rate of absorption for individuals depends on….
GUT MOTILITY
with gastric emptying modulated by:
- meal size
- meal composition (fat)
- drugs (opioids, anticholinergics) - physiological state (position)
- migraine (gastric stasis)
AND SPLANCHNIC BLOOD FLOW (CONC GRADIENT)
other routes of administration
- inhalation
- transdermal
- buccal and sublingual
- intranasal
- rectal
inhalation route of administration
aerosols absorption depends on particle size, lipid soluble anaesthetics has rapid absorption, avoids first pass metabolism
no first pass metabolism, straight to blood via the vocal cavity on the lungs
transdermal route of administration
outer layer is a rate limiting step because it’s a dead cornium layer, low input rates, only for highly lipid soluble molecules
rectal route of administration
suppository, there is first pass metabolism at the top of the rectum (lower rectum avoids it)
subcutaneous route of administration
under the dermis (not in muscle) Small volumes (0.5 to 2 ml) of drugs/vaccines
Passive diffusion to primary absorption membrane capillary wall: - Lipophilic molecules use transcellular passive diffusion - Water soluble molecules like pores/vesicular use channels by passive diffusion - Dependent on blood flow or release from dosage form. - Slow absorption rate
intramuscular injection (IM) route of administration
Large blood flow in muscles of upper arm
Route is reliable
Volume: 1-5 ml into muscle bed
Quick uptake into body (within ~ 20 minutes)
Suitable for irritant drugs
Good for depot preparations (long lasting)
Absorption is perfusion limited (increased with exercise)
No self administration
Can be painful
free drug
only the free drug is active, has an effect, can be toxic etc. when it is bound to the plasma protein, it is inactive
plasma protein binding
once in the bloodstream, the drug binds to proteins. 2 main ones are plasma albumin and B globulin acid glycoprotein
saturation of binding depends on…
Saturation of binding: (0.6 mmol/l,1.2 mmol/l binding)
non-linear relation between
dose and free (active) concentration
Small increase in drug concentration
LARGE increase in free drug concentration
Difficult to predict outcome
Possible drug interactions (ie aspirin/sulphonylureas)
blood brain barrier (BBB)
Layer of tightly joined endothelial cells.
Prevents many drugs entering the brain.
Lipid soluble drugs pass by passive diffusion.
Water soluble drugs only pass via carrier mechanisms.
problems of BBB
the brain barrier stops the influx of material and drugs
this poses a problem to trying to treat brain disease with drugs since fenestrations are so narrow and closed
metabolism of drugs (where, by what, how)
Most drugs metabolised in the LIVER by hepatocytes
- Some drugs converted to inactive metabolites
- Some drugs converted to active metabolites
(i. e. benzodiazepines) - Some drugs are excreted unchanged
drug metabolism phase 1
- Transforms molecular structure of the drug (introduce polar group, abolish activity, produce toxic/non-toxic metabolite, increase water solubility etc)
drug metabolism phase 2
CONJUGATION
attached an endogenous substance to parent drug or phase 1 metabolite
increases polarity or water solubility so that it can be eliminated by urine or bile
parent drug
Parent drug/ metabolites can inhibit/induce the metabolism of other drugs: possible interaction.
excretion of drugs by major route
major route used for excretion is renal
Renal blood flow ~ 1.5 l min-1
10% of glomerular filtrate, most is reabsorbed
only unbound drugs are excreted
Lipid soluble drugs can be reabsorbed in renal tubules:
prolongs action
we can also change urinary pH to aid excretion
excretion of drugs by minor routes
biliary into intestines
- particularly conjugates
- potential reabsorption
(enterohepatic circulation)
e.g. imipramine or morphine
OR BY
saliva, sweat, tears, expired air or breast milk
concentration of the drug equation
conc = amount of drug given (Q) / volume of the body (Vd)
Vd apparent volume of distribution explanation
called the apparent volume of distribution because it is not real
this is because the concentration of the drug is very small in the plasma so the apparent volume of distribution is is used and tells us if the drug has been distributed to the tissues or the plasma
Vd equation
Vd = (amount in body at equilibrium) / (plasma drug conc)
fraction extracted E equation in renal drug removal
E = (conc going in - conc going out) / conc going in
clearance equation (in vol per time)
clearance = (rate of elimination / concentration of input)
rate of elimination = [ the blood flow x (Cin - Cout) ] / Cin
the units are virtual volume of blood cleared of drug per unit time
creatinine clearance rate (Ccr)
creatinine is a break-down product of creatine phosphate in muscle
Renal clearance of drugs varies linearly with creatinine clearance
Serum creatinine = rate of production of creatinine / creatinine clearance
methods of measuring clearance
- single blood sample
- renal clearance (urine collection over 24h)
normal creatinine clearance for healthy women is 88-128 mL/min and 97-137 mL/min in males
First order elimination kinetics
Most drugs obey first order kinetics:
rate of elimination is proportional to drug concentration
(the rate of elimination is fastest when there is more drug)
K el
elimination rate constant (k) with units as time-1
(Proportion of drug eliminated per unit time)
K el = rate of elimination / amount left
half life
Half life is the time taken for the drug concentration to fall
by half
helps us to determine the dosing interval
half life = ln2/Kel
first order process of elimination
EXPONENTIAL CURVE
quick distribution phase, slower elimination phase
by logging that curve, we get 2 straight lines which give us the 2 elimination and distribution constants
first order process of absorption
Rate proportional to amount
of drug unabsorbed
Ka =absorption rate constant
area under a first order process curve
measuring the area under the curve is used to measure the systemic exposure of the drug which tells us about the bioavailability of the drug
(if area is the same for a drug taken orally or by injection, then oral route had a 100% bioavailability too)
AUC and its equation for bioavailability
units of AUC = g/l time-1
Bioavailability = AUC dosage form / AUC IV injection
AUC = dose/clearance
loading dose
in case of emergency and need of quick drug action, orally given drugs take a long time to be absorbed, so loading doses are used instead where the drug is injected (IV injection)
continuous infusion
continuous infusion is where you build up the concentration of the drug over time this prevents toxicity that might occur if you give a loading dose
zero order kinetics
(saturation kinetics)
Rate of elimination is not proportional to drug
concentration but is a constant
(eg ethanol, phenytoin)
plotted graph shows that it is not exponential, they are straight lines
the rate of elimination of the drug is a constant so it doesn’t matter how much alcohol you take the lines stay the same. this is called SATURATION LEVELS
variation in drug dosage requirements
Drug binding to plasma proteins (less binding in neonates and elderly - less plasma albumin)
Clearance (renal function is low at birth: for first 2 weeks clearance is erratic. Renal function is reduced in elderly)
Metabolism (low at birth and in the elderly)
therapeutic drug monitoring
- measuring the concentration of drug in the body
- to determine the most effective dose or to avoid toxicity.
- can measure drug in blood, urine (or saliva: unbound drug)
use of urine sampling
- useful as do not need blood sample
- useful for drugs which are fully/partially eliminated in the urine
- volume of urine is very variable so do not use drug concentration
- express quantity of drug as absolute amount
- look at either cumulative amount excreted between t=0 and
t=? Or amount excreted per interval of urine collection.
drugs’ multiple modes of action
enzyme inhibitors enzyme false substrates receptor activators (agonists) receptor blockers (antagonists) ion channel blockers ion channel modulators neurotransmitter uptake blockers
define receptors and name 4 different types of receptors
Proteins inserted into the membrane which
bind neurotransmitters, hormones etc and
produce a cellular response
- Ligand gated ion channels (ionotropic)
- G-protein coupled receptors (metabotropic)
- Kinase-linked receptors
- Receptors linked to gene transcription
(nuclear receptors)
define EC50
ec50 is the effective concentration which gives 50% of maximum response
what graph do you produce when you give the drug to a living mammal
in vitro, we know precisely what the agonist concentration is in the solution so we can produce a agonist concentration-response Curve.
however if we give a drug to a human or an animal and we don’t know the exact concentration so we produce instead a dose-response Curve (dose as X axis)
reasons why there is a maximum response
- finite number of receptors (all occupied). so the response is proportional to the amount of acetylcholine-receptor complex
- or not all receptors are applied but the property of the tissue or the selves don’t allow us to reach a higher muscle contraction.
define affinity
How well a drug (ligand) binds to the receptor
define efficacy
Once a drug is bound to the receptor a measure
of the response is defined by efficacy
define potency
The potency of an agonist is a combination
of both affinity and efficacy.
so a highly potent agonist means that you need very small amounts of that agonist in order to occupy all receptors and produce a big response. (drugs with a high potency tend to be more selective)
to measure the affinity of the drug, which steps do you measure?
when you measure the affinity of the drugs you only measured the First steps (where the agonist binds to the receptor)
affinity step is the binding of the agonist to the receptor
efficacy part is the response being given
what is affinity determined by?
affinity is determined by two rate constants: the association constant (K+1) and dissociation constant (K-1)
Kd equation
Kd = K-1 / K+1
The Kd gives the concentration of drug required to occupy 50% of the receptors
The lower the Kd the higher the affinity
proportion of receptors occupied equation for P
P = [D] / (Kd + [D])
can you measure ligand affinity?
Cannot measure a response as it involves a combination of affinity and efficacy
define the ligand binding assay
Displacement of radio-labelled ligand (3H, 14C or 125I) by cold ligand
[bound] = Bmax Xa/ (Xa + Kd)
Xa = concentration of ligand Bmax = total number of binding sites in prep (pmol/mg protein)
problem is, we must account for non specific binding since you get constant binding to these low affinity sites
what causes desensitisation?
when the agonist binds to the receptor, they form a complex
if the complex stays bound together and we enter a desensitized/inactivated state as opposed to activation for ion channels
so this will no longer signal
if it stays bound to the receptor for a long time, the receptor could become phosphorylated which could cause the receptor to become internalized
so the response decreases because there are less receptors because they are disappearing inside of the cells
define tachyphylaxis
it’s when the entire tissue or organ stops responding if the acetylcholine contracts the guts muscle, and we keep increasing its concentration then the guts will start to relax so can’t maintain the contraction
inverse agonists
Many G-protein receptors are active in the absence of ligand
This activity maybe too low to be important in physiological states
Inverse agonists reduce this constitutive activity
Many antagonists are in-fact inverse agonists
difference between agonists, antagonists and inverse agonists
agonists have a positive response
antagonists are blockers so they have no response
inverse agonists is a response in the other direction
the GABA-A receptor and the effect of benzodiazepines binding to it
GABA is the main inhibitory neurotransmitter in the brain
BZs bind to different site on the gaba receptor (not on the same site as where gaba binds)
they increase the opening when gaba is present, so that BZ can increase the opening of the channel
BZ is a full agonist
measurement of antagonist potency (pA2)
negative log of the molar concentration of antagonist
that reduces the effect of a known concentration of agonist
to that of half the concentration.
the better the antagonist, the bigger the pa2 value and the the lower the ec50.
types of anthihistamines
we have two types of antihistamines, the type that can can go through the blood-brain barrier and the one that can’t
why are receptor antagonists non-competitive
they could be non-competitive because they bind to the the recognition site for the agonist conveniently so that you cannot out compete them, or they could be allosteric modulators and they bind to another site on the receptor to where the agonist binds
define spare receptors
It is not always true that 100% of receptors need
to be occupied in order to get a full response.
May only need 80% of receptors for full response.
The other 20% are termed spare receptors
link between kd and EC50
Because of spare receptors:
Do not need to occupy all receptors for full response
Thus Kd does not always equal EC50
EC50 is the concentration of the drug that is needed to produce 50% of the maximum response
Kd if the concentration of the drug that occupies 50% of the receptors
if there was no spare receptors then you have to occupy 50% of the receptors to get 50% of the maximum response. if we did have spare receptors then the KD does not always equal ec50 because you don’t have to occupy all receptors for a full response
