Term
| What are Lipinski's rule of fives? |
|
Definition
Poor absorbtion and permeability of of potential drug candidates will occur with any of these violations:
• there are more than 5 hydrogen-bond donors (expressed as
the sum of –OHs and –NHs)
• the molecular weight is more than 500 Da
• the logP is more than 5 (high lipophilicity)
• there are more than 10 hydrogen-bond acceptors (expressed
as the sum of nitrogens and oxygens). |
|
|
Term
| What percentage of drugs obey Lipinski's rules? |
|
Definition
|
|
Term
| What is unusual about antibacterials compared to other drugs? |
|
Definition
| Chemical Diversity is much larger (compared to say CNS drugs) |
|
|
Term
| What is the difference between pharmacokinetics and pharmacodynamics? |
|
Definition
Kinetics deals with: the dose administered, the absorbtion and concentrationin systemic circulation, the distribution to various tissues, the elimination of the drug through metabolism or excretion, to the drug concentration at the site of action (DOSE - CONCENTRATION)
Phamacodymanics deas with the drug concentration at the site of action, the pharmacologic effect, the clinical respose,effectivity and toxicity (CONCENTRATION - EFFECT) |
|
|
Term
| What portion of drug willa ctually have an effect on the patient? |
|
Definition
| Portion that reaches its receptor target will provoke a biological response |
|
|
Term
| What is the main determinant in inter-individual variation in drug response? |
|
Definition
| Pharmacokinetics - not pharmacodynamics |
|
|
Term
| Summarise the role of Pharmacokinetics? |
|
Definition
| Right ammount of drug, producing the right effect, at the right intensity, at the right time, right duration, minimum risk of adverse reaction or harm |
|
|
Term
| What are the two major clases of drug administration? |
|
Definition
Enteral - straight into the GI Tract
Parenteral - strictly non-GI but can be considered to be injection |
|
|
Term
| What is first pass metabolism? |
|
Definition
The first-pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation.
Some drugs are
metabolised by metabolic
enzymes in the gut
mucosa, gut lumen, lung,
and/or liver before they
enter the systemic
circulation.
• Nb: amidases, esterases
and protease enzymes.
Also bacteria in lower
bowel can perform
metabolic rxns such as
hydrolysis.
• Transported to liver from
gut via the hepatic portal
vein.
• May need higher oral
doses of drug to account
for this ‘first-pass effect |
|
|
Term
| What (non injection) routes bypass first pass metabolism? |
|
Definition
| Rectal and sublingual and buccal |
|
|
Term
| What is the advantage of rectal or sublingual routes? |
|
Definition
Rectal good for those with nausea or have difficulty swallowing or eating
sublingual is good for nitroglycerine |
|
|
Term
|
Definition
| Hepatocytes of the liver and Enterocytes of the small intestine metabolise the drug dose |
|
|
Term
| In the context of pharmacology what is absorbtion? |
|
Definition
| The process by which a drug is transferred from its site of administration to the systemic circulationd |
|
|
Term
| What are the four mechanisms a drug can cross a cell membrane? |
|
Definition
passive diffusion (Fick’s law)
• carrier-mediated processes
• through pores or ion channels
• by pinocytosis/endocytosis |
|
|
Term
| What is the rate of penetration? |
|
Definition
| Permeability Constant*Surface Area*Concentration Gradient |
|
|
Term
| What is the Permeability constant? |
|
Definition
(Diffusion Coefficent * Partition thickness)/ membrane thickness
Diffusion coefficent is related to the square root of the molecular weight of the drug, the partition coefficient is related to the lipid solubility of the drug |
|
|
Term
In relation to Fick's law:
What direction does the transfer of a drug occur?
What happens to drugs that are too lipid or water soluble
When will passive diffusion stop?
What proteins are excluded from this law - what major biomolecules are excluded from this? |
|
Definition
Transfer of drug across cell membranes
occurs down a concentration gradient.
• Drugs that are too lipid soluble (eg
griseofulvin) or too water-soluble will not
diffuse properly. Require intermediate
level of hydrophilicity/lipophilicity.
• Passive drug diffusioncontinues until the
concentration on the two sides of the
membrane is equal.
• Only applies to small molecules (<1000 da),
thus excludes proteins. |
|
|
Term
| Explain Drug ionization & the pH-partition hypothesis? |
|
Definition
To be absorbed a drug must be in solution.
• Most drugs are either weak acids or weak
bases,
• Their lipid/water partition coefficients
depend on the extent to which the drug is
ionised.
• Degree of ionization depends on the local
pH and the drug’s pKa value ( at which it
is 50% ionised).
• Acidic drugs tend to be unionized in acidic
conditions which favours their absorption
from stomach (pH 1-2), eg aspirin,
barbiturates etc.
• Basic drugs will be absorbed better from
the small intestine (pH 6-8), eg morphine,
antihistamines etc.. Thus delayed action. |
|
|
Term
| How do drugs exploit natural charged particle transport mechanisms? |
|
Definition
Specific transport mechanisms in place,
for essential charged chemicals - drugs
can exploit them if they resemble natural
substance |
|
|
Term
| What are the two carrier mediated transport mechanisms? |
|
Definition
facilitated diffusion- down a
concentration gradient, no energy
requirement but protein aids uptake
process eg levodopa
• active transport- against conc.
gradient - requires energy - eg amino
acids, 5-FU chemotherapeutic drug |
|
|
Term
| What is pore mediated transport? |
|
Definition
| Small aqueous pores that allow the transport of small water soluble molecules |
|
|
Term
|
Definition
| the cell membrane invaginates enclosing fluid contianing the drug (protein drugs and polypeptides are the most affected |
|
|
Term
|
Definition
Defined as: proportion of drug that passes into systemic circulation from
site of administration (F).
Not all administered dose of drug reaches blood due to:
"• incomplete absorption
"• local metabolism |
|
|
Term
| Why might the same ammount of drug have a different biological effect? |
|
Definition
Same amount of drug may not have same biological effect if
• formulated in different ways
• given by different routes |
|
|
Term
| How do we compare bioavailabilities? |
|
Definition
| Plot time concentration graphs and then compare to IV route (AUC) |
|
|
Term
| How do drugs move around the body? Describe the three methods? |
|
Definition
Bulk transfer flow, Filtration and Diffusional Transfer
Bulk transfer flow:
- Large ammounts of drug in the bloodstream transported large distances dependant on flow rate and not chenmical properties
Filtration:
- Involves molecules dissolved in fluid crossing the endothelial cells, short distances, rate is dependant on concentration in the fluid, hydrostatic pressure gradient
Diffusional Transfer:
- individual molecules in or around cells, short distances, rate depends on lipid solubility, molecular weight, ionisation, protein binding and concentration gradient |
|
|
Term
How do drugs cross membranes during drug
distribution? |
|
Definition
Distribution begins with drug transit from plasma into
the interstitial fluid.
• This involves crossing a layer of vascular endothelial
cells.
• Normal endothelium
-near continuous layer of cells.
-gaps are packed with a loose matrix of proteins that
act as filters,
In some organs with specialised functions (e.g. the liver
and spleen) the endothelium is discontinuous, allowing
free passage of drugs in water that filters between
the cells.
In the CNS and the placenta, there are tight junctions
between the cells and the endothelium is enclosed in
an impermeable layer of periendothelial cells
(pericytes).
November(2013(
19 |
|
|
Term
| What factors affect drug distribution? |
|
Definition
This distribution of drug molecules between
compartments is dependent on
• their molecular size,
• lipid solubility,
• ionisation,
• binding to plasma proteins,
• rate of blood flow
• special barriers(e.g. blood-brain barrier).
some drugs have special affinity for specific
tissues.
Eg:
• calcium - bones,
• iodide and the iodine-containing
antiarrhythmic drug -thyroid gland
• Tetracycline (antibiotic) - bones and teeth. |
|
|
Term
| What happens to drugs that are bound to proteins in plasma? |
|
Definition
any drugs are bound to proteins in plasma.
• Weak acids bind to albumin
• weak bases - to alpha1-acid glycoprotein
• steroids bind to globulin.
• For most drugs that display this property,
association and dissociation are rapid and
reversible
• Drugs that are highly bound to plasma
proteins:
• persist in the body for longer
• have less efficient distribution
• Have lower therapeutic activity
• Are less available for dialysis after toxic
doses.
• Drug–plasma protein binding is of low
specificity and does not result in any
pharmacological effect;
November(2013( |
|
|
Term
| What is the clinical relevance of plasma binding protein? |
|
Definition
Clinical relevance of plasma protein binding
• Plasma protein binding is usually reversible, thus
bound drug may be considered a depot. Eg warfarin
95% PPB.
• If unbound drug conc decreases, generally some
protein-bound drug will dissociate.
• Competition for protein binding can occur between
ligands.
Interactions
• A highly protein-bound drug (eg aspirin) will
displace a drug such as warfarin that binds
reversibly to plasma proteins increasing its unbound
concentration and biological activity.
• In infants, sulphonamides compete for the same
albumin binding sites as endogenous bilirubin &
cause a potentially dangerous increase in its plasma
concentration. |
|
|
Term
| What are typical plasma protein binding values for commonly prescribed drugs? |
|
Definition
|
|
Term
| What is the aparent volume of distribution? |
|
Definition
VD = Mass/ Plasma Conc
Therefore:
- high concentration of drugs in the plasma - low VD (<9L)
- low concentration of drugs inplasma - high VD (>40L) - drug entered interstitial space
Vd - defined as the extent of distribution of the drug
throughout a single body compartment.
Or,
• the volume of fluid required to contain the total
amount of drug in the body ( A) at the same
concentration as that present in the plasma (C
P
).
• Volume into which a drug theoreticallyinstantaneously
equilibrates on entering the body compartment.
• Gives an indication of amount of drug remaining in
blood.
• Does not indicate where drug has accumulated.
• Is a property of the drug.
• Is independent of plasma conc or dose. |
|
|
Term
| What is the clinical relevance of Volume distribution? |
|
Definition
In humans, only the concentration in blood or plasma can be
measured, and therefore the extent of distribution has to be
estimated from the amount remaining in blood, or more
usually plasma, after completion of distribution.
• Vd is the parameter that relates the total body drug load
present at any time to the plasma concentration.
• Together with clearance, Vd determines the overall
elimination rate constant (k) and therefore the half-life & in
turn, the time interval between doses on repeated dosage
and the potential for accumulation. |
|
|
Term
| How do we calcualte the required dose with VD? |
|
Definition
VD = Mass(Dose)/ Plasma Conc
Dose = VD * Desired concentration |
|
|
Term
| What is the single compartment model? |
|
Definition
Simple model, in which the drug enters a single
‘compartment’ from which it is in due course eliminated
at a rate represented by the rate constant of elimination
(k).
• Assumes immediate distribution of drug around whole
body with elimination following first order kinetics - ie a
constant fraction of drug is eliminated.
• Loss of drug reflects drug that is distributed and
eliminated from body.
• Can use this model to calculate certain parameters.
• Because distribution is usually more rapid than
absorption from the intestine, the rate of distribution can
only be measured reliably following an IV dose.
Plasma concentration phase drops linearly during distribution and the decays exponentially during the elimination phase |
|
|
Term
| How do you calculate VD and elimination rate in a one compartment model |
|
Definition
Vd based on a back-extrapolation
of the drug concentration
measurements to the axis to
estimate the maximal concentration
(C
0
) at time zero.
• This can be combined with the
total amount of drug in the body
( A) at that time (i.e. the
intravenous dose) to calculate Vd
using the equation:
• Vd = A/C0
• The plasma concentration at any
time after dosing can be estimated
from the equation:
• C = C0.e–kt |
|
|
Term
| What is the Plasma half life? |
|
Definition
=0.69VD/Clearance
T1/2
- most common term used to describe
elimination
• Defined as time taken for plasma drug
concentration to decline by 50%.
• Since plasma drug concentrations decline linearly
over time, this will be constant irrespective of
dose taken.
• Nb to know T1/2
in terms of dosing regimes.
• The Vd is the volume of fluid that must be
clearedof the drug before elimination is complete
and therefore influences half-life.
• The other determinant of half-life is clearance,
the rate at which drug is removed from the
volume of distribution. |
|
|
Term
|
Definition
|
|
Term
| What is the key differnece between single and multi compartmental models of drug distribution? |
|
Definition
Instantaneous(and(slow(
distribu=ons(are(
described(by(different(
mathema=cal(models(
1"compartment,model%(B(
all(=ssues(are(in(
equilibrium(
instantaneously;((
2"compartment,model%(B(
drug(ini=ally(enters(&(
reaches(instantaneous(
equilibrium(with(one(
compartment((blood/
wellBperfused(=ssues).(
Equilibrates(more(slowly(
with(a(2nd
(compartment(
(poorly(perfused(=ssues) |
|
|
Term
| Describe the 2 compartmental model? |
|
Definition
The reality for most drugs is that
distribution often occurs from a central
compartment into other peripheral
compartments.
• It takes time for an equilibrium to be
established between these
compartments (depending on factors
such as organ blood flow and protein
binding)
• Requires back-extrapolation of the
slope of the terminal (β) phase to the
vertical axis to give an estimate of the
plasma concentration at the time the
dose was administered (C0
).
• This gives an estimate of what the
initial concentration would have been if
equilibration between compartments
had been instantaneous |
|
|
Term
| Describe drug distribution to the brain? |
|
Definition
Well-perfused but ‘privileged’ site that only very
lipophilic drugs can enter readily eg: thiopental
• Reflects reduced capillary permeability conferred by
‘blood-brain barrier’.
3 major physical components:
• tight junctions between adjacent endothelial cells (no
smooth muscle)
• reduced size and number of pores in the endothelial cell
membranes
• presence of a surrounding layer of astrocytes.
• Active transport mechanisms deliver critical compounds
(eg a.a.s) |
|
|
Term
| Describe drug distribution to the foetus? |
|
Definition
Lipid-soluble drugs can readily cross the placenta and enter the fetus.
• Since placental blood flow is low, fetal concentrations equilibrate slowly with the
maternal circulation.
• Highly polar and large molecules (eg heparin) do not readily cross the placenta.
• The fetal liver has only low levels of drug-metabolising enzymes. Thus, maternal
elimination processes dictate fetal concs of drug
• After delivery, the baby may show effects from drugs given close to delivery (eg
pethidine).
• These effects may be prolonged because the infant now has to rely on his own
immature elimination processes. |
|
|
Term
| what is the clinical relevance of drug (re)distribution? |
|
Definition
• The time delay between an intravenous bolus dose and the response may be
caused by the time taken for distribution to the site of action.
• Redistribution of intravenous drugs, such as thiopental, may limit their duration
of action.
• for water-soluble drugs, the rate of distribution depends on the rate of passage
across membranes, i.e. the diffusion characteristics of the drug
• for lipid-soluble drugs, the rate of distribution depends on the rate of delivery
(blood flow) to those tissues, such as adipose, that accumulate the drug. |
|
|
Term
| What are some general points on Drug Metabolism and elimination? |
|
Definition
Body generally v. good at inactivating & eliminating drugs/xenobiotics.
• Rare for a drug to be excreted unchanged, most undergo a variety of
chemical changes brought about by enzymes.
• All drugs that enter the body will eventually be eliminated
• Variations in elimination, associated with age or disease, are a common
cause of predictable (and therefore avoidable) adverse drug reactions.
• The most effective way of rendering a drug inactive is to render it
more hydrophilic.
• Metabolism confers a survival advantage. |
|
|
Term
| What is the most effective way to render a drug inactive? |
|
Definition
The most effective way of rendering a drug inactive is to render it
more hydrophilic. |
|
|
Term
| What is the difference between metabolism and elimination? |
|
Definition
Elimination is the removal of drug from the body & may or may not
involve metabolism and/or excretion.
• Body eliminates drugs unchanged or via their part or complete
conversion to water-soluble metabolites.
• Categories of elimination
• Renal
• Faecal via bile
• Pulmonary
• Via breast milk
• Clearance refers to the elimination of drug from plasma.
• Metabolism is a general term for chemical transformations in the
body. |
|
|
Term
| What does the effect of reducing lipid solubility have on drug metabolism? |
|
Definition
Reducing lipid solubility
Lipophilic molecules are generally reabsorbed from urine in the kidney tubule
whereas hydrophilic (polar) molecules are rapidly eliminated in the urine.
Metabolism is essential for the elimination of lipophilic chemicals since it renders
them more water-soluble via a series of rxns. |
|
|
Term
| What effect does metabolism have on biological activity? |
|
Definition
Altering biological activity
Metabolism of a parent drug produces a new chemical entity, which may show
different pharmacological properties:
• complete loss of biological activity - most drugs - detoxification
• decrease in activity,
• increase in activity - metabolite is more potent than the parent - (eg for prodrugs) - bioactivation
• change in activity, when the metabolite shows different pharmacological
properties which can be less active or more toxic. |
|
|
Term
| Where does most drug metabolism take place? Give some examples of drugs that are metabolised elsewhere? |
|
Definition
Liver
lungs: most prostanoids
"kidneys: serotonin, noradrenaline
"gut mucosa: salbutamol
"plasma: suxamethonium |
|
|
Term
| How many phases is metabolism divided into - what happens in each of these phases? |
|
Definition
2 Phases - some drugs can skip straight to phase 2
In phase one oxidation, reduction or hydrolysis takes place - the drug is most likely inactivated byut can be changed or activated too. Phase I metabolism usually produces a molecule that is a suitable substrate for a phase 2 or conjugation reaction (preconjugation). Introduction or unmasking of a functional chemical group by oxidation, reduction or hydrolysis:
• The enzymes involved in these reactions have low substrate
specificities and can metabolise a vast range of drug substrates &
most environmental pollutants.
• Oxidation by cytochrome P450 enzymes is the most important Phase
I metabolic event.
In phase 2 the drug is conjugated - and forms conjugation products (usually unactivated)
Most drugs that are not excreted
unchanged are excreted as Phase I
metabolites but some not sufficiently
hydrophilic.
• Undergo further metabolic
processing: Phase II
• Either parent drug or phase I
metabolite conjugated to a v.
hydrophilic species creating large,
polarised molecule. (also endogenous
substrates steroids etc.) |
|
|
Term
| Why is cytochrome P450 so important? |
|
Definition
Large number of important clinical drugs metabolised by cytochrome P450 - e.g. warfarin
CYP 450 are haem-containing
enzymes, with monooxygenase
activity. Bind drug and molecular
oxygen (1 to drug, 1 to water).
Act as sophisticated electron
transport system (via iron at active
site). |
|
|
Term
| What is the Therapeutic Index? |
|
Definition
= (LD50/ED50)
The therapeutic index (also known as therapeutic ratio) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death (in animal studies) or toxicity (in human studies). |
|
|
Term
When would the induction or inhibition of cytochrome P450 become an issue?
What substances induct CytochromeP450 and what substances inhibit it? |
|
Definition
• Becomes important when 2+ drugs/factors prescribed
or present together. Especially nb for drugs with narrow
therapeutic index.
Induction of CYP
barbiturates, smoking, St John’s wort, anticonvulsants
such as carbamazepine, ethanol, rifampicin all induce
CYP, may reduce clinical efficacy of other drugs by
increasing their metabolism. (eg rifampicin and oral
contraceptive)
Inhibition of CYP
Cimetidine, grapefruit juice, imidazole anti-fungal drugs,
anti-depressants (eg fluoxetine) all inhibit CYP
enzymes. Slow metabolism, thus plasma conc. may
become toxic. |
|
|
Term
| How can genes affect cytochrome P450? |
|
Definition
Genetic polymorphism
Eg CYP2D6 - can cause enzyme inactivity, increased activity |
|
|
Term
| Give some examples of conjugation reactions? |
|
Definition
| Acetylation, Methylation, Sulphation |
|
|
Term
| What is excretion and name some routes by which excretion takes place? |
|
Definition
Excretion
November 2013 Dr Helen Gallagher, UCD SMMS
The process by which a drug or its metabolite is
finally eliminated from the body:
Kidney– low molecular-weight compounds are
mostly eliminated via the kidney into the urine
Biliary tract– large molecular-weight compounds
(above 400-500 Daltons) are mostly eliminated by
excretion into the bile and subsequently faeces.
Eyes– a small number of drugs are excreted in
the tears, eg rifampicin, which can stain soft
contact lenses.
Lung– some gases and volatile anaesthetics are
eliminated in exhaled air via the lungs.
Breast– many lipid-soluble drugs diffuse into milk
and can be ingested by the infant
Other routes– a small number of drugs are found
in sweat, saliva and in hair. |
|
|
Term
| What happens in Renal excretion? What processes take place? |
|
Definition
Renal excretion
• Kidney excretes changed/unchanged
drugs.
3 processes "
• glomerular filtration(rate nb) –all
non-plasma protein bound drugs are
filtered.
• passive tubular reabsorption, depends
on:
• urine pH -alkalization of urine
with bicarbonate induces ionization
of weak acid (eg aspirin) reducing
reabsorption.
• Outflow - excretion facilitated by
high flow, less time for
reabsorption"
• tubular secretionof organic anions by
efflux transporters eg antibiotics,
NSAIDs" |
|
|
Term
| What processes take place in biliary excretion? |
|
Definition
Biliary excretion
• Principal route of excretion for large molecules
(eg glucoronide conjugates).
• Enterohepatic recirculation: Intestinal microflora
have enzymes capable of hydrolysing conjugates,
releasing the drug or active Phase I metabolite
for reabsorption.
• Thus entero-hepatic circulation prolongs the
residence timeof drugs in the body, sustaining
their effects.
• The recycling of glucuronide conjugates may be
prevented if the naturally occurring intestinal
micro-organisms are inactivated or killed by
broad-spectrum antibiotics. |
|
|
Term
|
Definition
|
|
Term
| How does clearance reflect re-absorbtion and tubular secretion? How is renal fuction tested? |
|
Definition
If a drug is excreted by a number of routes then
"Cltotal
= Cl
renal
+ Clother/hepatic
• If drug filtered but not reabsorbed or secreted
then Cl = GFR = 124 ml/min male, 109 ml/min
female
• If drug reabsorbed, Cl < GFR
• If drug secreted, Cl > GFR <renal plasma flow
(700 ml/min) (eg benzylpenicillin 480ml/min)
• Clearance may change in disease states that affect
organ involved.
• May need to measure creatinine clearance (marker
for renal function), and adjust dosage if patient
has renal impairment. |
|
|
Term
| What is pharmacokinetics? |
|
Definition
After a drug has been administered it is immediately subject to
absorption and distribution, both of which occur relatively quickly,
followed by a longer period during which the drug is eliminated.
• the rateat which the body absorbs, distributes, metabolizes and
eliminates drugs (ADME)
• can be examined using mathematical modelling
• time course of drug in plasma most nb
• ideal PK profile: right effect & intensity of effect, good timing of
effect and desired duration of action
• drug therapy may fail for pharmacokinetic reasons, even if drug is
efficacious and potent
• thus pharmacokinetic modelling must informdosage regimens |
|
|
Term
| What is first order kinetics? |
|
Definition
Constant fraction of the drug in the
body eliminated per unit time.
• Rate of elimination ∝amount of drug
in the body.
• A plot of concentration vs time yields
a curve. Usually linearized.
• The importance of this relationship to
prescribers is that it means the effect
of increasing doses on plasma
concentration is predictable
• Most drugs obey 1st order kinetics. |
|
|
Term
| What is the half life in first order kinetics? |
|
Definition
Time for plasma levels
to decrease by 50%. |
|
|
Term
| What does the elimination rate depend on? |
|
Definition
Elimination rate (k) depends on 2 variables, volume of
plasma cleared per unit time, and volume to be cleared:
Fraction of drug removed per unit time = Cl/Vd. Thus for
50% elimination |
|
|
Term
| What is zero order/ saturation kinetics? |
|
Definition
Rate independent of
amount of drug
• constant amount
processed/t eg 10 mg/
hour
• Elimination of alcohol
• Graph of
concentration vs time,
straight line, slope -k |
|
|
Term
| Can drug elimination move from zero order to first order? |
|
Definition
| Once enzymes satureated zero order kinetics can take over from first order as the rate will no longer be dependant on the concentration |
|
|
Term
| What factors affect plasma concentration after oral dosing? |
|
Definition
Gastric emptying:
for drugs not
absorbed at all
from stomach (eg
basic drugs)
Food
generally
slows
absorption
Ka smaller
Decomposition/metabolism of drug
before absorption complete.
Reduced bioavailability.
Modified release
formulation.
Dissolution of drug
dictates k |
|
|
Term
| What is chronic administration of drugs and how long does it take to reach steady state concentration? |
|
Definition
Most drugs are effectively removedfrom the
body in the hours and days after administration
by metabolism and excretion.
• This means that prescribers have to plan
repeated administrationof doses to ensure that
drug concentrations at the site of action remain
effective.
• Ideally an equilibrium (steady state) established
between blood and all tissues of the body,
including the site of action.
• In practice only achieved by constant infusion.
• Css = steady state concentration, usually achieve
after 4-5 T1/2 |
|
|
Term
| How is a steady state concentration reached? |
|
Definition
Intravenous infusionof a drug whose
kinetics are first-order easily
understood model of drug accumuation.
• Initially, drug is entering the body at
a constant rate. Although elimination
will begin immediately:
Rate of elimination = Clearance (Cl) ×
Concentration
As the plasma concentration rises, the
rate of elimination will increase.
The rate of rise of the plasma
concentration will lessen as the rate of
elimination rises to match the infusion
rate until the moment arrives when the
two are equal and plasma concentration
reaches a plateau. |
|
|
Term
| How can we change the steady state concentration? |
|
Definition
Increase the infusion rate
At steady state (Css)
rate in =rate out
Css = Rate of elimination/Cl = Rate
of infusion/Cl
• Rate out depends on dose (for most
drugs)
• Thus to adjust Css you must adjust
rate in (infusion rate).
• Irrespective of rate, it takes 4-5
half-lives to reach steady state
• Thus ‘time to steady state’ is a
property of the drug |
|
|
Term
| Why is the dosing interval important? |
|
Definition
The dosing interval is importan to reduce the variablility away from the css
Realistically oral infusions oscillate about the ideal css |
|
|
Term
| What is the formula for single versus repeated oral dosing? |
|
Definition
Single:
[Dose*Bioavailability]/ [Time Interval between dose]
For Repeated:
[Dose*Bioavailability]/ [Time Interval between dose*clearance] |
|
|
Term
| What are the considerations when we need to maintain a threshold plasma concentration to aproximate infusion? |
|
Definition
For drugs whose effects are critically dependent on maintaining a threshold plasma
concentration and which have a low therapeutic index, or both, the design of the
therapeutic regimen is a trade-off between efficacy and/or safety and patient
convenience. |
|
|
Term
| For drugs with a long halflife - what nmay we need to do? How is this managed? |
|
Definition
If a drug has a long T1/2
may
need a loading dose. (eg
doxycycline; benzylpenicillin;
digoxin)
• Followed by smaller
maintenance doses.
• Avoids delay between start of
treatment and reaching of Css.
• Preferable to higher doses
each time, which augment Css.
• Calculate loading dose as: Vd x
Css
Ideal time interval between doses
~ one T1/2 |
|
|
Term
| What is therapeutic drug monitoring? |
|
Definition
(TDM) determines whether the amount of a drug in the blood is within
therapeutic limits
It assists clinical judgement
Used to ensure that the dose and dose interval of the drug are sufficient to
maintain a therapeutic blood concentration throughout drug therapy without risk
of toxicity.
Used when dose-effect hard to predict but blood concentration-effect is a
reliable indicator
May also be performed to verify compliance.
Particularly important for drugs with narrow therapeutic index or known toxicity
that is not easily identifiable clinically. |
|
|
Term
| What patient related factors can affect pharmacokinetics? |
|
Definition
• genetic makeup
• race
• sex,
• age
• renal failure
• obesity
• hepatic failure
• dehydration |
|
|
Term
| What are receptors? What are ligands? |
|
Definition
Proteins situated in the cell
membrane or at an intracellular
site that specifically recognise and
bind to ligands.
• Receptors in human tissues have
evolved to bind endogenous ligands
such as neurotransmitters,
hormones, and growth factors.
• Usually defined and named
according to their most potent
endogenous agonist (e.g.
adrenergic, serotoninergic,
histaminergic, dopaminergic).
In biochemistry and pharmacology, a ligand (from the Latin ligandum, binding) is a substance (usually a small molecule), that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein. |
|
|
Term
| Name four Common receptor superfamilies |
|
Definition
- Ligand gated ion channel - entry/exit ions, Depolarisation or hyperpolarisation
- G Protein coupled - receptor protein associated with a g protein which activates an enzyme to produce a secondary messanger
- Receptor Tyrosine kinases - initiate protein phosphorylation
- Intracellular receptors (DNA Linked) - stimulate mRNA synthesis in the cell leading to protein synthesis |
|
|
Term
| What are the basic principles of dose-response relationships? |
|
Definition
Concentration of the drug at the site of action always controls the
size of the effect/response.
• May be complex phenomenon and is frequently, nonlinear.
• The relationship between the drug dose administered to patient and
the drug concentration at the cellular level is even more complex
(involves pharmacokinetics).
• Variation in magnitude of response among test subjects in the same
population given the same dose of drug also occurs (biological
variation).
• Most natural and synthetic ligands bind to receptors reversibly
and will dissociate from their receptor when the ligand
concentration is reduced. |
|
|
Term
| What bonds are involved in drug receptor binding? |
|
Definition
| Covalent, Polar Covalent, Ionic and Hydrogen, Van der Walls |
|
|
Term
| What law does drug binding follow, What is the KD? |
|
Definition
The dynamic relationship between a drug
and its receptor can be described in the
reversible equation D + R = DR where DR is
the drug-receptor complex.
• The interaction between ligands or drugs
and their receptors usually obeys the Law
of Mass Action:
• When a drug (D) combines with a receptor
(R), it does so at a rate which is dependent
on the concentration of the drug and the
concentration of the receptor.
• At equilibrium the rates of drug-receptor
association & dissociation are equal (KD
=
KA
) |
|
|
Term
| What determines the point at which equilibrium is reached? How is KD established? |
|
Definition
The point at which equilbrium is
reached in the drug-receptor
interaction process depends on the
affinitythe drug has for that
receptor.
• Systems requiring rapid fine
modulation(e.g. nerve synapses)
must have agonists with a low
receptor affinity.
• Determined in radioligand binding
studies - in which the maximum
number of receptors occupied by
that drug is established.
• Use the point of 50% occupancy
to establish Kd. |
|
|
Term
| How are radioligand binding studies performed? |
|
Definition
Receptor source (homogenized tissue) Brain
• Incubate with radiolabelled ligand
3
H-spiperone
• Wash &filter to remove unbound ligand & count Scintillation counter
amount of radioactivity present.
• Provides an indication of total binding of ligandto the tissue sample.
• Repeat assay with 10-fold xs of unlabelled
3
H-Spiperone + spiperone
ligand.
• ‘Cold’ ligand will bind to receptor as it is in xs. Provides an indication of how
much radiolabelled ligand is binding to non-specificsites that are not receptors.
• Subtract non-specific from total binding = Specific binding to receptors |
|
|
Term
| What is the difference between Intrinsic Activity versus affinity? Which do agonists have - which do antagonists have? |
|
Definition
Intrinsic activity versus affinity
• Affinityis the measure of the tightness with which a drug binds to
a receptor. Characterized by Kd.
• A drug or ligand may have high affinity for a receptor but not be
able to produce a large biological response.
• Intrinsic activity, efficacy or intrinsic efficacy may be defined
as: the measure of the ability of a drug, once bound to the receptor,
to produce a measurable physiologic effect.
• Affinity and intrinsic activity are independent properties of drugs.
• Agonists have bothaffinity and intrinsic activity while antagonists
have only affinityfor the receptor. |
|
|
Term
| How is intrinsic activity/efficacy measured? |
|
Definition
Bioassay - Use of a biological system to relate
drug concentration to a physiological
response.
• Isolated tissues
• Cultured cells
• Whole animals
• Patients
• A known concentration of drug goes
in & a response is measured.
• Typically repeat with various drug
concentrations to establish doseresponse curve |
|
|
Term
How dose-response relationships are
depicted graphically |
|
Definition
Dose-response data are typically graphed with the
dose or dose function (eg, log10
dose) on the x-axis
and the measured effect (response) on the y-axis.
• A drug effect is a function of dose and time, thus
such a graph depicts the dose-response
relationship independent of time.
• Measured effects are frequently recorded as
maxima at time of peak effect or under steadystate conditions (eg, during continuous IV infusion).
• Drug effects may be quantified at the level of
molecule, cell, tissue, organ, organ system, or
organism. |
|
|
Term
| What are the variable features of a dose response curve? |
|
Definition
Variable features of a
dose-response curve
• Potency
• Maximal efficacy
• Slope (response per
unit dose) |
|
|
Term
| What are Emax and ED50 Values? |
|
Definition
Progressive increases in drug
dose produce increasing drug
effects, but that these occur
over a relatively narrow part of
the overall concentration range.
• The maximum response on the
curve is the Emaxand the dose (or
concentration) producing 50% of
the maximum response.is the ED
50
(or EC
50
). |
|
|
Term
| What is therapeutic efficacy? |
|
Definition
The term therapeutic efficacy
is used to compare drugs that
produce the same therapeutic
effects on a biological system
but do so via different
pharmacological mechanisms.
Loop diuretics (e.g. furosemide)
have greater natriuretic
efficacy than thiazide diuretics
(e.g. hydrochlorothiazide); both
act as diuretics but have their
effects at different sites in the
renal tubule. |
|
|
Term
|
Definition
High potent drugs produce a response at low weight…
Potency is a measure of how’ good’
a drug is at evoking a response.
• Drugs are compared on a weightfor-weight basis - not necessarily
clinically relevant.
• Since it relates to concentration it
may be equated with ‘strength’.
• A drug can have good efficacy but
not be very potent.
• Evaluated by EC50
value - the
molar concentration that illicits
50% maximal response.
• Antagonist potency = affinity |
|
|
Term
| What are the different types of agonist? |
|
Definition
While full agonistsusually activate receptors due to similarity to a
natural ligand, they are usually different enough to resist degradation.
• salbutamol B receptor agonist - asthma treatment - longer duration
of action than adrenaline itself in bronchodilation.
Partial agonistshave ‘mixed’ agonist & antagonist activity.
They can activate receptors, but only weakly.
Inverse agonists
Bind to same receptor as natural ligand but produce different biological
effects.
Switch off ‘constitutive’ activity of some receptors.
• Benzodiazepines are agonists at GABA receptors - sedative effects
• B-carbolines are inverse agonists at GABA receptors - stimulatory
effects |
|
|
Term
| What are spare receptors or receptor reserves? |
|
Definition
In most physiological systems, the
relationship between receptor
occupancy and response is not
linear.
• The hyperbolic relationship
between occupancy and response
implies that maximal responses are
elicited at less than maximal
receptor occupancy.
• Thus a certain number of receptor
are ‘spare’. |
|
|
Term
| What is receptor desensitisation and tolerance? |
|
Definition
For cells to function normally, receptor
activation must be rapid but transient.
• Continuous exposure to a drug can lead to
decreased responsiveness - receptor
desensitization(tachyphylaxis).
• Occurs within minutes, considered a
homeostatic mechanism.
• Tolerance can occur with prolonged drug
exposure (days to weeks).
• Means higher doses may be required. Also
implications for drug withdrawal. |
|
|
Term
| What are the various different types of antagonism? |
|
Definition
Two main types are Receptor and non receptor
In non receptor chemical (binds to the drug) in non receptor physiological another chemical binds to a different receptor to prevent the action
In receptor there is active and allosteric controll which is further subdivided into reversible and irreversible
Types of antagonism
An antagonist may or may not bind to the agonist's binding site
(receptor).
Chemical
One drug binds another thereby inactivating it
• Protamine (basic peptide) & heparin (acidic sugar - anticoagulant)
• Protamine is used to neutralise heparin if bleeding is problematic
Physiological
Action of one drug opposes the action of another but via different
mechanism (Receptor)
• Salbutamol B-receptor agonist- relaxes smooth muscle in airways
(bronchodilator) - sympathetic neurotransmission
&
• Acetylcholine - Muscarinic receptor agonist - M3 receptors -
contract s.m. in airways - parasympathetic neurotransmission |
|
|
Term
| What mechanisms underly desensitisation? |
|
Definition
Pharmacokinetic - altered drug handling increased metabolism or excretion
Pharmacodynamic - changes in receptors (number or function) or exhaustion of chemical mediators |
|
|
Term
| What is the clinical relevance of tolerance? |
|
Definition
Organic nitrates are used to
treat or prevent angina
pectoris because of their
vasodilator activity.
• These same actions can lead to
reflex activation of the
sympathetic nervous and
renin-angiotensin systems.
This increases the work of the
heart and counteracts the
benefits of the nitrate.
• There are many other drugs
associated with withdrawal
effects. |
|
|
Term
| What is the difference between selectivity and specificity? |
|
Definition
Drug/Receptor selectivity and specificty
• A drug is selective if it interacts with only one receptor family.
• Rare, especially when subfamilies are considered - consider
spectrum.
• Eg propranolol - selective for β-adrenoreceptors but considered a
non-selective β-antagonist since it binds to β1 & β2 receptors.
• Selectivity is generally a desirable feature of drugs - minimizes
SIEs.
• Specificity really refers to interaction between a drug/ligand and
particular sequence of a.a.s in a receptor site & vice versa. |
|
|
Term
| What do we need to consider in design of dosing regimes? |
|
Definition
Dose-response relationships determine the required dose and frequency
as well as the therapeutic index for a drug in a population.
• The therapeutic index(ratio of the minimum toxic concentration to the
median effective concentration) helps determine the efficacy and safety
of a drug.
• Also defined as optimal range of plasma levels for a drug to produce the
appropriate pharmacological or therapeutic effect in vivo.
• Increasing the dose of a drug with a small therapeutic index increases the
probability of toxicity or ineffectiveness of the drug.
• These features differ by population and are affected by patient-related
factors (eg, pregnancy and age) |
|
|
Term
| How do you calculate the therapeutic index? |
|
Definition
| ED50 (toxic)/ED50 effective |
|
|
Term
| What is the autonomic nervous system? |
|
Definition
The Autonomic Nervous System
• Innervates smooth muscle, cardiac
muscle, and glands
• Regulates visceral functions
• Heart rate, blood pressure,
digestion, urination
• The general visceral motor division
of the PNS |
|
|
Term
| What is the difference between the sympathetic parasympatetic and enteric nerve system |
|
Definition
parasympathetic nervous system is SSLUDD (sexual arousal, salivation, lacrimation, urination, digestion and defecation).
Alongside the other two components of the autonomic nervous system, the sympathetic nervous system aids in the control of most of the body's internal organs. The sympathetic nervous system is responsible for up- and down-regulating many homeostatic mechanisms in living organisms.
The enteric nervous system (ENS) or intrinsic nervous system is one of the main divisions of the autonomic nervous system and consists of a mesh-like system of neurons that governs the function of the gastrointestinal system. |
|
|
Term
| What is the difference between somatic vs autonomic motor system? |
|
Definition
Somatic motor system
One motor neuron extends from the CNS to
skeletal muscle
Axons are well myelinated, conduct impulses
rapidly
Autonomic nervous system
Chain of two motor neurons
Preganglionic neuron
Postganglionic neuron
Conduction is slower due to thinly or
unmyelinated axons |
|
|
Term
| What is the differnece between the sympatetic and parasympathetic nervous system? |
|
Definition
• Sympathetic and parasympathetic divisions
• Innervate mostly the same structures
• Cause opposite effects
• Sympathetic – “fight, flight, or fright”
• Activated during exercise, excitement, and emergencies
• Parasympathetic – “rest and digest”
• Concerned with conserving energy |
|
|
Term
| What are the anatomical divisions in the sympatehtic and parasympathetic nervous systems? |
|
Definition
Issue from different regions of
the CNS
– Sympathetic – also called the
thoracolumbar division
– Parasympathetic – also called
the craniosacral division
• Length of postganglionic fibers
– Sympathetic – long
postganglionic fibers
– Parasympathetic – short
postganglionic fibers
• Branching of axons
– Sympathetic axons – highly
branched
• Influences many organs
– Parasympathetic axons – few
branches
• Localized effect |
|
|
Term
| What are the major effects of the parasympathetic system? |
|
Definition
The cranial parasympathetic
innervates the eye, salivary
glands etc.
• The vagus gives para supply to
heart lungs and entire git to
half of the transverse colon
• The sacral para supplies the
hindgut, bladder, external
genitalia and pelvic organs
• Vagus slows the heart
• Vagus increases motility of git
• Sacral parasymp contracts
bladder and relaxes its
sphincters |
|
|
Term
| What are the neurotransmitters in the peripheral nervous system? |
|
Definition
In both parts acetylcholine is
The neurotransmitter in the
ganglion.
• In the target organ the
transmitter is acetylcholine in
the parasymp and noradrenaline
in the
Sympathetic.
• An exception is the sympathetic
innervation of sweat glands
which is ach
• In the Kidneys, postganglionic
neurons to the smooth muscle of
the renal vascular bed release
dopamine |
|
|
Term
| What are the Major effects of sympathetic system |
|
Definition
Every part of the body
gets a sympathetic
supply
• It accelerates the
heart
• It constricts blood
vessels
• It reduces motility of
the gut
• It relaxes the bladder
and contracts its
sphincters |
|
|
Term
| How do drugs affect the ANS? |
|
Definition
Parasympathetic nervous system
• Mimic acetylcholine = cholinergic = muscarinic agonists =
parasympathomimetic
• Block acetylcholine = anticholinergic = muscarinic antagonist =
parasympatholytic
• Sympathetic nervous system
• Mimic norepinephrine = adrenergic = adrenergic agonist = sympathomimetic
• Block norepinephrine = antiadrenergic = adrenergic antagonist =
sympatholytic |
|
|
Term
| What are some general effects of cholinergenic Agonists? |
|
Definition
Eg Acetylcholine, Bethanechol, Carbachol, Pilocarpine
• Decrease heart rate and cardiac output
• Decrease blood pressure
• Increases GI motility and secretion
• Pupillary constriction
Side effects include Diarrhoeah, Miosis, Urinary urgency, Diaphoresis, Nausea |
|
|
Term
| What is referred pain and how does it relate to the ANS |
|
Definition
Pain arising in a visceral organ is not usually felt in
the anatomical location of the organ
• It is felt on the part of the surface of the body
whose somatic innervation comes from the same
segment as the sympathetic supply
• Eg the pain of cardiac ischaemia (angina pectoris) is
felt on the ulanar border of the left arm. This is
because the sympathetic innervation of the heart
comes from t1 which is also the sensory supply of
medial arm
• Eg an inflamed appendix will initially cause pain in
the centre of the abdomen (t10) |
|
|
Term
| What is Raynaud's disease? |
|
Definition
Disorders of the Autonomic Nervous System: Raynaud’s Disease
• Raynaud’s disease – characterized by constriction of blood vessels
– Provoked by exposure to cold or by emotional stress |
|
|
Term
| What is hypertension how does it relate to the ANS? |
|
Definition
Disorders of the Autonomic Nervous System: Hypertension
• Hypertension – high blood pressure
– Can result from overactive sympathetic vasoconstriction |
|
|
Term
| What is Achalasia of the Cardia? |
|
Definition
Disorders of the Autonomic Nervous System: Achalasia of the
Cardia
• Achalasia of the cardia
– Defect in the autonomic
innervation of the esophagus
Achalasia /eɪkəˈleɪziə/, also known as esophageal achalasia, achalasia cardiae, cardiospasm, and esophageal aperistalsis, is an esophageal motility disorder involving the smooth muscle layer of the esophagus and the lower esophageal sphincter (LES).[1] It is characterized by incomplete LES relaxation, increased LES tone, and lack of peristalsis of the esophagus (inability of smooth muscle to move food down the esophagus) in the absence of other explanations like cancer or fibrosis |
|
|
