What is pharmacodynamics?
The effects of a drug on the body.
What the body does to a drug.
What is pharmacokinetics?
Pharmacodynamics allows us to...
determine the appropriate dose range for patients and compare how safe or effective different drugs are.
design and optimise treatment plans for individuals.
determine the best route and frequency of administration of a new drug.
What does ADME stand for?
Administration
Affect
Absorption
Distribution
Dissolving
Metabolism
Modification
Excretion
Editing
Absorption is...
how a drug gets from the site of administration into the blood.
how a drug moves from the blood to target cells.
how the drug elicits its effect on the body.
how a drug is eliminated from the body.
Distribution is...
how the drug moves in the body, for example leaving the blood stream and distributing non uniformly into intracellular fluids.
how long the drug moves around in the blood for.
how the drug is inactivated by the body.
how the drug is eliminated from the body, for example in bile.
Metabolism is...
how the body inactivates the drug.
enzymatic modification.
how the drug travels through the body.
how the drug passes cell walls.
Excretion is...
how the drug is eliminated from the body, for example in urine, bile or faeces.
how long the drug can stay in the body unchanged.
how the drug gets from the site of administration to the GI tract.
how the drug elicits a cellular response.
From what sources can we create drugs?
Completely synthetic materials.
Plants.
Synthetic materials but using the template of a naturally occurring compound.
Biologics (derived from growth factors and recombinant proteins).
Electricity.
Nitrogen gas.
Laptops.
How many types of proteins act as drug targets?
1
2
3
4
5
What are the four types of proteins that can act as drug targets?
Receptors, Ion Channels, Enzymes and Carriers.
Hormonal Receptors, Gated Ion Channels, Metabolic Enzymes, Carriers.
Receptors, Ion Channels, Enzymes, Channels.
Ion Channels, Reception, Enzyme Inhibitors, Carriers.
Ion Channels, Receptors, Enzymes, Channels.
Drug interaction with the target is determined by two factors. What are they?
Shape
Charge Distribution
Colour
Name
Time
This determines the ability of a drug to bind to it's target. It it the right __________ to bind to the target or not? Lock and Key mechanism.
Charge
Mass
This determines the strength of associations between the drug and it's target, because it determines the bonds that the drug can make.
Order these forces, weakest to strongest.
Ionic Bonds Hydrogen Bonds Van der Waals Forces Covalent Bonds
Van der Waals Forces, Hydrogen Bonds, Ionic Bonds, Covalent Bonds
Covalent Bonds, Ionic Bonds, Hydrogen Bonds, Van der Waals Forces
Van der Waals Forces, Ionic Bonds, Hydrogen Bonds, Covalent Bonds
Covalent Bonds, Hydrogen Bonds, Ionic Bonds, Van der Waals Forces
Why are antidotes, antacids and laxatives unusual drugs?
They do not target proteins, they simply act by virtue of their physiochemical properties.
They target more than one type of protein.
They are never metabolised by the body, they stay unchanged in the liver forever.
They are always available as over the counter medicines.
They do not have to be licensed.
What is the target of an antidote?
Hormone
Ion Channel
Enzyme
Poison
Drugs that act on receptors...
always activate the receptor.
either activate the receptor or stop something else from activating it.
block the receptor.
denature the receptor.
Drugs that act on ion channels...
can block the channel.
can modulate the opening and closing of the channel.
can denature the channel.
can stimulate the production of many more channels than normal.
can break down the ion that normally uses the channel.
Drugs that act on enzymes...
either inhibit the enzyme or act as a false substrate.
block the enzymes active site.
denature the enzyme.
cause the release of neurotransmitter.
activate the enzyme.
Agonists are ligands. Which of these can be examples of ligands?
Drugs
Hormones
Neurotransmitters
Enzymes
Ion Channels
An antagonist is...
a drug which blocks the response to an agonist.
a drug that combines with a receptor to elicit a cellular response.
a drug that binds with an ion channel.
Receptors within a given family generally occur in several molecular varieties (subtypes). They often have similar structures but very different pharmacological responses.
All drug targets can be considered generally as...
receptors.
ion channels.
enzymes.
carriers.
Receptor subtypes are identified on the basis of selectivity of agonists and/or antagonists. What technique is used to determine this?
ligand binding assay
plaque assay
ELISA
dose/response curve
Channel linked (ionotrophic) receptors can be...
ligand gated
voltage gated
temperature gated
concentration gated
time centred
Ligand gated ion channels require...
an agonist to open the channel.
energy (in the form of ATP) to open the channel.
an antagonist to open the channel.
Voltage gated ion channels are not linked to receptors.
Which of these are true of voltage gated ion channels?
They are not linked to receptors.
They require a change in electrical charge across a membrane in order to open and close.
They can be blocked by antagonist drugs.
There are binding sites for agonist drugs.
They are linked to G-protein coupled receptors.
They require an agonist to open the channel.
How many transmembrane helices do G-Protein coupled receptors have?
7
9
What is another name for G-Protein coupled receptors?
Ionotrophic
Metabotrophic
Kinase
How many subunits do G-Protein coupled receptors have?
What are the subunits of a G-Protein coupled receptor?
alpha
beta
gamma
theta
delta
eta
zeta
omega
Which subunit of a G-Protein receptor alters between different receptors, giving variation?
Alpha
Beta
Gamma
Eta
Zeta
What do Gs receptors do?
activate adenyl cyclase and Ca2+ channels
inhibit adenyl cyclase and activate K+ channels
activate phospholipase C
What do Gi G-Protein receptors do?
What do Gq receptors do?
Another name for enzyme linked receptors is kinase linked receptors.
How many transmembrane domains do kinase linked receptors have?
Guanylyl cyclase-linked and cytokine are types of...
G-Protein linked receptor
Kinase linked receptor
Ion channel
There are four main types of kinase linked receptor, these are: receptor tyrosine kinase serine/threonine kinase cytokine guanylyl cyclase - linked
The mode of action of kinase linked receptors is:
ligand binding ➨ dimerisation ➨ autophosphorylation
dimerisation ➨ ligand binding ➨ autophosphorylation
ligand binding ➨ autophosphorylation ➨ dimerisation
change in membrane potential ➨ autophosphorylation ➨ dimerisation
change in membrane potential ➨ dimerisation ➨ autophosphorylation
Nuclear receptors are insoluble receptors.
There are two classes of nuclear receptors. Class 1 receptors...
are located in the cytoplasm
are located in the nucleus
form homodimers (dimers with other receptors of the same type)
form heterodimers
have endocrine ligands (steroids/hormones)
have lipid (fatty acid) ligands
have a positive feedback effect
Nuclear receptors are harder to target with drugs because...
they are intracellular.
they are extracellular.
they require ATP to be activated.
they are millions of different types of them.
The binding of hormone response elements to nuclear receptors directly initiates changes in what process?
Gene Transcription
Gene Translation
Protein Degredation
Apoptosis
Acidosis
Drug binding to nuclear receptors has rapid and dramatic effects.
Most receptors have multiple binding sites, what are the two kinds of sites that drugs can target?
Orthosteric
Allosteric
Left side
Primary
Orthosteric binding sites...
house full and partial agonists, and reversible competitive antagonists.
bind positive and negative, non competitive antagonists.
Allosteric binding sites...
An agonist is...
a ligand that combines with receptors to elicit a cellular response.
a ligand that served to block the effect of other ligands which combine with receptors to elicit a cellular response.
Dose/response curves are similar to concentration/effect curves.
Dose/response curves are semi logarithmic. The correct set up of the graph is...
X axis : [log] drug dose Y axis : % response
X axis : [log] agonist concentration Y axis : measure of response
X axis : % response Y axis : [log] drug dose
X axis : measure of response Y axis : [log] agonist concentration
Graded relationships use Concentration/Effect curves and are used to show...
the response of a particular system to a drug at varying concentrations.
the drug dose required to produce a specified response in each member of a population.
Quantal relationships use Dose/Response curves and are used to show...
the response of a particular system to varying concentrations of an agonist.
Why plot a concentration effect curve?
you can estimate Emax
you can estimate EC50 and ED50
you can compare the efficacy and potency of different drugs
you can calculate Emax
you can calculate half life
you can estimate clearance
KD is a physiochemical constant and is the same for a drug/receptor combination in any species, anywhere in the universe.
KD can be used to determine an unknown receptor.
KD can be used to quantitatively compare the ___________ of different drugs on the same receptor.
affinity
efficacy
The ________ the KD the greater the potency.
lower
higher
The lower the EC50 the ________ the potency.
greater
Efficacy describes...
the ability of an agonist to activate a receptor (refers to the maximum effect an agonist can produce regardless of dose).
the likelihood the an agonist will bind to a receptor (refers to the maximum binding of an agonist regardless of dose).
Full agonists have...
high efficacy (AR* is very likely)
low efficacy (AR* is unlikely)
Partial agonists have...
low efficacy (AR* is less likely).
Antagonists are...
drugs which block the response to an agonist.
the same as agonists.
endogenous molecules like hormones and neurotransmitters.
Pure agonists cause a cellular effect by binding to a receptor.
There three classes of antagonist. What are they?
chemical
physiological
pharmacological
enterohepatic
primary
active site
Pharmacological antagonists are also known as "receptor antagonists".
Which class of antagonists are also known as "chelating agents"?
Competitive antagonists bind to the ____________ site of a receptor.
active
allosteric
Non competitive antagonists bind to the ___________ site of receptors.
Reversible competitive antagonists...
directly compete with agonists for binding at the active site.
block the active site permanently because they form covalent bonds with it. The receptor must be replaced before more agonist can bind.
reversibly bind to an allosteric site on the receptor, altering binding at the active site.
irreversibly bind at an allosteric site, permanently altering the active site.
Irreversible competitive antagonists...
Non competitive reversible antagonists...
Irreversible non competitive antagonists...
Antagonists have no efficacy.
The effect of reversible competitive antagonists...
can be overcome with increased agonist concentration.
causes a shift to the right on the agonist response curve.
causes reduced maximum response on the agonist response curve.
reduces slope of the agonist response curve.
is due to covalent binding with the active site.
The effect of irreversible competitive antagonists...
is due to covalent bonding at the active site.
reduces slope on the agonist response curve.
Non-competitive antagonist effects...
cause reduced slope of the agonist response curve.
cause a shift to the right of the agonist response curve.
cause reduced maximum response on the agonist response curve.
Water soluble molecules cross membranes easier so are more rapidly absorbed than their lipid soluble counterparts.
Uncharged molecules are absorbed easier than charged molecules.
The route of administration of a drug is determined by...
physiochemical/pharmacokinetic properties of the drug
therapeutic objectives
patient preference
The parenteral route of administration (injected) is used for...
drugs that are poorly absorbed by or are unstable in the GI tract.
drugs that require rapid onset of action.
drugs that require slow onset of action.
for drugs that require a high level of control over dose.
Select the correct definitions:
bolus: all at once
infusion: over time
depot: solid/oil
bolus: over time
bolus: solid/oil
infusion: solid/oil
infusion: all at once
Sub routes of the parenteral route include...
intravenous
intramuscular
subcutaneous
submuscular
thyroidal
femural
What is the most important site of absorption in the body?
Stomach
Small Intestine
Large Intestine
Which of the following are properties of the small intestine that help it to absorb drugs?
large, highly permeable surface area
varies in pH along it's length
constant pH
enterocytes contain drug metabolising enzymes
enterocytes contain transporters in their membranes
tought, flat surface area
contains stomach acid
it is very short in length
The rectal route of administration is used when...
the drug causes vomiting
the patient is vomiting
the drug is excreted in the urine
the patient has a low blood count
Which of these is true of the vaginal route of drug administration?
It bypasses first pass metabolism.
It bypasses 2/3 of first pass metabolism.
It has a rich blood supply.
pH can vary.
pH is always around 8.
Which of these is true of the transdermal route of drug administration?
It has very slow absorption giving a continuous slow release of drug.
It has very fast local absorption giving a rapid release of the drug to a small area.
Drugs given as an inhaled substance are generally intended to be distributed via the systemic circulation.
How well a drug is absorbed when it is inhaled, depends strongly on particle size.
First pass metabolism occurs in both the _________ and ___________ . It occurs when a drug is metabolised before entering the ________________ .
liver
intestine
systemic circulation
pulmonary circulation
heart
kidneys
Factors affecting absorption include:
Formulation of the drug
Charge on the drug
Blood flow to the site of absorption
Surface area of the site of absorption
Contact time at absorptive surface
Gastric emptying
Cost of drug
Kidney function
Which of the correct description of this pharmacokinetic parameter?
Cmax
maximum concentration of a compound after administration
time at which Cmax is reached
area under the concentration/time curve
measure of the extent of absorption
absorption rate constant
Tmax
area under the concentration time curve (considered a measure of systemic exposure)
measure of the extent of absorption compared to IV
absorption rate constant (a measure of the speed of absorption)
AUC
area under the concentration/time curve (considered a measure of systemic exposure)
F (Bioavailability)
measure of extent of absorption compared to IV
Ka
maximum concentration of compound after administration
What is the correct equation for calculating Bioavailability?
F = (AUC oral/AUC IV) x (dose IV/dose oral)
F = (AUC IV/AUC oral) x (dose oral/dose IV)
A drugs ability to distribute around the body depends on...
it's ability to cross cell membranes (based on physiochemical properties)
the amount of blood flow to individual tissues (perfusion)
the extent of its plasma protein binding
the site of administration
CYP polymorphisms
Drugs with a high molecular weight and/or high degree of binding to plasma proteins will...
distribute quickly into tissues and organs.
tend to stay in the systemic circulation rather than distribute into tissues and organs.
Albumin...
is produced by the liver
binds mostly acidic and some neutral drugs
concentration is decreased in malnutrition and cirrhosis
is normally present at around 3.5-5g/L
binds basic and some neutral drugs
is normally present at around 0.4-1.1mg/L
Alpha 1 acid glycoprotein...
is a plasma protein
is produced by the kidneys
binds acidic drugs
is present at around 0.4-1.1mg/L
is present at around 3.5-5g/L
is an acute phase protein which elevated in some diseases such as cancer
Albumin is also known as HSA.
Only unbound (free) fraction of drug in the plasma is free to partition into cells.
What distribution parameter is being described below?
A measure of the extent of distribution. A 'dilution factor', representing the relationship between the amount of compound in the body and the plasma concentration. Expressed in units of volume or volume per weight e.g. L/Kg. Many ways to calculate but basically it is equal to: total amount of drug in the body/drug blood plasma concentration.
Volume of Distribution (VD)
Clearance (CL)
F
Volatile gases are eliminated...
by exhalation
in the urine
in faeces
after metabolism forming water soluble metabolites
Water soluble compounds are...
often eliminated unchanged in the urine.
eliminated in the urine or bile after metabolism to make them more water soluble.
always stored in the body.
eliminated by exhalation.
Lipid soluble compounds...
typically undergo metabolism to form water soluble metabolites before elimination.
are eliminated unchanged.
are stored as starch.
are eliminated by a process called first pass metabolism.
The best measure of the ability of eliminating organs to remove a drug from the body is...
Elimination Rate Constant (Ke)
Half-life
Clearance can be defined as...
the volume of plasma (or blood) cleared of the compound in a given time. (e.g. L/hr)
how long it takes for half of the drug to be eliminated.
the process by which the body metabolises a drug.
The elimination rate constant...
is known as Ke.
is the slope of the logged concentration-time graph.
has units of 1/time.
is linked to Ka.
is not relevant in humans.
Half-life is...
the time it takes for the concentration of active drug to reach half its current value.
half the time taken for all of the drug to be eliminated.
Cytochrome P450 enzymes...
are a large superfamily of heme-cofactor containing enzymes.
metabolise thousands of endogenous and exogenous compounds.
are abbreviated to CYPs.
are mostly highly concentrated in the heart and lungs.
are found in the cytoplasm of cells.
CYPs are only found in the endoplasmic reticulum of cells.
The largest concentration of CYPs in the human body is in the liver, in hepatocytes.
In phase 1 drug metabolism...
CYPs add a reactive functional group (e.g. -OH) to the active drug compound.
CYPs cleave active drug compounds to make them unreactive.
CYPs are not involved.
Inhibition of CYPs causes:
reduced metabolism of substrate drug
increased metabolism of substrate drug
increased drug exposure
reduced drug exposure
risk of toxicity
risk of lacking therapeutic effect
Induction of CYPs causes:
increase in biosynthesis of the enzymes (due to increased gene transcription)
increased metabolism of substrate
decreased metabolism of substrate
decreased drug exposure
toxicity risk
risk of lack of therapeutic effects
If phase 1 metabolites are too lipophilic they cannot be retained in kidney tubular fluid. They must be reacted with an endogenous substrate to make them more water soluble. What is the name of this reaction?
Conjugation
Acid/Base
Esterification
Elimination
If phase 1 metabolites are too lipophilic they cannot be retained in kidney tubular fluid. They must be reacted with an endogenous substrate to make them more water soluble. Which of these are examples of those endogenous substrates?
sulphuric acid
amino acids
glucuronic acid
