lecture 1 and 2

Question 1

What is pharmacology?

Answer 1

Study of the changes produced in living animals by chemical substances, especially the actions of drugs, used to treat disease
- or -
A branch of medicine that deals with the interaction of drugs with the systems and processes of living animals, in particular, the mechanisms of drug action as well as the therapeutic and other uses of the drug

Question 2

what does pharmacokinetics deal with?

Answer 2

dose of drug (absorption, distribution, biotransformation, excretion), and the resulting drug concentration in body over time

Question 3

What does pharmacodynamics deal with?

Answer 3

resulting drug concentration in body over time as well as the mechanism and magnitude of drug effect (receptor binding, signal transduction, biological effect)
A drug produces changes in the body – most of them are supposed to be beneficial (drugs are prescribed based on the known mechanism of action)
A drug can also have unwanted effects – expected side effects based on known mechanisms or unexpected effects due to some unknown mechanisms
E.g. tachycardia due to a β1 stimulation produced by a high dose of a β2 selective agonist for asthma is an expected side effect
An allergic reaction produced by drugs in some patients is an unexpected adverse reaction

Question 4

what is a receptor?

Answer 4

A receptor is a macromolecule whose biological function changes when a drug binds to it

Question 5

What is affinity?

Answer 5

Affinity is the measure of propensity of a drug to bind receptor; the force of attraction between drug and receptor

Question 6

What is signal transduction”

Answer 6

Drug-Receptor binding triggers a cascade of events known as signal transduction, through which the target tissue responds

Question 7

What types of bonds occur between drug and receptor?

Answer 7

Types of bonds between drug and receptor (Van der Waals force, ionic, or covalent interactions)
Protein molecules in the lipid bilayer floating around. Most molecules have a charge on the surface leading to dipoles. Most drugs designed now make sure the binding is reversible. So because of this covalent bonding which is irreversible is rare in drugs now.

Question 8

how many bonds are happening between a receptor and it’s ligand

Answer 8

Multiple bonds are involved in the stereospecific interaction between a receptor and its ligand.
TM stands for transmembrane. Purpose of this slide is to show that multiple bonds are formed. Vitamin E, there is a point where it increases oxidative stress and increases toxicity (see next slide (12).

Question 9

What happens with drugs at low doses and high doses?

Answer 9

Drugs produce specific actions at lower doses. They interact stereoselectively with their known receptor only.
Almost all drugs become non-specific in their actions at higher doses and start producing unwanted and toxic effects. Many drugs start interacting with other receptors (especially of the same family) when their concentration is increased.
There is a region of homeostasis.

Question 10

Do drugs combine with their receptor irreversibly in most cases?

Answer 10

Drug molecule – in most cases the binding is transient, i.e. the drug molecule binds and dissociates, binds again and so on.
Each binding triggers a signal
Because of this to decrease toxicity you can give a high concentration agonist to compete for those sites and reduce toxicity.

Question 11

How do we measure or quantify a drug-receptor interaction?:

Answer 11

Dose-response curve.

Generally we have the dose of the drug on the X-axis and the magnitude of the response on the Y-axis

Question 12

What form will most graphs be in?

Answer 12

log-dose scale.

Question 13

What is EC50 and Emax?

Answer 13

EC50 – dose or concentration of a drug that produces 50% of maximal (half maximal) response

Emax – maximal effect produced by a drug. It is a measure of efficacy of a drug

Question 14

What is efficacy or intrinsic activity?

Answer 14

Efficacy (or Intrinsic Activity) – ability of a bound drug to change the receptor in a way that produces an effect; some drugs possess affinity but NOT efficacy

Question 15

What is the potency of a drug?

Answer 15

Relative position of the dose-effect curve along the dose axis
Has little clinical significance for a given therapeutic effect
A more potent of two drugs is not always clinically superior
Low potency is a disadvantage only if the dose is so large that it is awkward to administer
The more potent drug will usually be further left on the graph. (you need less of a dose to get to EC50.

Question 16

What is an agonist?

Answer 16

An agonist is a drug which binds to the receptor and produces an effect.
Thus it has affinity + intrinsic activity

Question 17

What is a partial agonist?

Answer 17

A partial agonist has affinity for a receptor but less intrinsic activity (lower efficacy compared to an agonist acting at the same receptor)

Question 18

What is an antagonist?

Answer 18

An antagonist is a drug which binds (thus competes for binding against other ligands), but does not activate the receptor
It has affinity but no intrinsic activity

An antagonist can be
Competitive (reversible)
Noncompetitive (irreversible)

sometimes our bodies secrete too much hormones and so if there is an antagonist then it can help lower this.

Question 19

What’s the difference between an agonist and partial agonist acting at the same receptor

Answer 19

The partial agonist has less efficacy and a lower Emax compared to an agonist acting at the same receptor. So the dose needed for the agonist to reach EC50, the partial agonist at the same dose will be at less than EC50.

Question 20

What happens when a partial agonist is given alone?How does it act like an antagonist?

Answer 20

A partial agonist produces less than full effect when given alone
A partial agonist acts as an antagonist in the presence of a full agonist (blocks the full effect of an agonist)
Therapeutic use of a partial agonist
e.g. buprenorphine, an opioid analgesic
has a lower abuse potential
lower level of physical dependence
and greater safety in overdose compared with a full agonist such as morphine.
Antagonist properties of a partial agonist can be useful:
They provide some agonist activity and at the same time block the endogenous full agonists
Clinical example: pindolol for high blood pressure and abnormal heart rhythms
It will reduce the excessive stimulation due to norepinephrine in a person with high sympathetic nervous system activity
Pinodol a partial agonist at B-receptors, will decrease the tachycardia caused by norepinephrine (because it is a partial agnoist acting like an antagonist).

Question 21

What is an inverse agonist?

Answer 21

Some receptors have intrinsic (constitutive) activity even when no ligand is bound to them
When a ligand binds to them, their basal activity is reduced. Such agonists are called inverse agonists.
Thus, they are like competitive antagonists with a major difference that on their own they reduce receptor activity whereas competitive antagonists have no effect on their own.
Examples of receptors with basal activity: benzodiazepine, histamine, opioids, dopamine
Examples of inverse agonist drugs: famotidine, risperidone
Famotidine for example acts on H2 secretors in the stomach which has a base level of activity, but when these drugs bind, they decrease that activity.

Question 22

What is competitive antagonism?

Answer 22

When the agonist is alone, a lower dose can produce maximal effect. In the presence of a competitive antagonist a higher dose of agonist is required to produce the same effect
e.g. acetylcholine – agonist
atropine – competitive antagonist
at muscarinic receptors
An agonist can still produce maximal effect but higher doses are required in the presence of a competitive antagonist

Question 23

What is non-competitive antagonism?

Answer 23

When the agonist is alone, a lower dose can produce maximal effect
In the presence of a non-competitive antagonist even a higher dose of agonist cannot produce maximal effect
e.g. noradrenaline- agonist
phenoxybenzamine – non-competitive antagonist
at α receptors
This is usually covalent bonding with the non-competitive antagonism.
An agonist cannot produce maximal effect – Emax is depressed, in the presence of a non-competitive antagonist

Question 24

What is allosteric interaction? And what is inhibition and potentiation?

Answer 24

Allosteric interaction: the binding sites for the agonist and antagonist are different on the receptor. The interaction can produce inhibition or potentiation of the agonist response.
E.g. receptor for benzodiazepines and GABA

Question 25

What is a quantal dose response curve? What are the two ways to represent this?

Answer 25

Quantal dose response curve – indicates sensitivity of a given population to the doses of a drug for a given effect
Different doses of a drug are given to a group of people and a defined response is noted – e.g. induction of sleep
Frequency distribution
Each bar shows the number of people responding to that dose – at 100 mg 21 people respond, excludes people responding to lower doses
Cumulative frequency – each bar shows the number of people responding to that dose and to lower doses – at 200 mg all 100 people respond

Question 26

What is the therapeutic index?

Answer 26

Therapeutic index
= TD 50 / ED50
= 350 / 150 = 2.3
ED50 Effective dose working in half the population
TD50 Toxic effect or concentration used to induce toxic effect in 50% of the population.

Question 27

What is LD50?

Answer 27

lethal dose in 50% of people. supposedly the therapeutic index = TD50 or LD50/ED50. The higher the ratio, the safer the drug.

Question 28

What is the therapeutic window?

Answer 28

Therapeutic Window reflects a plasma concentration range that provides efficacy without unacceptable toxicity.
Therapeutic window is the difference between the minimum effective concentrations for a desired response and an adverse response
Anti cancer drug has a TI of 1 because they’re effective and toxic.

Question 29

What is a dose-cncentration response curve and a quantal dose-response curve?

Answer 29

A dose-(concentration)-response curve shows graded responses in a single individual, produced by increasing concentrations of a given drug
A quantal dose-response curve shows a specific response (quantal – all or none, either present or absent) in a group of individuals (population) produced by a drug (shows sensitivity of the population to a drug for a given effect – so different doses may be required for the same response in different individuals)

Question 30

What is signal transduction?

Answer 30

Drug – receptor interaction
- produces a response
The events involved in this response are known as signal transduction

Common responses in the body

• Transient increase in intracellular free calcium levels - Muscle contraction
• Activation of enzymes for various biochemical reactions
• Neurotransmission
• Secretion of neurotransmitters and hormones

Question 31

What are the 4 fundamental mechanisms or types of signal transduction mechanisms?

Answer 31

4 fundamental mechanisms or types
1. G-protein coupled receptor systems
(GPCRs, metabotropic receptors)
Half of all known drugs work through GPCRs
2. Ion-channel receptors
(Ionotropic receptors)
Ion-channel receptors - Has a central channel in it that allows ions to travel in and out. Fastest acting signal transduction.

3. Enzymes as receptors – tyrosine kinase, 					serine/threonine kinase
4. Nuclear receptors

Question 32

What’s the resting (or inactive) state like in the G-protein coupled receptor systems? what about the activated system?

Answer 32

Inactive receptor (G protein coupled receptor) has the inactive G-protein bound to GDP and there is for example an inactive adenylyl cyclse. 
In the agonist binding, the activated receptor GPCR is bound to GTP and it becomes GDP as it phosphorylates the activated enzyme adenylyl cyclase.

Question 33

What are three major second messengers activated by GPCRs?

Answer 33

Three major second messengers activated by GPCRs:
cAMP (cyclic adenosine monophosphate)
IP3 (inositol trisphosphate) to increase calcium
DAG (diacyl glycerol) leads to protein and kinase C. Adenylyl cyclase converts ATP to cAMP which then leads to protein kinase A.

Question 34

What are enzyme receptors?

Answer 34

The receptor consists of a pair of protein molecules (monomers) that are separate when inactive.
An agonist causes them to interact and form a dimer.
The interaction phosphorylates tyrosines in the intracellular region of the receptor and the receptor becomes an active enzyme.
The active receptor enzyme then activates a number of other enzymes that interact with the active tyrosine of the receptor.
e.g. insulin receptor, growth factor receptors

Question 35

What are ion channel receptors?

Answer 35

The receptor is a protein with a channel in the centre.
An agonist causes the channel to open and allows specific ions to cross the cell membrane to the other side.
e.g. Nicotinic acetylcholine receptor – conducts Na+ ions – causes muscle depolarization and contraction (Fig. B)
Gamma aminobutyric acid (GABA) receptor – conducts Cl- ions – inhibits neurotransmission

Question 36

What is a nuclear receptor?

Answer 36

These receptors are in the cell cytosol.
An agonist enters the cell and binds to the receptor.
The drug-receptor complex then enters the nucleus and stimulates gene transcription.
This leads to synthesis of new proteins and enzymes.
This kind of signal transduction extends over hours to days.
e.g. receptors for steroids, retinoids and thyroid hormones

Question 37

What is down-regulation of receptors? When is desensitization homologous or heterologous?

Answer 37

Agonists tend to desensitize receptors – e.g. Very commonly, frequent stimulation of a receptor by its agonist results in a decreased response - desensitization of receptors. Several mechanisms have been proposed: e.g. Decreased receptor number (downregulation) or decreased signal transduction
The desensitization is homologous when only a given receptor is desensitized
The desensitization is heterologous when desensitization of one receptor by an agonist also causes desensitization of another receptor (e.g. when the signal transduction pathways of two receptors cross each other)

Question 38

What is up-regulation?

Answer 38

Antagonists tend to up regulate receptors – e.g. treatment with a β-receptor antagonist causes a withdrawal rebound effect when the antagonist treatment is stopped suddenly. This is because the receptor number has increased and when the antagonist is suddenly removed from the receptor, there are more receptors available for the agonist resulting in a rebound response.
It is important to gradually decrease the dose of any antagonist to prevent such a rebound
Prolonged treatment with an agonist drug can desensitize the receptor. Pinodol a partial agonist at B-receptors, will decrease the tachycardia caused by norepinephrine (because it is a partial agnoist acting like an antagonist). Suddenly stopping prolonged treatment with an antagonist drug can produce a withdrawl (rebound) response due to receptor upregulation. The lower the dissociation constant the more affinity the drug has for its receptor.

Question 39

What is drug absorption?

Answer 39

Drug absorption refers to the passage of drug from the site of administration into the general circulation (except for drugs that are applied directly to the target tissue)

A drug that is injected intravenously is considered to be immediately and completely (100%) absorbed

Absorption of orally administered drugs is incomplete for most drugs. At the same time it can vary for a given drug in a given patient. If changes are observed in the therapeutic effect of a drug used over a long-term, one should think about changes in factors affecting oral absorption or bioavailability of the drug.

Question 40

Generally speaking what makes drugs better absorbed or poorly absorbed?

Answer 40

Better absorbed

• non-ionized
• small molecules
• lipid-soluble drugs

Poorly absorbed or not absorbed

• ionized
• large molecules

Lipid soluble drugs can go through a cell membrane. They can distribute to almost all the compartments of the body. They can cross the blood:brain barrier, the placental barrier and the skin. Therefore they can be applied as skin patches, but at the same time they can cause CNS or fetal toxicity.

Question 41

What are examples of drugs that are poorly absorbed?

Answer 41

They are destroyed by stomach acid or digestive enzymes (e.g Penicillin G, insulin)
Chelated to components of food to form insoluble complexes (e.g. tetracyclines)
So polar they won’t cross cell membranes (e.g aminoglycoside antibiotics) – streptomycin, gentamycin
Undergo extensive metabolism (e.g. nitroglycerin, adrenaline, dopamine)

Insulin is a peptide. All peptide drugs have the limitation that they cannot be given orally. The biggest challenge to treat type I diabetes is the development of an orally effective form of insulin. Drugs which get chelated to food components should be taken by the patient at least 2 hours before or after a meal. The aminoglycoside antibiotics are very effective to treat some serious infections, but they have to be injected because they are not absorbed orally. For drugs which undergo extensive first-pass metabolism, one solution is to give a very large dose so that the small fraction which is absorbed is therapeutic.

This is why you sometimes have to tell patients to not eat before treatment or before some medicines. Because it can chelate to the food.
The GI tract epithelium and the liver will metabolize nitroglycerin, adrenalin, and dopamine, if they are taken orally.

Question 42

What shows the ionization or the effect of pH on drug absorption? What is the pKa of a drug?

Answer 42

The pKa of a drug is defined as the pH at which half of the drug is ionized
Most drugs are either weak acids or weak bases
The Henderson-Hasselbach equation can be used to calculate the ratio of nonionized/ionized molecules:
log[protonated form]/[unprotonated form] = pKa - pH

Most drugs used clinically are either weak acids or weak bases. Therefore, when we put them in an aqeous phase they will become ionized. The pH of the solution will then determine how much of the drug becomes ionized and how much remains non-ionized. It is the non-ionized fraction which can cross cell membranes easily. This does not mean that the ionized fraction cannot go across a barrier at all. While the ionized molecule will not cross through a cell membrane it can still go through large gaps or channels between cells. Remember that in the capillaries of certain organs like the liver and the kidney glomerulus, there are large gaps between endothelial cells and thus almost all drugs will enter the liver or the kidney tubule from the circulation, even if they are ionized.

Question 43

What is the rule for acidic drugs being ionized in acidic medium? and for bases?

Answer 43

when a patient swallows aspirin for example, there are already a lot of hydrogen atoms ad so it will not be as ionized because it will shift back to the HA side of the HA H + A equation. Because the ionized side is H+ and A-

So acidic drugs become more ionized in a basic medium and less ionized in an acidic medium.

Basic drugs become more ionized in an acidic medium and less ionized in a basic medium.

B + H HB and so if you put this weak base into an acidic solution with lots of hydrogen in it it will want to shift to the ionized side. Because it’s actually BH+