Principles Of Pharmacology

Question 1

What is the difference between Parmacodynamics and pharmacokinetics?

Answer 1

Pharmacodynamics:
What the drug does to the body, what it’s effect is and how this is brought about.

Pharmacokinetics:
What the body does to the drug, how does the body get the benefits out of the drug

Question 2

What are the main questions to consider when looking at how a drug exerts it’s effect on the body?

Answer 2

Where is the effect produced (eg. Brain)

What is the target (eg. Receptor of a certain type)

What is the response produced after interaction between drug and target

Question 3

What are the possible types of drug targets?

Answer 3

Transport proteins
Ion channels
Receptors
Enzymes

The vast majority of drug targets are proteins

Question 4

What is selectivity?

Answer 4

Aka specificity

For a drug to be effective it must show a high degree of selectivity for its particular target

The fewer targets the drug binds to, the fewer the side effects. However many olecukes are structurally similar so this is hard to achieve

Question 5

What is dose?

Answer 5

The amount a drug given

Depends on selectivity, if a drug is 50x more selective for target A than target B and you figure out the dose required to effect target A. Then increasing the dose 50x will show an effect on target B too

As you increase dose, the drug will start acting in targets it has less specificity for. This will produce side effects

Question 6

How do drug-receptor interactions work?

Answer 6

Drugs interact with receptors through a variety of chemical interactions:

Electrostatic interactions - most common. Includes hydrogen and vdw forces

Hydrophobic interactions - important for lipid soluble drugs

Covenant bonds - least common as the interactions tend to be reversible

Stereo specific interactions - many drugs exist as stereoisomers

Drug interactions are always transient

They work in dynamic equilibrium. And bind reversibly

If you increase drug concentration, equilibrium shifts to the right and there are more complexes formed as more receptors are occupied

If you then drastically reduced the concentration of the drug, equilibrium shifts to the left and more receptors become available again

Question 7

What are agonists and antagonists?

Answer 7

Agonists - bind and activate receptors

Antagonists - bind and block the receptor

Question 8

What is meant by affinity with regards to drugs?

Answer 8

A property of agonists

The strength of binding of the drug to the receptor

The higher the affinity the stronger the drug-receptor complex. Therefore drug affinity is strongly liked to receptor occupancy

Drugs with a higher affinity are more likely to bind

Question 9

What is efficacy with relation to drugs?

Answer 9

A property of agonists

The ability of an individual drug molecule to produce an effect once bound to a receptor

When a drug binds to a receptor it doesn’t necessarily always bring about a response. There may be no response or a partial response instead

Question 10

What are the three classes of drug interaction based on efficacy?

Answer 10

Antagonist (kinda like an agonist with no efficacy)

Partial agonist

Full agonist

Question 11

What is potency?

Answer 11

The concentration or dose of a drug required to produce a defined effect

The standard measure of potency is the concentration/dose of a drug required to produce a 50% tissue response

Units: EC50 or ED50 (half maximal effective concentration/dose)

Half effective Concentration is worked out by applying different concentrations to in vitro tissue

Half effective Dose is worked out by changing the dose of a medication until 50% of people in a trial experience the desired effects

Question 12

What is the difference between efficacy and potency?

Answer 12

A highly potent drug produces a large response at relatively low doses

A highly efficacious drug can produce a maximal response and this effect is not particularly related to drug concentration

Partial agonists are less efficacious that full agonists. They cannot produce a miximal response

Efficacy is more important

Question 13

What are the 4 major pharmacokinetic factors?

Answer 13

Absorption

Distribution

Metabolism

Excretion

“What the body does to the drug”

Question 14

What is absorption with regards to pharmacokinetics?

Answer 14

The passage of a drug from the site of administration to the plasma

Question 15

What is bioavailability?

Answer 15

The fraction of the initial dose that gains access to the systemic circulation

Site of administration is a huge determinant of this

Ie. IV drugs are injected straight into the circulation so have 100% bioavailability

Question 16

What are some forms of drug administration?

Answer 16

Oral

Inhalation

Dermal

IV

Intra nasal

Many more

Question 17

What are the methods by which a drug can and cannot diffuse across plasma membranes? (4)

Answer 17

CAN

Simple diffusion:
Must be lipid soluble

Carrier mediated transport:
Involves a transmembrane protein which can bind molecules on one Side and transport them to the other side. In most cases this is down the concentration gradient. Sometimes active transport

CANT

Pinocytosis:
Cell membrane forms a vesicle and transports the drug across. Rarely used. Apart from insulin in the brain eg

Diffusion across aqueous pores:
Through gaps between the epithelial/endothelial cells making up the membrane. Most pores are smaller than 0.5nm in diameter and most drug molecules are bigger than this one

Question 18

Are drugs usually more lipid or water soluble?

Answer 18

Water, because many are taken orally so must be able to be dissolved in the aqueous environment of the digestional tract

Question 19

What does it mean that most drugs are either weak acids or weak bases?

Answer 19

Weak acids reversibly donate protons

Weak bases reversibly accept protons

Drugs that are either of these therefore exist in two forms.

The unionised form (no H*) of either acids or bases is more lipid soluble. So more likely to diffuse across plasma membranes

Whether the drug is ionised or not depends on:
pKa - dissociation constant
pH - of the tissue

Question 20

How do pKa and pH determine whether a drug is ionised or unionised?

Answer 20

If pKa and pH are equal:
There will be equal concentration of both forms. 50% ionised and 50% un

For weak acids (pKa ~3-5):
As pH decreases, the unionised form starts to dominate. At higher pH the ionised form dominates

For weak bases (pKa ~8-10):
pH decreases, ionised form dominates. pH increases, unionised form dominates

(They do their jobs (acids:donor so unionised) (bases:acceptor so ionised) at the opposite end of the pH scale).

So. Acids unionised at lower pH. Alkali unionised at higher pH

But most drugs eventually reach transport proteins so don’t become stuck in their respective pHs

Question 21

What are the main important carrier systems for drugs?

Answer 21

GI tract - absorption into the blood stream

Blood brain barrier - access to certain tissues

Biliary tract, renal tubule - excretion

Question 22

What factors effect the distribution of drugs into different tissues?

Answer 22

Regional blood flow

Plasma protein binding

Capillary permeability

Tissue localisation

Question 23

How does blood flow effect drug distribution?

Answer 23

The higher the blood flow the more of the drug will be delivered to that tissue

Remember that blood distribution can change ie. after a meal or during exercise

Some percentages:

Liver 27
Heart 4
Brain 14
Kidneys 22
Muscles 20

Question 24

How does plasma protein binding affect drug distribution?

Answer 24

Many drugs, especially acidic, bind to albumin. (Each albumin has two binding sites. Most drugs have a clinical effect at concentrations MUCH lower than albumin can hold. This means that the plasma proteins are never concentrated. Therefore plasma protein binding depends largely on the drugs affinity for those protein binding sites)

The amount a drug binds depends on:

• the free drug concentration
• the affinity for the protein binding sites
• the plasma protein concentration

DRUGS CANNOT LEAVE THE BLOOD WHILE THEY ARE STILL BOUND. They must dissociate

Question 25

How does capillary permeability effect drug distribution?

Answer 25

Lipid soluble drugs are able to diffuse across plasma membranes. As some do through continuous capillaries Drugs that are less lipid soluble have to be transported via carrier proteins The blood brain barrier is the most difficult tissue in the body for drugs to gain access to due to its tight junctions between endothelial cells Discontinuous capillaries (such as in the liver) allow drugs to easily diffuse out of the blood stream Fenestrated capillaries (such as in the kidneys) allow smaller drugs to leave the blood and enter the kidney tubules, aiding in their excretion

Question 26

What are the types of capillary structure?

Answer 26

Continuous: H2O filled gap junctions Eg. Nervous tissue Blood brain barrier: Tight junctions Fenestrated: Windows Eg glomeruli Discontinuous: Gaps Eg. Bone marrow, liver

Question 27

How does tissue localisation effect drug distribution?

Answer 27

Depending on how lipid or water soluble a substance is it will diffuse across the blood brain barrier at different rates. This places the equilibrium at different points depending on water or lipid solubility The brain has a higher fat content than water so lipid soluble drugs would be retained in the brain more than water soluble ones So lipid soluble drugs are better localised in the brain

Question 28

What is the main principle of drug metabolism?

Answer 28

Drugs are all at least a bit lipid soluble. However it would be easier to excrete drugs if they were water soluble as they would remain in the blood So drugs are converted to metabolites that are as water soluble as possible. Therefore easier to excrete The liver is the major metabolic tissue It is mainly cytochrome P450 enzymes that carry out this role

Question 29

What are the two main phases of drug metabolism?

Answer 29

Carried out by cytochrome P450 enzysmes in the liver PHASE 1 - introduce a reactive group to the drug PHASE 2 - add a conjugate to the reactive group These both decrease lipid solubility which aids excretion and elimination

Question 30

What happens during phase 1 of drug metabolism?

Answer 30

INTRODUCING A REACTIVe POLAR GROUP This occurs by oxidation. Or by hydrolysis and reduction. This depends on what type of molecule it is Most undergo oxidation All oxidation reactions start with a hydroxylation step using the cytochrome P450 system The aim is to incorporate oxygen into non-activated hydrocarbon *the whole point is to produce metabolites with functional groups that act as a point of attack for the conjugating systems of phase 2* Sometimes drugs will have no activity until they have undergone phase 1 of metabolism. These are pri-drugs.

Question 31

What happens during phase 2 of metabolism?

Answer 31

ATTACHMENT OF A SUBSTITUENT GROUP. The resulting metabolite is nearly always inactive and far less lipid soluble than the phase 1 metabolite This facilitates excretion in urine or bile ``` Example conjugated include: Glutathione Glucuronidation Acetylation Sulfation ``` Phase 2 enzymes are predominantly transferases

Question 32

What is first pass (presystemic) metabolism?

Answer 32

Orally administered drugs are predominantly absorbed from the small intestine and enter the hepatic portal blood supply. So they pass through the liver befor they have entered systemic circulation It can be heavily metabolised here, so little active drug will reach systemic circulation Solution- administer a larger dose Problem - the extent of first pass metabolism varies between individuals. This makes side effects difficult to predict as dose that will reach systemic circulation is hard to predict *pro-drugs have to undergo first pass metabolism to gain their active form*

Question 33

What are some examples of how drugs are excreted?

Answer 33

Lungs - exhalation Breast milk Kidney - urine Liver - bile

Question 34

What are the major routes of excretion through the kidneys?

Answer 34

1. Glomerular filtration : Low molecular weight drugs ``` 2. Active tubular secretion: Dependant of transporters Basic/acidic drugs Proximal convoluted tubule Most important method in kidney ``` 3. Passive diffusion (reabsorbtion) across tubular epithelium: Depends on urine pH and extent of drug metabolism Distal convoluted tubule/collecting duct Different drugs use these methods in different amounts It is also impacted by the rate of metabolism (more water soluble are easier to excrete)

Question 35

How does glomerular filtration excretion work?

Answer 35

Drug molecules of weight less that 20,000 diffuse into the glomerular filtrate. This is an extra method for small drugs So they are excreted faster

Question 36

How does active tubular secretion work?

Answer 36

Most important method in kidney Only 20% of plasma is filtered at the glomerulus. The remaining 80% is passed onto the blood supply of the PCT. so more blood is delivered to the PCT than glomerulus The endothelial cells also have two active transport carrier systems. Once for acidic drugs, the other for basic drugs. Both are good at transporting drugs against the Comcentration gradient

Question 37

How does the passive diffusion method of excretion work?

Answer 37

Passive diffusion generally leads to reabsorption from the kidney tubule 99% of filtered water is reabsorbed Particularly lipid soluble drugs are reabsorbed back into blood Rate of reabsorption is affected by two factors: 1. Drug metabolism - phase 2 metabolites are much more water soluble so much less well reabsorbed 2. Urine pH - varies from 4.5-8. Acidic drugs are better reabsorbed at acidic pH, and basic drugs are better absorbed at higher pH Ie If an acidic drug is passing through high pH urine. It will be more ionised, so less lipid soluble and less likely to be reabsorbed. The the effects of the drugs will last less time as it is peed out

Question 38

How does biliary excretion of drugs work?

Answer 38

Liver cells transport some drugs from plasma to bile via transporters. Particularly effective in removing phase 2 glucoronide metabolites The drugs in bile are then excreted into the intestines and will be excreted in faeces However enterohepatic recycling can occur, prolonging the effects of the drugs

Question 39

How does enterohepatic recycling work?

Answer 39

For example: 1. A glucuronide metabolite is transported into the bile 2. The metabolite is excreted into the small intestine, where it is hydrolysed by gut bacteria. Releasing the glucuronide conjugate 3. This increases the lipid solubility of the molecule 4. This allows for greater reabsorbtion from the small intestine back into the hepatic portal system and returned to the liver 5. The molecule returns to the liver where a portion will be remetabolised, but a portion may escape into systemic circulation and continue to have effects on the body