Principles Of Pharmacology Flashcards
What is the difference between Parmacodynamics and pharmacokinetics?
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
What are the main questions to consider when looking at how a drug exerts it’s effect on the body?
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
What are the possible types of drug targets?
Transport proteins
Ion channels
Receptors
Enzymes
The vast majority of drug targets are proteins
What is selectivity?
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
What is dose?
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
How do drug-receptor interactions work?
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
What are agonists and antagonists?
Agonists - bind and activate receptors
Antagonists - bind and block the receptor
What is meant by affinity with regards to drugs?
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
What is efficacy with relation to drugs?
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
What are the three classes of drug interaction based on efficacy?
Antagonist (kinda like an agonist with no efficacy)
Partial agonist
Full agonist
What is potency?
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
What is the difference between efficacy and potency?
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
What are the 4 major pharmacokinetic factors?
Absorption
Distribution
Metabolism
Excretion
“What the body does to the drug”
What is absorption with regards to pharmacokinetics?
The passage of a drug from the site of administration to the plasma
What is bioavailability?
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
What are some forms of drug administration?
Oral
Inhalation
Dermal
IV
Intra nasal
Many more
What are the methods by which a drug can and cannot diffuse across plasma membranes? (4)
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
Are drugs usually more lipid or water soluble?
Water, because many are taken orally so must be able to be dissolved in the aqueous environment of the digestional tract
What does it mean that most drugs are either weak acids or weak bases?
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
How do pKa and pH determine whether a drug is ionised or unionised?
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
What are the main important carrier systems for drugs?
GI tract - absorption into the blood stream
Blood brain barrier - access to certain tissues
Biliary tract, renal tubule - excretion
What factors effect the distribution of drugs into different tissues?
Regional blood flow
Plasma protein binding
Capillary permeability
Tissue localisation
How does blood flow effect drug distribution?
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
How does plasma protein binding affect drug distribution?
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
How does capillary permeability effect drug distribution?
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
What are the types of capillary structure?
Continuous:
H2O filled gap junctions
Eg. Nervous tissue
Blood brain barrier:
Tight junctions
Fenestrated:
Windows
Eg glomeruli
Discontinuous:
Gaps
Eg. Bone marrow, liver
How does tissue localisation effect drug distribution?
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
What is the main principle of drug metabolism?
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
What are the two main phases of drug metabolism?
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
What happens during phase 1 of drug metabolism?
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.
What happens during phase 2 of metabolism?
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
What is first pass (presystemic) metabolism?
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
What are some examples of how drugs are excreted?
Lungs - exhalation
Breast milk
Kidney - urine
Liver - bile
What are the major routes of excretion through the kidneys?
- Glomerular filtration :
Low molecular weight drugs
2. Active tubular secretion: Dependant of transporters Basic/acidic drugs Proximal convoluted tubule Most important method in kidney
- 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)
How does glomerular filtration excretion work?
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
How does active tubular secretion work?
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
How does the passive diffusion method of excretion work?
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:
- Drug metabolism - phase 2 metabolites are much more water soluble so much less well reabsorbed
- 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
How does biliary excretion of drugs work?
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
How does enterohepatic recycling work?
For example:
- A glucuronide metabolite is transported into the bile
- The metabolite is excreted into the small intestine, where it is hydrolysed by gut bacteria. Releasing the glucuronide conjugate
- This increases the lipid solubility of the molecule
- This allows for greater reabsorbtion from the small intestine back into the hepatic portal system and returned to the liver
- 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
