Intro to Pharmacology Flashcards
What is the difference between Pharmacology and Therapeutics?
Pharmacology = drug action Therapeutics = drug prescribing and treatment (patient-focused)
What is the difference between pharmacodynamics and pharmacokinetics?
Pharmacodynamics = what the drug does to the body Pharmacokinetics = what the body does to the drug
What 3 questions can be asked about a drug to understand its pharmacodynamics?
e.g. what would you comment on the pharmacodynamics of cocaine?
Where is this effect produced?
What is the target for the drug?
What is the response that is produced after interaction with this target?
Cocaine: effect = euphoria; target = dopamine reuptake protein on the pre-synaptic terminal; response = blocks dopamine reuptake
Drug target sites tend to be proteins.
What are the 4 main drug target sites in the body? Give an example of a drug for each type of target site:
Receptors - nicotine
Enzymes - aspirin
Ion channels - local anaesthetis
Transport proteins - prozac (anti-depressant)
What is selectivity?
Why do drugs require high levels of selectivity?
Why is it hard to achieve complete selectivity for drugs?
The degree to which a drug acts on a given site relative to other sites
To reduce the number of side effects
A lot of drugs and chemicals are structurally quite similar
How does the selectivity of a drug affect the dosage given? e.g. if a drug is 50 times more selective for target A than target B?
A specific dosage of a drug will begin to show effects at its primary target site e.g. target A. If the drug is 50x more selective for target site A than B, then 50x that dosage will be required to start seeing effects at target B
So why is it important to keep drug dosages as low as possible but still treating the issue?
At a low dose, the effect you see is more specific, due to the fact that the drug will only interact with one target. As the dose increases, the effect becomes less specific, because the drug starts to interact with other drug targets producing other unwanted effects
Pergolide is a drug used to treat Parkinson’s.
What receptor does it primarily act on and what other receptors can it affect at higher doses?
Dopamine receptors primarily
Can also bind to serotonin receptors and adrenergic receptors
What are the 4 different chemical interactions drugs can use to interact with target sites?
(HINT: think chemistry - bonding)
- Electrostatic interactions - most common, includes hydrogen bonds and Van der Waals forces.
- Hydrophobic interactions -lipid soluble drugs
- Covalent bonds - least common, interactions tend to be irreversible
- Stereospecific interactions - many drugs exist as stereoisomers and interact stereospecifically with receptors
What is the equilibrium formed by drugs, receptors, and drug-receptor complexes?
How does an increase or decrease in drug affect this equilibrium?
Drugs + receptors –> drug-receptor complex
Increase in drugs shifts equilibrium to the right as more complexes are formed
Decrease in drugs shifts equilibrium to the left as more receptors are remain unoccupied
What is the difference between agonists and antagonists?
Both fit the target site
Agonists = activate the target site
Antagonists = occupy the target site, so the true molecule cannot bind to the target site to activate it
What is meant by the affinity of a drug?
Strength of binding of the drug to the receptor
Higher affinity = stronger bond
What is meant by the efficacy of a drug?
Ability of an individual drug molecule to produce an effect once bound to a receptor
Higher efficacy = more complete response
So how does efficacy of drugs relate to antagonist / agonist effects?
No response from drug binding to target site = antagonist
Partial response from drug binding to target site = partial agonist
Complete response from drug binding to target site = complete agonist
What is meant by the potency of a drug?
So what is the standard measure of potency?
The concentration or dose of a drug required to produce a defined effect - higher potency = lower dosage required
Standard measure of potency is to determine the concentration (EC50) or dose (ED50) of a drug required to produce a 50% tissue response
What is the difference between EC50 and ED50?
The concentration that produced a 50% response would be the EC50
When responses are vague e.g. reduction in breathlessness, the dose of drug that produced the desired effect in 50% of the individuals tested
Why is only potency linked to dosage, but not efficacy?
Efficacy is to do with the response from the drug, so a more potent drug will require a smaller dosage for maximal response compared to a less potent drug. But both drugs still give a maximal response, just at different dosages
What are the 4 major pharmacokenetic factors affect the amount of drug reaching the tissues?
- Absorption
- Distribution
- Metabolism
- Excretion
What is meant by absorption in pharmacokenetics?
What is meant by bioavailability?
How are absorption and bioavailability different?
The passage of a drug from the site of administration into the plasma
The fraction of the initial dose that gains access to the systemic circulation
Absorption = process of drug getting into the system VS Bioavailability = how much drug gets into the system
What are some common forms of drug administration?
- Oral
- Inhalational
- Dermal (Percutaneous)
- Intra-nasal
What are the 2 main ways drugs can move around the body?
- Bulk flow transfer (i.e. in the bloodstream)
2. Diffusional transfer (i.e. molecule by molecule across short distances)
Other than intravenous administration, why do other forms of drug administrations not have 100% bioavailability?
With all other forms of administration, in order for the drug to reach the bloodstream it is first going to need to diffuse across at least one lipid membrane
What are the 4 ways chemicals can diffuse across plasma membranes?
Which of these 2 ways are used by drugs and why not the other 2?
- Pinocytosis - cell membrane envelopes drug into vesicle then releases the drug on other side of the membrane
- Diffusion across aqueous pores - gaps between endo/epi-thelial cells
- Diffusion across lipid membranes
- Carrier mediated transport - drugs binds to transmembrane protein, which then transfers them across to the other side of the membrane
3 and 4 are most common, 1 is rarely used by drugs, and 2 is also rarely used by drugs as the gaps between the cells are so small
Most drugs tend to be more water soluble than lipid soluble.
How can a drug exist in both forms - a water soluble and lipid soluble version?
The drug can exist as an ionised and unionised form. e.g. unionised = OH, NH3 | ionised = O-/H+, NH4+ depending on if they are a weak acid or base
How does pKa and pH affect whether the drug is in its ionised or unionised form?
pKa = dissociation constant pH = [H+]
- pKa of drug = pH of tissue, then the drug will be equally dissociated between the two forms
- Aspirin = weak acid = pKa of 3.5. For weak acids, as the pH decreases, the unionised form starts to dominate. As the pH increases, the ionised form starts to dominate.
- Morphine = weak base = pKa of 8.0. For weak bases, as the pH decreases, the ionised form starts to dominate. As the pH increases, the unionised form starts to dominate.
Why is it not an issue if weak basic drugs get trapped in the stomach, and weak acidic drugs get trapped in the blood?
Weak basic drug in stomach will pass through the stomach and get absorbed in the small intestine via transport proteins
Weak acidic drug in the blood will circulate the body until it meets transport proteins on tissues that allows it to get across the membrane
What are the 4 most important carrier systems relating to drug action?
What is the purpose of these carrier systems?
- Renal tubule
- Biliary tract
- Blood brain barrier
- Gastrointestinal tract
Carrier systems = drug access to the bloodstream, drug access to certain tissues, and excretion of drugs from the body
What factors influence different tissues to have different amounts of exposure to the drug?
- Regional blood flow: different tissues receive different percentages of the cardiac output - Liver = 27%, Heart = 4%, Brain = 14%, Kidneys = 22%, Muscles = 20%
- Plasma protein binding - drugs binding to proteins such as albumin
- Capillary permeability - different capillaries have different spaces between the endothelial cells
- Tissue localisation - whether they are more lipid based or water based as that affects equilibrium achieved when drugs diffuse in
What can regional blood flow be affected by?
Exercise - more blood flow to muscles
Ingestion / digestion - more blood flow to digestive system
What 3 factors is the amount of drug bound to plasma proteins dependent on?
How do the 3 factors link together?
The free drug concentration
The affinity for the protein binding sites
The plasma protein concentration
D (Free Drug) + P (Protein binding site) ↔ DP (Drug-protein binding site)
Can drugs bound to plasma proteins diffuse into tissues?
Are acidic or basic drugs more likely to bind to albumin?
No - drug must dissociate from protein first
Acidic
What are the 4 different types of capillary structures? Where are they found?
- Continuous - H2O filled junctions, most common
- Blood brain barrier - tight junctions, brain, highly controlled what can access brain tissue
- Fenestrated - allow passage of small molecular weight substances, found in the glomerulus (kidney)
- Discontinuous - found in the liver, random big gaps between capillary endothelial cells for metabolism
How can drugs be localised to certain tissues / areas?
If a drug is lipid based, it is more likely to be retained in lipid based tissue than water based tissue and vice versa
Lipid soluble drugs diffuse according to lipid gradient - and that affects equilibrium
Water soluble drugs diffuse according to water gradient - and that affects equilibrium
How are drugs metabolised in the liver to aid elimination and excretion of the drug? What are the 2 steps?
Phase 1: introduce a reactive group to the drug
Phase 2: add a conjugate to the reactive group
Both stages together act to decrease lipid solubility which then aids excretion and elimination
What does phase 1 metabolism in the liver do?
What is the most common method in phase 1 metabolism?
Introduce reactive polar groups into their substrates via oxidation, reduction and hydrolysis
Oxidation reactions = starts with a hydroxylation step utilising enzymes from cytochrome P450 family. The aim is to incorporate oxygen into non-activated hydrocarbons
What are pro-drugs?
Drugs that are given in an inactive form, then produce an effect once it has been metabolized to the respective metabolite
Usually occurs in Phase 1
e.g. liver damage from paracetamol overdose is from a metabolite, not paracetamol itself
What does phase 2 metabolism in the liver do?
The attachment of a substituent group so metabolite is nearly inactive and less lipid soluble than the phase 1 metabolite = facilitates excretion in the urine or bile
Enzymes = predominantly transferases
What is meant by first pass metabolism?
What is the problem with first pass metabolism?
What is the solution? What is the problem with the solution?
Usually for orally administered drugs - absorbed from the small intestine and enter hepatic portal blood supply where they first pass through the liver before they reach the systemic circulation.
Problem - the drug by then is heavily metabolized so little active drug reaches systemic circulation
Solution - administer a larger dose
Problem with solution - the extent of first pass metabolism varies amongst individuals, side effects hard to predict
What are the different routes via which drugs can be excreted?
The 2 most common are via the kidneys (in the urine) or via the liver (in bile)
Or else, via the lungs (e.g. alcohol breath test) or breast milk
What are the 3 major routes of drug excretion via the kidneys?
- Glomerular filtration - molecular weight less than 20,000
- Active tubular secretion (or reabsorption) - proximal tubule capillary endothelial cells have two active transport carrier systems (one for basic, one for acidic)
- Passive diffusion across tubular epithelium - generally leads to reabsorption (esp. if they are lipid soluble) from the kidney tubule but that can depend on pH of urine (acidic reabsorbed more at lower pH, basic reabsorbed better at higher pH)
How are drugs excreted via the biliary system?
Liver cells transport some drugs from plasma to bile – via transporters
Effective at removing phase 2 glucuronide metabolites. Drugs in the bile are then excreted into the intestines and eliminated in the faeces
What is enterohepatic recycling and why does it significantly prolong drug effect?
- A glucuronide metabolite is transported into the bile
- The metabolite = excreted into small intestine, hydrolysed by gut bacteria releasing the glucuronide conjugate
- Loss of the glucuronide conjugate increases the lipid solubility of the molecule
- Increased lipid solubility allows for greater reabsorption from small intestine back into the hepatic portal blood system for return to the liver
- The molecule returns to the liver where a proportion will be re-metabolised, but a proportion may escape into the systemic circulation to continue to have effects on the body
