Principles of pharamcology Flashcards
What is pharmacology?
The study of how a drug interacts with living organisms and how this influences the physiological function
What is therapeutics?
Drug prescribing and the treatment of disease
What is pharmacodynamics?
What the drug does to the body
What is pharmacokinetics?
What the body does to the drug
What are the 3 questions you want to consider?
- 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 - Consider euphoria
Where’s the effect produced?
Nucleus accumbens (brain)
Cocaine - Consider euphoria
What is the drug target?
Dopaminergic neurones
Cocaine - Consider euphoria
What is the response produced?
Blocks the dopamine reuptake protein
What are the types of drug targets?
- Receptors
- Enzymes
- Ion channels
- Transport proteins
What is the drug target for aspirin?
COX enzyme - prevents production of prostaglandins
What is the target for local anaesthetic?
Block sodium ‘ion channels’ and prevents nerve conduction
What is the target for prozac?
Block serotonin ‘carrier proteins’ and prevent serotonin from being removed from the synapse
What is the target for nicotine?
Binds to and activates the nicotinic acetylcholine ‘receptor’
What is the selectivity of an effective drug?
High
What is the relationship between selectivity and dose?
Increasing the DOSE of a drug can DECREASE the SELECTIVITY
What disease is pergolide used to treat?
Parkinson’s
What is the drug target for pergolide?
Dopamine receptors
At high doses where does pergolide attach and what are the effects?
Serotonin (5HT-28 receptor) - hallucinations
Adrenergic (alpha-1 receptor) - hypotension
Which endogenous compounds are similiar to dopamine?
Serotonin
Noradrenaline
How can drugs interact with receptors?
- Electrostatic interactions
- Van der Waal forces
- Hydrogen bonds
- Hydrophobic
- For lipid-soluble drugs
- Covalent bonds
- Tend to be irreversible
- Stereospecific isomers
- Many drugs exist as stereoisomers and interact stereospecifically
What are the two drug categories?
- Agonists - activate
- Antagonists - block
What are the two key properties of agonists?
- Efficacy
- Affinity
What is the affinity of a drug?
The strength of binding of the drug to the receptor
- Affinity is linked to receptor occupancy
If you were to introduce 2 drugs to the body, it is more likely the drug with the higher affinity will be bound to the receptors.
What is the efficacy of a drug?
The ability of an individual drug molecule to produce an effect once bound to a receptor
Consider 3 drugs:
A. Binds to the receptor but produces no response B. Binds and produces a partial response C. Binds and produces a maximal response **All 3 drugs have an affinity for the receptor** What type of drugs are they?
A is an antagonist as it produces no response
B is a partial agonist as it elicits some response
C is a full agonist as it gives the maximal response
What is potency?
The concentration or dose of a drug required to produce a defined effect
How is potency measured?
Determine the concentration or dose of a drug required to produce a 50% tissue response
- EC50 used for tissues when 50% of the tissue reponds
- ED50 used for people when 50% of the individuals have the desired effect
What are the 4 major factors of pharmacokinetics?
- Absorption
- Distribution
- Metabolism
- Excretion
What is absorption?
The passage of a drug from the site of administration into the plasma
What is bioavailability?
The fraction of the initial dose that gains access to the systemic circulation
Which site of administration gives 100% biovailability?
IV has 100% bioavailability because it’s administered straight into the circulation
Why might bioavailability be less than 100%?
Drugs move around the body via:
- Bulk flow transfer
- Diffusional transfer
In both cases, they must cross at least one lipid membrane.
What is pinocytosis?
A small part of the cell membrane envelops the chemical molecule and forms a vesicle containing the drug
- Insulin access to the brain
How do most drugs move across membranes?
- Diffusing across as they’re lipid-soluble
- Carrier mediated transport using a transmembrane protein
In what form do drugs exist?
- Most drugs are weak acids / bases
- Therefore they exist in two forms:
- Ionised
- Unionised
- Therefore they exist in two forms:
What determines whether a drug will be unionised?
- The dissociation constant (pKa)
- The pH in that part of the body
If the pKa = pH the ionised: unionised ratio will be 50:50.
What happens to weak acids in acidic & basic environments?
For weak acids the more acidic the environment the more the unionised form starts to dominate. If the pH becomes more basic the ionised form starts to dominate.
What happens to weak bases in an acidic or basic environment?
For weak bases the more basic the environment the more the unionised form starts to dominate. If the pH becomes more acidic the ionised form starts to dominate.
What do acids do in regards to their proton?
Donate proton
What do bases do in regards to the proton?
Accepts proton
What happens to weak acids in the stomach?
Weak acids would be unionised in the stomach so could be absorbed but in the blood would become ionised. Here they would be absorbed via transport proteins.
What happens to weak bases in the stomach?
Weak bases would be ionised in the stomach but could be absorbed via transport proteins in the small intestine.
Where are the most important carrier systems for drug action found?
1) Renal tubule
2) Biliary tract
3) Blood-brain barrier
4) Gastrointestinal tract
What factors affect distribution?
- Regional blood flow
- Plasma protein biding
- Capillary permeability
- Tissue localisation
What is the relationship between blood flow and distribution?
The higher the % of blood flow the more drug that will reach that tissue
- Distribution can be affected by factors such as:
- exercise - more blood to the muscles
- eating a large meal - more blood to stomach & small intestine
What proportion of drugs can be protein bound?
99%
What factors affect drug binding to plasma proteins?
- The free drug concentration
- The affinity for the protein binding sites
- The plasma protein concentration
What is the concentration of albumin in the blood?
0.6mmol/L
How many binding sites does albumin have?
2
Where are discontinuous capillaries found? Why?
Liver - Allows for drugs to easily diffuse out of the bloodstream and access the liver tissue.
Where are fenestrated capillaries found? What is the purpose?
Glomerulus - Allows for some small drugs to pass from blood to kidney tubules which will enhance excretion of these drugs
What are fenestrations?
Circular windows within endothelial cells that allow for the passage of small molecular weight substances
What type of capillaries are found within the body?
continuous
What are characteristics of the blood-brain barrier?
The blood-brain barrier has endothelial cells between the tight junctions, making the brain difficult to access.
What type of drugs are retained in the brain?
In an area where there is a higher proportion of fat i.e. the brain more of the lipid-soluble substance will be retained
- This means the equ^ for the lipid-soluble is more heavily weighted towards retention in the brain - This means the equ^ for the water-soluble is more heavily weighted towards retention in the plasma
Why is drug metabolism important?
So we can produce water-soluble metabolites to make excretion easier
What would occur without drug metabolism?
The drugs would eternally circulate within the bloodstream eliciting their effect.
What is the major metabolic tissue? Which enzyme is used?
The liver
P450
What are the 2 types of biochemical reactions for drug metabolism?
- Introducing a reactive group to the drug
2. Adding a conjugate to the reactive group
What occurs in phase 1 metabolism? By which reactions could this occur?
Introducing reactive polar groups into their substrates
- Oxidation (most common)
- Reduction
- Hydrolysis
What occurs in phase 2 metabolism? Which enzymes predominate during this phase?
Attachment of a substituent group
- Results in a metabolite nearly always inactive and far less lipid-soluble
- Facilitates excretion in the urine or bile
Mostly transferases
Which drugs are affected by first pass metabolism?
A problem for orally administered drugs
What is the issue with oral drugs and first pass metabolism? How is the problem solved?
Absorbed from the small intestine and enter the hepatic portal blood supply so they pass the liver before reaching the systemic circulation
- Administer a larger dose of the drug to ensure enough drug reaches the systemic circulation
What are the 3 major routes of kidney excretion?
- Glomerular filtration
- Active tubular secretion (or reabsorption)
- Passive diffusion across tubular
What occurs in glomerular filtration?
Molecules of a molecular weight less than 20,000 diffuse across into the filtrate
- Smaller drugs have a quicker excretion rate as they have an additional route
- Only 20% of renal plasma is filtered here
What occurs in active tubular secretion?
- 80% of renal plasma passes the proximal tubule
- Two active transport carrier systems
- One for acidic
- One for basic
What occurs in passive diffusion?
Reabsorption of water occurs in the tubule, so lipid-soluble drugs still present will also be reabsorbed
What factors affect reabsorption?
- Drug metabolism - phase 2 metabolites are more water soluble so less well absorbed
- Urine pH - acidic drugs reabsorbed better at a lower pH
What is biliary excretion?
Hepatocytes transport some drugs from plasma to bile via transporters
- They are then excreted into the intestines and will be eliminated in the faeces
Which type of metabolites are involved in enterohepatic recycling and what happens to them?
- A glucuronide metabolite is transported into the bile.
- It is excreted into bile the hydrolysed releasing the glucuronide conjugate, facilitated by gut bacteria
- Increases lipid solubility
- Allows reabsorption from the small intestine back into hepatic portal blood system
- 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.
