Pharma - Principles Flashcards
What is the difference between pharmacology and therapeutics?
→ pharmacology is more focused on the drugs
→ therapeutics is more focused on the patient
What is pharmacodynamics?
what the drugs do to the body
What is pharmacokinetics?
what the body does to the drugs
What are the 3 main questions one should ask themselves when considering how a drug exerts its effects on the body?
→ Where is this effect produced?
→ What is the target for the drug?
→ What is the response that is produced after interaction with this target?
Where is the effect of cocaine felt in the body?
euphoric feeling is felt in the dopaminergic neurones in the nucleus accumbens in the brain
What is the target for cocaine?
dopamine reuptake protein on the pre-synaptic terminal
What is the response that is produced after cocaine interacts with its target?
cocaine blocks the reuptake of dopamine from the synapse
more dopamine is available to bind to the the D1 receptors
activation of this receptors is what causes the euphoria
What the 4 different classes of drug targets?
→ Receptors
→ Enzymes
→ Ion channels
→ Transport proteins
What is the drug target of Aspirin?
enzyme
What is the drug target of local anaesthesia?
ion channel
What is the drug target of prozac (SSRI)?
transport protein
What is the drug target of nicotine?
receptor
What do drugs need to be effective therapeutically?
→ high selectivity for a particular drug target
→ drug dosage
Why was drug dosage important for Pergolide (drug for the treatment of Parkinson’s disease)?
→ at lower doses it targets the dopamine D2 receptor and produces an anti-parkinsonian effect
→ at higher doses it can target the serotonin and adrenergic receptors, causing hallucinations + hypotension, respectively
What are 4 ways in which drugs can interact with the receptors?
→ Electrostatic interactions
- this is the most common mechanism and includes hydrogen bonds and Van der Waals forces.
→ Hydrophobic interactions
- this is important for lipid soluble drugs.
→ Covalent bonds
- these are the least common as the interactions tend to be irreversible
→ Stereospecific interactions
- a great many drugs exist as stereoisomers and interact stereospecifically with receptors.
What are the 2 ways of classifying drug interactions with receptors?
→ agonist
→ antagonist
What is an agonist?
can bind + activate the receptor
What is an antagonist?
can bind to receptor but blocks the activation of said receptor
What is the affinity of a drug?
determines strength of binding of the drug to receptor
What is the efficacy of a drug?
ability of an individual drug molecule to produce an effect once bound to a receptor
What does high affinity of drug result in?
stronger drug-receptor complexes are formed
What the three different classes of drugs based on differences in efficacy?
→ antagonist = blocks receptor but has no actual effect
→ partial agonist = can only illicit a partial response from the receptor
→ full agonist = has maximum efficacy, illicits maximum response from the receptor
What is the potency of a drug? (general definition)
concentration or dose required to produce a defined effect
What is the standard measure of potency of a drug?
determine the conc. or dose of a drug required to produce a 50% tissue response
What is EC50?
the nomenclature for half maximal effective concentration
What is ED50?
the nomenclature for half maximal effective dose
What effects whether a drug can reach a relevant target at sufficient concentrations or not?
pharmacokinetics factors
List 4 major pharmacokinetic factors or phases.
→ Absorption
→ Distribution
→ Metabolism
→ Excretion
What is meant by absorption in pharmacokinetics?
→ passage of a drug from the site of administration into the plasma
→ process for drug transfer into the systemic circulation
What other concept is relevant to absorption in pharmacokinetics?
Bioavailability
What is meant by bioavailability in pharmacokinetics?
→ fraction of the initial dose that gains access to the systemic circulation
→ outcome of drug transfer into the systemic circulation
What is a huge determinant of bioavailability and absorption?
site of administration
What are the 2 ways in which drugs can move around the body from the site of initial administration?
→ bulk flow transfer (e.g. blood stream)
→ diffusional transfer (e.g. molecule by molecule over short distances)
What mode of drug transfer is going to have 100% bioavailability?
→ bulk flow transfer
→ e.g. IV fluids straight into the circulation
Why are other ways of administering drugs unlikely to have 100% bioavailability?
the rest are diffusional transfer, needs to cross at leats one lipid membrane to reach systemic circulation
What are some other forms of drug administration besides IV?
Oral
Inhalation
Dermal (percutaneous)
Intra-nasal
What are the 4 different mechanisms by which chemicals can diffuse across the plasma membrane?
Simple diffusion (across lipid bilayer)
Diffusion across aqueous pores
Carrier mediated transport
Pinocytosis
What 2 mechanisms of chemical diffusion across a plasma membrane are not relevant to drug absorption?
Pinocytosis
Diffusion across aqueous pores
What is Pinocytosis? Why is it not relevant to drug movement across the membrane?
Involves small part of cell membrane enveloping chemical and releasing it on other side
Rarely used by body to transport drugs
What is diffusion across aqueous pores and why is not used by drugs?
Movement across the gaps between endothelial / epithelial cells in the membrane
Gaps are usually too small for drug molecules to get through
How do drugs get transported through simple diffusion?
If lipid soluble, drugs will diffuse across lipid membranes from area of high conc to area of low conc.
How do drugs get transported through carrier mediated transport?
Transport proteins in the membrane can transport drugs across or against a conc. gradient
Do drugs tend to be water soluble or lipid soluble? Why?
Water soluble usually, as many are given orally, and need to dissolve in aqueous environment of GI tract to be available for absorption in the first place.
What are the 2 forms that most drugs exist in?
Ionised or unionised
Weak acids when ionised will donate protons
Weak bases when ionised will accept protons
What form of a drug retains more lipid solubility? Ionised or unionised?
Unionised
What determines whether a drug will remain ionised or unionised when administered?
Dissociation constant (pKa) for the drug pH in that particular part of the body
What is true if the pKa of a drug and the pH of a drug are equal?
Drug will equally dissociate between its 2 forms
50% will be ionised, 50% will be unionised
For a drug with a high pKa, how does its proportion of ionised and unionised change as the pH changes?
As pH decreases, ionised form will dominate
As pH increases, unionised form will dominate
For a drug with a low pKa, how does its proportion of ionised and unionised change as the pH changes?
As the pH decreases, the unionised form will dominate
As the pH increases, the ionised form will dominate
What is the pKa of weak acids usuallly?
pKa = 3 - 5
What is the pKa of weak bases usually?
pKa = 8-10
Where is a weak acid drug more likely to be ionised in the body?
Areas of low pH such as stomach
Where is a weak base drug more likely to be unionised in the body?
Areas of high pH like blood and urine
How do you prevent weak bases from being trapped in the stomach?
Weak base drug will be highly drug ionised and therefore poorly absorbed in stomach due to low pH
However, drug will eventually reach small intestine where transport proteins will enable absorption from GI tract
How does the body prevent weak acids from being trapped in the blood?
Weak acid would be absorbed from stomach due to low pH and high unionised state, but would become more ionised as it enter higher pH blood.
However, most tissues have transport proteins to allow drug to reach its target tissue
What are the most important carrier proteins relating to drug action in terms of pharmacokinetics?
Renal tubule
Biliary tract
Blood brain barrier
GI tract
What factors influence drug distribution to tissues?
Regional blood flow
Plasma protein binding
Capillary permeability
Tissue localisation
How does regional blood flow affect drug distribution?
What is the most common plasma protein for binding? What is it particularly good at?
Albumin (very common)
Very good at binding to acidic drugs
What does the amount of drug bound to a plasma protein depend on?
1) free drug conc.
2) affinity for protein binding sites
3) plasma protein concentration
What factor affecting plasma protein binding is most important when looking at drug distribution?
Affinity for protein binding sites
What are the 4 different types capillary structures found in the body?
What is the capillary permeability of a continuous capillary structure like? Why?
Continuous structure = endothelial cells aligned in single file with small gap junctions between cells.
If drugs lipid soluble = can diffuse across endothelial cell easily
If drugs less lipid soluble = can be transported using carrier proteins or can fit through gap junctions if very small
What is the capillary permeability of the BBB like? Why?
BBB = continuous structure but with very tight junctions between cells
Therefore brain is the most difficult tissue for drugs to gain access to - BBB is a protective mechanism
Where would you find a continuous capillary structure in the body?
Most of the capillaries in the body
Where would you find the discontinuous capillary structure in the body?
Liver
What is the capillary permeability like for discontinuous capillary structures? Why?
Very high - found mainly in the liver, key metabolic organ that needs metabolise a variety of chemicals
Discontinuous = big gaps between cells, allows for drugs to diffuse in out of blood stream to and from liver very easily
Where would you find the fenestrated structure of endothelial cells in the body?
Glomerulus of kidney
What is the capillary permeability of fenestrated capillary structures? Why?
High - found in kidneys, where excretion of drugs is necessary
Fenestrated = have fenestrations, big circular windows in structure to allow for small molecules to pass from blood to kidney tubules for excretion
Why does tissue localisation affect drug distribution?
Why is the process of drug metabolism important?
What is the main metabolic tissue in the body? Within this tissue, what mainly metabolises drugs?
Liver, P450 enzymes
What are the purposes of the main 2 biochemical reactions involved in drug metabolism?
Phase 1 - main aim to introduce a reactive polar group to the drug
Phase 2 - main aim to add a conjugate to the reactive group
Overall aim = to decrease lipid solubility to aid in excretion and elimination
What are the 3 ways in which phase 1 reactions can occur in drug metabolism?
Oxidation
Reduction
Hydrolysis
What is the most common method of phase 1 drug metabolism?
Oxidation
What does the process of oxidation in phase 1 drug metabolism involve? Why?
All oxidation reactions start with hydroxylation - this utilises the cytochrome P450 system
Aim = incorporate oxygen into non-activated hydrocarbons
What are pro-drugs?
Drugs that require the liver to convert it into a metabolite during Phase 1 in order for it to have a therapeutic effect
What happens in phase 2 of drug metabolism?
Metabolites from phase 1 are conjugated as a substituent group is attached to produce a metabolite usually inactive and far less lipid soluble than the phase 1 metabolite
What enzymes are involved in phase 2 of drug metabolism?
Transferases
What is first pass (presystemic) metabolism, and why is it a problem?
Many orally administered drugs are absorbed in the small intestine and enter hepatic portal blood supply - drug gets heavily metabolised in the liver and little active drug will reach systemic circulation
What is a solution to first pass (presystemic) circulation?
Administer a larger dose of drug to ensure enough drug reaches systemic circulation
What are some problems with the usual solution to first pass (presystemic) metabolism?
Extent of first pass metabolism and amount of drug reaching systemic circulation varies between individuals
Therefore drug effects and side effects can be difficult to predict
What are some of the routes through which drugs can be excreted?
lungs (e.g. alcohol)
Breast milk
Kidney (in urine)
Liver (in bile)
What are 3 major routes for drug excretion via the kidneys?
Glomerular filtration
Active tubular secretion
Passive diffusion across tubular epithelium
What determines whether a drug can be excreted through glomerular filtration?
Size - drug molecules of molecular weight less than 20,000 diffuse into the glomerular filtrate
This is an additional route of excretion for these drugs = allows for quicker rate of excretion
What determines whether a drug is actively secreted?
Most important route as 80% of renal plasma is passed back into blood supply
Proximal tubule capillary endothelial cells have 2 active transport carrier systems
= drug excretion is dependent on available transporters
1 active transport system for acidic drugs
1 active transport system for basic drugs
What determines whether a drug is passively reabsorbed?
Dependent on urine pH and extent of drug metabolism
Usually lipid soluble drugs
How does drug metabolism affect whether a drug is passively reabsorbed or not?
Phase 2 metabolites = more water soluble than normal drug = less well reabsorbed
How does urine pH affect passive reabsorption of drugs in the kidney’s tubules?
Based on pH and pKa hypothesis
Urine pH = 4.5 to 8
Acidic drugs better reabsorbed in lower urine pH
Basic drugs better reabsorped in higher urine pH
You take drug A as an analgesic. It’s a weak acid. Your urine pH increases from 6.5 to 8. Will the drug effect be prolonged or reduced? Explain.
Drug A = weak acid so will become more ionised in the urine with a pH of 8 (more alkaline environment)
Therefore less of the drug is unionised so less of it can be reabsorbed into the kidney tubules
More of the drug will excreted = drug effect is REDUCED
How does the liver allow for drug excretion?
Liver cells can transport some drugs from plasma to bile using transporters
Drugs from bile are excreted into intestines and eliminated in faeces
What drugs is the liver particularly good at excreting?
Phase 2 glucuronide metabolites
Through what process can the liver prolong drug effects?
Enterohepatic recycling
How does enterohepatic recycling work?
- 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.
- 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.
