Pharm - Principles of Pharmacology Flashcards
What is pharmacology?
Study of drugs and drug action
What is therapeutics?
Concerned with drug prescribing - more patient focused
What is pharmacodynamics?
What a drug does to the body
What is pharmacokinetics?
What the body does to a drug
What are the 3 key questions of pharmacodynamics?
Where is the effect produced?
What is the target of the drug?
What is the response produced after interacting with the target?
Where is the effect of cocaine?
Dopaminergic neurones of the nucleus accumbent in the brain
What is the target of cocaine?
Dopamine reuptake protein
What is the response cocaine produces at the target?
Blocks reuptake of dopamine therefore causes euphoria
What are drug targets typically in the form of?
Proteins which are either activated or prevented from activating
What are the 4 main types of drug target
Ion channel
Transport protein
Enzyme
Receptor
In terms of selectivity, what causes side effects?
When drugs have lower selectivity, they are more likely to bind to other receptors therefore cause unintended side effects
How does drug dose relate to side effects?
Increasing the drug dose means that drugs are more likely to bind to similar receptors due to their degree of selectivity
What are the 4 main types of drug-target interaction?
Electrostatic
Hydrophobic
Covalent bonds
Stereoisomeric
What is the most common drug-target interaction?
Electrostatic
What are the 2 broad classes of drugs?
Agonists and antagonists
What is the affinity of a drug?
How strong it binds to a receptor
What is the binding of a drug to a receptor described as?
Transient binding to form a temporary drug-receptor complex
What is the efficacy of a drug?
Refers to the effect produced by a drug when bound to a receptor
What is an antagonist in terms of efficacy?
When a drug produces no effect when binding to a receptor
What is a partial agonist?
When a drug produces a partial response it has sub-maximal efficacy
What is a full agonist?
Drug produces the maximum effect on the receptor
What is the potency of a drug?
Concentration or dose of a drug required to produce a defined effect
How do we measure potency?
ED50 or EC50
What is EC50?
Half maximal effective concentration - what is the concentration of a drug needed to produce a 50% tissue response
What is ED50?
Half maximal effective dose - what is the dose needed to produce a 50% tissue response
What is a scenario whereby EC50 and ED50 differs?
E.g. if we are measuring an in vitro tissue sample, we can alter concentration to see a 50% tissue response. However, if we are testing a drug with people, we will change dose to see what dose produces a defined effect in 50% of people
Is potency the same as efficacy?
No
What is bioavailability?
How much of an administered drug ends up in the systemic circulation and thus is expressed as a percentage
What can determine bioavailability?
Site of administration
What are the common sites of administration?
- IV
- Intra nasal
- Inhalation
- Oral
- Dermal (percutaneous)
When is bioavailability highest?
IV
How do drugs travel around the body?
Wither via bulk flow or diffusion in small groups of molecules
Why is IV 100% bioavailability but other administrations not?
IV is an example of bulk flow and is injected straight into the systemic circulation, other drugs travel by diffusion in small groups therefore need to pass at least 1 lipid membrane
What are the ways molecules travel across lipid membranes?
Pinocytosis
Diffusion via aqueous pores
lipid soluble diffusion
Carrier mediated transport
What is pinocytosis?
Membrane forming vesicle of chemical and releasing on other side (rare)
Why is diffusion via aqueous pores not common?
Most pores are less than 0.5nm wide, most drugs are larger than this
What is the most common diffusion method?
Lipid soluble diffusion
Why are drugs more commonly water soluble than lipid soluble?
Many are taken orally therefore need to be absorbed into aqueous environment of the GIT
What allows drugs to switch between solubilities?
Many drugs are weak acids or bases
What is aspirin an example of?
Weak acid
What does a weak acid do?
Donates protons when ionised
What is morphine an example of?
Weak base
What does a weak base do?
Accepts protons when ionised
What are unionised drugs more capable of doing?
Retains more lipid solubility therefore more likely to diffuse
What determines whether or not a drug is ionised?
pKa of the drug and the surrounding pH
What happens when the pKa is equal to the pH?
50% is ionised and 50% unionised
What is the typical pKa of weak acids>
3-5
What is the typical pKa of weak bases?
8-10
What happens to aspirin if the surrounding pH increases?
Ionised form dominates
What happens to aspirin if the surrounding pH decreases?
Unionised form dominates
What happens to morphine if the surrounding pH increases?
Unionised form dominates
What happens to morphine if the surrounding pH decreases?
Ionised form dominates
Where is a weak acid more unionised?
Acidic environment e.g. stomach acid
Where is a weak base more unionised?
Blood and urine
Why are weak bases poorly absorbed from the stomach?
Low pH leads to ionised form dominated therefore ion trapping
What enables weak bases to be absorbed in the small intestine?
Large number of transport proteins in small intestine
What stops ion trapping for weak acids?
In the blood. therefore are lots of transport proteins to stop ionised acid being trapped
Where are the most important carrier systems for drug action found?
Renal tubule
Biliary tract
Blood brain barrier
GIT
What factors affect tissue distribution of a drug?
Regional blood flow
Plasma protein binding
Capillary permeability
Tissue localisation
Which tissues receive the most regional blood flow?
Liver Kidney Muscles Brain Heart
What can affect regional blood flow?
Exercise, or eating a large meal
What is the most important plasma protein for binding
Albumin
What is albumin particularly good at binding
Acidic drugs
What determines the amount of drug that is bound?
Free drug concentration
Affinity for protein binding sites
Plasma protein concentration
What is the blood conc of albumin?
0.6mmol/l
What is the binding capacity of albumin?
1.2mmol/l
Why are plasma proteins never saturated with drugs?
Because the required clinical effect for all drugs is achieved with a concentration less than 1.2mmol/l
What drugs have the greatest affinity for plasma protein binding?
Acidic drugs
What is the structure of most capillaries?
Continuous structure with endothelial cells aligned in a single file with small gap junctions between the cells
What do most drugs need to be transported through the capillary
They need to be lipid soluble, if not then they will need transport proteins
Why is the brain particularly hard to access?
Blood brain barrier has tight junctions between cells instead of H20 filled gap junctions
Where is discontinuous capillary found?
Liver
Where is fenestrated capillary found?
Kidney
Why does the liver need discontinuous capillaries?
Highly metabolic therefore allows easy passage of drugs to diffuse in and out of the liver and the bloodstream
Why does the kidney need fenestrated capillaries?
Key organ for excretion therefore allows small drugs to pass from blood to kidney tubules which will enhance the excretion of drugs
Explain tissue localisation?
Lipid soluble drugs will more more heavily weighted to lipid areas such as the brain compared to the aqueous blood, contrast to water soluble drugs. This affects the proportion of a drug that is distributed to tissues
What is the best solubility for excretion?
Water soluble
What does drug metabolism involve?
Converting drugs to make them as water soluble as possible
What are the main enzymes involved in drug metabolism?
P450 enzymes in the liver
What is phase 1 metabolism?
Introduce a reactive group to the drug
What is phase 2 metabolism?
Add a conjugate to the reactive group
How can phase 1 metabolism occur?
Oxidation - most common
Reduction
Hydrolysis
How do oxidation reactions occur?
Start with hydroxylation via p450 to incorporate oxygen into non activated hydrocarbons.
This gives us us metabolites with functional groups serving as a point of attack for conjugating systems of phase 2
What are pro-drugs?
Parent drug has no activity - metabolism is required so that the metabolite has the pharmacological effect
How does paracetamol cause liver damage?
Certain metabolite of paracetamol, not the drug itself
What happens in phase 2 metabolism?
Attachment of a substituent group, and the resulting metabolite is nearly always inactive and far less lipid soluble compared to the phase 1 metabolite
What are the main phase 2 enzymes?
transferases to transfer the substituent group to the phase 1 metabolite
What is first pass (presystemic) metabolism?
Drugs that are absorbed by the GIT enter the hepatic portal blood supply where they will first pass through the liver and can be heavily metabolised reducing their activity.
What is first pass metabolism a problem for?
Orally administered drugs
What is the solution to first pass metabolism?
Administer a larger dose to ensure enough reaches the systemic circulation
What is the problem with giving a larger dose to bypass first pass metabolism?
Extent of first pass metabolism varies from person to person therefore we don’t know how much drug we increase
What are the ways in which drugs can be excreted
Lungs
Breast milk
Kidney (urine)
Liver (bile)
What are the 3 routes for kidney excretion?
Glomerular filtration
Active tubular secretion (or reabsorption)
Passive diffusion across the tubular epithelium
Why do drugs being excreted by the kidneys vary in their excretion?
As the extent to which drugs use different routes of excretion varies greatly in the kidneys
What does glomerular filtration allow for?
Allows drug molecules of less than 20,000 molecular weight to diffuse into the glomerular filtrate, allowing a quicker rate of excretion than larger drugs
Why is active tubular secretion the most important form of kidney excretion?
Only 20% of renal plasma is filtered at glomerulus, the rest (80%) passes onto the blood supply of the proximal tubule .
Proximal tubule capillary endothelial cells have 2 active transport carrier systems for acidic drugs and basic drugs against their concentration gradient
What drugs are typically reabsorbed in the kidneys?
Drugs that are particularly lipid soluble
What factors determine rate of drug reabsorption?
Drug metabolism - phase 2 metabolites less well reabsorbed
Urine pH - acidic drugs will be better reasborbed at lower pH and basic drugs at higher pH due to ionisation
What is biliary excretion effective for removing?
Phase 2 glucuronide metabolites
What does enterohepatic recycling do?
Significantly prolongs drug effect - glucuronide conjugate removed by gut bacteria, causing increased lipid solubility and thus greater reabsorption. The drug is then brought back to hepatic portal system, some is re-metabolised by the liver but some may escape to systemic circulation to have continued effects on the body
