Drug Action (l3-8) Flashcards
What are the 3 general classes of antagonists
- Chemical: binding of 2 agents that oppose each other and INTERACT stopping signalling
- Physiological: two agents with opposite effects NEGATE each other
- Pharmacological: binds to receptors and blocks normal action
What is the difference between competitive and non-competitive antagonists?
Competitive- has structural similarity. Need to know [drug] to overcome competitive antagonist. An agonist cannot knock off a bound c. Antagonist
Non-competitive- can either have alloseric binding or irreversible active site binding. Changing [agonist] won’t affect binding as it occurs at a different site. Downstream responses are blocked, along with secondary messenger effects
As antagonists have no efficacy, how can the effect of the antagonist on [product] be measured?
- For competitive: binding displaces agonist curves to the right and this range of shift measured. How linear the change is is calculated
- For irreversible: binding causes parallel shift to right of curve & reduced maximal asymptote
- For non-competitive: reduces slope and max of dose response curve
What is the formula for TI( therapeutic index)
TD50/ED50 (toxic/ therapeutic)
What factors affect absorption?
- blood flow
- surface area
- gastric mobility
- with food
- particle size
- whether or not the drug is coated
What is the formula for bioavailability?
(AUCoral/AUCiv) x (DOSEiv/DOESoral)
What factors affect distribution?
-blood perfusion of the tissue or organ
-plasma protein binding ability
-ability to cross a cell membrane
If drugs are bound they cannot move across membranes= stay in plasma= not pharmacologically active. ONLY UNBOUND DRUGS CAN MOVE AWAY INTO TISSUE
Give 2 examples of plasma proteins used in binding
- ALBUMIN: binds mostly ACIDIC drygs and a small number of basic drugs
- Alpha1 acid glycoprotein (AAG): binds mostly BASIC and NEUTRAL drugs but causes an increase in inflammatory disease
What affects the amount of drug bound?
- Concentration of free drug
- Affinity for the binding site (2 sites per albumin molecule)
- Concentration of protein
Even if a drug is free it still has to cross membranes between compartments
What is the formula for volume distribution(Vd) ?
Total amount of drug administered (Q)/ Plasma concentration (Cp)
What is the main drug excretion route?
Urine via the kidneys.
However, lipohilic drugs are not eliminated by the kidneys, and need to be metabolised to more polar products (water soluble metabolites)
What occurs in phase 1 of metabolism?
- Usually oxidation reactions occur but can be a reduction or hydrolysis
- CP450 is used to introduce/ expose a functional group e.g. OH = functionalism which decreases lipid solubility but increases pharmacological activity
Explain how ethanol is metabolised
- Ethanol is most broken down to acetaldehyde by alcohol dehydrogenase (2/3) and CYPE (1/3)
- With chronic administration acetaldehyde is broken down to acetic acid by aldehyde dehydrogenase
Explain what happens during phase II of metabolism
- The newly added functional group acts as a point of attack for conjugation
- Large groups are attached such as glucuronyl, sulphate and acetyl
- Aims to add more soluble groups to lower lipid solubility further so drug be excreted more easily
- Results in pharmacologically inactive metabolite
- Most common way is via GLUCURONIDATION
What happens in Glucuronidation?
- It is the common conjugation reaction
- Mediated for UDP-glucuronyl transferases
- Polar nature means glucuronides are usually pharmacologically inactive and quickly excreted
How is paracetamol metabolised?
- Either directly conjugated (so no phase I) through sulphate and glucuronic acid (60%), 35% is sulphated & 5% is oxidated by CYP450
- CYP450 is responsible for producing toxic& highly actuve NAPQI, which can bind and destroy liver cells. This can be quickly detoxified in phase II by adding glutathione
What happens in a paracetamol overdose?
- The pathways of conjugation are saturated, co factors are depleted and more paracetamol is metabloised via CYP450
- Toxic metabolite reacts with liver instead of glutathione as its depleted
- Tissue damage occurs leading to hepatic necrosis. The body starts to no longer be able to metabolise
Name endogenous factors affecting drug metabolism
- GENETIC CONSTITUTION: individuals are described a fast or slow metabolisers. Slow have lower [metabolite] and may lead to exaggerated therapeutic response
- AGE: children express metabolic profiles very different and may lack/ have lower activity, while the elderly have a drckine in enzyme production
- DISEASE
Name exogenous factors affecting metabolism
- DRUGS
- SMOKING/ ALCOHOL
- ENVIRONMENTAL EXPOSURE
Exposure to additives in these can either induce (increased metabolised so drug dose needs to increase) or inhibit drug metabolising enzymes (reduced metabolism and increased pharmacological effect)
What are the main processes in renal drug excretion?
- Glomerular filtration in the Bowmans Capsule (20%): highly ppb drugs found at lower conc here than in plasma. Entry rate dependent on [free drug] & Mr
- Tubular reabsorption in the pct (~1%): [drug] increases as water is reabsorbed. Highly lipid soluble drugs have higher permeability and excreted slower
- Tubular secretion in the dct (80%): has 2 carrier systems for acids and other for bases, transporting against electrochemical gradient
Lipid soluble drugs go through this before excretion in urine
What happens when tubular renal fluid becomes more alkaline?
An acidic drug ionises and becomes less lipid soluble, so its reabsorption decreases
A basic drug becomes un-ionised and its reabsorption increases
What impact does pH partition have on excretion?
- For weak bases ionisation is greatest at acidic pHs, while the opposite is true for weak acids
- A weak base is more rapidly excreted in acidic urine
- pH partition impacts the rate at which drugs permeate membranes
Name the main mechanisms of elimination
- Volatile gases are eliminated by EXHALATION
- Water soluble compounds are often eliminated to some degree unchanged in URINE, sometimes bile
- Lipid soluble compounds typically undergo metabolism then excreted in BILE or urine
Explain saturable elimination
Elimination mechanism (e.g. enzymes) are typically not saturated at therapeutic doses of drugs, although there are exceptions e.g. phenytoin
