Liam and James ADME Flashcards
Selectivity of drug binding to a receptor…
Allows the drug to have an action at one receptor subtype while having little or no effect at other subtypes.
The structure is also important.
What is drug action dependent on?
- Drug action is dependent on drug properties i.e. selectivity of receptor subtypes
- Dependent on tissue properties
Distribution of receptor subtypes throughout tissues e.g. histamine
Explain where the H1 receptors are and their effects?
H1 = are antagonist antihistamines, Loratidine
Explain where the H2 receptors are and their effects?
H2= antag inhibits gastric acid secretion, cimetidine
Explain where the H3 receptors are and their effects?
H3= potentially used for treating pain and inflammation, thioperamide
Why is receptor structure functionally important?
selectivity, important for characteristics of signalling
Desensitization speed?
Quickly after changing the activity of receptors
Down/up regulation speed?
slow
What are non receptor drug targets?
Enzymes, Carrier proteins, ion channels
How do indirect acting drugs work?
They modify the synthesis, storage or realase of the endogenous neurotransmitter.
Give some examples of drugs that act on enzymes
Cyclooxygenase, NSAIDS i.e ibuprofen which treats pain and inflammation
ACE inhibitors i.e. captopril that are used to treat hypertension
What are the effects of cyclo-oxygenase inhibition?
NSAID inhibition of COX1/2 reducing inflammation, pain, fever and homoeostatic pathways involved in kidney function and maintenance of gastric mucosa. Which means you can get renal failure and ulcers.
What is the function of COX 2 selective inhibitors? What are COX 2 selective inhibitors?
they might have renal COX inhibition and cardiovascular effects. There are two types Rofecoxib and celecoxib which are selective for the inducible enzyme isoform - COX 2. They have greater safety with respect to GI adverse effects, less likelihood of GI bleeds.
How and which drugs interact with carrier proteins?
Fluoxetine-SSRI. Good examples are drugs that act on monoamine neurotransmitter uptake proteins.
Fluoxetine inhibits the uptake of serotonin by active transport at the presynaptic terminal.
What are examples of ion channels affecting drugs?
Voltage gated ion channels i.e. local naesthetics (Na+ blockers) and Ca2+ channel blockers i.e verapamil
What are the barriers that work against the drug to reach the cells?
Metabolism (liver or extrahepatic), Metabolites (inactive or active), Biliary excretion (enterohepatic recirculation), Renal excretion (glomerular filtration, tubular secretion, passive reabsorption), Binding to plasma proteins (albumin), Binding and storage in tissues (protein, fat)
Describe the importance of passive diffusion.
• Most important mechanism • Applies to non‐polar drugs – (ie, lipid/oil/fat soluble) • Conc gradient is the driving force • No energy required
What does the rate of passive diffusion depend on?
Rate of diffusion (R) = ((C1 – C2) x A x D)/d
C1= high concentration gradient
C2 low concentration gradient
Increased the surface area directly increases the rate of passive diffusion. Therefore the gut is good at absorbing because gut has increased surface area. Increased thinkness if inversely proportional to diffusion. Diffusion coefficient (D) depends of the physical chemical properties like molecualr weight. So increased solutbility increased diffusion coefficient.
What happens if C2 is extremely smaller than C1
Then the rate of diffusion is dependent upon C1 x constant which is the same as saying (AD/d). The constant is for a particular molecule travelling through a particular membrane.
What is a partition coefficient?
The ability of a drug to dissolve in lipids. The higher the partition coefficient the more lipid soluble a molecule is. The partition coefficient graph can also tell you how much of the drug therefore is absorbed by a membrane.
In the graph you need molecules with roughly equivalent pKa so that you remove the ionisation factor in movement through a lipid membrane.
What do weak acids and or bases easily do?
easily ionize in solution
How do weak acids ionise?
give up their H+ proton.
pKa – pH = Log [AH]/[ A-]
How do weak bases ionise?
accept a proton, this happens when ph decreased. ionised drugs aren’t lipid soluble.
What is the law of mass action?
Rate of reaction is dependent on the concentration of active masses. Therefore, [ A- ] [ H+ ]/[ HA]= Ka
When does ph = pka?
When the drug is 50% ionised and/or pka-ph equals one
Why is the ph of the environment important?
drugs react differently in varying ph environments. It can affecct how and where drug is absored and how well excreted in urine. The degree of ionisation of molecule changes as it passes through differing ph environments.
How does the henderson hasselbach equation help?
it can be used to calculate how much of the drug crosses a membrane.
What happens when a drug is metabolised? i.e. more polar?
Less likely to diffuse into cells to reach receptors
Favours increased excretion in urine or bile
Usually abolishes activity and terminates drug action,
but :
Can promote activity - prodrug
– eg, acetylsalicylate salicylate
– Codeine morphine
No change in activity – eg, diazepam -> nordiazepam
Produce toxic metabolites – eg, paracetamol
Give an example of a drug metabolism that promotes produg activity?
Codine metabolised by 2D6 to morphine
Give an example of a drug that doesn’t change its activity even when metabolised.
diazepam metabolised to nordiazepam
Give an example of a drug that produces troxic metabolites.
paracetamol
Describe phase 1 of drug metabolism.
This phase is known as functionalisation. This is where oxidation mainly, reduction and hydrolysis processes occur to make the molecule more susceptible to phase 2 processes. Cytochrome p450 is the mos important oxidative enzyme. Oxidation of a drug requires drug oxygen, hydrogen and NADPH and cytochrome p450. This produces oxidised drug, water and nadp+. The CYPS family oxidises many endogenous molecules.
Describe the oxidation procress occuring in phase 1.
1) Drug combines with cytochrome P450 in the oxidised state which has iron.
2) The ferric is reduced to ferrous. So, the complex is reduced by the reductase which transfers an eletron from NADPH.
3) A 2nd electron from the same source (NADPH) serves to reduce O2 which forms an activated O2-CYP complex which is unstable.
4) Splits into oxidised drug, H2O and oxidised CYP.
The ability of oxidation and reduction allow electrons and drugs to be passed on.
What is the nomenclature of CYP34A
C=cytochrome P= p450 3= Family = 30% aminoacid homology A = Subfamily = greater than 60% amino acid homology 4 = isoform
Where does metabolism occur?
hepatically and extrahepatically
describe CYP1A1/2
Procarcinogens & promutagens, caffeine,
theophylline (induced by benzo[a]pyrenes in
cigarette smoke & BBQ meat)
CYP2D6
codeine - (inhibited by quinidine, fluphenazine, fluoxetine)
CYP3A4
very susceptible to drug to drug interactions
(inhibited by grapefruit juice)
(induced by rifampicin, glucocorticoids & barbiturates)
theophylline
What are the conswquences of induction of CYP enzymes?
Enzyme synthesis, initiated within 24 h of
exposure, increasing over 3 –5 days
Effect decreases over 1 – 3 weeks after inducing
agent is discontinued
Environmental Factors:
– Cigarette smoking; eating BBQ meat, cruciferous veges,
high protein diet, ethanol, exposure to insecticides (DDT,
Lindane) & polychlorinated biphenyls (PCBs)
Other drugs:
– Barbiturates, phenytoin, carbamazepine, rifampicin &
dexamethasone
What are the consequences when you inhibit CYP enzymes?
Rapid onset within 1 day
Exaggerated response with increased risk of
toxicity because no CYP to metabolise the drug
Name the competitive reversible inhibitors of CYP
– Cimetidine, ketoconazole, quinolone antibiotics, oestrogens, grapefruit juice
Name the heavy metals that inhibit CYP enzymes
Heavy metals: (complex with CYPs)
– Lead, cadium, mercury
These aren’t competitive they just shut down activity of CYP
What are the processes in phase 2 metabolism?
Glucuronidation, Sulphation, Amino-acid/peptide conjugation, Acetylation
how does glucoronidation work in phase 2 metabolism?
– by uridine glucuronosyl transferases (UGT) (microsomal) – transfers a glucuronic acid (MW =177) residue from uridine diphosphate glucuronic acid (UDPGA) to steroids , bilirubin and drugs
how does sulphation work in phase 2 metabolism?
– Sulphotransferases (cytosol)
Cofactor – 3’-phosphoadenosine 5’-phosphosulphate (PAPS). Adds sulfate to drug
how does amino-acid/peptide conjgation work in phase 2 metabolism?
With glycine or glutamine or glutathione (GSH) (Glut-Cyst-Gly)
Glutathione S-transferases (GST) – adds a tripeptide GS (MW = 307) onto electron deficient C, N, S or O atom (i.e.,electrophiles)
How does acetylation work in phase 2 metabolism?
– N-acetyl transferase (cytosol)
Requires Acetyl CoA
Sulphonamide drugs
Describe the metabolism of phenytoin in phase 2
The active drug is highly lipophilic and hydroxylation occurs via CYP 2C9 enzyme making the drug slightly soluble in water. UDP glucuronosyl transferase adds glucoronic acid i.e. conjugation to the drug making the drug very soluble in water.
What are the overlapping variables that influence rate and extent of drug metabolism?
Organ function of the liver cardio and endocrine i.e. GI, Diseases and drugs, environment i.e. what you do counts, age, sex, pregnancy and circadian rhythms.
Why does one dose not fit all?
When you give one dose of drug to a group of patients they don’t all get the therapeutic effects. this is because there is a varying ability to metabolise drugs. Variation in drug concentration is affected by the presence of metabolic CYPs int he blood.
What is the main sight of metabolism in the body?
Liver where Phase 1 and 2 occur
What is the most common excretion organ of a drug?
Kidney where renal excretion occurs.
