Pharmacology L2: Pharmacokinetics- ADME Flashcards
How does the body deal with drugs that are taken?
- Absorption : how a drug gets into the body
- Into bloodstream
- Distribution: how a drug moves around the body
- Through blood stream
- Metabolism: how a drug is changed in the body
- Excretion: how a drug is removed from the body
What happens with ADME?
______ is a major challenge of drugs. What is a factor?
Crossing membranes
Size is a factor, as smaller compounds can more easily cross the cell membrane.
Lipophillicity (uncharged nonpolar) is an advantage.
Charge is not.
What is Uncharged molecules cross membranes?
pH may affect this… Most drugs are weak acids or weak bases.
Body pH = 7.4-7.4
Stomach pH = 2-3
What is the route of administration?
Routes are optimised for delivery of required concentrations of drug, taking solubility and chemical factors, as well as adverse effects into account.
Enteral: absorption through the GI tract Oral, rectal
Parenteral: all other routes Injections, sublingual, inhalation, topical
What is Metabolism by liver hepatocytes?
- Drugs that are absorbed from the gut reach the liver via the hepatic portal vein before entering the systemic circulation.
- Some drugs may have low bioavailability/distribution due to this first-pass effect.
- Some drugs can be given as pro-drugs, relying on the body’s metabolic processes to make an active metabolite.
- Some metabolites are active, most are inactive.
Drugs that are absorbed from the gut reach the liver via the hepatic portal vein before entering the systemic circulation. Some drugs may have low _______/______ due to this first-pass effect. What does that look like?
bioavailability/distribution
What is the first-pass effect and bioavailability?
To avoid first pass metabolism, what are 5 types of parenteral administration for injections?
- Intravenous (i.v)
- Intramuscular (i.m)
- Subcutaneous (s.c)
- Intraperitoneal (i.p)
- Intrathecal (i.t)
What are 3 advantages of parenteral administration to avoid first pass metabolism?
What are 3 disadvantages of parenteral administration to avoid first pass metabolism?
What are 6 characteristics of intravenous (i.v) injection?
What are 2 characteristics of subcutaneous (s.c) injection?
What are 3 characteristics of intramuscular (i.m) injection?
What are 2 types of intramuscular?
What are 3 characteristics of dissolving tablet under the tongue (sublingual)?
- Good vascularisation
- Rapid absorption into bloodstream
- No “first-pass” metabolism in the liver
What are 2 characteristics of sublingual medication?
a
What are 2 characteristics of topical medication?
What are the 3 sites of absorption?
What are 3 membranes that drugs need to cross?
- GI tract
- Blood-brain barrier
- Cell membrane
What are the 2 absorption transport across membranes?
Passive diffusion- passage along concentration gradient Facilitated transport- involves carrier or transport
What is passive diffusion?
Passive diffusion is the movement of substances across cell membranes without any energy needed. Sufficient concentration and time are needed if the drug molecules can pass through the membrane.
What are 3 principles of the distribution of drugs requiring the crossing of barrier?
- Free or unbound drugs can move into tissues (receive the most blood)
- Brain, heart (receives most blood –> affected by blood most)
- Drugs are delivered from site of injection/absorption to site of action via the blood
- Drugs generally diffuse into peripheral tissue depending on their physiocochemical characteristics
- Only free (unbound) drug can diffuse out of the blood circulation into peripheral tissue
- Tissues which receive the greatest amount of blood may receive the greatest amount of drug over time.
What is metabolism in term soft drugs as foreign compound?
What are 2 purposes of metabolism of xenobiotics?
- Increase the rate of excretion
- Decrease likely toxicity
How does drugs turn into a metabolite by enzyme?
Drug
- Xenobiotic
- Toxic
Metabolites
- More polar
- More rapidly excreted
- Less pharmacological activity
- Less toxicity
Drug molecules are enzymatically processed using ____ (same/different) pathways as “natural” compounds
same
A drug may have its actions _____ or _____
increased; decreased
Individual _____, _____ determined, can be significant in drugs.
variation; genetically
Combination of drugs can be fine for one person and dangerous for another
- Due to difference in metabolism
May be multiple _____ of metabolism in drugs.
routes
May not terminate ____ action initially
drug
Drug metabolism may take place in various places BUT _____ is prime site
liver
_____ is what the body does to the drug
metabolism
What are the 2 major types of enzymatic reaction?
What are 3 types of phase I reactions?
- Oxidations (cytochrome P450)
- Reduction (reductases)
- Hydrolysis (esterases)
What are 4 types of phase II reactions?
Add water-soluble moiety to drug
- Glucuronide
- Glutathione
- Sulfate
- Acetate
What are 2 characteristics of Phase 1 reaction: Oxidation (cytochrome P450s)?
- More than 50 different forms of cytochrome P450 enzymes exist, with different substrate specificities and mechanisms.
- Most lipophilic drugs and environmental chemicals are substrates for one or more forms of P450.
What is a characteristics of Phase 1 reaction: Reduction and Hydrolytic reactions (reductases and esterases)?
Each reaction, whether oxidation, reduction or hydrolysis, increases the water solubility of the resulting metabolite.
What are Phase 2 reactions?
What are 5 general phase 2 metabolites?
- More highly ionised
- More water soluble
- More likely to be excreted by the liver and kidneys
- Less pharmacologically active
- Less toxic
What is the metabolism involving multiple enzymes can occur in series?
What is the metabolism of aspirin?
What are 5 factors affecting drug metabolism?
- genetics (e.g. metabolism of codeine to morphine)
- age (aged patients & children may metabolise at different rates compared to adults)
- Pregnancy = increased metabolism
- gender (e.g. women are slower ethanol metabilisers
- Depends on exposure –> upregulate if frequently taken
- other drugs being taken (induction or inhibition of P450s)
- food (charcoal grill ++CYP1A2- Hyperactivated) or grapefruit juice –CYP3A4 (Reduces metabolism (eg. unable to metabolism drug) = toxicity)
Many drugs can affect the metabolism of other drugs by inhibiting or reducing CYP enzyme activity. How did this happen?
- and this is a potential problem when drugs are given at the same time which are both metabolised by the same enzymes (cytochrome P450s).
- Other drugs may induce or stimulate CYP function, which may stimulate breakdown of medications.
- Grapefruit juice slows the breakdown of multiple drugs by inhibiting cytochrome CYP3A4, potentially leading to adverse effects.
What is the flowchart for administration, absorption, distribution and elimination?
_____ metabolism and ____ clearance of most drugs is crucial to avoid toxicity.
Liver; kidney
What happens when there is impaired kidney function in drug metabolism?
Impaired kidney function = poor ability to clear metabolites
What is the renal function?
which is poorly developed in neonates and tends to decrease in the elderly.
This may prolong the time course and efficiency of excretion. Also, when a patient has chronic renal failure, excretion of drugs is almost non-existent, and in patients with cardiac failure, reduced blood flow to the kidneys may decrease renal excretion of unchanged drugs and metabolites. Monitoring of patients is a must in these situations.
What are the factors that impact oral dosing of medication?
One dose of drug will give you a curve similar to this one. This means that you know the time that the drug needs for ADME, and that you know the therapeutic drug concentration required as well. But you want to keep the drug concentration in the therapeutic range to treat the disease.
So what do you do in regards to oral dosing of medication?
Take drugs every 4-6 hrs (as prescribed)
- ADME can overlapping
Ideally, you take your medication on time per instructions. This helps with maintaining the “_____” concentration of drug in your body, while the drug is going through ADME. The balance between dose and timing is structured so that plasma concentrations are, on _____, constant during treatment.
steady-state; average
A drug is not a medicine until it has an acceptable ____profile.
ADME
Sometimes unexpected things can happen (side effects) = needs lots of proof
Every drug is a potentially a ____, so ADME must not make it more so.
poison
Drug administration must be matched to the ____ condition, and applied sensibly with regard to ADME.
clinical
Drug levels in plasma/body are _______— never static.
dynamic
Metabolism usually detoxifies, but can ____ drugs or produce ____.
activate; toxins.
Most pharmacologically active drugs do not make it to the clinic because of ____ or ADME problems (which may be related).
toxicity
Intramuscular injection of drug is much faster for patient treatment than intravenous injection. True and false.
False
Active transport mechanisms are responsible for most aspects of drug distribution in the body. True and false.
False
Oxidation of drugs in the body is usually carried out by hepatic microsomal enzymes. True and false.
True
Drug metabolism occurs predominantly in the liver. True and false.
True
Phase I reactions include hydrolysis and oxidation. True and false.
True
Phase II reactions include hydrolysis and oxidation. True and false.
False
It is important to know what other medications a patient may be taking when adding new drugs to their treatment. True and false.
True
If you miss a dose in treatment, it is 100% fine if you simply double the dose when you remember. True and false.
False
How might dosages of medications be modified if a patient has liver issues?
Take less more frequently
