Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

pharm > pharmocokinetics > Flashcards

pharmocokinetics Flashcards

1
Q

What is pharcokinetics?

A

What the body does to the drug

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is absorption?

A
  • Passage of a drug from the site of administration into the plasma
  • Deals with the process for drug transfer into the systemic circulation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is bioavailability?

A

Fraction of the initial dose that gains access to the systemic circulation

Deals with outcome of a drug transfer into the systemic circulation (i.e. how much)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the common forms of drug administration?

A
  • Oral
  • Inhalational
  • Intranasal
  • Dermal
  • IV
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What are the 2 ways drugs can move around the body?

A

1) Bulk flow transfer (i.e. in the bloodstream)

2) Diffusional transfer (i.e. molecule by molecule across short distances)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

How do most drugs cross the lipid bilayer of cells?

A
  • Diffusion across lipid membranes or by carrier transport
  • Diffusion across aqueous pores is not a major movement route for drugs because most pores are <0.5nm in diameter and there aren’t many drugs that small
  • Majority of drugs tend to be more water soluble than lipid soluble (since most are taken orally so need to be water soluble)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

How does drugs being either weak acids or bases work for diffusion across membranes?

A
  • Most drugs are either weak acids or bases so exist in 2 forms: ionised and unionised
  • e.g. below, aspirin is a weak acid- when ionised it donates protons (H+)
  • Morphine is a weak base- when ionised it accepts protons i.e. B(Morphine)H+
  • The unionised form of the drug for both retains more lipid solubility and is more likely to diffuse across plasma membranes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What 2 factors contribute to whether a drug is ionised or not and how does this affect weak acids/bases?

A
  • Dissociation constant (pKa) for the drug and the pH in that particular body part
  • If the drug’s pKa and the tissue’s pH are equal, the drug will be equally dissociated between the 2 forms (50% ionised and 50% unionised)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Describe the ionisation of aspirin

A
  • Aspirin is a weak acid with pKa of 3.5 (most weak acids have a pKa between 3-5)
    • When pH is 3.5, aspirin is equally dissociated between the 2 forms
    • For weak acids as the pH decreases the unionised form starts to dominate
    • For weak acids as the pH increases the ionised form starts to dominate
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Describe the ionisation of morphine

A
  • Morphine is a weak base with pKa of 8 (most weak bases have a pKa between 8-10)
    • When pH is 8, morphine is equally dissociated between the 2 forms
    • For weak bases as the pH decreases the ionised form starts to dominate
    • For weak bases as the pH increases the unionised form starts to dominate
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Give a general rule for ionisation of weak acids/bases

A

A weak acid is more unionised in low pH areas like stomach and weak bases are more unionised in high pH areas like blood and urine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is ion trapping and how does our body work around it?

A
  • Weak bases will be poorly absorbed from stomach due to the low pH leading to high drug ionisation so will be ‘trapped’ there
    • However once drug reaches small intestine there will be many transport proteins that can absorb it from the GI tract
  • Weak acids could be absorbed from the stomach in their unionised state but they’ll become more ionised at physiological pH and become ‘trapped’ in the blood
    • However, most tissues have transport proteins that could move the ionised drug from the blood into the tissue
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

In which body parts are the most important carrier systems for drug action found?

A
  • Renal tubule (responsible for drug excretion)
  • Biliary tract (responsible for drug excretion)
  • Blood brain barrier (responsible for absorption of drugs into brain)
  • GI tract (responsible for absorption of drugs into bloodstream)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What factors influence distribution of drugs to tissues once they’re absorbed?

A
  • Regional blood flow
  • Plasma protein binding
  • Capillary permeability
  • Tissue localisation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What does regional blood flow mean?

A
  • Different tissues receive different amounts of cardiac output. At rest these are the percentages:
    • Liver- 27%
    • Heart- 4%
    • Brain- 14%
    • Kidneys- 22%
    • Muscles- 20%
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What does regional blood flow mean for drug distribution?

A
  • More drug is distributed to tissues with more blood flow
  • But, blood distribution to tissues can increase or decrease depending on circumstance e.g. during exercise more blood is diverted to muscles but after a large meal more is diverted to stomach and intestines
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What does plasma protein binding mean?

A
  • It is common for drugs to bind to plasma proteins in blood- some drugs can be 99% bound to them
  • Albumin is the most important plasma protein for this- it’s very good at binding acidic drugs
  • Only free drug is available to diffuse out of blood and access tissues- any drug bound to plasma proteins can’t leave the blood until it dissociated from the protein
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What 3 factors determine the amount of drug bound?

A
  • Free drug conc
  • Affinity for protein binding sites
  • Plasma protein conc
19
Q

What is albumin’s binding capacity?

A
  • Albumin conc in blood is 0.6 mmol/L
  • Each albumin protein has 2 binding sites so binding capacity is 1.2 mmol/L
20
Q

Why is albumin’s binding capacity important?

A

The plasma conc required for clinical effect of nearly all drugs is a lot lower than 1.2 mmol/L so plasma proteins are never saturated with drugs

So, differences in extent of plasma protein binding is mostly due to affinity for the protein binding sites for a particular drug

21
Q

What are the four types of capillary permeability?

A
  • Continuous
  • Blood brain barrier
  • Discontinuous
  • Fenestrated
22
Q

How do molecules interact with continuous permeability?

A
  • Most capillaries have the continuous structure with small gap junctions between lined up endothelial cells
  • If drugs are very lipid soluble they can diffuse across the endothelial and access the tissue
  • If they’re very small they can pass through the gap junctions
  • If they’re less lipid soluble, they need to be transported into the tissue via carrier proteins
23
Q

How do molecules interact with BBB?

A
  • There is a continuous structure with addition of tight junctions between endothelial cells
  • Makes the brain the most difficult tissue for drugs to gain access to
24
Q

How do molecules interact with discontinuous permeability?

A
  • e.g. in liver
  • Liver is one of most key metabolic tissues in body and deals with metabolism of many chemicals including most drugs
  • This capillary structure with big gaps between endothelial cells allows for drugs to easily diffuse out of bloodstream and access liver tissue
25
Q

How do molecules interact with fenestrated permeability?

A
  • e.g. in kidney glomerulus
  • Kidney is key tissue involved in excreting chemicals including many drugs
  • Fenestrations are circular windows within endothelial cells that allow for passage of small molecular weight substances including some drugs
  • Allows for small drugs to pass from blood to kidney tubules which enhances excretion of them
26
Q

What does tissue localisation mean?

A
  • Let’s take a very lipid soluble substance like delta9-tetrahydrocannabinol (delta9-THC: active component in weed)
  • delta9-THC will diffuse out blood down its conc grad into brain to produce effects and eventually an equilibrium is reached between blood and brain
  • Let’s now take a very water soluble drug accessing the brain- same applied of it diffusing down conc grad into brain from blood until it reaches equilibrium
  • Difference between these 2 drugs is the relative position of the equilibrium- brain has higher fat content but blood has higher water content
  • This means for delta9-THC the equilibrium will be more heavily weighted towards retention in brain and for water soluble drug it’ll be more towards plasma
  • So, you can say a larger proportion of delta9-THC will be ‘localised’ in brain compared with water soluble drug
27
Q

Why do we want to metabolise drugs and into what form?

A
  • Drugs must be excreted or else they would circulate in body forever and have continual effect
  • For them to be excreted, they should ideally not be lipid soluble so they’re retained in blood to be sent to excretion sites
  • However for therapeutic effectiveness we want drugs to have some lipid solubility so they can actually easily access tissues to produce their effects
  • Metabolism involves conversion of drugs to metabolites that are as water soluble as possible and easier to excrete
28
Q

What is the major metabolic tissue and how does it metabolise drugs?

A
  • Liver- it’s mainly cytochrome P450 enzymes in liver that are responsible for drug metabolism
  • Drug metabolism includes 2 kinds of biochemical reaction
29
Q

What are the two kinds of biochemical reaction of drug metabolism?

A
  • Phase 1 metabolism
  • Phase 2 metabolism
30
Q

What happens in phase 1 metabolism?

A
  • Main aim is to introduce reactive polar groups into their substrates to serve as a point of attack for the conjugating systems in phase 2
  • This occurs via oxidation, reduction and hydrolysis
    • most common is oxidation, but all oxidation reactions start with hydroxylation step by cytochrome P450 system to incorporate oxygen into non-activated hydrocarbons
31
Q

Where would hydroxylation step for aspirin happen?

A

Phase 1 reactions would likely incorporate one of these functional groups into the parent drug: -OH, -COOH, -SH, -NH2

Phase 1 reactions may also unmask existing functional groups

32
Q

What are pro-drugs?

A

Where parent drug has no activity on its own and only produces effect once it’s been metabolised to the respective metabolite- metabolism is required for the pharmacological effect

33
Q

What problem could active metabolites have?

A

Active metabolites could have negative unintended effects

Liver damage as a result of paracetamol overdose is due to a certain metabolite and not paracetamol itself

34
Q

What happens in phase 2 metabolism?

A
  • Result of phase 2 metabolism is attachment of a substituent group
  • The resulting metabolite is nearly always inactive and much less lipid soluble than phase 1 metabolite
  • This facilitates excretion in urine or bile
  • Phase 2 enzymes are mostly transferase enzymes to transfer the substituent group onto the phase 1 metabolite
35
Q

What is first pass (presynaptic) metabolism?

A
  • Problem for orally administered drugs- they’re mostly absorbed from small intestine and enter hepatic portal blood supply where they first pass through liver before reaching systemic circulation
  • At this point, the drug can be heavily metabolised resulting in little active drug reaching blood (although first pass metabolism is a prerequisite for activity of prodrugs)
36
Q

What is the solution to presynaptic metabolism?

A

Administer a larger drug dose to ensure enough drug reaches systemic circulation

HOWEVER:

The extent of first pass metabolism varies among individuals so the amount of drug reaching bloodstream also varies

As a result, drug effects and side effects are difficult to predict

37
Q

What are some different ways drugs can be excreted?

A
  • Kidney (in urine)- most important
  • Liver (in bile)- also most important
  • Lungs (basis of alcohol breath test is to measure alcohol excreted via lungs)
  • Breast milk (care needs to be taken therefore that drugs excreted in milk don’t affect baby)
38
Q

What are the 3 major routes for kidney drug excretion?

A
  • Glomerular filtration
  • Active tubular secretion (or reabsorption)
  • Passive diffusion across tubular epithelium

The extent to which these 3 processes are used by drugs differs a lot- this along with rate of metabolism is why drugs have different excretion rates

39
Q

What does glomerular filtration do?

A
  • Allows drug molecules of weight below 20,000 to diffuse into glomerular filtrate
  • Means drugs of this weight have this additional excretion route compared with larger drugs resulting in quicker excretion rate
40
Q

What does active tubular secretion do?

A
  • The most important method for kidney drug excretion
  • Where only 20% of renal plasma is filtered at glomerulus, 80% of renal plasma passes onto blood supply of proximal tubule so more drug is delivered to PCT than glomerulus
  • Within PCT capillary endothelial cells there are 2 active transport carrier systems
    • One is very effective at transporting acidic drugs
    • One is very effective at transporting basic drugs
  • Both are good at transporting drugs against a conc gradient
41
Q

What does passive diffusion across tubular epithelium do?

A
  • Leads to reabsorption from kidney tubule
  • As glomerular filtrate moves through kidney, most of water filtered (90%) is reabsorbed
  • If drugs are lipid soluble, they’ll also be reabsorbed, passively diffusing back into blood across tubule
42
Q

What are the 2 factors influencing the extent of reabsorption?

A
  • Drug metabolism- phase 2 metabolites tend to be a lot more water soluble than the parent drug and so are less well reabsorbed
  • Urine pH- this can vary from 4.5-8 and based on pH partition hypothesis mentioned previously, acidic drugs are better reabsorbed at lower pH and basic drugs are better reabsorbed at higher pH
43
Q

How does liver excretion work?

A

Liver cells transport drugs from plasma into bile primarily via transporters similar to those in kidney

It’s particularly effective at removing phase 2 glucuronide metabolites

Drugs transported to bile are then excreted into intestines and eliminated in faeces

44
Q

What is enterohepatic recycling and what does it do?

A

It significantly prolongs drug effect

An example:

1) A glucuronide metabolite is transported into bile

2) Metabolite is excreted into small intestine where it’s hydrolysed by gut bacteria releasing glucuronide conjugate

3) Loss of glucuronide conjugate increases the lipid solubility of the molecule

4) Increased lipid solubility allows for greater reabsorption from small intestine back into hepatic portal blood circulation back to liver

5) The molecule returns to liver where a proportion is re-metabolised, but a proportion may escape into systemic circulation to continue to have effects on body

pharm (10 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions