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Foundations 511 > Pharmacology Kinetics > Flashcards

Pharmacology Kinetics Flashcards

1
Q

What factors determine the drug’s plasma concentration versus time profile

A

-absorption, distribution, metabolism, excretion
->metabolism and excretion refers to elimination

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2
Q

What is the importance of ADME for clinicians

A

-prescribing errors are made in 7% of prescriptions written
->with 50% of patients admitted to hospitals
-many errors are dosing errors, resulting in not understanding ADME principles

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3
Q

What is absorption

A

-the net movement of drug from the site of administration into the bloodstream
-> no absorbption after intravenous injection

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4
Q

What is distribution

A

-net movement of drug from the bloodstream into organs and tissues

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5
Q

What are routes of administration

A

Parenteral
->bypassing the intestine

Enteral
->intestinal

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6
Q

What are the different types of parenteral administrations

A

-IV
->intravenous injection
-Intramuscular injections
-Subcutaneous injections
-Topical
->transdermal, inhalation, insufflation, eye/eyedrops
-Buccal/sublingual(goes straight to systemic circulation, initially avoiding the liver)

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7
Q

What are the different types of enteral administrations

A

-Oral(by mouth)
-Rectal
->can be absorbed parenterally by going through GI to lymphatic and bypassing the liver and going to the systemic circulation

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8
Q

What are pharmaceutics

A

-pharmaceutics accounts for a drugs GI tract transit time

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9
Q

What are the pharmaceutics of the stomach, proximal small intestine and the large intestine

A

Stomach
-pH of 1-2 with food, pH of 3-5 when fasting, it takes 0.5-3 hours

Proximal small intestine
-pH of 6
->it takes 3 hours

Large intestine
->pH of 6.8-7
->it takes 12-24 hours

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10
Q

What is drug formulation

A

-it is used to optimise absorption

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11
Q

What sort of factors play into drug formulation

A

-drug particle size affects
dissolution extent and rate
->small drugs packed into a pellet will have a large surface area and dissolve faster or be available sooner to the body

-protective coatings on tablets and capsules
->protect them from dissolving in stomach and only when it reaches the small intestine

-slow and fast release pellets, polymers, osmotic technology

-depot injections
->lipid soluble injections
->oil droplets will sit in the muscle and will have slow release over many days and many weeks
->this is used with drugs treating schizophrenia

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12
Q

Where must all drugs absorbed from the stomach and intestines into the blood enter

A

-they enter the portal vein
->they then pass through the liver before reaching the systemic(general) circulation

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13
Q

Does metabolization in the liver result in loss of drug activity

A

-yes but now always
->you lose a certain percentage of the dose on one pass through the liver

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14
Q

Do orally-administered drugs pass through the liver before entering the systemic circulation

A

-yes
->drugs may pass through the liver on each circuit
->on average, about once every four circuits, the drug passes through the liver again

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15
Q

What is first pass metabolism

A

-the loss of drug to metabolism on its first passage through the liver

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16
Q

What is the definition of oral bioavailability

A

-the fraction of an oral dose of a drug that reaches the systemic circulation as an intact drug

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17
Q

How would you calculate oral bioavailibility

A

-fraction escaping the gut x fraction escaping the liver
->f(g) x f(H)

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18
Q

How does lymphatic absorption occur

A

-some drugs can interact with a lipoprotein chylomicron
->the chylomicron carries through lymphatic vessel, bypassing the liver
->this will increase the oral bioavailability of that drug

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19
Q

Do drugs need to be lipid soluble

A

-yes
->because they need to have an ability to diffuse through lipids
->they must also be water soluble to an extent

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20
Q

Do charged drugs diffuse across lipid bilayers

A

-no

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21
Q

Are most drugs weak acids or weak bases

A

-yes
->they can exist in a charged form
->charged molecules do not diffuse across the lipid bilayers
->they are in the form depending on the pH and the pKa

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22
Q

What is the pKa

A

-the pH at which 50% of the drug is ionized

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23
Q

What does a weak acid do in the stomach

A

-it is rapidly and extensively absorbed from the stomach

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24
Q

What does the absorption of weak bases look like in the stomach

A

-they are slowly and unpredictably absorbed from the stomach
->in the small intestines, they are better absorbed

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25
Q

When is concurrent use of drugs like laxatives problematic

A

-when they reduce GI transit time reducing absorption
->problematic for drugs which dissolve very slowly(griseofulvin)
->drugs that are absorbed by active transport(vitamin B)
->polar drugs with low lipid solubility(antibiotics)

26
Q

How does polarity affect a drug

A

-more Nitrogen and Oxygen atoms=higher polarity=less lipid-soluble

27
Q

What is a logP value

A

-how effectively a drug will partion from a water layer into an oil layer
-logP 0 means that it is in equlibirum in water and oil
->anything above 0 means that it dissolves more extensively in oil

-higher logP value means the drug is more lipid soluble in its neutral form or non-charged form

28
Q

What is polar surface area

A

-it refers to 3 dimensional diagram of the drugs
-it is the area of composed of red and blue(outer shells of electrons)
->the more red and blue, the larger the polar surface area

-the lower the polar surface area, the more lipid soluble the uncharged form of the drug is

29
Q

What is Fick’s Law of Diffusion

A

-a drug will flow from an area of high concentration to an area of lower concentration
->with the rate of flow being higher with a larger gradient

30
Q

Can drugs that are more lipid soluble move more quickly and distribute more rapidly in cells, tissues, etc?

A

-yes

31
Q

How does equilibrium differ between a highly-perfused tissue and a poorly-perfused tissue?

A

-drug reaches peak tissue concentration (equilibrium) soon after drug concentration peaks in the plasma for a highly perfused tissue

-for a poorly-perfused tissue, there is a lag
->it needs a continuous dose to reach that equilibrium
->but after a single dose, drugs may never reach equilibrium concentration in the tissue

32
Q

How does drug diffusion back to plasma from tissue differ from a highly perfused tissue to a low perfused tissue

A

-it is much more rapid for the highly perfused tissue

33
Q

What does it mean for the plasma concentration of the drug if the drug more extensively distributes from the plasma into the tissues

A

-it means there is a smaller amount of the drug remaining in the plasma
->and a lower concentration of the drug remaining in the plasma

34
Q

What is the apparent volume of distribution of drugs

A

-the apparent volume of plasma that would contain the total body content of the drug at a concentration equal to that in the plasma once distribution is complete

35
Q

What are the factors that determine the AVd or the apparent volume of distribution?

A

-fat is present
->drug is lipid soluble and will distribute into the fat
-there is soluble plasma proteins as well
->they have binding sites for acidic and basic drugs
->they are significant in the plasma and can bind to the drugs in the plasma, preventing absorption into the tissue

36
Q

What happens to tissue water in an elderly person and fat and plasma albumin? What impacts does this have

A

-tissue water is reduced, fat isn increased and plasma albumin is reduced

-if administered same dose as in a younger healthy individual, you get reduced plasma protein bounding and more protein present in fat but lower concentrations in plasma(unbound) and tissue water

-the apparent volume distribution is increased because there is more of the drug in the fat

37
Q

What is the definition of drug elimination

A

-the irreversible removal of a drug compound from the blood so that it is no longer able to exert a pharmacological effect
->excretion fo unchanged drug into urine, faeces, expired air, sweat
->most important is renal elimination

38
Q

Can metabolites be produced during drug elimination

A

-yes
->enzymatic metabolism of the parent drug into a different chemical compound is a metabolite
->it goes through the liver to produce this metabolite

38
Q
A
39
Q

What is drug clearance

A

-refers to the volume of plasma cleared of drug in inut time
->ml/min or l/h

-each organ clearing its drug has its own drug clearance value

-for most drugs, the total body clearance is sum of renal clearance and hepatic clearance
->if others involved too, you add those organ clearances too

40
Q

What is the organ extraction ratio

A

-the proportion of drug removed by a single transit of that drug through the organ
->it is between 0 and 1

41
Q

How do you calculate clearance

A

-clearance=Q(bloodflow through organ) x organ extraction ration

42
Q

How much of the blood volume is leaked from nephron into Bowman’s capsure in terms of the drug

A

-10%
->the 90 % of the blood containing the 90% of the drug passes out of the Bowman’s capsule and the walls of the capillaries

43
Q

What factors affect renal drug clearance

A

-clearance by glomerular filtration
->drugs of MW<20, 000 pass from the blood into the filtrate in the Bowman’s capsule
->only drug molecules not bound to plasma proteins can be filtered

-clearance by secretion
->transporters exist for acidic and basic drugs that pump these drugs from the circulation into the tubules
->this is a major route of excretion
->only drug molecules that are not bound to plasma proteins can be secreted

44
Q

What factors affect GFR

A

-it changes with age, sex and disease

45
Q

What happens to fraction of drugs unbound with age and disease

A

-it changes in a variety of conditions due to age and disease
->for example, serum albumin drops 20% from 20 to 80 and acidic drugs are most affected

46
Q

Does fraction of drugs reabsorbed change with urinary pH

A

-yes
->a possible increase in pH can reduce the drug reabsorption

47
Q

What does the hepatic extraction ratio depend

A

-fraction of drugs unbound
->only drug molecules that are not bound to plasma proteins can be metabolized

-hepatic bloodflow
->with slower blood flow, drug is in contact with liver enzymes for longer
->this increased contact means with enzymes means increased metabolism and extraction from the liver

-intrinsic clearance
->theoretical maximum limit of liver enzyme activity versus a particular drug
->it has a value of litre/hour

48
Q

Why are drugs metabolized

A

-so it is easier to excrete

49
Q

What are the different phases of drug metabolism

A

-there are two phases

-phase 1 is the functionalisation step
->phase 1 gets the drug ready for phase 2
->for example, it can introduce a hydroxyl group
->making the metabolite easier to excrete

Phase 2
->it is a conjugation step
->creates a conjugate that is very water soluble

50
Q

What are the major conjugation steps in Phase 2 of metabolism

A

-glucuronic acid(major)
-sulphate(major)
-acetyl group(minor)
-glutathione(detoxification)

51
Q

Is phase one a major determination of the Clint value

A
52
Q

Is there significant phase 1 enzyme variability in different individuals

A

-yes
->causing differences in drug responses for different individuals

53
Q

What are the different types of phase 1 reactions

A

-oxidations, reductions, hydrolysis, hydrations, isomerisations

54
Q

What enzymes carries out most oxidations?

A

-they are carried out primarily by the cytochrome P450 enzyme

55
Q

Where are cytochrome 450 enzymes mostly found

A

-in the liver

-cytochrome P450 3A4 is one of the most important and 2D6
->note CYP450(3A4) makes up 30% and CYP450(2D6) makes up 5%
->these two are involved in 60% of all oxidation processes

56
Q

What are some endogenous factors affecting CYP enzymes

A

-genetic polymorphisms
->differences between races/ethnicity
->poor/extensive metaboliser phenotypes

-age
->some CYPs are low or missing in neonates
->CYP also decreases with age

Sex
->differences in drug metabolism due to hormones

Bodyweight
->hepatic clearance varies with bodyweight due to liver size

Disease
->CYP reduced with liver diseases
->infections, endocrine disorders often reduce CYP

57
Q

What is the area under the curve of a concentration time profile after oral administration mean

A

-it is the oral bioavailability

58
Q

Can CYP inhibition occur

A

-yes
->grapefruit juice inhibits CYP3A4 irreversibly

59
Q

What are external factors affecting CYP enzymes

A

-cigarettes, charcoal-broiled beef, cruciferous vegetables affect CYP1As

-pesticides, barbiturates affect CYP2B

-many drugs, including St. John’s wort affect CYP3As

60
Q
A

Foundations 511 (8 decks)

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