Pharmacokinetics Flashcards

1
Q

Describe how a drug works to have its desired effect safely

A

§ To achieve its effect a drug must first be presented in a suitable formulation at an appropriate site of ADMINISTRATION and then (usually) ABSORBED and DISTRIBUTED through the body to its site of action. For the effect to wear off the drug must almost always be METABOLISED and/or EXCRETED with these residues being VOIDED (REMOVED) from the body.

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2
Q

Ultimately, what is meant by pharmacokinetics

A

The journey of a drug through the body (ADME)

Administration
Distribution
Metabolism
Excretion

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3
Q

What does pharmacokinetics ultimately determine

A

Determines how much of the drug you need to put in so that it can get to the tissues to have its desired effect. Therefore it is important because it Determines ‘dose’ of drug available to tissues- therefore we need to understand how the body deals with the drug (pharmacokinetics) to ensure that we give the correct, safe dose

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4
Q

Summarise the drug administration routes

A

§ Drugs can be:
o Systemic – across the entire organism.
o Local – restricted to one area of the organism.
§ Sites used for administration are (examples left);
o Enteral – Gastro-intestinal administration.
o Parenteral – Outside the GI tract.
§ IV administration has a rapid onset of action but is invasive and requires training.

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5
Q

Why do we need to administer some drugs systemically

A

So that they can access tissues deeper in the body- hence we need to administer drugs to the bloodstream.

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6
Q

Why do we need to administer some drugs locally

A

Don’t need to access the bloodstream- they just need to act in a certain, readily accessible part of the body

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7
Q

List the drug administration routes

A
dermal
intramuscular
subcutaneous
intraperitoneal
intravenous
inhalation
ingestion 

all are paraenteral EXCEPT for ingestion which is enteral

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8
Q

Give some examples of systemic drugs

A

Cannabis- want it to enter bloodstream once inhaled- to get to the brain
aspirin
nicotine- diffuse into the skin and enter the bloodstream

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9
Q

Give some examples of local drugs

A

Salbutamol (Ventolin)
Betnovate ((Betamethasone)- steroid cream to reduce inflammation- don’t want it in the bloodstream
Antacids- only want them to work in the stomach

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10
Q

What do we need to think about when administering drugs

A

Where exactly we want the drugs to have their effects

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11
Q

Describe the two ways in which drugs can move around the body

A
bulk flow (i.e in the bloodstream, lymphatics or CSF)
diffusion (molecule by molecule- over short distances)
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12
Q

Describe bulk flow

A

Movement with the flow of fluid in that system
The chemical nature of the drug makes no difference to its transfer by bulk flow. The cardiovascular system provides a rapid long-distance distribution system for drugs

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13
Q

Why do we need drugs to be water and lipid soluble

A

Drugs have to traverse both aqueous and lipid environment
Compartments = Aqueous e.g. Blood, lymph, extra-cellular fluid, intra-cellular fluid

Barriers = Lipid i.e. cell membranes (epithelium/endothelium

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14
Q

How can drugs cross these lipid barriers

A

By diffusing directly through the lipid
By combination with a solute carrier (SLC) or other membrane transporter
By diffusing through aqueous pores formed by special membrane glycoproteins (aquaporins) that traverse the lipid
By pinocytosis- drug engulfed by membrane and flipped to the cytosolic side

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15
Q

Which of these methods of transport are most important for drugs

A

Diffusion through lipid and carrier-mediated transport.
Although diffusion through aquaporins is important in the transfer of gases, the pores are too small in diameter <0.5nm to allow most drug molecules (which usually exceed 1nm in diameter) to pass through. Consequently, drug distribution is not notably abnormal in patients with genetic diseases affecting aquaporins

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16
Q

Describe pinocytosis

A

Pinocytosis involves invagination of part of the cell membrane and the trapping within the cell of a small vesicle containing extracellular constituents. The vesicle contents can then be released from the cell, or extruded from its other side. This mechanism is important for the transport of some macromolecules (e.g insulin which crosses the BBB by this process), but not for small molecules.

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17
Q

Compare the rates of absorption for the different methods of administration

A

§ IP and IV are fast absorption while IM, dermal and subcutaneous are slower.

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18
Q

Describe the diffusional characteristics

A

Ability to cross hydrophobic diffusion barriers is strongly influenced by lipid solubility. Aqueous diffusion is part of the overall mechanism of drug transport, because it is the process that delivers drug molecules to and from the non-aqueous barriers.
The rate of diffusion of a substance depends mainly on its molecular size, the diffusion coefficient being inversely proportional to the square root of molecular weight.

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19
Q

What is the number of molecules crossing the membrane per unit time determined by

A

The permeability coefficient, P, and the concentration difference across the membrane. Permeant molecules must be present within the membrane in sufficient numbers and must be mobile if rapid permeation is to occur.
Thus, two physiochemical factors, contribute to P, namely solubility in the membrane (which can be expressed as a partition coefficient for the substance distributed between the membrane phase and the aqueous compartment). And diffusivity, which is a measure of the mobility of molecules within the lipid and is expressed as a diffusion coefficient.

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20
Q

Summarise the flow of drug through the body- using aspirin as the example

A

Aspirin- ingested- travels by bulk flow down to the stomach.
First barrier it encounters is the microvilli on the intestinal wall- needs to cross this (and then the capillary endothelium) to get into the blood (portal circulation)- goes to the liver to be metabolised- then goes to the systemic circulation
Encounters its third barrier (capillary wall) to get into the ECF
It may then need to cross the lipid bilayer to get into individual cells- however most drug targets are on the outside of the cell

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21
Q

What can non-polar substances dissolve in

A

Non-polar substances can freely dissolve in non-polar solvents i.e. can penetrate lipid membranes freely

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22
Q

What is important to remember about drugs

A

Most drugs are either weak acids or weak bases.

Therefore drugs exist in ionised (polar) and non-ionised (non-polar) forms – the ratio depends on the pH

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23
Q

What is important to remember when drugs cross epithelial barriers

A

An epithelial barrier, such as the G.I mucosa or renal tubule, consist of a layer of cells tightly connected t each other so that molecules must traverse at least two cell membranes (inner and outer) to pass from one side to the other.

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24
Q

What are the dissociation reaction for weak acids and weak bases

A

BH+ – B+ H+
pKa = pH +log10 BH+/B

AH – A- + H+
pKa= pH +log10 AH/A-

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25
Q

What is the dissociation constant pKa determined by

A

The dissociation constant (pKa) for the loss of protons are determined by the Henderson-Hasselbalch equation:

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26
Q

Show the ionisation of aspirin (weak acid) and morphine (weak base)

A

See diagram!

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27
Q

What are the effects of the ionisation states on the diffusional properties of the drug

A

The unionized forms of aspirin and morphine are going to be more lipid soluble than the ionized (charged) forms of the drugs. Charged molecules are more polar and thus less lipid soluble and will find it difficult to cross membranes.

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28
Q

What does the lipid solubility of the uncharged species, B or AH, depend on

A

Depends on the chemical nature of the drug; for many drugs the uncharged species is sufficiently lipid-soluble to permit rapid membrane permeation, although there are exceptions.

29
Q

Summarise the effect of ionisation states on drugs

A

§ IMPORTANT: Most drugs are either weak acids or weak bases.
o Therefore, drugs exist in ionised (polar) or non-ionised (non-polar) forms.
o The drug will be in dynamic equilibrium with the ionised and unionised form – the ratio of the ionised to un-ionised will then depend on pH of the environment and pKa of the molecules (tutorial).
o When pKa = pH, the drug is in perfect dynamic equilibrium (look below).

30
Q

In which environments will weak acids and weak bases be mostly unionised

A

pH will be a huge determinant of absorption of drugs across lipid membranes. Weak acids will be more unionized in acidic environments and weak bases will be more unionized in alkaline environments.

31
Q

Ultimately, what effects the ionisation state of the drug

A

pKa of drug DOES NOT change

pH of different body compartments DO change

32
Q

Explain the use of logs

A

Maths recap – logs are just another way of writing exponential equations. If y = log b(x), then the equation 4 = log 2(16) tells you that y (4) is the power of the exponent that b (2) is raised to in order to get x (16). If we rearrange the equation for the weak base above - then pKa-pH is the power of the exponent that 10 is raised to in order to get [BH+]/[B] i.e. 10[pKa-pH] = [BH+]/[B]. 10x is also often referred to as the antilog of x. In this case x = pKa-pH.

33
Q

Rearrange the Henderson-hasselbach equation so that we can find out the ratio of unionised:ionised for weak acids and weak bases

A

10^pKa- pH = AH/A- or BH+/B

34
Q

Describe ion trapping

A

Drugs can get localised in certain compartments.
Aspirin doesn’t diffuse well in the bloodstream (because it is ionised)- pH 7.4
Therefore we need to change its dose to ensure that a certain proportion of drugs reaches the tissues to illicit their intended effect

35
Q

Summarise pH partition and ion trapping

A

§ In order to undergo passive diffusion, the drug best diffuses when it is in unionised form.
§ (The pKa of the drug/molecule describes how readily the molecule dissociates (but the pH must be known to predict the level of ionisation)). So in medium A (stomach) the aspirin (pKa of 3.5) is mainly unionised and thus is absorbed but in medium B (late GI tract) the aspirin is mainly ionised and thus diffuses more slowly and so is absorbed more slowly.
§ Absorption might occur in the intestine if the aspirin had an enteric coating so it could reach the intestinal environment.

36
Q

For a drug to be excreted, which state does it need to be in

A

Ionised state- so that it stays in the kidney tubules and can’t cross the membrane and enter the blood.

37
Q

Why is pH partition not the main determinant of the site of absorption of drugs from the G.I tract

A

This is because of the enormous absorptive surface area of the villi and microvilli compared with the much smaller absorptive surface of the stomach is of overriding importance
Thus absorption of an acidic drug such as aspirin is promoted by drugs that accelerate gastric emptying and retarded by drugs that slow gastric emptying, even though the acidic pH of the stomach contents favours absorption of weak acids

38
Q

In reality, why does pH partitioning not create large gradients between compartments

A

First, assuming total impermeability of the charged species is not realistic, and even a small permeability will attenuate considerably the concentration difference that can be reached.
Second, body compartments rarely reach equilibrium. Neither the gastric contents nor the renal tubular fluid stands still, and the resulting bulk flow of drug molecules reduces the concentration gradients well below the theoretical equilibrium conditions.

39
Q

Where is pH partitioning particularly prominent

A

Renal excretion

Penetration of the BBB

40
Q

Q: Why might treatment with IV sodium bicarbonate increase aspirin excretion?

A

A: Increased urine pH ionises the aspirin making it less lipid soluble and less reabsorbed from the tubules, increasing its rate of excretion – remember IONISED drugs DO NOT pass through barriers easily!

41
Q

Describe some of the consequences of changing plasma pH

A

Increasing plasma pH (by administration of sodium bicarbonate) causes weakly acidic drugs to be extracted from the CNS and into the plasma
Conversely reducing plasma pH (carbonic anhydrase inhibitor) causes weakly acidic drugs to become concentrated in the CNS, potentially increasing their neurotoxicity.
This has practical consequences in choosing a means to alkalise urine in treating aspirin overdose

42
Q

List the factors the effect drug distribution

A

Regional blood flow
Extracellular binding (Plasma-protein binding)
Capillary permeability (tissue alterations – renal, hepatic, brain/CNS, placental)
Localisation in tissues

43
Q

Describe the percentage of cardiac output reaching each tissue

A
Liver 27%
Heart- 4%
Brain- 14%
Kidneys- 22%
Muscles- 20%
44
Q

Describe how blood flow can influence drug distribution

A

Highly metabolically active tissues
— denser capillary networks
When metabolically active, receives more cardiac output- more blood reaches that tissue- more drug delivered to this part.

45
Q

Describe Extracellular binding (Plasma-protein binding)

A
if the drug binds to plasma proteins- they can't access the tissues- therefore you need to adjust the dose so that the free form dose is enough to produce an effect
Acidic drugs ( like aspirin and warfarin) are heavily protein bound. 
Albumin is the most important plasma protein.
46
Q

When can plasma protein binding be dangerous

A

When you administer multiple drugs that can bind to plasma proteins. One drug can displace another drug- which can be dangerous because it could double the dose of a drug present in the bloodstream- need to consider this

47
Q

What free factors affect the binding of drugs to plasma proteins

A

Concentration of free drug
Affinity for the binding sites
Concentration of the plasma protein

48
Q

Which type of drugs are particularly plasma protein bound

A

Acidic drugs

Aspirin can be 50-80% plasma protein bound

49
Q

Compare the accessibility of water and lipid soluble drugs

A

Lipid soluble drugs have good access to all tissues (even the brain) and will be well distributed across body tissues.
Water soluble drugs have poor access to tissues and are dependant on saturable carrier proteins for access to tissues. As a result, they tend to be less well distributed across body tissues.

50
Q

Describes fenestrated capillaries

A

‘Fenestrated’ – an example of a tissue with this capillary structure is the glomerulus of the kidney. The kidney is a key tissue involved in excretion of chemicals including a large number of drugs. Fenestrations are circular windows within endothelial cells that allow for passage of small molecular weight substances including some drugs. This allows for some small drugs to pass from blood to kidney tubules which will enhance excretion of these drugs.

51
Q

Describe discontinuous capillaries

A

‘Discontinous’ – an example of a tissue with this capillary structure is the liver. The liver is one of the key metabolic tissues in the body and deals with metabolism of a huge variety of chemicals including the majority of drugs. A discontinuous capillary structure (big gaps between capillary endothelial cells) allows for drugs to easily diffuse out of the bloodstream and access the liver tissue.

52
Q

Describe tight junctions in capillaries

A

In some regions, especially the blood-brain barrier of the CNS, and the placenta, there are tight junctions between the cells, and the endothelium is encased in an impermeable layer of periendothelial cells (pericytes). These features prevent potentially harmful molecules from penetrating to brain of foetus and have major consequences for drug distribution and activity.

53
Q

What is the formation of fenestrated endothelium controlled by

A

Formation of fenestrated endothelium is controlled by a specific endocrine-gland derived vascular endothelial growth factor (VEGF)

54
Q

Describe the localisation in body tissues

A

Blood flow to the body fat is very low – approximately 2% of the cardiac output. As a result, at any given moment in time, only small amounts of the non-ionised drug is being delivered to the body fat.
The lipid solubility of the drug. We mentioned morphine above. Morphine can access the brain, which suggests it is fairly lipid soluble. However, its oil/water partition coefficient (i.e how well it dissolves in fat versus how well it dissolves in water) is 1. If 98% of the drug is being distributed to body water (i.e. other tissues) and only 2% of it to body fat, then very little will distribute to body fat. However, some drugs have high oil/water partition coefficients. For example some general anaesthetics can have an oil/water partition coefficient of 5000. As a result, the 2% that reaches the body fat will accumulate in this tissue very effectively. The drug that resides in the body fat will then slowly leak back into the bloodstream (due to the poor blood flow to this tissue and the preference of the drug for the body fat versus the aqueous blood)

55
Q

What can happen if a drug is really lipid soluble

A

If a drug is really lipid soluble- the drug may localise in adipose tissue and a large portion of the equilibrium will exist here
it will then slowly leak back into the blood- why some people feel drowsy suddenly 24 hours after taking general anaesthesia.

56
Q

Where else can drugs partition

A

Chloroquinines- affinity for retina and so taken up by retina
Tetracyclines- high affinity for calcium- taken up by bones and teeth

57
Q

What are the two major routes for drug excretion

A

Kidney and liver

58
Q

Summarise drug excretion

A

§ There are 2 major routes of drug excretion;
Ø Liver – some drugs are concentrated into bile (usually the large molecular weighted drugs that can’t be filtered in the kidneys).
Ø Kidneys – responsible for MOST drug excretion

59
Q

Summarise excretion in the kindeys

A
  1. Glomerulus – the drug-protein complexes are not filtered (too big) but the bioactive drug is.
  2. Proximal tubule – active secretion of acids and bases occur, some lipid-soluble drugs reabsorbed.
  3. Proximal and DTs – some lipid-soluble drugs reabsorbed. Note that some active secretion of drugs does occur.
60
Q

What does the reabsorption of lipid soluble drugs depend on

A

urine pH and extent of drug metabolism.

61
Q

describe the transporters involved in active secretion

A

OAT- transports acidic drugs in their negatively charged anionic forms (as well as various endogenous acids, such as uric acid)- transports drugs against conc gradient and so can reduce plasma conc nearly to zero
OCT- organic bases in their protonated form- facilitated transport

62
Q

What is the most effective method of clearing drugs in the kidneys

A

Because at least 80% of the drug delivered to the kidney is presented to the carrier, tubular secretion is potentially the most effective method of renal drug elimination. Unlike glomerular filtration, carrier-mediated transport can achieve maximal drug clearance, even when most of the drug is bound to plasma protein.
Because filtration involves isosmotic movement of both water and solutes, it does not affect the free conc of drug in the plasma- equilibrium between free and bound drug not disturbed- no tendency for the bound drug to dissociate

63
Q

Describe biliary excretion

A

Drug made more water soluble in the liver (hydrophilic drug conjugates include glucuronides), taken up by bile transporters (OATs and OCTs)- are concentrated in the bile by active transport systems - here they are concentrated in the bile and delivered to the intestine via the bile duct- where the glucuronide can be hydrolysed by gut bacteria- regenerating the free active, lipid-soluble drug- which can be reabsorbed and the cycle repeated, a process referred to as enterohepatic circulation- can re enter systemic circulation- leading to drug persistence.

64
Q

List some other routes for drug excretion

A

lungs, skin, gastrointestinal secretions,

saliva, sweat, milk, genital secretions

65
Q

Define bioavailability

A

Bioavailability (linked to absorption)

Proportion of the administered drug that is available within the body to exert its pharmacological effect

66
Q

Define apparent volume of distribution

A

Apparent volume of distribution (linked to distribution)
The volume in which a drug appears to be distributed
- an indicator of the pattern of distribution

67
Q

Define biological half life

A

Biological half-life (linked to metabolism/excretion)

Time taken for the concentration of drug (in blood/plasma) to fall to half its original value

68
Q

Define clearance

A

Clearance (linked to excretion)
Blood (plasma) clearance is the volume of blood (plasma) cleared of a drug (i.e. from which the drug is completely removed) in a unit time

(Related to volume of distribution and the rate at which the drug is eliminated. If clearance involves several processes, then total clearance is the sum of these processes.)

69
Q

What is half life linked to

A

How quickly you can metabolise and excrete the drug

Important when chronically prescribing the drug- know when to top it up