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PHAR > PHAR2 - Pharmacokinetics > Flashcards

PHAR2 - Pharmacokinetics Flashcards

1
Q

Define absorption.

A

Movement of a drug from the site of administration into theblood plasma.

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2
Q

Define bioavailability.

A

Proportion of the initial drug dosage which gains access to systemic circulation.

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3
Q

What are the differences between absorption and bioavailability?

A

Absorption is the process by which the drug enters systemic circulation. Bioavailability is the amount of drug that enters systemic circulation.

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4
Q

Give types of drug administration methods.

A

Intra-venous. Oral. Inhalation. Dermal (percutaneous). Sub-lingual.

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5
Q

Which type of drug administration has the highest drug bioavailability?

A

Intravenous as drug is injected directly into systemic circulation.

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6
Q

What method does intra-venous drug administration use to move drugs around the body?

A

Bulk flow transfer.

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7
Q

What are the two methods by which drugs move around the body?

A

Bulk flow transfer and diffusional transfer.

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8
Q

What are the four main mechanisms for diffusional transfer?

A

Diffusion through lipid, diffusion through aqueous pores, carrier proteins and pinocytosis.

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9
Q

Describe intra-venous drug administration.

A

Drug injected directly into systemic circulation.

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10
Q

Describe oral drug administration.

A

Drug is administered through the mouth.

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11
Q

Describe inhalation all drug administration.

A

Drug is administered as small droplets via the nose or mouth.

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12
Q

Describe dermal or percutaneous route of drug administration.

A

Drugs that are administered via the skin e.g. steroid creams.

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13
Q

Describe sub-lingual drug administration route.

A

Drug that is administered by placing on tongue therefor becomes absorbed into blood.

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14
Q

What is pinocytosis?

A

Type of endocytosis. Cell membrane is used to form vesicle which delivers molecules from one side to the other side of the membrane.

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15
Q

What are the two main diffusional transfer methods used for drug molecules?

A

Diffusion through lipid membrane. Facilitated diffusion via carrier proteins.

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16
Q

What chemical property affects drug absorption, drug penetration and drug elimination?

A

Lipid solubility.

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17
Q

Which lipid membranes are required to be crossed by drugs that are orally administered?

A

Into the microvilli of the small intestine.
Into the blood vessel via the wall.
Accessing of target tissue.

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18
Q

Which lipid membranes are required to be crossed by drugs that are inhalationally administered?

A

Membrane of alveolar sac. Membrane of blood vessel. Membrane of target tissue.

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19
Q

Which lipid membranes are required to be crossed by drugs that are intra-nasally administered?

A

Mucous membranes of nasal sinus. Wall of blood vessel wall. Accessing target tissue.

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20
Q

What is the main factor affect overall lipid solubility of the drug?

A

Ionised to unionised ratio.

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21
Q

Give one example of weak acidic drug and one weak basic drug.

A

Aspirin - weak acid.

Morphine - weak base.

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22
Q

What happens to aspirins chemical structure at physiological pH?

A

Aspirin becomes ionised. It is a weak acid so donates H+ forming anion.

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23
Q

What happens to morphines chemical structure at physiological ph?

A

Morphine is weak base so accepts proton. Forms cation.

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24
Q

Explain link between ionised/unionised and lipid/water solubility.

A

Ionised chemical species have an increased water solubility and decreased lipid solubility. Polar region in ionised species interacts with polar water molecules.

Unionised chemical species have an increased lipid solubility and decreased water solubility. Non polar regions are lipid soluble.

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25
Q

Discuss the effect of pH on the ionisation of weak acids.

A

Acidic conditions favour unionised weak acids. Basic conditions favour ionised weak acids.

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26
Q

Discuss the effect of pH on weak bases.

A

Acidic conditions favour ionised weak bases. Basic conditions favour unionised weak bases.

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27
Q

What is the purpose of the Henderson-Hasselbach equation?

A

Allows determination of the ionised to unionised ratio for weak acids and weak bases.

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28
Q

Define a weak acid.

A

Partial dissociation into protons.

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29
Q

Define a weak base.

A

Partial association with protons.

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30
Q

What is physiological pH?

A

7.4

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31
Q

Calculate the ionised to unionised ratio of aspirin in stomach.
pKa of aspirin - 3.5
pH of stomach - 3.0
What does the value tell us? What does the drug do?

A

10^(3.5-3.0) = 3.16
Greater than 1 means there is more unionised acid than ionised acid. More unionised means it is lipid soluble. Passes across lipid membrane of stomach so can move to other body compartments.

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32
Q

Calculate the ionised to unionised ratio of morphine in blood.
pKa of morphine - 8.0
pH of blood - 7.4
What does the value tell us? What does the drug do?

A

10^(8.0-7.4) = 3.98
Greater than 1 means there is more ionised base than unionised base. Ionised base has lower lipid solubility so remains in blood as it cannot cross lipid membrane of blood vessel.

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33
Q

Discuss the pH partition hypothesis.

A

Drugs are able to become trapped in different body compartments based on the pH in that compartment and whether the drug is acidic or basic.

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34
Q

Is pH high or low in body compartments that trap acidic drugs? Why?

A

Acidic drugs trapped in high pH body compartments. High pH means more ionised drug. More ionised drug means less lipid soluble. Unable to cross lipid membranes so cannot move out of body compartment.

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35
Q

Is pH high or low in body compartments that trap basic drugs? Why?

A

Basic drugs are trapped in body compartments with low pH. Low pH means more ionised basic drug. More ionised means less lipid soluble. Unable to cross lipid membranes so remains trapped in body compartment.

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36
Q

What is the role of carrier transport systems in drug absorption?

A

Uses carrier proteins that are transmembrane to move drugs across lipid membranes. Process is facilitate diffusion.

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37
Q

Give four examples of locations of carrier proteins.

A

Renal tubule. Biliary tract. Blood-brain barrier. Gastrointestinal tract.

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38
Q

Define the difference between systemic and local effects.

A

Systemic effects - blood enters systemic circulation and can have effects in various locations.
Local effects - blood has localised effects in one area and usually does not enter systemic circulation.

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39
Q

Discuss advantages of local effects over systemic effects.

A

Drug delivered directly to site of action. High dosage can be administered without fear of systemic side effects.

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40
Q

Can a drug effect be completely localised? If no/yes, why?

A

No as most tissues have some access to blood. Results in drug entering blood so can be circulated systemically.

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41
Q

What factor increases the likelihood of a drug for local effects, causing systemic effects?

A

Drugs with high lipid solubility are likely to enter blood rapidly as they can cross lipid membrane of blood vessel.

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42
Q

Give two examples of drugs taken via the inhalational route and whether their effects are systemic or local.

A

Salbutamol - local - dilates airways.

Cannabis - systemic - alters function of brain.

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43
Q

Give two examples of drugs taken via the oral route and whether their effects are systemic or local.

A

Aspirin - systemic - analgesic/pain relieving effect.

Antacid - local - neutralises stomach acid.

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44
Q

Give two examples of drugs taken via the trans-dermal route and whether their effects are systemic or local.

A

Betnovate Steroid - local - anti inflammatory effect.

Nicotine - systemic - alters brain functioning.

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45
Q

What is drug distribution?

A

The process by which drugs are distributed to different body compartments following drug absorption.

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46
Q

What are the four factors that affect drug distribution?

A

Regional blood flow.
Plasma protein binding.
Capillary permeability.
Tissue localisation.

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47
Q

Discuss the effect of regional blood flow on drug distribution.

A

Body compartments that receive more blood of the cardiac output would receive more drug in systemic circulation.

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48
Q

Which organ receives the greatest regional blood flow?

A

Liver.

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49
Q

Which organ receives the least regional blood flow?

A

Heart.

50
Q

Discuss the effect of plasma protein binding on drug distribution.

A

Drugs bind to plasma proteins in the blood as they enter systemic circulation. This prevents the, from leaving the blood, which means the drug is not distributed to different tissues. Leaving blood to enter tissues requires unbinding from plasma proteins.

51
Q

What is the most common plasma protein?

A

Albumin.

52
Q

What factors affect drug binding to plasma proteins ?

A

Free drug concentration.

Affinity of drug for protein binding sites. Plasma protein concentration.

53
Q

What type of drugs do albumin plasma proteins commonly bind to?

A

Acidic drugs.

54
Q

What is the concentration of albumin in the blood and the binding capacity?

A

Concentration is 0.6 mmol/L. Each albumin protein contains two binding sites. Binding capacity is therefore 1.2 mmol/L.

55
Q

What factor affecting plasma protein binding is least important and why?

A

Plasma protein concentration. Plasma proteins are unlikely to become saturated with drug molecules as their concentration is relatively high. Factors such as drug concentration and affinity of binding play larger role in determining how much drug is bound to plasma protein.

56
Q

What are the four types of capillary structure?

A

Continuous.
Blood-brain barrier.
Fenestrated.
Discontinuous.

57
Q

Why does capillary permeability affect drug distribution?

A

Capillaries with higher permeability mean drugs can be distributed greater.

58
Q

Discuss structure of continuous capillaries.

A

Endothelial cells aligned in single file. Small water filled gap junctions.

59
Q

Discuss movement of drugs across continuous capillaries.

A

Highly lipid soluble drugs cross endothelial cells readily. Water soluble small drugs are able to move across capillary through water filled gap junctions.

60
Q

Discuss structure of capillaries at blood-brain barrier.

A

Continuous endothelial cells in single file. Tight junctions between endothelial cells. Very few drug molecules able to move past due to tight junctions. Require drugs to be extremely lipid soluble. Ensures safety of brain functioning.

61
Q

Discuss fenestrated structure of capillaries.

A

Endothelial cells with windows within the cells.

62
Q

Which body region contains a fenestrated capillary structure?

A

Kidney glomerulus.

63
Q

Discuss drug access of a tissue and the fenestrated capillary structure.

A

Fenestrated capillary structure provides easy access of drug to the tissue. Vital in kidney to ensure drug excretion/elimination.

64
Q

Discuss discontinuous capillary structure.

A

Large gaps present between endothelial cells making up the capillary wall.

65
Q

Discuss drug access in discontinuous capillaries.

A

Easy access for drugs as they can move readily between the large gaps.

66
Q

Give example of tissue with discontinuous capillaries. Discuss its importance in this tissue.

A

Liver. Vital for drug metabolism meaning drug must readily enter this tissue.

67
Q

Discuss the effect of tissue localisation in drug distribution.

A

Concerns where drugs remain localised, which depends on chemical properties e.g. lipid/water solubility.

68
Q

Discuss process of tissue localisation for drugs localising in adipose tissue.

A

Drugs with high lipid solubility with localise in adipose tissue and remain there.

69
Q

What two factors affect drug localisation in adipose tissue?

A

Blood flow to adipose tissue is low suggesting little drug localises in this tissue. Lipid solubility - drugs with higher lipid solubility more likely to localise in adipose tissue.

70
Q

What does the oil/water partition coefficient tell us?

A

Quantifies how lipid or water soluble a drug is.

71
Q

What do different values for oil/water partition coefficient tell us? E.g less than or more than 1.

A

Equal to 1 - equally soluble in water and lipid.
Less than 1 - more water soluble.
More than 1 - more lipid soluble.

72
Q

A general anaesthetic has a high oil/water partition coefficient. What does this mean?

A

Highly lipid soluble. Likely to localise in adipose tissue depending on cardiac output.

73
Q

Morphine has a oil/water partition coefficient of 1. What does this mean?

A

Equally lipid and water soluble. Likely to form equilibrium between blood plasma and adipose tissue.

74
Q

Define the process of metabolism and what it entails.

A

Process by which large molecules are broken into smaller molecules. Aids the elimination of drugs.

75
Q

What would happen if drugs were extremely lipid soluble?

A

Therapeutic effects would occur strongly and for long duration as drug is able to access all tissues by crossing lipid membranes.

76
Q

What would happen if a drug is not lipid soluble at all?

A

Unable to cross lipid membranes and have desired effects in specific tissues however is effectively retained in the bloodstream so it eliminated rapidly.

77
Q

What enzymes are mainly responsible for drug metabolism in the liver?

A

Cytochrome P450 enzymes.

78
Q

What is the main purpose of hepatic metabolism?

A

To produce water soluble metabolite, aiding the excretion of drug from the body.

79
Q

What are the two stages of hepatic metabolism? Describe purpose of each stage.

A

Phase 1 - introduces reactive group to drug.

Phase 2 - adds a conjugate to the reactive group making it more water soluble.

80
Q

What are the three types of chemical reaction that occur in phase 1 metabolism?

A

Oxidation. Reduction. Hydrolysis.

81
Q

Define lipophilic.

A

Lipid loving.

82
Q

What is a active metabolite?

A

A product of metabolism that is able to produce pharmacological effects.

83
Q

What is a pro-drug?

A

Drugs that only produce pharmacological therapeutic effects once metabolism is underway and metabolites have been produced. Parent drug is not active.

84
Q

Give one example of pro-drug.

A

Liver damage caused by paracetamol overdose is specifically caused by metabolite produced in paracetamol metabolism not paracetamol itself.

85
Q

What is the most common type of chemical reaction for phase 1 metabolism?

A

Oxidation.

86
Q

Which initial step is required for oxidation reactions as part of phase 1 metabolism?

A

Hydroxylation. Useful for non-activated hydrocarbons which need oxygen incorporated into it.

87
Q

What compound is formed by the hydroxylation of aspirin?

A

Salicylic acid.

88
Q

What are the key differences between phase 1 metabolites and phase 2 metabolites?

A

Phase 2 metabolites have a decreased lipid solubility and increased water solubility.

89
Q

Which group of enzymes are primarily involved in phase 2 metabolism?

A

Transferases.

90
Q

What are two common ways in which drugs are excreted?

A

Via urine or bile.

91
Q

Name four types of reactions possible for phase 2 metabolism?

A

Glucuronidation. Glutathione conjugation.
Acetylation.
Sulfation.

92
Q

What is first pass metabolism?

A

Drugs can be metabolised immediately in the liver if they enter the hepatic portal blood supply from the small intestine. Common for orally administered drugs.

93
Q

What type of drug is benefitted from first pass hepatic metabolism?

A

Pro-drugs. Require metabolism to cause therapeutic effects.

94
Q

What is one problem faced by drugs due to first pass hepatic metabolism? What is the solution? What is the problem with the solution?

A

Problem - little drug may reach systemic circulation if already metabolised.
Solution - large dose administered to ensure drug reaches systemic circulation.
Problem - rate of first pass metabolism differed so cannot conclude how much drug reaches circulation. Also may cause side effects.

95
Q

Give four ways in which drugs can be excreted from the body, naming tissues involved.

A

Via lungs - e.g. alcohol breath test.
Via breast milk.
Via kidney through urine.
Via liver through bile.

96
Q

What are the three major routes for drug excretion via the kidney?

A

Glomerular filtration.
Active tubular secretion.
Passive diffusion across tubular epithelium.

97
Q

What factor affects drug excretion via glomerular filtration at the kidney?

A

Size of the drug molecule. Only small drug molecules can diffuse into glomerular filtrate.

98
Q

What factor affects active secretion as an excretion route for drugs at the kidney?

A

Availability of transporter proteins.

99
Q

What factor affects passive reabsorption as an excretion method for drugs at the kidney?

A

pH of urine and how far drug metabolism has gone.

100
Q

How are small drug molecules excreted faster from the kidneys? Name processes involved.

A

Can be removed by multiple routes including glomerular filtration as the drug molecule is small.

101
Q

Which route is considered most important for drug excretion via the kidney?

A

Active tubular secretion.

102
Q

What percentage of blood is filtered at the glomerulus? What happens to the rest?

A

20% filtered at glomerulus. 80% passes to proximal tubule.

103
Q

How do proximal tubule capillary endothelial cells aid active secretion?

A

Contain transporter carrier proteins for acidic and basic drugs.

104
Q

How is a drug reabsorption from the kidney tubule?

A

Passive diffusion across tubular epithelium.

105
Q

What molecule is mainly filtered from the glomerular filtrate?

A

Water

106
Q

What is the chemical property of drugs that affects their reabsorption at the kidney? State the effect.

A

Lipid solubility. Drugs with high lipid solubility are passively diffused across the tubular epithelium so re-enter the blood.

107
Q

What are two main factors affecting passive diffusion/reabsorption? (Not lipid solubility directly)

A

Drug metabolism - phase 2 metabolism produces water soluble compounds that would not be reabsorbed.
Urine pH - affects reabsorption based on acidity or basicity of drugs.

108
Q

What pH of urine is needed for more effective reabsorption of acidic/basic drug?

A

Low pH - acidic drugs better reabsorbed so not lost.

High pH - basic drugs better reabsorbed so not lost.

109
Q

State what would happen if pH of urine increases for excretion of acidic drug?

A

Alkaline conditions cause acidic drug to become ionised. Ionised drug is more water soluble and less lipid soluble. Less lipid soluble means less reabsorption due to less passive diffusion across tubular epithelium. More drug excreted so fewer therapeutic effects.

110
Q

State what would happen if pH of urine decreases for excretion of basic drug?

A

Alkaline conditions cause basic drug to become ionised. Ionised drug is more water soluble and less lipid soluble. Less lipid soluble means less reabsorption due to less passive diffusion across tubular epithelium. More drug excreted so fewer therapeutic effects.

111
Q

What type of metabolite is commonly excreted via bile?

A

Phase 2 glucuronide metabolites.

112
Q

How are drugs transported from the liver to the bile?

A

Hepatic cells transport drug in blood to the bile via transporter proteins.

113
Q

How do drugs in bile become removed from the body?

A

From bile they enter the intestines. Formation of faeces. Excreted from body.

114
Q

What is the main effect of enterohepatic recycling?

A

Increased duration for drug elimination therefore prolonged drug effect.

115
Q

What is the total clearance of a drug?

A

Drug cleared by metabolism plus drug cleared by renal excretion.

116
Q

Are drug effects constant across a population if considering pharmacokinetics factors?

A

Pharmacokinetic factors vary between individuals so no.

117
Q

What factors affect volume of distribution of a drug?

A

Lipid solubility. Bioavailability.

118
Q

What is half life and why is it useful?

A

Time required for half of a drug dosage to be removed from the body. Useful for comparing drugs.

119
Q

What factors affect time course of drug action?

A

Absorption. Metabolism. Distribution. Excretion. Route of administration.

120
Q

Give one route of administration that has low bioavailability if the drug is highly water soluble.

A

Transdermal.

121
Q

Paracetamol is metabolised to a sulfate and a glucuronide species. Which is the species is present in the urine? Why?

A

Both metabolites and paracetamol parent drug. Some drug may not undergo any form of metabolism and will simply pass through the system.

122
Q

Discuss distribution between brain and adipose for drug with high octanol/water partition coefficient.

A

Likely to accumulate in adipose tissue despite there being a low regional blood flow to adipose tissue.

PHAR (9 decks)

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