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Principles > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Define receptor

A

A term used in pharmacology to denote a class of cellular macromolecules concerned specifically and directly with chemical signalling

  • a substance for the ligand to bind to
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2
Q

Define ligand

A

A substance that is bound to a protein

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3
Q

Define affinity

A

The tendancy of a ligand to bind to its receptor

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4
Q

Define antagonist

A

A drug that reduces the action of another drug, generally an agonist. Many antagonists act at the same receptor macromolecule as the agonist.

  • can get in the keyhole but not turn the lock, simply prevents the agonist action to reduce the action of another drug.
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5
Q

Define agonist

A

A ligand that binds to a receptor and alters the receptor state resulting in a biological response.

  • Has an affinity for the receptor but can also allow it to carry out its function- fits the lock and can turn the key
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6
Q

Define the term drug

A

A chemical that affects physiological function in a specific way

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7
Q

What must a drug do to be useful?

A

A drug must act selectively for a specific receptor, i.e., it must have a high degree of specificity for the binding site.

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8
Q

What is drug specificity?

A

Specificity is a reciprocal arrangement:

  • Certain classes of drugs bind only to certain receptors
  • certain receptors only recognise certain classes of drug
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9
Q

Describe The Law of Mass Action

A

A + R ⇔ AR

  • ligand= A
  • Ligand receptor = R
  • k+1 is the association (forward) rate constant
  • k-1 is the dissociation (backward) rate constant
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10
Q

How is the dissociation equilibrium constant (aka the dissociation constant or equilibrium constant) denoted?

A

KA

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11
Q

Which equation models the relationship between ligand concentration and receptor occupancy?

A

The Hill-Langmuir equation:

PAR = XA / XA + KA

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12
Q

What is the equilibrium constant, KA, equal to?

A

The concentration of ligand required to occupy 50% of the receptors. This is sometimes referred to as the KD in binding experiments

  • concentration of ligand at which 50% of receptors are bound
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13
Q

What does the KA allow us to compare and determine?

A

Allows us to compare ligands to determine which has the greater affinity.

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14
Q

The lower the KA, the greater the ___________ of the ligand for the receptor.

A

Affinity

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15
Q

Why does a lower KA mean a greater affinity?

A

Because a lower concentration of ligand is required to get 50% of receptors bound.

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16
Q

What is another method to estimate affinity?

A

Competition experiments

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17
Q

What is the difficulty when it comes to competition experiments?

A

Not all ligands are radioactively tagged.

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18
Q

How do we estimate the affinity using competition experiments?

A
  • We inhibit a known standard radioligand and produce an inhibition curve
  • point at which we inhibit the radioligand by 50% is the Ic50
  • smaller Ic50 = greater affinity
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19
Q

How does specificity create side effects?

A

Drugs being specific for and binding to other receptors is the reason for side effecs.

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20
Q

Define efficacy?

A

The tendancy for an agonist to activate the receptor.

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21
Q

How do we expand the receptor theory to a two state model and why?

A

A + R ⇔ AR ⇔ AR*

k+1 and k-1 above and below first arrow respectively

k+2 and k-2 above and below the second arrow respectively

To take into account affinity and efficacy as some agonists only need to occupy a small % of receptors to give a mazimal response.

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22
Q

What happens to a receptor when the response terminates?

A

It returns to its original conformation and the agonist dissociates.

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23
Q

Why is the EC50 useful?

A

In determining drug potency.

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24
Q

Define drug potency

A
  • An expression of the activity of a drug, in terms of the concentration or amount needed to produce a defined effect such as EC50
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25
Q

Drug potency depends on both _________ (affinity, efficacy) and _______ (receptor numbers, drug accessibility) parameters.

A
  • receptor
  • tissue
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26
Q

What is a partial agonist?

A

An agonist that in a given tissue, under specified conditions, cannot ellicit as large an effect (even when applied at high concentration with 100% receptor occupancy) as another agonist acting through the same receptors in the same tissue.

  • response is sub-maximal, even when 100% of the receptors are occupied.
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27
Q

What is the key distinction between agonists and antagonists?

A

In agonists there is a tissue response, in antagonists there is no tissue response.

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28
Q

Name the most common and most important type of antagonist action

A

Reversible competitive antagonism

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29
Q

What happens in reversible competitive antagonism?

A
  • The antagonist ‘competes’ with the agonist for the same binding site on the receptor.
  • the interaction between the antagonist and the receptor is reversible (weak ionic bonds)
  • eventually antaonists dissociate.
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30
Q

Is reversible competitive antagonism surmountable over a wide range of agonist concentrations?

A

Yes

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31
Q

In the presence of an antagonist, the agonist concentration-response curve ia shifted in which direction? Is it altered in any other way?

A
  • Shifted to the right
  • without a change in maximal response or change in slope (i.e., the ‘shape’ of the concentration response curve remains unchanged).
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32
Q

What is the ‘shift to the right’ in reversible competitive antagonsim best expressed as?

A

As a concnetration ratio

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33
Q

What is the concentration ratio?

A

The factor by which the agonist concentration must be increased to restore a given response (e.g., EC50 ) in the presence of an antagonist.

  • concentration we have to increase to get back to the set max response.
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34
Q

pA2 is an indication of antagonist potency, define pA2

A

pA2 is the negative log of the molar concentration of an antagonist that makes it necessary to double the concentration of the agonist needed to elicit the original response obtained in the absence of an antagonist.

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35
Q

What is irriversible competitive antagonism?

A

The antagonist forms a long-lasting or irreversible combination with the receptor.

  • covalent binding

The antagonist action is insurmountable, i.e., the maximal response cannot be fully restored with increasing concentrations of agonist.

  • no matter how much agonist concentration increases you don’t get back to the original max response.
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36
Q

What happens to the percentage maximal response in the presence of irreversible competitive antagonism?

A

It is reduced

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37
Q

What is non-competitve antagonism?

A
  • the antagonist acts by combining with a separate inhibitory site on the receptor (allosteric)
  • agonist and antagonist molecules can be bound to the receptor at the same time
  • the receptor can become activated only when the agonist site alone is occupied, not both the antagonist and agonist or the antagonist alone.
  • the antagonist action can be reversible or irreversible.
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38
Q

What are open channel blockers with regards to non-competitive antagonism?

A
  • specific for ion channels
  • molecule which blocks the ion channel pore
  • so even though it is open via activation of an agonist molecules still cannot flow through.
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39
Q

What is chemical antagonism?

A

The antagonist combines in solution directly with the chemical being antagonised

e.g. chelating agents, used to treat lead poisoning, bind to heavy metals and form a less toxic chelate.

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40
Q

Define physiological antagonism

A

Two agonists that produce opposing physiological actions and cancel eachother out. Each drug acts through its own receptors.

e.g. adrenaline relaxes bronchial smooth muscle reducing bronchoconstriction of histamine

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41
Q

Define phamacokinetic antagonism

A

The ‘antagonist’ reduces the concentration of the active drug at its site of action.

e.g. phenobarbitone increases hepatic metabolism of the anticoagulant drug warfarin.

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42
Q

Name the 4 classes of receptor molecule

A
  1. ligaind-gated ion channels (iontropic receptors)
  2. G protein-coupled receptors (metabotropic)
  3. kinase-linked receptors
  4. nuclear receptors
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43
Q

Why are receptors important for drug action?

A

As drugs can activate or block receptors therefore creating a response or inhibiting them.

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44
Q

What happens in ligand-gated ion channels?

A

Activation of the ligand which is at the gate causes a conformational change which leads to a de-polarization or a hyper polarization.

The agonist can be a neurotransmitter or a hormone.

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45
Q

What does a cation do at a ligand-gated ion channel?

A

Causes depolarization

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46
Q

What does an anion do at a ligand-gated ion channel?

A

causes polarization

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47
Q

Describe nicotinic acetylcholine receptors

A
  • permeable to sodium, potassium and calcium ions
  • nonspecific cation channels
  • modulate fast synaptic excitation
  • channel is widened by the conformational change of acetylcholine binding
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48
Q

How does cholinergic neuro-transmission occur?

A
  • voltage gated ion channels
  • activate in response to a change in voltage
  • action potential travels down the axon and reaches the channels (which are also drug targets). There is a conformational change and then influx of calcium which causes movement of the vesicles. membrane of vesicles binds with the pre-synaptic membrane and acetyl choline is released.
  • Acetyl choline binds to its post-synaptic receptors, sodium flows in which causes depolarization. if this happens at threshhold you get excitation and another action potential.
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49
Q

Name 3 drugs that act as agonists at nicotinic acetylcholine receptors (nAChRs)

A
  • Acetylcholine
  • nicotine
  • vareniciline
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50
Q

Describe the action of acetylcholine at acetylcholine receptors

A

Full agonist at both nAChRs and mAChRs

  • indicated for cataract surgery
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51
Q

Describe the action of nicotine at nicotinic acetylcholine receptors

A

Full agonist

  • delivery of nicotine via controlled release is indicated for smoking cessation
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52
Q

Describe the action of varenicline at nicotinic acetylcholine receptors

A

Inhibits the binding of nicotine to the alpha4beta2 nicotinic acetylcholine receptor (predominant brain nAChR), and exerts partial agonist activity at the receptor, eases nicotine withdrawal symptoms. affinity for the alpha4 subunit.

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53
Q

How can a partial agonist be used?

A

As an antagonist to produce a clinical effect (e.g. reduce drug craving). This is seen with varenicline.

  • almost acts like a reversible competitive antagonist.
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54
Q

How long does the response at ligand-gated ion channels take?

A

Milliseconds

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55
Q

Give 2 examples of G-protein coupled receptors

A
  • adrenaline binding to beta 2- adrenoceptors
  • adrenaline binding to alpha 1-adrenoceptors
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56
Q

Describe the mechanism of action at Beta-2 adrenoceptors

A
  • adrenaline is a signalling molecule which binds to the beta 2 adrenoceptor causing a conformational change.
  • when this happens there is an exchange of the GDP for the GTP.
  • when adrenaline dissociates from the receptor it goes back to the original conformation.
  • Adenylyl cyclase converts ATP to cAMP
  • you also have the beta gamma dimer whcih goes to an adjacent potassium channel, opens it up and allows potassium to efflux resulting in a hyperpolarization.
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57
Q

how immediate is the response at g-protein coupled receptors?

A

happens in seconds

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58
Q

Where are alpha-1-adrenoceptors expressed?

A

In the blood vessels

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59
Q

Describe the mechanism of action at alpha 1 adrenoceptors

A
  • adrenaline is released and makes its way to the alpha 1 adrenoceptors
  • GDP gets exchanged for GTP
  • IP3 causes release of intracellular calcium stores.
  • these contribute to an excitatory response.
  • results in physiological vasoconstriction in blood vessels
  • GTP hydrolysing to GDP switches off the phospholipase C
  • everything goes back to the start and the adrenaline dissociates.
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60
Q

Is it true that when it comes to G-protein coupled receptors you don’t need many receptors to bring on a full physiological response?

A

Yes, a small percentage of receptors bound by the agonist can lead to a very noticeable cellular or physiological response.

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61
Q

What are adrenoceptors bound and activated by?

A

The neurotransmitters/hormones adrenaline and noreadrenaline.

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62
Q

What happens when binding to alpha-1 receptors transduces the activation of phospholipase C?

A

Vasoconstriction of blood vessels

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63
Q

What happens when Beta2-adrenoceptors are stimulated?

A

Dilation of the bronchi

increased heart rate and cardiac muscle contraction (lesser extent than Beta 1)

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64
Q

What is the main strategy in drug design?

A

Targetting a specific receptor to evoke a desired physiological response.

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65
Q

What is the response to adrenaline?

A

Binds/activates all adrenoceptors= full sympathetic physiological response.

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66
Q

What is the response to isoprenaline?

A

Binds/activates Beta 1 & 2 adrenoceptors = tachycardia (big side effect) and bronchodilation

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67
Q

What is the response to salbutamol in asthma?

Salbutamol is indicated to treat the acute symptoms of asthma.

A

Binds/activates B2 adrenoceptors= bronchodilation, desired therapeutic effect for asthma.

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68
Q

What is another name given to kinase-linked receptors?

A

enzyme-coupled receptors

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69
Q

Give an example of kinase linked receptors

A

Insulin receptors

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70
Q

What are nuclear receptors and how do they work?

A

Intracellular receptors that are generally bound by steroid hormones.

These receptors are protein monomers located in the nucleus of the target cell and contain DNA-binding domains allowing for the control for gene transcription.

  1. activated hormone-receptor complex forms within the cell
  2. the complex binds to DNA & activates specific genes –> gene activation leads to production of key proteins.
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71
Q

How long do kinase-linked receptors take to produce a response?

A

Hours

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72
Q

How long do nuclear receptors take to produce a response?

A

Hours

73
Q

Drug targets can be divided into 4 main categories, name them

A
  • receptors
  • enzymes
  • ion channels
  • carrier proteins
74
Q

Define pharmacodynamics

A

Pharmacodynamics is what the drug does to the body.

75
Q

Define pharmacokinetics

A

What the body does to the drug. It affects the final blood plasma concentration of the drug in the body.

76
Q

Drugs have a particular route of administration (ROA). ROA eventually influences the amount of the drug which exists in _________ ____________

A

Blood plasma

77
Q

What is the bioavailability of a drug? This directly influences the ROA

A

The amount available for pharmodynamic action.

78
Q

What is the simplest ROA?

A

IV, the drug goes directly into the plasma.

79
Q

What is first pass metabolism for orally administered drugs?

A

This is where the drug is hepatically absorbed by enzymes in the liver which alters the blood plasma concentration.

Reduction in oral administration is due to the first pass metabolism where some passes out into the urine.

80
Q

What other ROA avoids first pass metabolism?

A

inhalation

81
Q

Why is oral administration preferred over IV?

A

IV usually requires a hospital or clinical setting.

Orally can be taken home with little instruction.

82
Q

A ____ is the amount of a drug in mg given which then after absorption and metabolism gives the plasma ____________.

A
  • dose
  • concentration

Dose is the one we want to give the therapeutic effect.

83
Q

What are the three kinds of effects a drug can have?

A
  • sub-therapeutic
  • therapeutic
  • toxic
84
Q

What is the no observed adverse effect level (NOAEL)?

A

The highest dose before you get an adverse effect.

85
Q

What does pharmacokinetic analysis allow?

A

It helps us determine the dose (e.g. mg of a drug) that will result in the appropriate blood plasma concentration (mg/L or mol/L) to be safe and effective.

86
Q

What does ADME stand for?

A

Absorption

Distribution

Metabolism

Excretion/elimination

87
Q

What is absorption?

A

Drug is absorbed from the site of administration-entry into the plasma

88
Q

What is distribution?

A

Drug reversibly leaves the bloodstream and is distributed into interstitial and intracellular fluids.

89
Q

What is metabolism?

A

Drug transformation by metabolism by the liver and other tissues.

90
Q

What happens at excretion?

A

Drug and/or drug metabolites excreted in urine, faeces or bile.

91
Q

What are the 2 modes of drug movement around the body?

A
  • bulk flow- this would be via the circulatory system (blood stream)
  • diffusion of drug molecules over short distances
92
Q

Describe 2 important factors in the movement of drugs around the body?

A
  • solubility is important- lipid soluble drugs are more likely to diffuse across lipid bilayer membranes.
  • large molecules move more slowly than small ones.
93
Q

What are cell membranes?

A

Barriers between the aqueous compartments of the body.

94
Q

What does the plasma membrane do?

A

Separates the extracellular ‘compartment’ from the intracellular ‘compartment’

95
Q

Name the 4 ways in which small molecules can cross cell membranes

A
  1. passive diffusion
  2. facilitated diffusion
  3. active transport
  4. endocytosis (pinocytosis)
96
Q

Describe movement of small molecules via passive diffusion

A

Passive diffusion directly through the lipid or through aqueous pores formed by aquaporins that transverse the lipid bilayer. Many lipid soluble drugs cross cell membranes this way.

97
Q

Describe the movement of small molecules in the body via facilitated diffusion

A

Via specialised carrier proteins that bind the drug on one side of the bind molecule on one side of the membrane then change conformation and release on the other side. Does not require energy, but does require a concentration gradient.

98
Q

Describe the movement of small molecules via active transport

A
  • Via specialised carrier proteins requires energy and can move drug molecules against the concentration gradient.
  • water soluble drugs can enter the cell through specialised carrier proteins.
  • can show saturation kinetics for the carrier.
99
Q

Describe the movement of small molecules via endocytosis (pinocytosis)

A

Invagination of part of the membrane. The drug is encased in a small vesicle then ‘released’ inside the cell.

large drugs e.g. vitamin B12

100
Q

Is it true or false that a drug with high lipid/membrane solubility has a high/steep transmembrane gradient while a drug with low lipid solubility entails facilitated diffusion so has a much lower transmembrane gradient as a carrier is needed.

A

True

101
Q

Does facilitated diffusion require energy?

A

No, water-soluble drugs can enter the cell through specialised carrier proteins down a concentration gradient.

102
Q

Facilitated diffusion can show saturation kinetics. What does this mean?

A
  • Proteins are involved in facilitated and active transport and metabolism- whether enzymes, transporters, etc. As they exist in finite amounts, they follow saturation kinetics.
  • If you have a high dose, resulting in a high concentration, you do not increase the rate of transport through the transporters. When this plateues at a max the transporters become saturated. You end up with an accumulation of drug in the extracellular space.
103
Q

What are the 5 principal sites of mediated drug transport (both facilitated diffusion and active transport)?

A
  1. blood brain barrier
  2. Gastrointestinal tract
  3. placenta
  4. renal tubule (particularly important in elimination)
  5. biliary tract

Carrier-mediated transport is important for some drugs that are chemically related to endogenous substances such as neurotransmitters.

104
Q

Many drugs are weak ______ or weak ______.

A
  • Acids
  • Bases
105
Q

What does the proportion of ionisation of a drug depend on?

A
  • The pKa of the drug
  • The local pH
106
Q

Define pKa

A

The pH at which 50% of the drug is ionised and 50% un-ionised.

107
Q

For many drugs, can the ionised or non-ionised form penetrate the membrane?

A

The non-ionised form

108
Q

When it comes to drug absorption, weak bases accumulate in compartments with ____ pH, weak acids accumulate in compartments with ____ pH.

A
  • low
  • high
109
Q

The low pH of the stomach facilitates the absorption of ____ ______, whilst the higher pH of the interstine facilitates absorption of _____ _____.

A
  • weak acids
  • weak bases
110
Q

Why does most oral route drug absorption occur in the small intestine?

A

Due to the large surface area

111
Q

What does the field of pharmaceutics look into?

A

Developing devices for drug delivery and release in the optimal physiological environment to facilitate drug absorption.

112
Q

State 5 body compartments and how drug distribution varies i.e. which drugs are distributed

A
  • total body water- small water-soluble molecules
  • extracellular water- large water-soluble molecules
  • blood plasma- highly plasma protein-bound molecules, large molecules, highly charged molecules
  • adipose tissue- highly lipid soluble molecules
  • bone and teeth- certain ions
113
Q

What is the apparent volume of distribution?

A

The apparent volume of distribution (Vd) describes the extent to which a drug partitions between the plasma and tissue compartments.

  • essentially the result of the “pull” between blood and tissue
114
Q

How is the apparent volume of distribution calculated?

A

Vd= dose/ [drug] plasma

  • Vd is a reproducible and clinically relevant value
  • apparent volume of distribution (Vd) is an extrapolated volume based upone [drug] plasma
  • NOT a physical volume -> many drugs have an apparent volume of distribution greater than the body’s total volume of water (41L), hence ‘apparent’.
115
Q

how is the [drug]plasma calculated?

A

By dividing the amount added by the volume of the beaker.

116
Q

How is the volume of the beaker calculated?

A

By dividing the amount added by the [drug] plasma

117
Q

How do physiochemical properties largely determine a drugs Vd?

A

It is more difficult for hydrophilic or ionized drugs to cross membranes -> Vd is closer to total body volume of water (41L).

Lipophilic drugs cross membranes easily and Vd is generally greater than total body volume.

118
Q

How do you calculate the apparent volume of distribution (Vd) from drug blood plasma concentrations

A
  • administer drug dose
  • obtain blood sample
  • separate plasma from RBCs
  • assay for [drug] plasma
  • Calculate Vd using dose/[drug] plasma
119
Q

In what parts of the body are lower Vd drugs retained?

A

Vascular compartments

120
Q

In what parts of the body are higher Vd drugs retained?

A

In adipose, muscle and other non-vascular compartments

121
Q

What is Ec50 a measure of?

A

Potency

122
Q

Describe the distribution of drugs throughout the body in relation to Vd

A
  • initial restriction of drug to highly vascularised parts of the body, hydrophilic or ionized drugs with a low Vd
  • Eventual free access of drug to many areas of body following slow equilibriation, lipophilic drugs or un-ionised drugs with a high Vd.
123
Q

True or false: For drugs of equal potency (same Ec50) , a drug with a high Vd will require a higher dose than a drug with a lower Vd if they are both acting at the same receptor.

A

True

124
Q

Name the most abundant plasma protein

A

Albumin

125
Q

Many drus bind with low affinity to albumin via which forces?

A

electrostatic and hydrophobic

126
Q

How does the plasma protein binding of drugs effect the distribution?

A

Plasma protein binding reduces the availability of the drug for diffusion to the drug target organ.

May also reduce the transport of the drug to non-vascular components.

127
Q

What is the apparent volume of distribution of a drug which exhibits high plasma protein binding?

A

Low, there is a high concentration of the drug in plasma but it is unable to access the target organ as it is very highly plasma protein bound.

128
Q

What is the Vd of a drug that does not exhibit high plasma protein binding?

A

High, the drug concentration in plasma is low

129
Q

What is drug metabolism?

A

Enzymatic conversion of the drug to another chemical entity

130
Q

Name the most important drug-metabolising organ?

A

The liver

131
Q

Name 4 other organs which also contribute to drug metabolism

A
  • kidney
  • gut mucosa
  • lungs
  • skin
132
Q

What happens when orally administered drugs are metabolised in the liver (and/or gut)?

A

Their bioavailability is reduced.

133
Q

What are the possible metabolites and their consquences in drug metabolism?

A
  • chemical entity/metabolite may be pharmacologically active or inactive
  • chemical entity which is inactive may be toxic and covalently bind to surface proteins on the liver and accumulate (saturation kinetics)
  • a substantial portion of the drug may be metabolised to an inert chemical entity which reduces bioavailability
134
Q

What does oral/rectal administration of a drug lead to?

A

Decreased drug plasma concentration

135
Q

For IV administration, what happens as the drug experiences first pass metabolism?

A

It doesn’t, IV administration avoids the liver and goes straight to the systemic circulation.

Drug goes straight into blood circulation, avoiding first pass metabolism and absorption. Bioavailability of all routes are usually compared to IV bolus administration.

136
Q

Define bioavailability

A

The amount of drug that eventually reaches systemic circulation (and hence is available for drug action on the target) of an administered dose of the drug is the drugs bioavailability for that route of administration.

137
Q

How do you calculate the bioavailability (F)?

A

F= quantity of the drug reaching systemic circulation (AUC)/ quantity of drug administered (dose)

138
Q

What factor can influence the bioavailability of a drug?

A

The route of administration. This may require a rethink of the dose needed to produce a therapeutic effect.

139
Q

What happens to determine a route of administration in phase one of clinical trials?

A

An IV bolus is given and the decrease in blood plasma concentration over time measured and compared with the proposed route of administration.

The absorption phase produces a curved line in oral administration whereas there is a downward line for IV bolus as elimination starts instantly.

140
Q

How many phases are there of drug metabolism and where do they take place?

A
  • 2 phases- Phase I and Phase II
  • both phases take place mainly in the liver
141
Q

Where can hepatic drug metabolising enzymes (microsomal enzymes) be found?

A

Embedded in the smooth endoplasmic reticulum of the liver hepatocytes.

142
Q

Are polar or non-polar molecules metabolised more easily?

A

Non-polar molecules cross the plasma membrane to be metabolised more readily than polar molecules- logical since non-polar and lipophilic drugs can moe readily cross membranes in contrast to hydrophilic drugs.

143
Q

What is involved in phase I metabolic reactions?

A

change in the drug by oxidation, reduction or hydrolysis.

144
Q

Descrive phase I reactions and how they are carried out

A
  • oxidation- accomplished by cytochrome P450 enzymes, microsomal haem proteins. During oxidation the drug molecule incoprorates one atom of oxygen to the drug to form a hydroxyl group.
  • cytoplasmic enzymes can metabolise the drug
  • hydrolytic reactions- ester and amide bonds are susceptible to hydrolysis
  • usually form chemically reactive metabolites that can be pharmacologically active and/or toxic.
145
Q

Is it true that enzymes which convert drugs in phase I can become saturated preventing conversion and leading to accumulation of a metabolite and tissue damage?

A

Yes

146
Q

What are cytochrom P450 enzymes in the liver?

A

haem proteins which comprise a large super family

Other drugs can interact with the P450 systems

147
Q

Which of the 74 CYP gene families are involved in drug metabolism in the human liver?

A

CYP1, CYP2 and CYP3

148
Q

How is P450 activity determined?

A

Genetically

  • some persons lack such activity this leads to higher drug plasma levels (adverse actions)
  • some persons have high levels this leads to lower plasma levels (and reduced drug action)
149
Q

What is tolerance?

A

The gradual decline in responsivity to a drug

150
Q

What do phase II metabolism reactions involve?

A

The combination of the drug with one of several polar molecules to form a water-soluble metabolite.

So phase II reactions are addition of naturally present molecules in the body to the drug.

151
Q

Can drugs go directly into phase II metabolism?

A

Yes

152
Q

Describe conjugation in phase II metabolsim

A
  • usually involve the reactive group produced by phase 1
  • Usually terminates all biological activity
  • conjugated products can be readily excreted via the kidney
153
Q

Name the involved enzyme and co-factor in glucuronidation (phase II mechanism)

A

involved enzyme- uridine diphosphate-glucuronosyltransferases

co-factor- uridine diphosphate-glucoronic acid

154
Q

Name the principal organs for drug elimination

A

The kidneys

155
Q

How is drug elimination mostly accomplished?

A

By renal filtration of blood plasma

156
Q

What happens during renal filtration?

A
  • water and most electrolytes are reabsorbed into blood circulation in the renal tubules.
  • Drug metabolites rendered polar (and water soluble) by phase II metabolism are not reabsorbed, thus excreted in the urine.
157
Q

What does understanding how the drug concentration will change over time help clinicians to do?

A

Maintain drug concentrations at therapeutic levels and avoid the patient experiencing toxic side effects.

158
Q

Can absorption and elimination occur simultaneously?

A

Yes

159
Q

If you monitor [drug] plasma against time on a graph at which point are elimination and absorption equal?

A

The peak

160
Q

What is clearance? Define it.

A

Broadly, clearance (CL) is an expression of the elimination of a drug from the body.

Specifically, CL is the volume of blood removed (or cleared) of drug per unit of time (e.g. L/hour or mL/minute)

It is a flow parameter and does NOT tell you how much drug is removed.

161
Q

What can clearance of a drug be broken down into?

A

Renal (CLR)

Hepatic (CLH)

or other elimination routes (CLO)

or described as total clearance (CLT)

162
Q

Why is clearance important?

A

It helps determine the dosage rate needed to maintain a desired [D] plasma.

163
Q

CL is independent from Vd but what do they both determine?

A

The elimination half life of a drug

164
Q

How is clearance calculated?

A

CL= Rate of drug elimination/ [drug] plasma

165
Q

Describe first order kinetics in relation to to the elimination rate.

A

Rate of drug elimination increases as plasma drug concentration increases.

166
Q

What is zero order kinetics?

A

Elimination mechanisms become saturated and reach Vmax, the maximal elimination rate. This then becomes zero order kinetics.

167
Q

What are Vmax and Km?

A

Vmax is the maximum rate of drug elimination

Km is the drug concentration at which the rate of elimination is 1/2 vmax.

168
Q

What is steady state?

A

Steady state exists when the rate of drug administration (R0) = rate of drug elimination (RE)

  • what goes in is what goes out
169
Q

CL is used to calculate the dosage required to maintain [drug]plasma at steady state ([drug]plasmaSS), write the formula

A

Dosage rate= [drug]plasma x CL

170
Q

If you double the dosage rate can you rach steady state more quickly?

A

No. This can lead the [drug]plasma to reach the adverse/toxic range.

171
Q

What is the only 2 factors which the elimination half life depends on?

A

Volume of distribution

Clearance

172
Q

What things does the elimination half life t1/2 determine?

A
  • may place major constraints on dosage regimen
  • determines the time required for [drug]plasma to achieve [drug]plasna SS.
  • determines how much time is required for drug to be eliminated from the body –> this is extremely useful when designing a therapeutic dosage regimen.
173
Q

How many 1/2 lives does it generally take to reach the steady state?

A

5

174
Q

What happens when an IV infusion stops?

A

When the infusion stops the plasma concentration washes out to zero with the same time course observed in approaching steady state.

175
Q

How many half-lives are normally required to wash out?

A

5

176
Q

As clearance increases does the half life increase or decrease and vice versa

A

t1/2 decreases

177
Q

As VD increases does t1/2 increase or decrease?

A

Increases

178
Q

Name 3 factors which affect the elimination half life by having an effect on volume distribution.

A
  • ageing (decrease in muscle mass) = decreases t1/2
  • obesity (increase in adipose tissue)= increases t1/2
  • pathologic fluid = increases t1/2
179
Q

Name 5 factors which affect elimination half life by having an effect on clearance

A
  • cytochrome P450 induction = decrease t1/2
  • cytochrome P450 inhibition= increase t1./2
  • cardiac failure= increase t1/2
  • hepatic failure= increase t1/2
  • renal failure= increase t1/2

Principles (10 decks)

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