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Year 2 - BRS > 1.1 - Pharmacodynamics: principles of pharmacology > Flashcards

1.1 - Pharmacodynamics: principles of pharmacology Flashcards

1
Q

What is the difference between pharmacology and therapeutics?

A
  • pharmacology is the study of drug action - how a drug interacts with living organisms and how this influences physiological function
  • therapeutics is concerned with drug prescribing and the treatment of disease
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2
Q

What are the three questions you ask when you want to consider how a drug exerts its effects on the body?

A
  1. where is this effect produced?
  2. what is the target for the drug?
  3. what is the response that is produced after interaction with this target?
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3
Q

What are most of the drug targets in the body?

A

Proteins

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4
Q

What are the four classes of drug targets?

A
  1. receptors
  2. enzymes
  3. ion channels
  4. transport proteins
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5
Q

Why is selectivity important?

A

For a drug to be an effective therapeutic agent it must show a high degree of selectivity for a particular drug target

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6
Q

Why is dose important?

A
  • some drugs can bind to other receptors since the molecules that bind to them are similar in structure to the drug
  • if we use a high dose of a drug, it can bind to these other receptors to cause unwanted side effects
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7
Q

What are the different types of drug-receptor interactions?

A
  • electrostatic interactions - the most common mechanism and includes hydrogen bonds and Van der Waals forces
  • hydrophobic interactions - important for lipid soluble drugs
  • covalent bonds - least common as interactions tend to be irreversible
  • stereospecific interactions - many drugs exist as stereoisomers and interact stereospecifically with receptors
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8
Q

What is the equation for a drug-receptor equilibrium?

A
  • drug + receptor <–> drug-receptor complex
  • for a specific concentration of the drug, a specific number of drug receptor complexes are formed
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9
Q

What happens to a drug-receptor equilibrium if you were to increase the concentration of the drug?

A

The equilibrium is shifted to the right because there is more drug available to bind to free receptors

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10
Q

What happens to a drug-receptor equilibrium if you were to reduce the concentration of the drug?

A

More receptors would become available again due to lower drug concentration, shifting the equilibrium to the left

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11
Q

What is the difference between agonists and antagonists?

A
  • both possess the ability to bind to receptors, but only agonists can bind and activate them
  • agonists fit into the ‘lock’, whereas antagonists can fit the ‘lock’ but would jam the mechanism and prevent the lock from being ‘opened’
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12
Q

What are two key properties of agonists?

A

Affinity and efficacy

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13
Q

What is the affinity of a drug?

A
  • the strength of binding of the drug to the receptor
  • the strength of each drug-receptor complex is determined by the affinity of the drug
  • affinity is strongly linked to receptor occupancy
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14
Q

What is the efficacy of a drug?

A

Ability of an individual drug molecule to produce an effect once bound to a receptor

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15
Q

Drugs A, B, C all act on the same receptor
- Drug A binds to the receptor but doesn’t produce a response- has no efficacy
- Drug B binds to the receptor and produces a partial response, but not capable of inducing the maximal response
- Drug C binds to the receptor and produces the maximal response that could be expected from that receptor
How do drugs A, B and C work in terms of affinity and efficacy?

A
  • drug A has affinity for the receptor but no efficacy = receptor antagonist
  • drug B has affinity for the receptor and sub-maximal efficacy = partial agonist
  • drug C has affinity for the receptor and maximal efficacy = full agonist
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16
Q

What is the potency of a drug?

A

Concentration or dose of a drug required to produce a 50% tissue response

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17
Q

What is the standard nomenclature for potency of a drug?

A
  • EC50 (half maximal effective concentration) or the ED50 (half maximal effective dose)
  • ED50 is usually used to look at the desired effect of a drug being in 50% of all individuals in a group (instead of 50% response from one individual)
  • EC50 is usually used to see a concentration of a drug that produces a 50% response
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18
Q

What is the difference between a highly potent and highly efficacious drug?

A
  • a highly potent drug produces a large response at relatively low concentrations
  • a highly efficacious drug can produce a maximal response and this effect is not particularly related to drug concentration
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19
Q

Which out of efficacy and potency is more important?

A
  • efficacy - you want to know if the drug you give can induce a maximal response
  • if two drugs have equal efficacy it does not matter if one is more potent since you can still produce the maximal response with the less potent drug (just need higher conc)
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20
Q

What is pharmacokinetics?

A

What the body does to the drug

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21
Q

What are the four major pharmacokinetic factors?

A
  • absorption
  • distribution
  • metabolism
  • excretion
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22
Q

What is absorption?

A
  • passage of a drug from the site of administration into the plasma
  • deals with the process of drug transfer into the systemic circulation
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23
Q

What is bioavailability?

A
  • fraction of the initial dose that gains access to the systemic circulation
  • deals with outcomes of drug transfer into the systemic circulation (i.e. how much)
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24
Q

What are the common forms of drug administration?

A
  • oral
  • inhalational
  • intranasal
  • dermal
  • intravenous (IV) - 100% bioavailability as injected straight into bloodstream
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25
Q

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

A
  1. bulk flow transfer (i.e. in the bloodstream)
  2. diffusional transfer (i.e. molecule by molecule across short distance)
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26
Q

How do most drugs cross the lipid bilayer of cells?

A
  • diffusion across lipid membranes or by carrier transport
  • diffusion across aqueous pores is not a major movement route for drugs as most pores are <0.5nm in diameter and most drugs are larger
  • majority of drugs tend to be more water soluble than lipid soluble (since most are taken orally so need to be water soluble)
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27
Q

What two forms do drugs that are weak acids/bases exist as?

A

Ionised and unionised

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28
Q

What does a weak acid e.g. aspirin do when in ionised state?

A

Donates protons (H+)

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29
Q

What does a weak base e.g. morphine do when in ionised state?

A

Accepts protons i.e. B(morphine)H+

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30
Q

What do the unionised forms of weak acids/bases do?

A

Retains more lipid solubility and is more likely to diffuse across plasma membranes

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31
Q

What two factors contribute to whether a drug is ionised or not?

A
  1. dissociation constant (pKa) for that drug
  2. the pH in that particular body part
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32
Q

What happens if the drugs pKa and the tissues pH are equal?

A

The drug will be equally dissociated between the two forms (50% ionised and 50% unionised)

33
Q

What happens to weak acids as the pH decreases lower than the pKa?

A

The unionised form starts to dominate

34
Q

What happens to weak acids as the pH increases higher than the pKa?

A

The ionised form starts to dominate (i.e. it donates protons as it is in a basic environment)

35
Q

What happens to weak bases as the pH decreases lower than the pKa?

A

The ionised form starts to dominate (i.e. it accepts protons as it is in an acidic environment)

36
Q

What happens to weak bases as the pH increases higher than the pKa?

A

The unionised form starts to dominate

37
Q

Where are weak acids more unionised in?

A

Areas of low pH like the stomach

38
Q

Where are weak bases more unionised in?

A

Areas of high pH like blood and urine

39
Q

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

A
  • weak bases will be poorly absorbed from stomach due to low pH leading to high drug ionisation so will be ‘trapped there’
  • however once drug reaches small intestine there will be many transport proteins that can absorb it from the GI tract
40
Q

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

A
  • weak acids could be absorbed from the stomach in their unionised state but they will become more ionised at physiological pH and become ‘trapped’ in the blood
  • however, most tissues have transport proteins that could move the ionised drug from the blood into the tissue
41
Q

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

A
  • renal tubule (responsible for drug excretion)
  • biliary tract (responsible for drug excretion)
  • blood brain barrier (responsible for absorption of drugs into brain)
  • GI tract (responsible for absorption of drugs into bloodstream)
42
Q

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

A
  • regional blood flow
  • plasma protein binding
  • capillary permeability
  • tissue localisation
43
Q

What does regional blood flow mean (in relation to drug distribution)?

A
  • different tissues receive different amounts of cardiac output at rest
  • as a result, more drug will be distributed to those tissues that receive most blood flow
  • but blood distribution to tissues can increase/decrease depending on circumstance e.g. during exercise more blood –> muscles, but after a meal more blood –> stomach and intestines
44
Q

What % of cardiac output do different tissues receive at rest?

A
  • liver - 27%
  • heart - 4%
  • brain - 14%
  • kidneys - 22%
  • muscles - 20%
45
Q

What does plasma protein binding mean (in relation to drug distribution)?

A
  • it is common for drugs to bind to plasma proteins in blood - some drugs can be 99% bound to them
  • albumin is the most important plasma protein for this - very good at binding acidic drugs
  • only free drug is available to diffuse out of blood and access tissues - any drug bound to plasma proteins cannot leave the blood until it is dissociated from the protein
46
Q

What three factors determine the amount of drug bound to plasma protein?

A
  • free drug concentration
  • affinity for the protein binding sites
  • plasma protein concentration
47
Q

What is the drug-plasma protein binding reaction?

A

D (free drug) + P (protein binding site) <–> DP (drug-protein binding site)

48
Q

What is albumin’s binding capacity?

A
  • [albumin] in blood is 0.6 mmol/L
  • each albumin protein has 2 binding sites so binding capacity is 1.2 mmol/L
  • important as plasma conc required for clinical effect of most drugs is <1.2 mmol/L = plasma proteins are never saturated with drugs
  • differences in extent of plasma protein binding is mostly due to affinity for binding sites for a particular drug
49
Q

What are the four types of capillary structure?

A
  • continuous
  • blood brain barrier
  • fenestrated
  • discontinuous
50
Q

How do molecules interact with continuous capillaries?

A
  • most capillaries are continuous with H2O filled small gap junctions between lined up endothelial cells
  • if drugs are very lipid soluble they can diffuse across the endothelial and access the tissue
  • if they are very small they can pass through the gap junctions
  • if they are less lipid soluble they need to be transported into the tissue via carrier proteins
51
Q

How do molecules interact with the blood brain barrier?

A
  • there is a continuous structure with addition of tight junctions between endothelial cells
  • makes brain most difficult tissue for drugs to gain access to
52
Q

How do molecules interact with fenestrated capillaries?

A
  • e.g. in kidney glomerulus
  • kidney is involved in excreting chemicals including many drugs
  • fenestrations are circular windows within endothelial cells that allow for passage of small molecular weight substances including some drugs
  • allows for small drugs to pass from blood to kidney tubules which enhances excretion of them
53
Q

How do molecules interact with discontinuous capillaries?

A
  • e.g. in liver
  • liver is a key metabolic tissue and deals with metabolism of many chemicals including most drugs
  • this capillary structure with big gaps between endothelial cells allows for drugs to easily diffuse out of bloodstream and access liver tissue
54
Q

What does tissue localisation mean with an example (in relation to drug distribution)?

A
  • lipid soluble substance like delta9-tetrahydrocannabinol (delta9-THC - active component in weed)
  • delta9-THC will diffuse out blood down its conc grad into brain to produce effects and eventually an equilibrium is reached between blood and brain
  • water soluble drug accessing brain - also diffuses down conc grad into brain from blood until it reaches equilibrium
  • difference between the two drugs is the relative position of the equilibrium - brain has higher fat content but blood has higher water content
  • this means for delta9-THC the equilibrium the equilibrium will be more heavily weighted towards retention in brain and for water soluble drug it will be towards plasma
  • larger proportion of delta9-THC will be localised in brain vs water soluble drug
55
Q

Why do we want to metabolise drugs?

A

Drugs must be excreted or else they would circulate in body forever and have continual effect

56
Q

What form do we want to metabolise drugs into?

A
  • for them to be excreted, they should ideally not be lipid soluble (we want them water-soluble so they are retained in blood to be sent to excretion sites)
  • however, for therapeutic effectiveness we want drugs to have some lipid solubility so they can easily access tissues to produce their effects
57
Q

What is metabolism?

A

Metabolism involves conversion of drugs to metabolites that are as water soluble as possible and easier to excrete

58
Q

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

A
  • liver - mainly cytochrome P450 enzymes in liver that are responsible for drug metabolism
  • drug metabolism includes two kinds of biochemical reaction - phase 1 and phase 2
59
Q

What happens in phase 1 metabolism?

A
  • main aim is to introduce reactive polar groups into their substrates to serve as a point of attack for the conjugating systems in phase 2
  • this occurs via oxidation, reduction and hydrolysis
60
Q

What is the most common form of phase 1 metabolism?

A

Oxidation, but all oxidation reactions start with hydroxylation step by cytochrome P450 system to incorporate oxygen into non-activated hydrocarbons

60
Q

Where would the hydroxylation step for aspirin happen?

What are the most likely functional groups incorporated into the parent drug in phase 1 reactions?

A
  • phase 1 reactions would likely incorporate one of these functional groups into the parent drug: -OH, -COOH, -SH, -NH2
  • phase 1 reactions may also unmask existing functional groups
  • aspirin: hydroxylation takes place at the CH3COO
  • e.g. aspirin –> salicyclic acid
61
Q

What are pro-drugs?

A

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

Relies on hepatic first pass metabolism

62
Q

What problems could active metabolites have?

A
  • could have negative unintended effects
  • liver damage as a result of paracetamol overdose is due to a certain metabolite and not paracetamol itself
63
Q

What happens in phase 2 metabolism?

A
  • result of phase 2 metabolism is attachment of a substituent group
  • the resulting metabolite is nearly always inactive and much less lipid soluble than phase 1 metabolite
  • this facilitates excretion in urine or bile
  • phase 2 enzymes are mostly transferase enzymes to transfer the substituent group onto phase 1 metabolite
64
Q

What are the common phase 2 conjugates that complement the common phase 1 metabolites?

A
  • electrophiles (R=O, -R-O-R-) –> glutathione conjugation –> R-SG
  • nucleophiles (R-OH, R-SH, R-NH2) –>
    • glucuronidation –> R-GI
    • acetylation –> R-Ac
    • sulfation –> R-SO2H
65
Q

What is first pass (presynaptic) metabolism?

A
  • problem for orally administered drugs - mostly absorbed from small intestine and enter hepatic portal blood supply where they first pass through liver before reaching systemic circulation
  • at this point, the drug can be heavily metabolised resulting in little active drug reaching blood
  • note first pass metabolism is a prerequisite for activity of prodrugs
66
Q

What is the solution to first pass metabolism?

A
  • administer a larger drug dose to ensure enough drug reaches systemic circulation
  • problem with this is the extent of first pass metabolism varies among individuals so the amount of drug reaching bloodstream also varies
  • as a result, drug effects and side effects are difficult to predict
67
Q

What are some different ways drugs can be excreted?

A
  • kidney (in urine) - most important
  • liver (in bile) - also most important
  • lungs (basis of alcohol breath test is to measure alcohol excreted via lungs)
  • breast milk (care needs to be taken so drugs excreted in milk do not affect baby)
68
Q

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

A
  • glomerular filtration
  • active tubular secretion/reabsorption
  • passive diffusion across tubular epithelium
69
Q

What does glomerular filtration do?

A
  • allows drug molecules of weight below 20000 to diffuse into glomerular filtrate
  • means drugs of this weight have this additional excretion route compared with larger drugs = quicker excretion rate
70
Q

What does active tubular secretion (or reabsorption) do?

A
  • most important method for drug excretion via kidney
  • where only 20% of renal plasma is filtered at glomerulus, 80% of renal plasma passes onto blood supply of PCT = more drug is delivered to PCT than glomerulus
  • within PCT capillary endothelial cells there are two active transport carrier systems - one effective at transporting acidic drugs and one basic
  • both good at transporting against conc gradient
71
Q

What does passive diffusion across tubular epithelium do?

A
  • leads to reabsorption from kidney tubule
  • as glomerular filtrate moves through kidney, most of water filtered (90%) is reabsorbed
  • if drugs are lipid soluble, they will also be reabsorbed, passively diffusing back into blood across tubule
72
Q

What two factors influence the extent of reabsorption in passive diffusion from kidney tubule?

A
  • drug metabolism - phase 2 metabolites tend to be a lot more water soluble than the parent drug so less well reabsorbed
  • urine pH - can vary from 4.5-8 and based on pH partition hypothesis previously, acidic drugs are better absorbed at lower pH and basic drugs at higher pH
73
Q

Why do drugs have different excretion rates?

A
  • the extent of the three processes used by drugs (glomerular filtration, active secretion/reabsorption at PCT, passive diffusion across tubule) differs a lot
  • this along with rate of metabolism explains different excretion rates
74
Q

How does liver excretion work?

A
  • liver cells transport drugs from plasma into bile primarily via transporters similar to those in kidney
  • particularly effective at removing phase 2 glucuronide metabolites
  • drugs transported into bile are then excreted into intestines and eliminated in faeces
75
Q

What is the result of enterohepatic recycling?

A

It significantly prolongs drug effect

76
Q

What is an example of enterohepatic recycling?

A
  1. a glucuronide metabolite is transported into bile
  2. metabolite excreted into small intestine where it is hydrolysed by gut bacteria releasing glucuronide conjugate
  3. loss of glucuronide conjugate increases lipid solubility of the molecule
  4. increased lipid solubility allows for greater reabsorption from small intestine back into hepatic portal blood circulation back to liver
  5. molecule returns to liver where a proportion is re-metabolised, but a proportion may escape into systemic circulation to continue to have effects on body
77
Q

What are the seven steps of prescribing in pharmacology?

A
  1. Identify the patient’s problem - (Problem solving/cognitive skill)
  2. Specify the therapeutic objective - (Problem solving/cognitive skill)
  3. Select a drug on the basis of comparative efficacy, safety, cost and suitability - (Problem solving/cognitive skill)
  4. Discuss choice of medication with patient (and carer) and make a shared decision about treatment - (Practical skill)
  5. Write a correct prescription - (Practical skill)
  6. Counsel the patient on appropriate use of the medicine - (Behavioural skill)
  7. Make appropriate arrangements for follow up (Monitor/stop the treatment) - (Behavioural skill)

Year 2 - BRS (84 decks)

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