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Pharmacology Year 1 > Introduction to Pharmacokinetics and Pharmacodynamics. > Flashcards

Introduction to Pharmacokinetics and Pharmacodynamics. Flashcards

1
Q

Why is the liver a common site of drug interactions?

A

One drug interferes with another’s clearance because it induces the formation of more metabolising enzymes or competes for/inhibits metabolism.

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2
Q

Why is pharmacokinetics important?

A

Accounts for most of individual variation in drug response and often explains some prescriptions sub-optimal or excessive effects.

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3
Q

Why is only a proportion of original drug dose available when administered orally?

A

After being swallowed it must survive gastric acid, avoid unacceptable food binding, be absorbed across the small bowel mucosa and survive the intestinal and hepatic first pass metabolism.

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4
Q

Why is drug dose represented on a log base 10 logarithmic scale?

A

It is more useful as as it expands dose scale in region where responses changes rapidly and compresses scale when large change in dosage has little effect.

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5
Q

Whis the difference between pharamcological competitive and non-competitive antagonists

A

Competitive antagonists = bind effectively to receptors but don’t produce conformational change necessary for signal transduction, hence preventing binding of other ligands “competing” for the receptor.

Non-competitive = antagonists inhibit receptor-mediated agonist by binding to allosteric binding site or interfering with associated signals. Increasing agonist concentration levels cannot overcome their effects so max. response to agonist (Emax) is reduced.

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6
Q

Where does drug metabolism mostly occur and what is its purpose (2)?

A

Mostly occurs in Liver

  • Deactivates the drug
  • Changes the chemical nature of the drug so that it is sufficiently water soluble to be excreted into the urine or bile.
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7
Q

What mechanisms does the phase 2 metabolism consist of?

A

Conjunction reactions with glucuronide, sulfate or acetyl groups, that make the drug or its phase 1 metabolite more soluble so it can be excreted in bile/urine.

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8
Q

What mechanisms does phase 1 metabolism consist of?

A

oxidation, reduction or hydrolysis reactions by cytochrome P450 system.

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9
Q

What is therapeutics?

A

The application of the principles of clinical pharmacology to the use of drugs as medicines to treat human disease.

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10
Q

What is the volume distribution?

A

The volume that must be cleared of the drug before elimination is complete, and, along with the rate of clearance, is one of 2 determinants of half-life.

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11
Q

What is the Rate of absorption across a membrane determined by?

A

Surface area and concentration gradient between the two sides, maintained by the removal into circulation.

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12
Q

What is the overall stoichiometry of a hydroxylation reaction in the Cytochrome P450 system?

A

RH + O2 + NADPH + H+ –> ROH + H2O + NADP+

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13
Q

What is the law of mass action in pharamcology? (4)

A
  • The Law of Mass Action dictates that the rate of a reaction is dependent on the concentration of reagents.
  • At equilibrium, the ratio of the reagents to products of a reaction is constant.
  • Therefore, at equilibrium the rate of association and the rate of dissociation are constant
  • When plotted on a semilogarithmic scale of receptor occupancy and drug concentration, this relationship presents as a sigmoid curve
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14
Q

What is the effective dose range?

A

Range between which most of change in response occurs.

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15
Q

What is the difference in drug accumulation kinetics between drugs with long and short half-lifes? (5)(4)

A

Long half life:
- less frequent dosing required
- Improved adherence
- slow to reach steady state
- Loading dose may be needed
- slow to be eliminated

Short half life:
- Rapid steady state after initiation or dose titration
- Fine control of pharmacological effets
- Frequent doses (reduced adherence) may not be orally administered
- wide spread between peak and trough

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16
Q

What is the difference between Tolerance and Tachyphylaxis

A

Tolerance = a gradual desensitisation to a drug
Tachyphylaxis = rapid desensitisation to a drug, sometimes after only one dose.

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17
Q

What is the coupling mechanism of nuclear receptors?

A

Stimulates messenger RNA synthesis in the cell nucleus leading to protein synthesis.

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18
Q

What is the coupling mechanism of g-protein coupled receptors?

A

receptor protein associates with a g-protein to active either an enzyme which produces “secondary messengers” or opens an ion channel.

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19
Q

What is the coupling mechanism of an enzyme linked receptor?

A

Initiates enzymatic conversions

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20
Q

What is the coupling mechanism of a channel linked receptor?

A

Altered conductance of ions leading to depolarisation or hyperpolarization of membranes.

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21
Q

What is the apparent volume distribution and how can this be estimated?

A

The apparent volume distribution is the volume of fluid required to contain total amount of drug in the body at the same concentration as it is in the plasma.

It is estimated by measuring plasma drug conc. shortly after dose.

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22
Q

What is signal transduction?

A

When extracellular binding -> intracellular signal.

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23
Q

What is selectivity and how can it be quantified?

A

Selectivity is the differential responsiveness of a drug at different receptor sub-types.

Can be quantified by measuring the ED50 of a drug at two different receptor subtypes.

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24
Q

What is potency?

A
  • Potency is the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect.

The amount of drug required to produce a given response. More potent drugs produce biological effects at lower doses.

25
Q

What are pharmacological agonists?

A

ligands that when bound to receptor induce conformational changes that lead to signal transduction and intracellular effects

26
Q

What is efficacy?

A

Efficacy (Emax) is the maximum effect which can be expected from this drug (i.e. when this magnitude of effect is reached, increasing the dose will not produce a greater magnitude of effect, when all available receptors/binding sites are occupied)

27
Q

What is clearance and how is it calculated?

A

Clearance = the rate of elimination / plasma conc.

Clearance is the volume that is completely cleared of a drug over a period of time. The total ability of the body to clear a drug from the plasma is renal clearance plus hepatic clearance plus clearance from all other tissues.

28
Q

What happens if you increase drug dose beyond effective range?

A

increasing drug dose beyond effective dose range has little extra beneficial effects form response however may increase likelihood of adverse effects

29
Q

What factors effect dose strategy? (3)

A
  • Half life = determines how quickly steady state is achieved and rate of elimination
  • Risk of ineffective trough conc. or adverse affects at peak plasma conc.
  • how quickly effective drug conc. needs to be achieved.
30
Q

What effects diffusion rate of drugs and how can they be removed?

A

Diffusion rate is controlled by:
Conc. grad. Lipid solubility, Size, membrane chemistry

Removal by binding, diffusion and destruction

31
Q

What components make up the first pass metabolism? (2)

A
  • Cells of the intestinal wall contain many enzymes capable of metabolizing drug molecules.
  • Passage of portal blood flow through liver accounts for most first pass metabolism of oral drugs due to the phase 1 metabolising enzymes of the cytochrome P450 system.
32
Q

What assumptions are made by the law of mass action? (4)

A

> All ligands and all receptors are equally available to each other

> The binding of drug and receptor is reversible (it frequently is not, as in the case of phenoxybenzamine)

> The binding of drug and receptor does not alter either the drug or the receptor (that’s not the case when the drug is a substrate for a receptor which is a metabolic enzyme, for one example)

> The receptor and drug are either bound to each other, or are not bound to each other (i.e. there are no ambiguous partial states).

33
Q

What are the characteristics of first order kinetics? (4)

A

Exponential
- a constant fraction of drug is cleared out in a unit time.
- means there is a predictable effect of increasing drug dose.
- Faster rate of elimination as dose increases prevents accumulation
- Half-life describes the time over which the plasma concentration halfs.

34
Q

What are the 4 main types of receptors?

A
  1. Channel linked
  2. G-protein coupled receptors
  3. Enzyme linked receptors
  4. Nuclear receptors
35
Q

What are the 4 aspects of pharmacokinetics?

A

Absorption
Distribution
Metabolism
Excretion

Collectively they determine the time course of drug action.

36
Q

What are some types of molecular receptor targets and signalling pathways? (6)

A
  • Interaction with the cell membrane (amphotericin)
  • Regulation of transmembrane protein activity

> Ligand-gated or voltage-gated ion channel permeability (lignocaine, suxamethonium)
Transmembrane transport protein activity (SSRIs)
Regulation of transmembrane enzymes with intracellular signalling pathways, eg. tyrosine kinases (insulin)
G-protein coupled receptor activity (β-blockers)

  • Acting as a substrate for enzyme activity (oxygen, glucose)
  • Acting as a false substrate for an enzyme (methyldopa)
  • Regulation of enzyme activity
    Intracellular enzymes eg. phosphodiesterase (milrinone)
    > Extracellular enzymes eg. acetylcholinesterase (neostigmine)
    > Interaction with intracellular nuclear macromolecules (Regulation of gene transcription, Interaction with genetic material)
37
Q

What are some pharmacokinetic mechanisms of drug densensitisation?

A

Increased elimination of the drug by:
- Increased drug metabolism
- Increased capacity to remove drug from cells

38
Q

What are some pharmacodynamic causes of desensitisation? (4)

A
  • Reduction in receptor number
  • Changes in receptor structure or function
  • Exhaustion of mediators
  • Physiological adaptations
39
Q

What are pharmacokinetics and pharmacodynamics in simple terms?

A

Pharmacokinetics is what what the body does to the drug i.e. how the drug dosage regimen -> drug conc in plasma.

Pharmacodynamics is what the drug does to the body i.e. hoe the drug concentration and site of action -> drug effects.

40
Q

What are 3 ways drugs can move across membrane w/o receptors?

A

Passive diffusion, pore-mediated diffusion and pinocytosis

41
Q

What are 3 physicochemical properties of drugs?

A

Chemical nature
Molecular weight
Lipid solubility

42
Q

What 2 effects occur when drugs bind to blood plasma proteins and are confined to plasma compartment?

A
  • Slows the process and distribution and delays elimination.
  • Drugs that are highly bound to plasma persist in the body for longer, have less efficient distribution lower therapeutic activity and are less available for dialysis after toxic dose.
43
Q

How does the limitation of rate of absorption differ between low solubility and high solubility drugs?

A

Rate of absorption of drugs with low solubility is limited by rate of membrane penetration

highly lipid soluble drugs cross membrane rapidly so it is primarily limited by tissue perfusion

44
Q

How can you help sustain pharmacological effects of drugs? When is steady state reached? how can you reduce fluctuations?

A
  • most drugs must be administered regularly to sustain effects.
    Following regular doses, plasma drug conc. rises to steady state where rate of administration = rate of elimination after approx. 5 half-lifes.
  • Fluctuation between peak and trough of effectiveness minimised by more frequent dosing by this is inconvenient and may lead to non-adherance.
45
Q

How can the kidney excrete drugs?

A

The kidney excretes low molecular weight molecules that can be filtered at the glomerulus.

But they must be sufficiently water soluble to avoid passive diffusion back into the body in renal tubules.

46
Q

How can drugs target ion channels?

A

Usually glycoproteins in cell membrane. Binding of endogenous ligand or drug leads to conformational change linked to intracellular biochemical events, often through the activation of intracellular enzymes.

47
Q

How can drugs be excreted in the bile?

A

Drugs excreted in the bile high are molecular weight molecules that are either eliminated in feces or reabsorbed as part of the enterohepatic cycle is they are sufficiently soluble.

48
Q

How can drugs affect each others absorption? (2)

A
  • After an oral dose they can interact with the gut lumen altering the rate of gastric emptying and first pass metabolism
  • After Intravenous injection they can affect absorption by altering blood flow to the injection site.
49
Q

how are drug dose and response related?

A

It is assumed that drug dose is directly related to resulting ligand concentration, and therefore the response

However this is often not the case as ingested drug dose and revelant tissue conc. in humans is complex.

In reality it is ligand concentration and resulting receptor occupation that affects response.

50
Q

How are absorbed drugs distributed through body compartments?

A

Based on molecular size and lipid solubility.

51
Q

Describe the characteristics of zero-order kinetics: (4)

A
  • elimination is constant per unit time, so change to plasma conc. following dose change is unpredictable.
  • Elimination metablosm has limited capacity, becomes saturated.
  • If administered faster than eliminated then drug will accumulate.
  • Overall expose = area under the curve -> risk of severe toxicity as dosage rises.
52
Q

Describe kinase linked receptors, and give an example.

A

Directly linked to an intracellular protein kinease that triggers a cascade of phosphorylation reactions

e.g. insulin receptors.

53
Q

Describe g-protein coupled receptors and give example.

A

Receptors coupled to the intracellar effector mechanisms via a family of closely related g-proteins that participate in signal transduction by coupling receptor binding to intracellular enxyme activation or the opening of an ion channel.

E.g. muscarinic cholinergic receptors, adrenoreceptors, opioid receptors.

54
Q

Define receptors

A

Receptors are proteins that have a specific site capable of binding to a ligand, leading to conformational changes and biological effects.

55
Q

Define clinical pharmacology.

A

The study of drug action in humans providing the scientific basis for rational, safe and effective prescribing.

56
Q

Describe nuclear/DNA-linked receptors and give an example.

A

Intracellular receptors that influence the synthesis of new proteins, which may take hours or days.

e.g. glucocorticoid receptors

57
Q

Describe channel linked receptors and give one example.

A

Coupled directly to an ion channel, their activation opens the cahnnel making a cell membrane more permeable to specific ions.

e.g. Nicotine acetylcholine receptor.

58
Q

Decipher CYP2C9*2 categorization of drugs:

A

CYP2C9*2

CYP = super family
2 = family
C = sub-family
9 - isoform
*2 = allele

Pharmacology Year 1 (6 decks)

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