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Applied Pharmacology > Pharmacokinetics and Pharmacodynamics > Flashcards

Pharmacokinetics and Pharmacodynamics Flashcards

0
Q

What is the definition of Pharmacokinetics and clinical pharmacokinetics?

A

It determines what the body does to the drug.
Absorption, distribution, metabolism, excretion.
Clinical pharmacokinetics is the tailoring of the drug to your patient, e.g. the dose rate given by the drug company is modified to suit the patient.

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1
Q

What are the certain requirements of a drug?

A

1) efficacy- it does what it says it will do
2) safety- for both the patient and the vet
3) minimal side effects
4) residues for commercial animals

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2
Q

What is the definition of pharmacodynamics?

A

it determines what the drug does to the body.

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3
Q

What are the three different models of kinetics?

A

1) open model- drug is eliminated from the body (most common)
2) closed model- drug is re-circulated (enterohepatic)
3) compartments- central, peripheral and deep. e.g. Blood, muscle, CNS

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4
Q

What is entero-hepatic recirculation?

A

drug is released into the GI tract in the bile and a proportion of it may then be reabsorbed from the GI tract. This means that the drug will last much longer and if it is metabolised then it can be altered in the GI tract back to its original form.

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5
Q

What is first order kinetics?

A

1) first order kinetics- rate of drug elimination changes and is proportional to the drug concentration. The equation for this is (delta)C/(delta)t=-KC. As drug concentration increases then excretion will increase to compensate (enzymes can respond) -the drug conc. decreases exponentially.

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6
Q

What are 0 order kinetics?

A

The rate at which the drug concentration changes is constant and independent of drug concentration. In this case the enzymes are working at their limit and so increasing the concentration of the drug will not increase the amount excreted. (delta)C/ (delta)t=-K0, C is not involved here. Rel is fixed.

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7
Q

What will happen in a one compartment, open model, first order elimination by IV admin and how is it graphed?

A

It will enter the central compartment directly because of the IV, elimination will occur, Rel is proportional to conc. and there is no absorption. The graph will be a straight line (1st order), K is the slope of the line and C is the concentration, C0 is the conc. at time 0

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8
Q

What happens in a one compartment open model with first order absorption and elimination and how is it graphed?

A

Here the drug is given orally so absorption into the central compartment needs to be taken into account. So the graph will have two phases: The absorption phase is curved and represents the drug getting into the central compartment and the elimination phase is a straight line.

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9
Q

What happens in a two compartment open model, IV with first order elimination and how is it graphed?

A

This is different because once into the central compartment the drug then has two ways that it can be lost: to the peripheral compartment or it can be eliminated. The movement from central to peripheral will reach equilibrium but elimination can only come from the central so the drug move from peripheral to central then out.
It is a biphasic graph with the rate of conc falling rapidly at the start as it is lost in two ways, it then slows as equilibrium is reached and loss is purely due to elimination.

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10
Q

How do drugs interact when they are free and bound?

A

Only the free drug is able to move, it cannot be metabolised, excreted or move into cells when bound. There is an equilibrium between free and bound drug in receptors, tissue reservoirs and in the main body compartments.

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11
Q

What influences the movement of a drug?

A

The molecular size, shape, degree of ionisation, lipid solubility of ionised and non-ionised forms, protein binding. These are the physico-chemical properties of the molecule.

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12
Q

How does variation in membranes influence movement of a drug?

A

capillaries have intercellular gaps to allow movement of the drug, the CNS have tight junctions to form the BBB. So the size of the gap determines what size of molecule can pass through.

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13
Q

How can drugs enter the BBB?

A

If the drug has an affinity receptor it can bind to it and enter. Once in, the drug will bind to P-glycoprotein and be removed, it is actively transported out of the CNS immediately.

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14
Q

What are the two ways that drugs can move across membranes?

A

Passive transfer- depends on how lipid soluble the drug is and the drug concentration gradient and, if the drug is hydrophillic, aqueous pores.
Carrier mediated transport- relies on chemical nature, it can become saturated and undergo competitive inhibition. e.g. active transport- against conc. grad. or facilitated diffusion- relies on movement down the conc. grad.

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15
Q

What is ‘ion trapping’?

A

When most of the drug is in its ionised form and is more concentrated in one area. (move across membranes when non-ionised).

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16
Q

What is the Henderson-Hasselbach equation in relation to degree of ionisation?

A

The degree of ionisation depends on the pKa and pH of the drug.
pKa= conc at which 50% is ionised.
Acids- pH-pKa= log (ionised/non-ionised)
Bases- pH-pKa= log (non-ionised/ionised)

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17
Q

What is the effect of ionisation of movement of a weak acid from the stomach?

A

The low pH in the stomach means that the acidic drug is non-ionised (Acid in acid= non-ionised). It is therefore lipid soluble and so is rapidly absorbed into the plasma where the pH is higher. It is ionised here and will stay in the plasma.

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18
Q

How is the effect of ionisation on erythromycin (base antibiotic) important for treatment of mastitis?

A

It remains less ionised in the plasma because of the higher pH, it will therefore move easily into the milk which has a lower pH. It is ionised here and cannot move across the lipid membranes, it is therefore ion trapped in the area that needs treated.

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19
Q

What is absorption and what dictates how well it is absorbed?

A

The passage of a drug from the site of administration to the blood stream. Its bioavailability- quantifies the level of drug absorption. it route of administration. Ka can also describe absorption.

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20
Q

What is parenteral absorption?

A

The GI tract is bypassed- refers to administration by injection or inhalation.

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21
Q

What are the three examples of parenteral absorption?

A

Intravenous- most rapid onset, given slowly, irritant drugs have to be given this way e.g. chemotherapy.
Intramuscular- delay in action, depends on the muscle group.
Subcutaneous- not that much slower than i/m

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22
Q

Parenteral vs oral administration?

A

parenteral- for rapid effects at systemic level and reliable. But the owner cannot do this. Advantageous if the animal if vomiting or inappetant.
Oral- avoid in LA due to ideosyncrancies in the GI tract, good for a pet on long-term medication. But consider pH differences in stomach vs SI, a basic drug has an enteric coating to prevent it from being ionised in the stomach and staying there.

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23
Q

What is the first pass effect?

A

the removal of a percentage of the drug as it passes through the liver via the portal circulation- before it reaches the systemic circulation.

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24
Q

What are some examples of drug formulation that may affect its release?

A

addition of other agents e.g. enteric coat. addition of other agents e.g. adrenaline in local anaesthetics to cause local vasoconstriction and reduce absorption from the site= prolonged effect.

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25
Q

How do we quantify bioavailability?

A

AUC- area under then curve.

used to calculate clearance and identify total exposure to the drug as well. e.g. plasma conc vs time.

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26
Q

What is Bioavailability?

A

defines the extent to which an administered dose of a drug enters the systemic circulation intact. Referred to as F and calculated from AUC so F=AUCoral/AUCiv.

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27
Q

What affects drug distribution?

A

Similar to absorption, movement across membranes, blood flow to different organs, lipid solubility and plasma protein binding.

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28
Q

How does plasma protein binding affect drug distribution?

A

Certain drugs bind highly to plasma proteins, this binding is reversible. It affects distribution because bound drug cannot move across membranes, bound drug acts as a reservoir.

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29
Q

Which protein do drugs tend to bind to, happens when the drug is bound and what can occur if there isnt enough protein?

A

Albumin is the main one, binding in excess of 80% is considered high. Bound drug tends to stay centrally and cannot be filtered by the kidney but carrier mediated transport is not affected. Hypoalbuminaemia may increase free drug= toxicity. If two high PPB drugs are used they can displace each other and cause toxicity.

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30
Q

Give 7 examples of drugs with high protein plasma binding?

A

Phenylbutazone (anti-inflammatory), Digitoxin (cardiac drug), Phenytoin (anticonvulsant), ceftiofur ( antimcrobial), warfarin (anticoagulant), furosemide (diuretic), diazepam (sedative)

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31
Q

What is volume of distribution?

A

the amount of tissue to which the drug distributes is directly related to the plasma drug concentration. It is a theoretical volume and calculated from =: Vd= dose/C0

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32
Q

How is Vd=Dose/C0 used?

A

A known dose is given via IV so that F=100%
C0 is the peak plasma drug concentration after equilibrium is achieved and before elimination has begun. It is derived from extrapolating the PDC/time curve back to time 0. (pharmodynamics conc.)

33
Q

How is Vd graphed and what is the relationship?

A

For a two compartment model the elimination phase is extrapolated back to the Y axis and time 0 to determine the peak PDC. It is an inverse relationship between con. and Vd so larger Vd = lower conc. of drug.

34
Q

What does Vd of a drug tell you?

A

TBW is approx 0.6L/kg and the ECF is about 0.1-0.3L/Kg.
So if the Vd is in the region of 0.1-0.3L/kg then the drug will be water soluble and distributes mainly to the ECF. (no good for intracellular bacteria)
If Vd is high (2L/Kg) then the drug will accumulate at a particular site, its gets into ECF and ICF, this is good for deep compartments (CNS and fat- especially if lipid soluble.)

35
Q

What is elimination and what can influence it?

A

It is the removal or metabolism of the drug by biotransformation or excretion. If it is lipid soluble then it will enhance the access to sites of metabolism, if it is water soluble then it enhances the possibility of renal excretion.

36
Q

Where does biotransformation occur?

A

Mainly in the liver, but also in plasma- pseudocholinesterase that hydrolyses a number of drugs e.g. atropine.
Kidney, gut and lung.

37
Q

What are the two different types of reaction involved in biotransformation?

A

Phase I- hydrolysis, reduction, oxidation (most common). These makes drugs more reactive as it exposes the functional groups.
Phase II- conjugation to amino acids, acetylation, glucuronidation. These put on side chains to make them look more polar and less lipid soluble. They then undergo elimination.

38
Q

Give an example of a phase I reaction?

A

Undergone by hepatic microsomal enzymes, these are mixed function oxidases. e.g P450 is reduced by NADPH. It binds oxygen which oxidises the drug = The enzyme (P450) is released and water is produced.

39
Q

How can drugs alter the mixed function oxidase system?

A

They inhibit or induce hepatic microsomal enzymes.
Inducers- e.g. phenobarbitol, diazepam, phenylbutazone, phenytoin. They enhance their own metabolism and that of other drugs.
Inhibitors- reduce their own metabolism and that of other drugs. Can increase toxicity e.g. cimetidine, organophosphates.

40
Q

What does biotransformation do to the drug?

A

in most cases metabolism renders the drug inactive but sometimes it makes them more active than the parent drug. But the metabolites can be toxic- e.g. cats and paracetamol.

41
Q

What is the most important phase II reaction and what can happen?

A

Glucuronidation, cats cannot perform this due to the lack of glucuronyl transferase. Enterohepatic re-circulation can remove the glucuronidation and re-release the active form. The glucuronide conjugates are excreted in bile, some degree of hydrolysis in the gut can occur along with reabsorption of the active drug.

42
Q

How is the drug eliminated and what are the important factors?

A

The kidney is the main organ. Water solubility is important.
Elimination will occur by glomerular filtration (passive, depends on blood flow and the size of the molecule), active transport in the PCT, reabsorption (lipid sol, ion trapping and pH of urine), biliary, skin and pulmonary routes too.

43
Q

How do we quantify elimination?

A

We use the half life of elimination. The time taken for the plasma drug concentration to fall by 50%. Calculation of half life depends on first order kinetics- it wont work on 0 order. There is exponential decline, or if a semi-log base it will be a straight line.

44
Q

How are dosing regimens determined and what factors affect half-life?

A

Half life data and plasma drug concentration (PDC).
effects on access to sites of biotransformation or elimination.
interaction with other drugs.
physiological/pathological states e.g. pregnancy vs renal disease.

45
Q

What is clearance?

A

It is defined as the volume of blood cleared of the drug by all elimination processes per unit time and is measured in ml/min- it encompasses biotransformation as well as elimination processes.
Basically number of mls cleared/min.

46
Q

How do we work out our dosing regimens?

A

They are based on: Half life to help determine dose interval and Vd to determine the therapeutic range. We also need to reach the point where the levels of a drug remain stable or consistent from dose to dose, this is called the steady state.

47
Q

When is 95% Steady state reached?

A

it is achieved after 5 half lives and 99% after seven half lives.

48
Q

What does steady state rely on?

A

it relies on first order kinetics e.g. the rate at which the drug leaves the body is proportional to its concentration. So as the drug reduced, concentration reduces. If it was 0 order the drug would leave at a fixed rate irregardless of the concentration. Some drugs will start at 1st and then go to 0 order due to saturated elimination pathways.

49
Q

What are the three ways that steady state can be achieved?

A

1) IV continuous infusion
2) loading dose followed by a regular dose at fixed intervals
3) fixed interval of a regular dose which will take about 5 half lives to achieve a steady state. If the dose is the same as t1/2 then fluctuation of the SS will be 50%, if the dose is twice t1/2 (every second half life) then fluctuations of 75% will occur.

50
Q

What is the relationship between half life and clearance?

A

t1/2= 0.693 x Vd/Clb

51
Q

Using phenobarbitol as an example- describe steady state option, fixed dose, regular interval.

A

It has a long half life of 24-36hrs. This means it will take >2weeks to reach the steady state (24-36 x5). Therefore plasma levels continue to rise until the steady state has been reached, so a blood sample after two days will show a low drug level but do not up the dose as the drug conc. will continue to rise, if the dose it upped it can cause toxicity.

52
Q

What is the equation for clearance?

A

Cl= VdxK

53
Q

What is the equation for dose?

A

Dose= (Cmax) x Vd

54
Q

In the terms of pharmacodynamics what is drug action and drug effect?

A

drug action is the interaction of the drug with its receptor.
the drug effect is the subsequent chain of events caused by the drug/receptor interaction.

55
Q

What is the definition of a drug receptor and drug action?

A

A macromolecular structure with which the drug reacts.
Drug action is the drug receptor interaction. It can be- protein (muscarinic), enzyme (AChE), nucleic acid and other less specific ones.

56
Q

What is the definition of an agonist and what are the two types?

A

It is a drug receptor that binds to a physiological receptor and mimics the effect of the endogenous ligand.
Full agonist- can achieve max response even if not all the receptors are occupied.
Partial agonist- is incapeable of achieving max response even if all the receptors are occupied.

57
Q

What is the dose response curve (DRC)?

A

The interaction response between the receptor and the ligand. The curve is the log of the drug conc to achieve the sigmoidal shaped curve- this ensures more detail. If it wasnt the log it would be a straight line.

58
Q

What is the definition of affinity?

A

Affinity is the tendency of the ligand to bind the receptor.

59
Q

What is the definition of efficacy?

A

how good the drug is at eliciting a response e.g. partial agonists have less efficacy than full ones. On a graph the partial agonist will not ever reach maximal response.

60
Q

What is the definition of potency?

A

It is a relative term, it is used to compare two drugs. It compares the concentration that is required to elicit the same response. e.g. measure the EC50 and graph conc at 50% max response.

61
Q

What is the definition of an antagonist and what are the two types?

A

They block the effect of the agonist, they can have affinity but have no intrinsic activity. It can be a competitive reversible antagonist where by increasing the amount if agonist can compete off the antagonist. It can be a non-competitive irreversible antagonist that will not be overcome by increasing the amount of agonist.

62
Q

What would a dose response curve (DRC) of a competitive antagonist and a non competitive look like?

A

You would see a higher concentration required to reach the EC50 than just the agonist, the graph would be shifted to the right.
A non competitive one would never reach max.

63
Q

What are the other types of antagonism?

A

pharmacological, chemical e.g. mixing drugs before injection.

64
Q

What is the significance of the Law of Mass Action?

A

R+L<> RxL- describes how increasing the drug and receptor will drive the reaction forward.

65
Q

What equation shows the number of receptors occupied by the drug at equilibrium?

A

(A)/(A)+Kd, Kd is the equilibrium dissociation constant.

66
Q

What is selectivity and specificity?

A

Often drugs produce more than one effect, selectivity defines the capacity to preferentially produce on particular effect.
Specificity is an absolute term, it tends to only act on one particular receptor type.

67
Q

What is the therapeutic index?

A

It tells us how safe the drug is, it is the ratio of the dose giving an undesirable effect over the dose required to give the desired effect. The LD50 on the graph is the concentration of the drug at which adverse effects start to appear.

68
Q

What is an ionotropic receptor?

A

It is an ion channel cell transmembrane receptor. It can rapid effects and examples are: Ach (nicotinic), Glutamate and GABA.

69
Q

What is a GPCR?

A

It consists of 7 transmembrane domains. An extracellular part is where the ligand binds to and the intracellular part is the part that is coupled to the G protein, it activates the 2nd messenger system. e.g. Ach Muscarinic receptors, alpha and beta adrenoreceptors.

70
Q

Which GPCR pathway should we know?

A

The phospholipase C pathway. The GPCR activates PLC, PLC activates IP3 and DAG.
IP3 causes release of Ca from the SR.
DAG activates PKC which opens Ca channels. (slower acting)

71
Q

What is a protein kinase receptor?

A

They have a binding site outside of the cell which causes a catalytic effect inside the cell (fast acting), they mediate the action of proteins such as insulin.

72
Q

What is a cytosolic receptor?

A

The ligand interacts and translocates the signal into the nucleus, it is a long process as it involves regulation of transcription factors.

73
Q

What is receptor desensitisation?

A

When a receptor is exposed to a ligand the response may reach a peak and then despite the continued presence of the ligand it will fall off. It recovers in time, especially if the ligand is removed. e.g. Beta adrenoreceptors such as BARK and B arrestin.

74
Q

What is receptor down regulation?

A

Receptors become internalised and degraded within the cell. This takes longer to recover. e.g. the tyrosine kinase family.

75
Q

What is tachyphylaxis?

A

the rapid loss of responsiveness to a drug following initial dosing. Could involve receptor desensitisation.

76
Q

What do individual characteristics affect to alter dose requirements?

A

changes in Vd, changes in PPB, changes in metabolism.

e.g. pregnancy, age, hepatic or renal disease.

77
Q

How can renal disease alter dosing requirements and how can the dose be modified?

A

reduced glomerular filtration and tubular secretion. So dose rate or dose interval should be reduced.
The dose is modified by using creatinine clearance or serum clearance to modify the dose:
new interval= old interval x patient Cr/normal Cr
new dose= old dose x normal Cr/patient Cr.

78
Q

How does hepatic disease affect dose?

A

The hepatic blood flow, protein binding, metabolism. It is difficult to change the dose/interval as there is no formula. A tiny change in hepatic function can make metabolism of the drug totally different. The metabolism of drugs also relies on the liver producing albumin which can be compromised.

79
Q

What is therapeutic dose monitoring? (TDM)

A

The best way is to monitor the drug plasma levels at key times and know what the ideal target range is. this is done for phenobarbital, digoxin and gentamicin. But make sure the drug has reached its steady state!

Applied Pharmacology (5 decks)

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