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Phase 2a - ICS > Principles of pharmacokinetics > Flashcards

Principles of pharmacokinetics Flashcards

1
Q

What is pharmacodynamics?

A

The biochemical, physiological and molecular effects of a drug on the body.

What the drug does to the body.

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2
Q

What is pharmacokinetics?

A

The fate of a chemical substance administered to a living organism.

What the body does to the drug.

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3
Q

What are the processes of pharmacokinetics?

A

Absorption
Distribution
Metabolism
Excretion

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4
Q

Describe absorption

A

Transfer of a drug molecule from site of administration to systemic circulation (barriers vary with route of administration)

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5
Q

What are examples of route of administration?

A

IV
IA (intra arterial)
IM
SC
PO
SL
INH
PR
PV
TOP
TD
IT (intrathecal)

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6
Q

Which routes of administration allows 100% of a drug to reach circulation?

A

IV and IA

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7
Q

How do drugs penetrate membranes?

A
  1. Passive diffusion via the hydrophobic membrane. (Lipid soluble molecules).
  2. Passive diffusion aqueous pores. (Very small water soluble drugs (Lithium). Most drugs are too big.
  3. Carrier mediated transport. (Proteins which transport sugars; AA, neurotransmitters and trace metals).
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8
Q

What factors affect absorption?

A

Lipid solubility + drug ionisation

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9
Q

Ionised drugs

A

Poor lipid solubility -> poorly absorbed.

Most drugs are weak acids or weak bases with ionisable groups.

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10
Q

What does the proportion of ionisation depends on?

A

pH of the aqueous environment.

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11
Q

Weak acids are best absorbed where?

A

In the stomach.

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12
Q

Weak bases are best absorbed where?

A

In the intestine.

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13
Q

What factors affect oral drug absorption in the stomach?

A

Gastric enzymes - molecules may be digested.

Low pH - molecule may be degraded.

Food - full stomach = slower absorption.

Gastric motility - altered.

Previous surgery - gastrectomy.

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14
Q

What factors affect oral drug absorption in the intestine?

A

Drug structure - lipid soluble/unionised diffuse down conc. gradient.
Large/hydrophilic - poor absorption.

Medicine formulation - coating controls time between administration and release.

P-glycoprotein - substrates removed from intestinal endothelial cells back into the lumen.

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15
Q

What is first pass metabolism?

A

Metabolism of drugs preventing them reaching systemic circulation.

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16
Q

What affects first pass metabolism?

A
  • Degradation by enzymes in intestinal wall.
  • Absorption via hepatic portal vein -> metabolism via liver enzymes.
  • It varies between individuals.
  • Avoid giving via routes that avoid sphlanchnic circulation (i.e. rectal)
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17
Q

What is the proportion of a dose which reaches the systemic circulation called?

A

Bioavailability (F)

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18
Q

Bioavailability depends on

A
  1. Extent of drug absorption.
  2. Extent of first pass metabolism.
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19
Q

Is bioavailability affected by the rate of absorption?

A

No

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20
Q

Does bioavailability varies with route of administration?

A

Yes

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21
Q

What other factor causes variation in bioavailability between individuals?

A

Genetics
Disease state

22
Q

Bioavailability is expressed as a

A

Fraction

23
Q

What are the four compartments in the body for drug distribution?

A

Plasma (5%)

Fat (20%)

Interstitial fluid (15%)

Intracellular fluid (35%)

24
Q

How does molecule size affect distribution?

A

Small molecules high distribution between plasma and ECF.

Large molecules low distribution between plasma and ECF.

25
Q

How does lipid solubility affect distribution?

A

Hydrophilic molecules low distribution between plasma and ECF.

Lipophilic molecules high distribution between plasma and ECF.

26
Q

How does protein binding affect distribution?

A

Increased protein binding leads to low distribution between plasma and ECF.

Decreased protein binding leads to increased distribution between plasma and ECF.

27
Q

Volume of distribution (Vd)

A

Theoretical volume of a drug distributed in the body.

Volume of plasma required to contain the total administered dose.

28
Q

Well distributed drugs have

A

High Vd

29
Q

Poorly distributed drugs have

A

Low Vd

30
Q

BBB

A

Membrane that separates foreign substances in the blood from the CNS.

Continuous layer of endothelial cells with tight junctions

Efflux pumps remove water soluble molecules

BBB maintains a stable environment and protects the brain, but poses a challenge for treating CNS conditions

Ways for drugs to reach the CNS
High lipid solubility. e.g. Ѱ drugs usually very lipid soluble (therefore large Vd)

Intrathecal administration (e.g. baclofen in MS and spinal cord injury, chemotherapy)

Inflammation (causes barrier to become leaky)

Can be advantageous (e.g. naloxegol for opioid induced constipation)

31
Q

Aciclovir administration in obese patients

A

Based on ideal body weight.

32
Q

Drug elimination

A

Process by which the drug becomes no longer available to exert its effect on the body.

33
Q

Drug metabolism

A

Modification of chemical structure to form a new chemical entity (metabolite).

34
Q

What are the two phases of metabolism?

A

Phase 1 reactions: oxidation/reduction/hydrolysis to introduce reactive group to chemical structure.

Phase 2 reactions: conjugation of functional groups to produce hydrophilic, inert molecules.

35
Q

Excretion

A

Of unchanged drug (hydrophilic, polar molecules).

36
Q

Phase 1 metabolism

A

CYP450 (mostly located in the liver, also in small intestine and lung)

Lipophilic, unbound drug will readily cross hepatocyte membrane.

Produces a reactive metabolite (creating/unmasking a reactive functional group).

37
Q

What causes variation in CYP enzyme function?

A

Genetic variation
Reduced function in severe liver disease
Interaction enzyme inhibiting/inducing drugs or food can reduce/increase enzyme activity.

38
Q

How many CYP450 enzymes are there?

A

57

39
Q

What are the most significant CYP enzymes?

A

3A4, 2C9, 2C19, 1A2, 2D6

40
Q

What are the substrates for CYP1A2?

A

Caffeine, paracetamol, theophylline, warfarin

41
Q

What are the substrates for CYP2C9?

A

Ibuprofen, warfarin

42
Q

What are the substrates for CYP2C19?

A

Omeprazole, phenytoin

43
Q

What are the substrates for CYP2D6?

A

Codeine, warfarin

44
Q

What are the substrates for CYP3A4?

A

Simvastatin, warfarin, DOACs (apixaban), carbamazepine, diltiazem

45
Q

Pharmacogenomic variation in CYP450

A

Codeine example.

Pro-drug is activated by CYP2D6

Poor metabolisers: minimal therapeutic benefit

Intermediate metabolisers: reduced benefit

Extensive metabolisers: 10% of dose converted to morphine

Ultra-rapid metabolisers: greater proportion converted to morphine - risk of toxicity.

46
Q

Phase 2 metabolism

A

Conjugation of an endogenous functional group (glycine, sulfate, glucuronic acid) to produce a non-reactive polar molecule.

Hydrophilic metabolite can be renally excreted.

47
Q

Paracetamol toxicity

A

Reduced paracetamol dose in low body weight and severe hepatic impairment.

48
Q

What is paracetamol toxicity treated with?

A

N-acetylcisteine (NAC)

49
Q

Excretion (ways)

A

Liquids (small polar molecules): urine, bile, sweat, tears, breast milk

Solids (large molecules): faeces (through biliary excretion)

Gases (volatiles): expired air

50
Q

What three processes account for renal excretion of drugs?

A
  1. Glomerular filtration rate (20% of plasma filtered, free/unbound drug molecules, very large molecules excluded).
  2. Active tubular secretion (80% of renal blood flow passes on to peritubular capillaries, drug molecules transported by carrier system (organic anion/cation transport), can clear protein bound drug, most effective renal clearance mechanism).
  3. Passive reabsorption (diffusion down the conc. gradient from tubule into peritubular capillaries, hydrophobic drugs diffuse easily, highly polar ones will be excreted).
51
Q

Gentamicin in reduced kidney function

A

Reduced renal excretion -> plasma levels rise -> nephrotoxicity and ototoxicity.

Phase 2a - ICS (43 decks)

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