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YR1 - Pharmacology SEM 1 > 6. Pharmacokinetics 4 > Flashcards

6. Pharmacokinetics 4 Flashcards

1
Q

How may a drug be excreted via the GIT?

A

Gastrointestinal Excretion

  • Some drugs and their metabolites are excreted by the gastrointestinal tract in the faeces
  • Drugs and metabolites may enter the gastrointestinal tract for excretion in a number of ways including
    • transport by carrier proteins e.g. organic anion transports (OAT), organic cation transporters (OCT) and p-glycoprotein
    • excretion in the bile (note enterohepatic circulation)
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2
Q

What is Enterohepatic Circulation?

A

Enterohepatic Circulation

  • Exits the liver → Into gut → Reabsorbed back into liver (via portal system)
  • Enterohepatic circulation occurs by biliary excretion and intestinal reabsorption of a compound, sometimes with hepatic conjugation and intestinal de-conjugation
  • Many natural products including cholesterol, bile acids and oestrogen undergo enterohepatic circulation
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3
Q

Which drugs are excreted in the bile and may undergo enterohepatic circulation?

A

Enterohepatic Circulation - Examples

A number of drugs which are metabolised by Phase 2 conjugation with glucuronide are excreted in the bile and may undergo enterohepatic circulation

  • e.g. morphine, paracetamol
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4
Q

What may intestinal reabsorption to complete the enterohepatic cycle depend on?

A

Intestinal reabsorption to complete the enterohepatic cycle may depend on hydrolysis of a drug conjugate by gut bacteria

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5
Q

What is the pharmacological significance of enterohepatic circulation and drug effects?

A

Enterohepatic circulation may prolong the pharmacological effect of some drugs

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6
Q

Which 2 types of reactions are involved in Drug Metabolism?

A

Drug Metabolism

Drug metabolism basically involves two types of reaction:

  1. Phase 1 reactions → oxidation, reduction and hydrolysis
    • e.g. by enzymes of the cytochrome P450 system
  2. Phase 2 reactions → conjugation reactions and involve the attachment of a chemical group to the parent drug or metabolite
    • e.g. glucuronidation, sulphation
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7
Q

How is estrogen metabolised?

A

Enterohepatic Circulation - Oestrogen

  • Oestrogen is metabolised by CYP 3A4 (phase 1 reaction)
  • Oestrogen is also conjugated in the liver (phase 2 reaction) and excreted in the bile
  • Bacteria in the intestine hydrolyse the conjugate and release free oestrogen
  • This free oestrogen is then reabsorbed (enterohepatic circulation)
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8
Q

What is the Volume of Distribution of a drug?

How is it calculated?

A

Volume of Distribution (VD) of a drug = a measure of the extent to which the drug leaves the blood and distributes into the tissues

  • It is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood/plasma
  • It is calculated by the following formula
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9
Q

What is the volume of distribution of a drug that:

  • Remains primarily in the blood?
  • Distributes primarily into the extracellular fluid?
  • Distributes freely throughout the tissues?
A

Volume of Distribution (VD)

  • Some drugs tend to remain primarily in the blood e.g. those which are highly protein bound and these drugs have a LOW volume of distribution
  • Some drugs distribute primarily into the extracellular fluid and these drugs have an INTERMEDIATE volume of distribution
  • Some drugs distribute freely throughout the tissues, or may be stored in the tissues e.g. fat stores, and these drugs have a HIGH volume of distribution
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10
Q

What are 4 examples of drug VDs?

A

Volume of Distribution (VD) - Examples

  1. Naproxen 8L
  2. Paracetamol 80L
  3. Digoxin 500L
  4. Chloroquine >7000L
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11
Q

What is the clinical significance of a drugs VD?

A

Volume of Distribution (VD) - Clinical Significance

  • The volume of distribution gives information on the distribution of the drug in the body
  • The volume of distribution helps in determining the correct dose, any loading dose, and whether the drug is dialysable (in treatment of overdose)
  • The volume of distribution also affects the half-life of the drug, and the clearance of a drug
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12
Q

What is a Drugs half life?

A

Half Life (t1/2) of a drug = the time taken for the blood level of the drug to halve

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13
Q

What is First Order Kinetics in pharmacological terms?

A

Half Life (t1/2) and First Order Kinetics

  • For most drugs the time taken to go from a blood level of 100μg/ml to 50μg/ml is the same time to go from 50μg/ml to 25μg/ml, and the same time to go from 25μg/ml to 12.5μg/ml etc
  • The blood level halves every half-life (t1/2), but the actual amount of drug eliminated each half-life varies
  • The rate of elimination is proportional to the drug concentration
  • This is called first order kinetics, and this applies to the vast majority of drugs
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14
Q

What are some examples of the half lives of drugs?

What does half life determine clinically?

A

Half Life (t1/2)

  • The half-lives of drugs can vary considerably
  • Some examples are
    • paracetamol = 3 to 4 hours
    • ibuprofen = 2 hours
    • methadone = 15 to 60 hours
    • atorvastatin = 14 hours
    • sertraline = 26 hours
    • amiodarone = 14 to 110 days
    • alendronate = 10 to 12 years
  • The half-life is an important factor in determining the dosage interval (how often a drug is taken)
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15
Q

What is Steady State?

How long does it usually take to reach steady state?

A

Steady State

  • With first order kinetics if a patient takes a drug regularly there comes a time when the amount of drug taken by the patient in each dose is equal to the amount of drug eliminated
  • When this situation is reached it is referred to as “steady state“
  • It takes around 5 half lives of a drug to reach steady state
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16
Q

What is Zero Order Kinetics in pharmacological terms?

A

Zero Order Kinetics

  • A few compounds are excreted (eliminated, cleared) from the body by zero order kinetics
  • With zero order kinetics a constant amount of drug is eliminated per unit of time
  • With zero order kinetics the rate of elimination (clearance) is constant and independent of the amount of drug present in the body at the time
  • With first order kinetics the rate of elimination (clearance) varies and is proportional to the amount of drug present at the time
17
Q

How is Alcohol metabolised in the body?

Which kinetics is it excreted by?

How much alcohol can the average person metabolise per hour?

A

Metabolism of Alcohol

  • Alcohol (ethyl alcohol) is excreted by zero order kinetics
  • Alcohol (ethyl alcohol) is metabolised to acetaldehyde by the enzyme alcohol dehydrogenase
  • Alcohol dehydrogenase becomes saturated at relatively low blood alcohol concentrations
  • The average person can metabolise around 8 to 10 grams of alcohol per hour
  • A standard drink contains 10 grams of alcohol
  • The average person can thus metabolise (clear, eliminate) one standard drink per hour
18
Q

What controls the rate of metabolism of alcohol?

What does this mean if someone consumes 2/4 standard drinks?

A

Metabolism of Alcohol

  • The enzyme alcohol dehydrogenase becomes saturated
  • This means that
    • if someone consumes 2 standard drinks after an hour they will have one standard drink (10 grams of alcohol) left in the body
    • if someone consumes 4 standard drinks after an hour they will have 3 standard drinks (30 grams of alcohol) left in the body
19
Q

What blood alcohol level (BAC) does 1 standard drink give?

How much does the BAC reduce by per hour?

A

Alcohol Metabolism

  • One standard drink (10 grams of alcohol) gives a blood alcohol level of approximately 0.015 grams per 100ml (0.015)
  • The body can metabolise around 8 to 10 grams of alcohol per hour, and thus reduce the blood level by 0.015 per hour
  • If a person has a blood alcohol level of 0.15 and they stop drinking, it will take approximately 10 hours to get to zero
20
Q

What are Adverse Drug Reactions (ADRs)?

A

Adverse Drug Reactions (ADRs)

  • All drugs produce adverse drug reactions (side effects, toxicity) - even a placebo will produce adverse reactions in some people
  • ADRs are listed in the product information for each medicine
  • Doctors, nurses, pharmacist etc. have a responsibility for counselling patients, and monitoring and documenting ADRs
  • The Database of Adverse Event Notifications (DAEN) also provides information about ADRs
21
Q

What are some examples of minor and severe/life threatening ADRs?

A

Adverse Drug Reactions (ADRs)

  • Some adverse drug reactions are relatively minor - eg. dyspepsia, headache, nausea,
  • Others maybe very severe and life threatening - eg. anaphylactic reaction e.g. amoxycillin
22
Q

What are Type A (“augmented”) adverse reactions?

Give 3 examples?

How can these be resolved?

A

Type A ADRs

  • Some adverse drug reactions are an extension of a drug’s therapeutic effect
  • These are predictable and are often referred to as Type A (“augmented”) adverse reactions
  • Examples:
    1. insulin may produce hypoglycaemia
    2. anticoagulants may produce bruising and bleeding
    3. antihypertensive therapy may produce dizziness and lightheadedness
  • Can be treated by reducing the dose
23
Q

What are Type B ADRs?

Give 1 example

A

Type B ADRs

  • Some adverse drug reactions are unrelated to the therapeutic effect of the drug
  • These reactions are unpredictable, rare, idiosyncratic, independent of the dose and may be severe
  • They are often referred to as Type B (“bizarre”) adverse reactions
  • Examples:
    1. anaphylactic reaction to penicillin
  • Drug must be stopped and appropriate treatment initiated
24
Q

What is Therapeutic Index of a drug?

What does a low/high TI mean?

Give examples of each?

A

Therapeutic Index of a drug = the ratio of the dose which produces adverse reactions (toxic, lethal) to the dose which produces the therapeutic response (LD50/ED50)

  • Gives an indication of the safety margin of the drug
  • Drugs with a low (narrow) therapeutic index have a low margin of safety
    • e.g. digoxin
  • Drugs with a high (wide) therapeutic index have a high margin of safety
    • e.g. benzodiazepines

YR1 - Pharmacology SEM 1 (14 decks)

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