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Transition block 1 > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

What happens when a drug is administered IV?

A

It by-passes absorption

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2
Q

What is the rate of elimination of a drug?

A
  • The fraction of the amount of drug in the body (A) that is eliminated per unit time
  • Rate of elimination = ke x A e.g. if ke=0.02 and A=100mg, rate of elimination = 2mg/min
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3
Q

If a drug exhibits first order kinetics what does this mean?

A
  • The rate of elimination is directly proportional to drug concentration
  • The dose administered changes Cp (plasma conc) in direct proportion but does not affect ke (rate of elimination) or t1/2 (half-life)
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4
Q

What is clearance?

A
  • The volume of plasma cleared of drug in unit time
  • A constant relating the rate of elimination to plasma concentration
  • Rate of elimination = CL x Cp
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5
Q

What does steady state mean?

A

Rate of drug administration = rate of drug elimination

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6
Q

For drugs that exhibit first order kinetics, what is the relationship between steady state Cp and infusion rate?

A

The steady state plasma concentration (Css) is linearly related to the infusion rate

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7
Q

What determines the time to reach steady state plasma concentration (Css)?

A
  • Half life (t1/2) but NOT the infusion rate
  • Css is reached after approximately 5 half-lives
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8
Q

What is volume of distribution?

A
  • The volume into which a drug appears to be distributed with a concentration equal to that of plasma
  • A proportionality constant relating the plasma concentration (Cp) to the amount of drug in the body (A)
  • A = Vd x Cp
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9
Q

What is the loading dose?

A

An initial higher dose of a drug given at the beginning of a course of treatment before stepping down to a lower maintenance dose

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10
Q

Why is a loading dose used?

A

To decrease time to steady state for drugs with long half lives e.g. digoxin and phenytoin

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11
Q

What is the half life of a drug?

A

The time for the concentration of drug in plasma to halve

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12
Q

What does zero order kinetics mean?

A

A few drugs (e.g. ethanol and phenyotoin) are initially eliminated at a constant rate, rather than at a rate that is proportional to their concentration

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13
Q

What is the function of drug metabolism?

A
  • To covert parent drugs to more polar metabolites that are not readily reabsorbed by the kidney, facilitating excretion
  • Convert drugs to metabolites that are usually less pharmacologically active than the parent compound
  • Less frequently, metabolites may be converted from inactive pro-drugs to active compounds or gain activity or have unchanged activity or possess a different type or spectrum of action
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14
Q

Drug metabolism often proceeds in 2 sequential phases, phase I and phase II. Describe these and where they occur

A
  • Phase I - oxidation, reduction and hydrolysis.
    • Makes drug more polar, adds a chemically reactive group, permitting conjugation
  • Phase II - conjugation.
    • Adds an endogenous compound increasing polarity
  • Mainly occur in the liver
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15
Q

What are the cytochrome P450 (CYP) family of monooxygenases?

A

Haem proteins located in the endoplasmic reticulum of liver hepatocytes mediating oxidation reactions (phase I) of many lipid soluble drugs

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16
Q

What happens in the monooxygenase P450 cycle?

A
  • Drug enters the cycle as drug substrate, RH
  • Molecular oxygen provides 2 atoms of oxygen
  • One atom of oxygen is added to the drug to yield the hydroxyl product, ROH, which leaves the cycle, the second oxygen combines with protons to form water
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17
Q

What is glucuronidation?

A
  • Reaction involving the transfer of glucuronic acid to electron-rich atoms of the substrate
  • Many endogenous substances are subject to glucuronidation e.g. bilirubin
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18
Q

Why can paracetamol cause hepatotoxicity?

A
  • In normal dosage paracetamol is metabolised to a glucuronate and a sulphate (phase II) but in overdose these processes are saturated and P450 mixed function oxidases (phase I) produce a toxic metabolite NAPBQI
  • NAPBQI can be inactivated by conjugation with glutathione but if toxic dose deplete GSH stores
  • NAPBQI interacts with cellular proteins causing hepatocellular necrosis and rarely renal tubular necrosis
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19
Q

How is paracetamol poisoning treated?

A
  • If within 1 hour - activated charcoal PO
  • If at least 4 hours since ingestion determine plasma concentration of paracetamol to determine likelihood of liver damage
  • If Cp is above the normal treatment line administer IV N-acetylcysteine (antidote)
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20
Q

How does N-acetylcysteine work as an antidote for paracetamol poisoning?

A

Increases the synthesis of GSH permitting the increased conjugation and elimination of NAPBQI

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21
Q

What are the 3 basic processes involved in renal excretion of drugs and drug metabolites?

A
  1. Glomerular filtration
  2. Active tubular secretion
  3. Passive reabsorption by diffusion across the tubular epithelium
22
Q

Which drugs can be filtered at the glomerulus freely?

A
  • Drugs with a molecular weight <20,000 provided they are not bound to large plasma proteins such as albumin and alpha1-acid glycoprotein
  • Hence if a drug binds to a plasma protein its concentration in the glomerular filtrate will be less than total plasma concentration
  • CL(filtrate) = GFR x fraction of drug unbound in plasma
23
Q

Up to 20% of renal plasma flow is filtered through the glomerulus, but the remaining 80% is delivered to the peritubular capillaries of the proximal tubule. What are the 2 transporter systems that actively secrete drugs into the lumen of the nephron?

A
  • Organic anion transporter (OAT) - handles acidic drugs (e.g. penicillins), endogenous acids (e.g. uric acid) and the marker for renal plasma flow (PAH)
  • Organic cation transporter (OCT) - handles basic drugs (e.g.morphine)
24
Q

What drugs are used for a selective action on the kidney as a diuretic agent and what transporter do they use?

A
  • Acetazolamide, frusemide, thiazides - OAT
  • Amiloride, triamterene - OCT
25
Q

What factors influence tubular reabsorption?

A
  • Lipid solubility (drugs with high lipid solubility will be extensively reabsorbed and excreted slowly)
  • Polarity (highly polar drugs will be excreted without reabsorption)
  • Urinary flow rate (diuresis decreases reabsorption)
  • Urinary pH (alkaline pH increases excretion of acids, acidic pH increases excretion of bases)
26
Q

Why is urinary pH important clinically in aspirin overdosage?

A

Urinary alkalinisation can be used to accelerate the excretion of aspirin (weak acid) in cases of overdosage

27
Q

How is a safe and effective drug dose reached?

A

To achieve an effect, a drug must reach a critical concentration in the plasma (minimum effective concentration, MEC) but ideally be well below that causing significant unwanted effects (maximum tolerated dose, MTC)

28
Q

What is a therapeutic window?

A
  • The difference between the MEC and the MTC is the therapeutic window
  • Safe drugs have a large window e.g. BZDs, penicillins
  • Unsafe drugs will have a narrow window e.g. cardiac glycosides (digoxin) and barbituates
29
Q

What is the quantal dose response relationship?

A
  • Plots the fraction of the population that responds to a given dose of drug against the drug dose
  • Response if quantal (present or not present) rather than a scale
  • Doses of drug that produce such responses in 50% of the population are, for example, the median effective dose (ED50), median toxic dose (TD50) and median lethal dose (LD50)
30
Q

What is a drug interaction?

A

A drug interaction occurs when the effects of one drug are increased, or decreased, by the previous, or concurrent, administration of another

31
Q

What is a pharmacodynamic drug interaction?

A
  • Drug A modifies the pharmacological effect of drug B without altering its concentration in tissue fluid
  • Usually predictable
32
Q

What is a pharmacokinetic drug interaction?

A
  • Drug A modifies the concentration of drug B that reaches its site of action
  • Not easily predicted - can involve changes in absorption, distribution, metabolism and excretion
33
Q

What kind of drugs can affect absorption of other drugs?

A
  • Drugs that increase (e.g. metoclopramide) or decrease (e.g. atropine), the rate of emptying of the stomach may affect absorption
  • Enterohepatic recirculation of oral contraceptives may be reduced by antibiotics, causing failure of contraception
34
Q

What kind of drugs can affect distribution of other drugs?

A

Drugs bound to plasma protein may be displaced by a 2nd drug, increasing their free concentration - this is probably of little importance, except for drugs that are extensively protein bound and which have a low therapeutic range e.g. phenytoin

35
Q

What kind of drugs can affect metabolism of other drugs?

A
  • Induction of hepatic enzymes by drugs can decrease the efficacy of other drugs metabolised by the same enzyme
  • Conversely, enzyme inhibitors may potentiate the effect of other drugs metabolised by the same enzyme
  • e.g. phenytoin induces an enzyme, causing decreased efficacy of warfarin whereas cimetidine inhibits an enzyme causing increased efficacy of warfarin
36
Q

What kind of drugs can affect excretion of other drugs?

A

Drugs may share a common transporter, for example in the proximal tubule of the nephron

37
Q

What substance commonly causes myopathy due to a drug interaction involving simvastatin?

A

Grapefruit juice + simvastatin = myopathy

38
Q

What drugs enhance anticoagulation in a patient on warfarin?

A

Clarithromycin, fluconazole, aspirin, NSAIDs

39
Q

Why should atenolol and salbutamol not be taken together?

A

It inhibits the bronchodilator effect of salbutamol

40
Q

Which drug class when used in combination with catecholamines e.g. adrenaline, NA, dopamine can cause hypertensive crisis?

A

Monoamine oxidase inhibitors e.g. phenelzine

41
Q

What can increase sedation and risk of falls in patients on BZDs?

A

Alcohol

42
Q

When is impaired drug metabolism particularly important?

A
  • In severe disease, particularly for extensively metabolised drugs with a low therapeutic range
  • Severe disease causes either decreased enzyme metabolising capacity or decreased liver blood flow
43
Q

What happens as a result of reduced synthesis of plasma proteins in liver disease?

A

Causes increased toxicity of highly protein bound drugs with low TR e.g. phenytoin

44
Q

What happens as a result of reduced synthesis of clotting factors in liver disease?

A

Causes enhanced sensitivity to oral anti-coagulants e.g. warfarin

45
Q

When can impaired excretion of drugs eliminated by the bile occur?

A

Occurs in cholestasis, where the flow of bile to the duodenum is compromised

46
Q

What is hepatic encephalopathy and what drugs can worsen it?

A
  • A deterioration of brain function associated with severe liver disease
  • Worsened or precipitated by several drug classes e.g. all sedatives, opioid analgesics
47
Q

What drugs can worsen ascites?

A

Drugs that cause fluid retention e.g. NSAIDs

48
Q

How can renal impairment be measured and what must be done to the maintenance dose to account for this?

A
  • Renal impairment can be identified by a low eGFR and clearance of creatinine (from skeletal muscle)
  • If a drug is eliminated by the kidneys it will accumulate and the maintenance dose must be reduced
49
Q

How is the drug adjustment dosage calculated for someone with renal impairment?

A

Can be determined from the rate of creatinine clearance and knowledge of the fraction of drug that is excreted by the kidney in unchanged form

50
Q

Why are elderly patients more vulnerable to adverse effects of drugs?

A
  • Impaired renal elimination
  • Increased sensitivity of target organs to drugs e.g. brain, kidney
  • Polypharmacy
  • Difficulty swallowing
  • Cognitive impairment and confusion
51
Q

What can affect drug efficacy in pregnancy?

A
  • Vomiting in early stages
  • Decreased plasma albumin
  • Increased GFR

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