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HSF 2013: 21-46 > Lectures 36 & 37: Drugs are poisons and Mechanism based adverse effects > Flashcards

Lectures 36 & 37: Drugs are poisons and Mechanism based adverse effects Flashcards

1
Q

Give a use of Nicotine sulphate.

A

Nicotine was sulphate powder used as an insecticide

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2
Q

How does a nicotinic ACh receptor agonist work as a poison?

A

Too much activation of the nicotinic receptor can lead to

1. Death of the cell, or;
2. Desensitization of the cell to nicotine, leading to death (respiratory arrest)
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3
Q

What is the main deadly component of amanita muscara?

A

Muscamol, and other alkalines, not actually muscarine.

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4
Q

What chemical acts as an antagonist to mAChRs?

A

Atropine

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5
Q

Why would Spanish women drip juice of the Deadly Nightshade?

A

Atropine, because it is an mAChR antagonist, and so it dilates the smooth muscle of the eye.

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6
Q

Give a physical description of AChE.

A

This guys here is AChE
Tetramer of enzymatic parts on a stalk that is attached to the cell membrane
Projects into the synaptic regions
Concentrated around the edges of the synapse

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7
Q

Persistent activation of nAChRs on skeletal muscle leads to what?

A

Tetani/tetenus

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8
Q

What is the earliest muscle that is often affected by AChE inhibitors?

A

Jaw muscle - locked jaw

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9
Q

Drugs that inhibit AChE does what at synapses? What condition may this lead to?

A

Enhance the transmission of signal by ACh, can induce tetani

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10
Q

What is the action of physistigmine?

A

Inhibits AChE

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11
Q

What is the action of digitalis on the heart? (Lay description)

A

Makes the heart beat more efficiently – slightly harder, and apparently at a lower metabolic cost

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12
Q

What is the action of digitalis on the heart? (Pharmacological description)

A

Inhibits Na+/K+ ATPase

Thus indirectly reduces the movement of calcium across the cell membrane

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13
Q

What is the main symptom of digitalis intoxication?

A

Cardiac arrhythmia

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14
Q

What class of drugs should mixed only with caution with digitalis? Why?

A

Some diuretics because they may cause hypokalemia, thus exacerbating cardiac arrhythmia.

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15
Q

What is an antidote to digitalis induced cardiac arrhythmia?

A

Banana - has potassium in it

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16
Q

What probably causes the analgesic effect of paracetamol?

A

A brain metabolite activates the CB1 receptors in certain parts of the brain.

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17
Q

Why can’t you get high on paracetamol?

A

The metabolite that activates the CB1 is restricted to a certain part of the brain.

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18
Q

At what point does paracetamol illicit a negative effect in the brain?

A

TRICK Q: there is no concentration at which paracetamol has negative effects are seen in the brain.

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19
Q

What negative effect of paracetamol is seen at high concentrations? On- or off-target?

A

Off: damaging actions occurs as a consequence of its metabolism by the endothelial cells of the liver. When the liver metabolises large amounts of paracetamol it suffers oxidative damage. Endothelium, and thus the liver, dies.

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20
Q

Give an example of a drug in which the negative effect is the same as the beneficial effect. Explain why it is potentially dangerous.

A

Atropine, used to increase cardiac output; it can cause cardiac arrhythmia and if you inhibit ATPase pump completely then you stop all cardiac APs and you die.

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21
Q

What is the therapeutic ratio?

A

Therapeutic ratio = (largest tolerated dose)/(minimal effective dose) (ie, x2/x1)

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22
Q

Is the therapeutic window the same for everyone? Is it all or none?

A

No - different people have different sensitivities. No - therapeutic window is a continuum.

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23
Q

What is the benefit of on-target compared to off-target effects?

A

On-target effects are predictable whereas off-target effects are more difficult to predict because you don’t necessarily know where it could happen.

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24
Q

What is the pharmacological name of Teldane and what is it a precursor to?

A

Terfenadine - a precursor to Telfast/fexofenadine.

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25
Q

How was terfenadine first marketed?

A

As a non-drowsy antihistamine

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26
Q

What is the bioavailability of teldane? What type of drug does this make terfenadine?

A

Zero bioavailability until it is metabolized into fexofenadine by CYP 3A4 in the liver - therefore teldane is a pro-drug.

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27
Q

How is terfenadine metabolized in the liver?

A

Metabolized in the liver by CYP 3A4 on the cytochrome P450s

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28
Q

What percentage of terfenadine is converted to fexofenadine upon first pass?

A

Nearly 100%

29
Q

What is the action of dihydrobergamottin in the liver?

A

It is an irreversible/covalent inhibitor of CYP 3A4

30
Q

In what food is dihydrobergamottin found?

A

Grapefruit and grapefruit juice.

31
Q

Why should grapefruit juice not be consumed on the same day as Terfenadine?

A

Dihydrobergamottin in the grapefruit is an irreversible/covalent inhibitor of CYP 3A4 which means that terfenadine becomes bioavailable, thus people accidentally self dose with teldane.

32
Q

What is the negative cardiac effect of terfenadine?

A

Torsades do pointes (twisting of the points - ie, spastic ECG)

33
Q

What other drug is made more bioavailable by grapefruit juice? What is its action?

A

Simvastatin - anti-cholesterol drug

34
Q

What happens if two drugs that are both metabolized by CYP 3A4 are taken simultaneously?

A

Enhance each other’s bioavailability and increase half-life.

35
Q

What is rule one of pharmacology?

A

All drugs have more than one action

36
Q

What word is more realistic in describing a useful drug: selective or specific?

A

Selective - no drug is completely specific, so drugs that are more selective at high concentrations are more useful.

37
Q

What is a Type A ADR?

A

A for augmented - on target and predictable.

38
Q

What is a Type B ADR?

A

B for bizarre - idiosyncratic and unpredictable

39
Q

What is a Type C ADR?

A

C for continuous - long-term use.

40
Q

What is a Type D ADR?

A

D for delayed - after the drug is gone

41
Q

Which type of ADR is the most predictable and why?

A

Type A - since it is on target we can predict what it might do at that tissue.

42
Q

Give an example of a Type B ADR.

A

Penicillin - most people are fine with it but some people have an allergy to it.

43
Q

What type of ADR is diarrhea caused by penicillin?

A

Type A because it is somewhat predictable.

44
Q

Give two examples of Type C ADRs.

A

Tolerance and dependence to opioids.

Adrenal insufficiency after corticosteroids.

45
Q

What is the role of ACTH (and what does it stand for?)

A

Adrenocorticotropic hormone (ACTH) stimulates adrenals early in the morning and causes the release of cortisol

46
Q

What is the negative feedback loop that decreases ACTH and thus cortisol?

A

ACTH stimulates cortisol release from adrenals
Cortisol feedback to thalamus
Negative feedback on ACTH

47
Q

What can happen if you take exogenous glucocorticoids for extended periods?

A
  • Activates anti-inflammatory pathways AND the feedback control pathway
  • Brain does NOT release ACTH
  • Adrenal is not stimulated to secrete the endogenous cortisol
  • Cells of the adrenal gland atrophy (at least in the cortex)
48
Q

Why are inhaled glucocorticoids not a risk of causing adrenal insufficiency?

A

INHALED GLUCOCORTISOIDS ARE NOT SUBSTANTIALLY ABSORBED INTO THE BODY SO THEY DO NOT (NORMALLY) INTERFERE WITH NORMAL PHYSIOLOGY.

49
Q

Can topical glucocorticoids cause adrenal insufficiency?

A

Yes, if used in excess.

50
Q

What type of ACR is analgesic nephropathy?

A

Type C

51
Q

What can cause analgesic nephropathy?

A

Long term overuse of APC analgesic mixtures.

52
Q

What does APC stand for, with regards to an APC analgesic mixture?

A

Aspirin, phenacetin, caffeine

53
Q

What makes the APC mixture addictive?

A

Caffeine, and possibly bioavailable phenacetin (that has not been converted to paracetamol in the liver.)

54
Q

What causes analgesic nephropathy in APC mixtures?

A

Large does of aspirin, and probably the excess paracetamol.

55
Q

Why was analgesic nephropathy reasonably restricted to Swiss and Australian (and some other countries) housewives in the 1960s?

A

Boring lives; Aus and Switzerland had fairly high concentration mixtures

56
Q

Give 2 examples of Type D ADR.

A

Cancer and infertility

57
Q

‘Type D ADRs always involve the patient.’ True or false?

A

False; eg, thalidomide-induced phocomelia.

58
Q

What was thalidomide originally prescribed to treat?

A

Nausea, especially morning sickness in pregnant women.

59
Q

What is a negative action of thalidomide?

A

Antagonist of vascular growth factors.

60
Q

Morphine can have ADRs in all four categories. What are they specifically?

A

A - respiratory depression, constipation
B - allergic-like mast cell reactions
C - addiction
D - withdrawal syndrome

61
Q

Cortisone can have ADRs in three of four categories. What are they specifically?

A

A - immunosuppression, fluid retention
C - thin skin after topical treatment
D - long-lasting adrenal suppression

62
Q

What is the active driver of the ion gradient in the nephron?

A

Na+/K+ ATPase

63
Q

Does glucose and amino acids move passively or via active transport across the cells of the nephron? In which part of the nephron does this occur?

A

Glucose and amino acids transport across the first membrane of cells of the PROXIMAL TUBULE via secondary process (Na+ cotransporter) and then they passively diffuse out of the cell on the basal side.

64
Q

Name two places in the body where counter current exchange occurs.

A

Testes and nephrons of the kidney

65
Q

Explain why there the relative concentration of O2 in the renal medulla is so low despite receiving such large amounts of blood.

A

Anatomical arrangement in which counter current exchange is unavoidable - vein of one nephron is adjacent to the artery of the next. O2 takes a short cuts across from the arterial capillary to the venous capillary, thus the net concentration of O2 in the medulla of the kidney is LOW

66
Q

What sort of conditions can lead to renal damage and why?

A

Conditions leading to low renal perfusion (eg, extended periods of dehydration) because the medulla is already in a state of relative hypoxia in a healthy individual (because of counter current exchange.)

67
Q

What combination of drugs is effective for treating hypertension?

A

Diuretic and ACE inhibitor (or AT1 antagonist)

68
Q

What class of drugs, when take with diuretics and ACE inhibitors, can cause acute renal failure? (Tripple whammy)

A

NSAID

69
Q

What do the kidneys produce during hypoxia? What does this cause? What is the trade-off?

A

Prostanoids - cause vasodilation, which increases renal perfusion but reduces glomeruli filtration.

HSF 2013: 21-46 (12 decks)

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