Lectures 36 & 37: Drugs are poisons and Mechanism based adverse effects Flashcards
Give a use of Nicotine sulphate.
Nicotine was sulphate powder used as an insecticide
How does a nicotinic ACh receptor agonist work as a poison?
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)
What is the main deadly component of amanita muscara?
Muscamol, and other alkalines, not actually muscarine.
What chemical acts as an antagonist to mAChRs?
Atropine
Why would Spanish women drip juice of the Deadly Nightshade?
Atropine, because it is an mAChR antagonist, and so it dilates the smooth muscle of the eye.
Give a physical description of AChE.
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
Persistent activation of nAChRs on skeletal muscle leads to what?
Tetani/tetenus
What is the earliest muscle that is often affected by AChE inhibitors?
Jaw muscle - locked jaw
Drugs that inhibit AChE does what at synapses? What condition may this lead to?
Enhance the transmission of signal by ACh, can induce tetani
What is the action of physistigmine?
Inhibits AChE
What is the action of digitalis on the heart? (Lay description)
Makes the heart beat more efficiently – slightly harder, and apparently at a lower metabolic cost
What is the action of digitalis on the heart? (Pharmacological description)
Inhibits Na+/K+ ATPase
Thus indirectly reduces the movement of calcium across the cell membrane
What is the main symptom of digitalis intoxication?
Cardiac arrhythmia
What class of drugs should mixed only with caution with digitalis? Why?
Some diuretics because they may cause hypokalemia, thus exacerbating cardiac arrhythmia.
What is an antidote to digitalis induced cardiac arrhythmia?
Banana - has potassium in it
What probably causes the analgesic effect of paracetamol?
A brain metabolite activates the CB1 receptors in certain parts of the brain.
Why can’t you get high on paracetamol?
The metabolite that activates the CB1 is restricted to a certain part of the brain.
At what point does paracetamol illicit a negative effect in the brain?
TRICK Q: there is no concentration at which paracetamol has negative effects are seen in the brain.
What negative effect of paracetamol is seen at high concentrations? On- or off-target?
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.
Give an example of a drug in which the negative effect is the same as the beneficial effect. Explain why it is potentially dangerous.
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.
What is the therapeutic ratio?
Therapeutic ratio = (largest tolerated dose)/(minimal effective dose) (ie, x2/x1)
Is the therapeutic window the same for everyone? Is it all or none?
No - different people have different sensitivities. No - therapeutic window is a continuum.
What is the benefit of on-target compared to off-target effects?
On-target effects are predictable whereas off-target effects are more difficult to predict because you don’t necessarily know where it could happen.
What is the pharmacological name of Teldane and what is it a precursor to?
Terfenadine - a precursor to Telfast/fexofenadine.
How was terfenadine first marketed?
As a non-drowsy antihistamine
What is the bioavailability of teldane? What type of drug does this make terfenadine?
Zero bioavailability until it is metabolized into fexofenadine by CYP 3A4 in the liver - therefore teldane is a pro-drug.
How is terfenadine metabolized in the liver?
Metabolized in the liver by CYP 3A4 on the cytochrome P450s
What percentage of terfenadine is converted to fexofenadine upon first pass?
Nearly 100%
What is the action of dihydrobergamottin in the liver?
It is an irreversible/covalent inhibitor of CYP 3A4
In what food is dihydrobergamottin found?
Grapefruit and grapefruit juice.
Why should grapefruit juice not be consumed on the same day as Terfenadine?
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.
What is the negative cardiac effect of terfenadine?
Torsades do pointes (twisting of the points - ie, spastic ECG)
What other drug is made more bioavailable by grapefruit juice? What is its action?
Simvastatin - anti-cholesterol drug
What happens if two drugs that are both metabolized by CYP 3A4 are taken simultaneously?
Enhance each other’s bioavailability and increase half-life.
What is rule one of pharmacology?
All drugs have more than one action
What word is more realistic in describing a useful drug: selective or specific?
Selective - no drug is completely specific, so drugs that are more selective at high concentrations are more useful.
What is a Type A ADR?
A for augmented - on target and predictable.
What is a Type B ADR?
B for bizarre - idiosyncratic and unpredictable
What is a Type C ADR?
C for continuous - long-term use.
What is a Type D ADR?
D for delayed - after the drug is gone
Which type of ADR is the most predictable and why?
Type A - since it is on target we can predict what it might do at that tissue.
Give an example of a Type B ADR.
Penicillin - most people are fine with it but some people have an allergy to it.
What type of ADR is diarrhea caused by penicillin?
Type A because it is somewhat predictable.
Give two examples of Type C ADRs.
Tolerance and dependence to opioids.
Adrenal insufficiency after corticosteroids.
What is the role of ACTH (and what does it stand for?)
Adrenocorticotropic hormone (ACTH) stimulates adrenals early in the morning and causes the release of cortisol
What is the negative feedback loop that decreases ACTH and thus cortisol?
ACTH stimulates cortisol release from adrenals
Cortisol feedback to thalamus
Negative feedback on ACTH
What can happen if you take exogenous glucocorticoids for extended periods?
- 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)
Why are inhaled glucocorticoids not a risk of causing adrenal insufficiency?
INHALED GLUCOCORTISOIDS ARE NOT SUBSTANTIALLY ABSORBED INTO THE BODY SO THEY DO NOT (NORMALLY) INTERFERE WITH NORMAL PHYSIOLOGY.
Can topical glucocorticoids cause adrenal insufficiency?
Yes, if used in excess.
What type of ACR is analgesic nephropathy?
Type C
What can cause analgesic nephropathy?
Long term overuse of APC analgesic mixtures.
What does APC stand for, with regards to an APC analgesic mixture?
Aspirin, phenacetin, caffeine
What makes the APC mixture addictive?
Caffeine, and possibly bioavailable phenacetin (that has not been converted to paracetamol in the liver.)
What causes analgesic nephropathy in APC mixtures?
Large does of aspirin, and probably the excess paracetamol.
Why was analgesic nephropathy reasonably restricted to Swiss and Australian (and some other countries) housewives in the 1960s?
Boring lives; Aus and Switzerland had fairly high concentration mixtures
Give 2 examples of Type D ADR.
Cancer and infertility
‘Type D ADRs always involve the patient.’ True or false?
False; eg, thalidomide-induced phocomelia.
What was thalidomide originally prescribed to treat?
Nausea, especially morning sickness in pregnant women.
What is a negative action of thalidomide?
Antagonist of vascular growth factors.
Morphine can have ADRs in all four categories. What are they specifically?
A - respiratory depression, constipation
B - allergic-like mast cell reactions
C - addiction
D - withdrawal syndrome
Cortisone can have ADRs in three of four categories. What are they specifically?
A - immunosuppression, fluid retention
C - thin skin after topical treatment
D - long-lasting adrenal suppression
What is the active driver of the ion gradient in the nephron?
Na+/K+ ATPase
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?
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.
Name two places in the body where counter current exchange occurs.
Testes and nephrons of the kidney
Explain why there the relative concentration of O2 in the renal medulla is so low despite receiving such large amounts of blood.
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
What sort of conditions can lead to renal damage and why?
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.)
What combination of drugs is effective for treating hypertension?
Diuretic and ACE inhibitor (or AT1 antagonist)
What class of drugs, when take with diuretics and ACE inhibitors, can cause acute renal failure? (Tripple whammy)
NSAID
What do the kidneys produce during hypoxia? What does this cause? What is the trade-off?
Prostanoids - cause vasodilation, which increases renal perfusion but reduces glomeruli filtration.
