11 Drug Toxicity

Question 1

Drug Toxicity

Answer 1

• also called adverse drug reaction(ADR);
• An injury caused by taking a medication;
• WHO definition: Any noxious and unintended effect of drug that occurs at doses used in human for prophylaxis, diagnosis or treatment;

Question 2

ADR: “On-target” / “Off-target” Intended tissue

Answer 2

On-target adverse effects

• dose too high
• chronic activation or inhibition effects

Off-target adverse effects
- incorrect receptor is activated or inhibited

Question 3

ADR: “On-target” / “Off-target” Unintended tissue

Answer 3

On-target adverse effects

• correct receptor but incorrect tissue
• dose too high
• chronic activation or inhibition effects

Off-target adverse effects
- incorrect receptor is activated or inhibited

Question 4

“on-target” ADR on intended tissue Warfarin

Answer 4

draw

Question 5

“on-target” ADR
on non-intended tissue
Atropine - tert amine

Answer 5

– A non-selective muscarinic blocker;
– Lipid soluble, crosses membrane barriers (incl. BBB), well distributed in the CNS and other organs;
– Dilates the pupils, Increases heart rate, Reduces salivation and other secretions, Relaxes smooth muscle, and Produces excitatory effects on the CNS;
– Treatment is usually directed at one organ.
Other organ injuries caused are considered as ADR.

Question 6

“off-target” ADR nephrotoxicity

Answer 6

Aminoglycosides
– active (saturable) transport into the tubular cells
– tubular toxicity (e.g. ROS production, lysosomal enlargement and phospholipids inside, apoptosis)
– reduced glomerular filtration, increased creatinineamia, and blood urea – renal failure!

Question 7

“off-target” ADR Cardiotoxicity

Answer 7

Lots of marketed drugs bind to the hERG channel, with apparently diverse structures.

• astemizole (antihistamine)
• terfenadine (antihistamine)
• grepafloxacin (antibiotic)
• sertindole (neuroleptic)

Question 8

Why is hERG important?

Answer 8

• hERG = ‘human ether-a-go-go related gene’
• Potassium channel
• Activation causes prolongation of electrical impulses regulating heart beat
• Can lead to fatal arrhythmias

Activation of hERG causes a delayed T wave

Question 9

Drug ADR: homologous targets

Answer 9

•The b1 and b2 receptors are homologous receptors
•Drugs binding to these may not be selective for one subtype •Antagonists of b1 used to control heart rate after heart failure •Antagonist which also bind the b2 receptor can cause airway constriction
•Non-selective b antagonists, e.g. Propranolol,
are contraindicated in patients with asthma

Question 10

HEART

Which receptors are found

Answer 10

b1 adrenergic receptors

-Heart rate & Contractility

Question 11

SMOOTH MUSCLE -airway & vasculature

Which receptors are found

Answer 11

b2 adrenergic receptors

-Relaxation & dilation

Question 12

Drug ADR: toxic metabolites

Answer 12

Binds IRREVERSIBLY to Hepatic Cell membranes

Resulting in LIVER NECROSIS - hepatoxcity

Question 13

Drug ADR: immune response

Drug allergy

Answer 13

Molecular weight of most drugs is low (Mr<1000) which is NOT enough for direct immunogenicity
– Exception: peptides and proteins of non-human origin
– By binding of LMW drug (as a hapten) on the macromolecular carrier
• E.g. penicillin is covalently bound to albumin
– LMW drug (prohapten) is metabolized to the reactive metabolite, which acts as a hapten and is bound to the carrier
• E.g., sulfamethoxazole
– LMW drug interacts with receptors of immunity systems
• Direct binding to T-cell receptors

Question 14

Anaphylactic reaction

Answer 14

• Almost all occur within 4 hours;
• Most occur within 1 hour of taking the drug; • many occur within minutes or even seconds.
• Symptoms
-Skin reaction
Hives, redness/flushing, sense of warmth, itching
-Difficulty breathing
Chest tightness, wheezing, throat tightness
-Fainting
Light-headness or loss of consciousness due to drastic decrease in blood pressure (“shock”)
Rapid or irregular heart beat
-Swelling of face, tongue, lips, throat, joints, hands, or feet

Question 15

Treatment for anaphylaxis

Answer 15

For mild reactions
0.3-0.5 ml adrenaline 1:1000 SQ;
an oral antihistamine should be given;

For more severe reactions (massive angioedema)
Diphenhydramine 50-100 mg IV ; long acting adrenaline 1:200 SQ; Oral antihistamine should be given for the next 24hr

For asthmatic reactions that do not respond to adrenaline
IV fluids should be started; Theophylline 5mg/kg IV;
Endotracheal intubations or tracheotomy with oxygen administration if necessary;

For severe reactions involved the cardiovascular system
Hypotension (caused mainly by hypovolemia): fluid replacement/ vasopressor drugs e.g. dopamine, noradrenaline;

Cardiac arrest
immediate resuscitation;
Diphenhydramine maybe followed;

Question 16

Prophylaxis of penicillin allergy

Answer 16

• Skin test: for immediate-type (IgE-mediated) hypersensitivity are very useful in diagnosis of reactions to penicillin, enzymes, and some vaccines.
• If the patient has a history of a severe explosive reaction, the reagents should be diluted 100-fold for initial testing.

Question 17

Idiosyncratic toxicity

Answer 17

• Rare toxicity that isn’t immediately understandable - no obvious mechanism
• May reflect genetic variation between individuals.

Question 18

Drug toxicity due to interactions

Answer 18

• Drug-drug interactions represent 3-5% of preventable in-hospital ADRs
• Drug-food interaction
• Drug-disease interaction
– Liver disease
– Renal disease
– Cardiac disease
– Acute viral infection – Hypothyroidism
– Hyperthyroidism

Question 19

Drug ADR: enantiomeric effects

Answer 19

S-Thalidomide Teratogenic

R-Thalidomide Sedative