# 01 - 1. Types of adverse reactions

# 1. Types of adverse reactions

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1. Types of adverse reactions 
 
Type of reaction 
Mnemonics 
Features 
A: dose-related 
Augmented 
e.g., Lithium toxicity – ataxia, coarse tremors, vomiting. 
B: non-dose 
related 
Bizarre 
Idiosyncratic e.g. malignant hyperthermia, or lamotrigine 
induced Steven Johnson syndrome 
C: dose and time 
related 
Continuous 
use 
Related to cumulative drug use—e.g. long term lithium use 
and renal damage 
D: delayed effect 
Delayed 
Not due to dose per se but due to the length of use of a 
medication e.g. tardive dyskinesia in some cases. 
E: Withdrawal 
End of use 
Related to abrupt discontinuation e.g. SSRI discontinuation 
reaction, opioid withdrawal effects, etc. 
 Tolerance is defined as the need to use increased doses of a drug to maintain a clinical effect. 
Tolerance is seen for both therapeutic effects and side effect. This may be due to decreased 
sensitivity of the target receptors due to down-regulation (decrease in numbers in case of 
agonists), up-regulation (increase in number of receptors in case of antagonists), or reduced 
responsivity without alterations in receptor numbers. 
 Drugs with similar pharmacological actions can exhibit cross-tolerance e.g. benzodiazepines 
and barbiturates. 
 Sensitization (aka reverse tolerance) manifests when sensitivity to a drug effect increases 
over time i.e. the same dose typically produces more pronounced effects as treatment 
progresses. This is reported with the street use of cocaine. 
Note that up or down-regulation can be a mechanism of therapeutic effect e.g. in case of SSRIs, the 5HT1A 
autoreceptors in somatodendritic zones undergo downregulation secondary to increased serotonin 
availability in the vicinity when reuptake is blocked; this in turn leads to an increase in serotonergic tone 
of the neurons. 
 Withdrawal: When drugs are administered for a reasonable period of time, a physiological 
adaptation develops which on withdrawal of the drug can get disturbed and leads to 
withdrawal symptoms. Abrupt withdrawal of treatment especially for an agent with shorter 
elimination half-life leads to clinically significant withdrawal symptoms. Hypnotics, opiates, 
barbiturates, SSRIs, Venlafaxine are some of the drugs associated with discontinuation 
reaction or withdrawal symptoms. The variables influencing withdrawal symptoms are listed 
below:

© SPMM Course 
1. Half life 
Methadone has less withdrawal than heroin as methadone has longer 
t1/2 
2. Range of action 
Paroxetine has anticholinergic properties; withdrawal causes cholinergic 
rebound=d symptoms 
3. Enzyme 
interference 
Paroxetine inhibits its own metabolism via CYP2D6. So withdrawal 
leads to loss of inhibition Æ excessive paroxetine breakdown Æ sudden 
steep drop in levels Æ withdrawal symptoms 
4. Active metabolites 
Fluoxetine has active metabolite norfluoxetine with long half-life – 
hence it produces fewer withdrawal symptoms 
5. Rate of withdrawal 
Slow, gradual tapering is the best. 10% dose reduction every 2 weeks is 
advocated for benzodiazepines. 
6. Co-prescribed drug 
effects 
Prescribing an enzyme inducer can reduce the effects of a drug acutely if 
its metabolism depends on the induced enzyme; Similarly prescribing 
an antagonist can precipitate withdrawal symptoms. This is the 
rationale for leaving at least 72 hours before prescribing naltrexone for 
an opioid detoxified patient. 
7. Receptor profile 
Full agonists on withdrawal produce more discontinuation reactions 
than partial agonists e.g. clonazepam produces lesser benzodiazepine 
withdrawal symptoms. 
 
Sustained-release preparations influence the absorption kinetics– not elimination kinetics, hence 
upon withdrawal, the drop in plasma levels occur at same rate in both XL and plain preparations; 
e.g. venlafaxine XL has similar discontinuation reaction as venlafaxine normal release. But depot 
preparations have less withdrawal propensity that corresponding oral drugs.