severity. On the other hand, a headache is not usually serious (but may be in case of subarachnoid haemorrhage, subdural bleed, even a migraine may temporally fit criteria), unless it also satisfies the criteria for seriousness listed above. Location Adverse effects may be local, i.e. limited to a certain location, or systemic, where medication has caused adverse effects throughout the systemic circulation. For instance, some ocular antihypertensives cause systemic effects, although they are administered locally as eye drops, since a fraction escapes to the systemic circulation. Mechanisms As research better explains the biochemistry of drug use, fewer ADRs are Type B and more are Type A. Common mechanisms are: Abnormal pharmacokinetics due to genetic factors comorbid disease states Synergistic effects between either a drug and a disease two drugs Antagonism effects between either a drug and a disease two drugs Abnormal pharmacokinetics Comorbid disease states Various diseases, especially those that cause renal or hepatic insufficiency, may alter drug metabolism. Resources are available that report changes in a drug's metabolism due to disease states. The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D) criteria warns that people with dementia are more likely to experience adverse effects, and that they are less likely to be able to reliably report symptoms. Genetic factors Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation. Pharmacogenomics is the study of the inherited basis for abnormal drug reactions. Phase I reactions Inheriting abnormal alleles of cytochrome P450 can alter drug metabolism. Tables are available to check for drug interactions due to P450 interactions. Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine Phase II reactions Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as isoniazid, hydralazine, and procainamide. Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine. Interactions with other drugs The risk of drug interactions is increased with polypharmacy. Protein binding These interactions are usually transient and mild until a new steady state is achieved. These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are: albumin α1-acid glycoprotein lipoproteins Some drug interactions with warfarin are due to changes in protein binding. Cytochrome P450 Patients have abnormal metabolism by cytochrome P450 due to either inheriting abnormal alleles or due to