**3.2.2 Drugs**

Delirium is characterised by a global cerebral dysfunction resulting in a generalized reduction in cerebral oxidative metabolism and an imbalance of several neurotransmitters in the brain. Any drug that interferes with these neurotransmitter systems or with the supply or use of substrates for metabolism of the central nervous system can cause delirium (Gray et al., 1999; Moore & O'Keeffe, 1999; Nayeem & O'Keeffe, 2003). For a drug to be clearly implicated as an etiological factor in delirium, the administration of the drug should precede the onset of symptoms of delirium within a short time duration and withdrawal of the drug should result in a return to baseline cognitive functioning (Moore & O'Keeffe, 1999).

#### **3.2.2.1 Anticholinergic drugs**

The causal association of drugs to delirium is most clear for anticholinergic drugs with muscarine receptor affinity (White et al., 2007). Antihistaminics, antipsychotics, tricyclic antidepressants, digoxin, frusemide, isosorbide dinitrate, warfarin, dipyridamole, codeine,

A Review of the Etiology Delirium 195

Cholinergic neurons play an important role in cognition and memory (Kopelman, 1986). Evidence from electroencephalographic and pharmacologic studies supports the role of cholinergic deficiency in genesis of delirium. Electroencephalographic studies have shown that delirium is associated with occipital slowing, peak power and alpha decrease, delta and theta power increase and slow wave ratio increase during active delirious states (Thomas et al., 2008). Cholinergic thalamo-cortical pathways responsible for attention, alertness and vigilance regulation modulate the basic EEG alpha rhythm (Nunez et al., 2001). Centrally acting anticholinergics result in a pattern very similar to the electroencephalographic

Pharmacologic studies have shown an association between delirium and administration of anticholinergic drugs and serum anticholinergic activity (Inouye, 2006). High serum anticholinergic activity is associated with severity of delirium (Mussi et al., 1999; Trzepacz, 1999). Also, the importance of cholinergic deficiency in pathophysiology of delirium is supported by studies showing that acetylcholine neurotransmission decreases with age, which is consistent with the finding that increasing age is a risk factor for delirium (Flacker & Lipsitz, 1999). Several mechanisms can result in cholinergic deficiency and predispose to delirium, including impairment in acetylcholine synthesis and cholinergic synaptic mechanisms,

Another neurotransmitter system supposed to have a role in pathogenesis of delirium is monoamine neurotransmitter system (Gaudreau & Gagnon, 2005). Dopamine, norepinephrine and serotonin have roles in arousal and sleep-wake cycle, they modulate physiological responses to stimuli (Robbins & Arnsten, 2009). This system, which is composed of three monoamine neurotransmitters, dopamine, norepinephrine and serotonin, has a balancing role for the cholinergic activity. The development of delirium involves interaction between these two neurotransmitter systems (Cole, 2004; Trzepacz & van der Mast, 2002). But instead of deficiency, dopamine excess has been reported to play a role in delirium (Moyer, 2011). It is suggested that dopamine increase during the stress of surgery can cause postoperative agitation and delusions in the patient. In laboratory studies, stress has been shown to elevate levels of mesocortical dopamine (Cassem et al., 2004). Haloperidol, a dopamine blocking agent has been used successfully to treat delirium for

Depending on the serotonin receptor bound, both serotonin excess and deficiency may be associated with cholinergic deficiency and predispose to delirium (Hshieh et al., 2008). Selective serotonin reuptake inhibitors like fluoxetine and buproprion have been reported to cause delirium (Chan et al., 2006). Delirium has been reported in a patient taking paroxetine preoperatively, the authors have contributed that postoperative delirium was indicating an

Delirium has been hypothesized to result from increased release of proinflammatory cytokines in cases of trauma, infection or surgery (Eikelenboom et al., 2002; Rudolph et al.,

adverse drug interaction involving, paroxetine (Stanford & Stanford, 1999).

**3.3.2 Neural injury, inflammation, and stress response** 

ischemia and global stressors and neurotransmitter imbalance (Hshieh et al., 2008).

**3.3.1 Imbalance in neurotransmitter systems**

findings in delirium (Renner et al., 2005; Sloan et al., 1992).

**3.3.1.2 Monoamine neurotransmitter system** 

years (Moore & O'Keeffe, 1999).

**3.3.1.1 Cholinergic deficiency** 

and captopril are among the mostly used durs that have primary or secondary anticholinergic effects contributing to risk of delirium (Burns, 2004,). Many commonly used drugs in the elderly, that are the principal treatments of clinical conditions, such as urinary incontinence and cardiovascular disease, have anticholinergic properties (Scheife & Takeda, 2005; Uusvaara et al., 2011). Older patients and those with mental illness are particularly vulnerable to the adverse neuropsychiatric effects of anticholinergics as they may already have cognitive impairment (Gerretsen & Pollock, 2011).
