Question 86#

Which of the following opioids produces metabolites with clinically useful analgesic activity?

A. Naloxone

D. Naloxone is an opioid antagonist and has no analgesic activities. Naltrexone is a longer acting opioid antagonist with no clinically useful analgesic actions. Nomifensine is not an opioid; it is a cyclic antidepressant with norepinephrine and dopamine reuptake inhibition. It was withdrawn from the clinical market due to hepatotoxicity and renal damage, in addition to fears regarding abuse potential. Propoxyphene has mild to moderate analgesic properties but its metabolite, norpropoxyphene, is devoid of clinically useful analgesia. Codeine, on the other hand, is a strong analgesic and breaks down to morphine which has potent analgesic activity. Codeine is ineffective as an analgesic at usual doses in 7 to 10% of the white population with low activity CYP2D6 alleles. It is reported that in those with ultrarapid CYP2D6 metabolism, codeine intake may result in an increase in morphine production, occasionally resulting in opioid intoxication.

Reference:

1. Yue QY, Alm C, Svensson JO, and Sawe J. Quantification of the O- and N-demethylated and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid, and poor debrisoquine hydroxylators. Therapeutic Drug Monitoring 1997; 19: 539–542.

Question 87#

The mechanism of action of opioids in producing an analgesic effect is:

A. Blockade of sodium channels on the neuronal membrane (membrane stabilization)

C. There are three important types of opioid receptors; most analgesic effects are associated with µ receptors. The δ and κ receptors also contribute to the analgesic effect to some extent. Morphine and codeine mainly act via µ receptors to produce clinical analgesia. Opioids are coupled to Gi proteins that decrease cAMP. When opioids bind to µ receptors, hyperpolarization of the nociceptive neurone (sensory neurone for pain) takes place via opening of K⁺ channels and inhibition of the Ca²⁺ channels. This reduces neuronal activity and reduces the transmission of pain signals via ascending pathways to the brain.

Reference:

1. Stein C, Schäfer M, and Machelska H. Attacking pain at its source: new perspectives on opioids. Nature Medicine 2003; 9: 1003–1008.

Question 88#

Methylxanthines produce stimulation of the CNS via their action on which of the following receptors?

A. NMDA receptors

B. Methylxanthines include caffeine and theophylline. They have CNS stimulatory properties. At therapeutic doses, these drugs block adenosine receptors; at higher concentrations inhibition of the phosphodiesterase enzyme takes place. Adenosine is released from neurones and glia. It acts via G-protein-coupled receptors (A₁ , A_2A, A_2B, and A₃ ). A₁ receptors have inhibitory role while A₂ receptors have stimulatory properties.A₁ receptor antagonism may enhance cognition and facilitate arousal. At higher doses where inhibition of phosphodiesterase occurs, intracellular levels of cAMP increase.

Reference:

1. Abbracchio MP and Cattabeni F. Brain adenosine receptors as targets for therapeutic intervention in neurodegenerative diseases. Annals of the New York Academy of Science 1999; 890: 79–92.

Question 89#

Which of the following medications used for Parkinson’s disease is correctly paired with its side-effect? 

A. Levodopa–hypoglycaemia

C. Livedo reticularis refers to a characteristic purple mottling of the skin see in patients taking amantadine. It is usually seen as a lacy, net-like pattern of vascular change on the legs. It is also associated with vasculitis such as lupus. Mostly, the livedo reticularis disappears when the drug is discontinued, usually within several weeks. The appearance of livedo does not always warrant the cessation of the drug. The common side-effects of levodopa include insomnia, postural hypotension, gastrointestinal disturbances, tremors, mood changes, and fatigue. Bromocriptine can cause postural hypotension, nausea, oedema, confusion, dry mouth, and depression. Tolcapone is a COMT inhibitor and can cause abdominal pain, back pain, constipation, nausea, diarrhoea, and liver failure.

Reference:

1. Sladden MJ, Nicolaou N, Johnston GA et al. Livedo reticularis induced by amantadine. British Journal of Dermatology 2003; 149: 656–658.

Question 90#

Which of the following agents acts through glial/ neuronal GABA reuptake inhibition? 

A. Zopiclone

D. Tiagabine is an add-on antiepileptic drug developed by modifying a GABA uptake inhibitor called nipecotic acid. Tiagabine is a potent inhibitor of GABA uptake into both neurones and glial cells. It acts via selective inhibition of the GABA transporter, GAT-1. Through this mechanism, tiagabine enhances GABA_A receptor-mediated tonic inhibition. Vigabatrin is a selective and irreversible GABA-transaminase inhibitor. Topiramate produces its antiepileptic effect through several mechanisms such as modification of Na⁺-dependent and/or Ca²⁺- dependent action potentials, enhancement of GABA-mediated Cl– fluxes into neurones, and inhibition of kainate-mediated conductance at AMPA glutamate receptors. Gabapentin is a structural analogue of GABA and though originally designed as a GABA-mimetic, its mechanism of action is still unknown.

Reference:

1. Perucca E. Clinical pharmacology and therapeutic use of the new antiepileptic drugs. Fundamental and Clinical Pharmacology 2001; 15: 405–417.