On administration of an unknown dose of a new antipsychotic, a 55-yearold man develops extra pyramidal symptoms.
The dose at which this effect appears would be established in which phase of clinical trials?
A. The dose at which side-effects develop is often determined at phase 1 of clinical trials. The pathway that a drug must follow before approval and marketing starts with animal studies, where the molecule is demonstrated to have specific actions. These extensive, preclinical animal studies must be carried out on at least two different animal species. Mutagenicity, carcinogenicity, and organ system toxicity are studies at this phase. A new drug under investigation then enters human trials. The first phase consists of determining if the drug is safe on human subjects. It is administered to a small group of volunteers and safety, tolerability, and pharmacokinetics of the drug are ascertained. In phase 2, effectiveness in comparison to placebo is studied in hundreds of patients with the target disease to see if it works at all against the disease. In phase 3, the drug undergoes extensive double-blind, randomized controlled trials to determine how well it works and what are the common side-effects. Phase 4 takes place if all the previous phases are successfully crossed—the drug undergoes the approval process by regulatory bodies and post-marketing surveillance ensues. Less common side-effects, which sometimes could lead to a drug’s withdrawal, can be picked up when large-scale prescribing takes place during post-marketing surveillance.
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Haloperidol is more potent than chlorpromazine. Potency of a therapeutic formulation refers to:
C. Potency of a drug with receptor-binding action refers to the amount of the drug needed to produce a particular effect compared to another standard drug with similar receptor profile (‘vigour’). Affinity refers to the ability of the drug to bind to its appropriate receptor (‘affection’). Efficacy refers to how well the drug produces the expected response, that is the maximum clinical response produced by a drug (‘productivity’). Efficacy depends on affinity, potency, duration of receptor action in some cases, and kinetic properties such as half-life, among other factors. Haloperidol is more potent than chlorpromazine as approximately 5 mg of haloperidol is required to achieve the same effect as 100 mg of chlorpromazine. These drugs, however, are equal in the maximal clinical response achievable using them, that is equally efficacious but not equipotent.
Absorption of orally administered drugs is affected by which of the following:
E. After oral administration, a drug may be incompletely absorbed. This is mainly due to lack of absorption from the intestine related to the presence of inhibitory factors such as food or gastric acid, or to changes in intestinal motility; for example having diarrhoea or vomiting can affect drug absorption. Inherent properties of certain drugs can also affect their absorption, for example highly hydrophilic drugs cannot cross the lipid cell membrane, while highly lipophilic drugs will struggle to cross the water layer in extracellular space. Presence of reverse transporters, such as P-glycoprotein, can affect drug absorption. P-glycoprotein pumps certain drug molecules actively out into the gut lumen from gut cells. Inhibition of P-glycoprotein and gut wall metabolism, for example by grapefruit juice, can increase absorption of certain (mostly non-psychotropic) medications.
Which of the following conditions predisposes to a higher rate of transport through the blood–brain barrier?
D. The blood–brain barrier poses a special challenge to the transit of drug molecules into the brain, which is very important to ensure the activity of most psychotropics. The blood–brain barrier is a structural and functional barrier comprised of capillary endothelium of brain, which possesses tight junctions, acting in unison as a single sheet or membrane. These junctions are disrupted when meningitis or other inflammation affects the structure. The ability of a drug to pass the blood–brain barrier depends on its molecular size, lipid solubility, and ionic status. Unionized molecules that are freely available and less protein bound are transported across the barrier easily. In general, the higher the lipid water partition coefficient, the greater the ability to cross the barrier. Exceptionally, there are a few molecules that pass the barrier effectively in spite of having a low lipid–water partition coefficient. These have specific carrier mechanisms, for example amino acid transport system (this is stereo specific, so that L amino acids but not D amino acids are easily transferred). L-dopa and valproate have specific carrier mechanisms. Some areas of brain lack this barrier—subfornical organ, area postrema, and median eminence. These circum-ventricular organs allow transfer of many compounds from blood to brain. This may have a survival benefit as certain toxic substances stimulate the area postrema and induce nausea and vomiting.
A 72-year-old patient with bipolar illness experiences more side-effects when taking the same medication that he was prescribed 30 years ago, when he was 42 years old.
Which of the following is a possible explanation?
A. Pharmacokinetic changes in old age are pertinent when considering initiation, dosing, and coadministration of medications in the elderly. In general, the ability to absorb an orally administered medication is not greatly affected, but elderly patients have less body fat, and so lipid-soluble drugs may be distributed to brain tissue more avidly. However, this effect is not universal for all drugs. Protein binding and hepatic metabolism are reduced in elderly people, especially when malnourished. Renal function invariably drops with age. Note that this question is non-specific with respect to the prescribed drug.
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