Question

Case #2

A 30 year old female patient comes to your retail pharmacy to pick up a prescription for Tylenol #3 (acetaminophen + codeine) for pain control. You enter the prescription into the computer system and the computer’s interaction checker flags an interaction between Tylenol #3 and the patient’s fluoxetine prescription. Answer questions 1-3 regarding this case.

. What would you expect to see if you give codeine to: a) a poor metabolizer for the enzym CYP2D6 and b) an ultra-rapid metabolizer of the enzyme CYP2D6.

Case #3

C.G., A 29 year-old female (yof) patient, presents for inpatient care. You are working as a staff pharmacist in the hospital pharmacy and are asked to verify/fill her prescriptions. Her current medications are for rifampin, nifedipine, amitriptyline, and fluoxetine, valproate sodium, and lamotrigine. Please identify at least three potential biotransformation-related drug interactions in the scenario above and describe the potential mechanism for the interaction. Describe the expected effect (i.e., increased/decreased parent drug concentration, increased/decreased metabolite concentration).

Interaction #1 & effect on plasma concentrations –

Interaction #2 & effect on plasma concentrations –

Interaction #3 & effect on plasma concentrations -

A week later, C.G. is still in the hospital. She is very hypertensive and the physician elects to start IV propranolol 2 mg. Is this an appropriate dose of propranolol for hypertension management when the patient goes home? If not, why not?

In addition to her hypertension, C.G. developed an arrhythmia. The physician ordered lidocaine to be given IV. Initially, this drug produced a therapeutic plasma concentration (Css total of 4 mg/L). This drug has a high extraction ratio and is highly bound to alpha-1-acid glycoprotein. A few days after starting the drug, the total plasma concentration remained the same, but the free drug concentration was found to be increased.

What is a potential explanation for this change in free drug concentration?

Why would total concentration stay the same? What factors would alter the total drug concentration (Css) of lidocaine?

Answer 1

Case 2.

Cytochrome P450 CYP2D6 is an extensively characterized polymorphic drug metabolizing enzyme. This mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body.  CYP2D6 converts codeine in to its active metabolite, morphine, which provides its analgesic effect. In a poor metabolizer of CYP2D6 ( who carry two inactive copies of CYP2D6) there would be very little or near negative enzymatic activity. So analgesic effect of codein would be inadequate in those individuals.

Where as,  individuals who carry more than two normal function copies of the CYP2D6 gene (“ultrarapid metabolizers”) are able to metabolize codeine to morphine more rapidly and more completely. As a result, even with normal doses of codeine, these individuals may experience the symptoms of morphine overdose, which include extreme sleepiness, confusion, and shallow breathing.

Case 3.

Interaction 1. Rifampin & Nifedipine - Rifampicin markedly reduces the plasma levels of calcium channel blockers (Nifedipine) by increasing its metabolism. Rifampicin is a strong inducer of CYP3A4, while nifedipine is a substrate for the same xenobiotic enzyme.

Interaction 2. Fluoxetine & Amitriptyline - Being a inhibitor of CYP2C19, the psychotropic drug, Fluoxetine increases the plasma level of TCAs ( amitryptylline) by blocking its xenobiotic metabolism. Amitryptylline is a substrate for metabolism by CYP2C19.

Interaction 3. valproate sodium & Amitriptyline -  valproate sodium is a strong enzyme inducer of CYP2C19. So naturally, it will reduces the plasma levels of amitryptylline by increasing its metabolism, and clearing the drug out of the system.

First of all Propranolol,being a first generation Nonselective Beta blocker, now a days, is not used to treat Hypertention and as IV formulation for a patient going home, this would be the last choice to think of.

Being a  Nonselective Beta blocker, major disadvantage of propranolol is the fact that they will block beta₂ receptors associated with airway or vascular smooth muscle. This unwanted action can exacerbate airway diseases (asthma, emphysema, chronic bronchitis) or peripheral vascular disease (Raynaud’s Disease). To overcome this disadvantage, "selective" beta₁ blockers have been developed. These agents have the ability to preferentially block beta₁ receptors. Even there is possibilities of dyslipidaemia, severe bradycardia and hypotention.

In Hypertntion, Propranolol can be given as dose of -

• 40 mg PO q12hr initially, increasing every 3-7 days; maintenance: 80-240 mg PO q8-12hr; not to exceed 640 mg/day ( Immideate release formulation )
• 80 mg/day PO initially; maintenance: 120-160 mg/day ( Long acting formulation )

Alpha-1-acid glycoprotein (AGP) or orosomucoid (ORM) is a 41-43-kDa glycoprotein, involved in the binding and transport of many drugs, especially basic compounds.  the plasma concentration of AGP is relatively low and there is only one drug-binding site in each AGP molecule. Thus, binding to AGP is saturable and displaceable. So, Changes in AGP concentration could potentially alter the free fraction of drugs in plasma or at their target sites and eventually affect their pharmacokinetic disposition and pharmacological action.

In this patient lidocaine given to the same dose persistently, which is able to maintain the therapeutic plasma concentration (Css total of 4 mg/L). But at the same time AGP production is not increased, rather being an Acute phase reactant, after the initial stress period is over, the hepatic synthesis of AGP reclines. So for the binding sites to the drugs.

Thus the dose of lidocaine given, maintain the plasma concentration but with the decrese in the synthesis of AGP, the bound form of drug content get reduced and the free from increase.

Inhibitors of P450 3A4 isoenzyme, co administered with lidocaine can increase the total drug concentration (Css), by blocking their xenobiotic metabolism. Such inhibitors are - Erythromycin, Fluconazole, Fluvoxamine fluoxetine, Tamoxifen Valproic acid, etc.

Thanks for asking.