Question

Patient AO has a history of obesity and has recently gained 9 pounds. The patient has been diagnosed with hypertension and hyperlipidemia. Drugs currently prescribed include the following:

Atenolol 12.5 mg daily

Doxazosin 8 mg daily

Hydralazine 10 mg qid

Sertraline 25 mg daily

Simvastatin 80 mg daily

Post an explanation of how the factor you selected might influence the pharmacokinetic and pharmacodynamic processes in the patient from the case study you selected. Then, describe how changes in the processes might impact the patient’s recommended drug therapy. Finally, explain how you might improve the patient’s drug therapy plan.

Answer 1

an explanation of how the factor you selected might influence the pharmacokinetic and pharmacodynamic processes in the patient from the case study you selected. Then, describe how changes in the processes might impact the patient’s recommended drug therapy. Finally, explain how you might improve the patient’s drug therapy plan.

Influnce of the Atenolol in Pharmokinetic Nature:

The goal of therapeutics is to achieve a desired beneficial effect with minimal adverse effects. When a medicine has been selected for a patient, the clinician must determine the dose that most closely achieves this goal. A rational approach to this objective combines the principles of pharmacokinetics with pharmacodynamics to clarify the dose-effect relationship

The “standard” dose of a drug is based on trials in healthy volunteers and patients with average ability to absorb, distribute, and eliminate

Dose of Drug Adiministered

  

Volume of Distribution:

Volume of distribution (V) relates the amount of drug in the body to the concentration of drug (C) in blood or plasma: The volume of distribution may be defined with respect to blood, plasma, or water (unbound drug), depending on the concentration used in equation (1) (C = C b , C p , or C u ). That the V calculated from equation (1) is an apparent volume may be appreciated by comparing the volumes of distribution of drugs such as digoxin or chloroquine with some of the physical volumes of the body. Volume of distribution can vastly exceed any physical volume in the body because it is the volume apparently necessary to contain the amount of drug homogeneously at the concentration found in the blood, plasma, or water. Drugs with very high volumes of distribution have much higher concentrations in extravascular tissue than in the vascular compartment, ie, they are not homogeneously distributed. Drugs that are completely retained within the vascular compartment, on the other hand, have a minimum possible volume of distribution equal to the blood component in which they are distributed, eg, 0.04 L/kg body weight or 2.8 L/70 kg for a drug that is restricted to the plasma compartment. Clearance Drug clearance principles are similar to the clearance concepts of renal physiology. Clearance of a drug is the factor that predicts the rate of elimination in relation to the drug concentration: Clearance, like volume of distribution, may be defined with respect to blood (CL b ), plasma (CL p ), or unbound in water (CL u ), depending on the concentration measured. It is important to note the additive

Volume Distribution Formula:

V=  Amount of drug in the body

C

Clearance Formula:

CL= Rate of elimanation

C

character of clearance: Elimination of drug from the body may involve processes occurring in the kidney, the lung, the liver, and other organs. Dividing the rate of elimination at each organ by the concentration of drug presented to it yields the respective clearance at that organ.

1.Drug:Atenolol:Atenolol   

2.Oral Availability (F) (%)-56

3.Urinary Excretion (%)1-94

4.Bound in Plasma (%) -5

5.Clearance (L/h/70 kg)2-10.2

6.Volume of Distribution (L/70 kg) -67

7.Half-Life (h)-6.1

8.Target Concentration

9.Toxic Concentration 1mg/dl

1.Drug:Atenolol:Hydralazine

2.Oral Availability (F) (%)-40

3.Urinary Excretion (%)1-10

4.Bound in Plasma (%) -87

5.Clearance (L/h/70 kg)2-234

6.Volume of Distribution (L/70 kg) -105

7.Half-Life (h)-1

8.Target Concentration-01mg/ml

9.Toxic Concentration- ....

the pharmacodynamics of doxazosin and atenolol were compared on single study days in 39 patients with mild to moderate hypertension receiving long-term double-blind treatment. The pharmacokinetics of doxazosin were investigated in the 20 patients receiving doxazosin. Individually titrated once daily doses of doxazosin were 1, 2, 4, 8 or 16 mg and of atenolol 50 or 100 mg. Patients were first investigated after at least one month on constant dose and then again after at least a further three months. Mean plasma concentrations of doxazosin were proportional to dose and the plasma half-life was 11.5 h and independent of dose. There was low variability of doxazosin plasma concentrations between patients receiving the same dose. Concentrations and half-life were unchanged during the period between investigations. Mean reductions of AUC (0–12 h) blood pressure during the 12-h period post-dose and of blood pressure at 24 h post-dose were not statistically different between doxazosin and atenolol. There was effective control of blood pressure by both drugs at all time points of the day. The pharmacokinetic and pharmacodynamic results obtained in this study are compatible with the use of doxazosin in a once daily dose regimen for the treatment of essential hypertension.

Drug recommendations:

Combination treatments of anti-obesity drugs showed disappointing results. The first important clinical study for weight reduction combining drugs used phentermine and fenfluramine as previously mentioned. The trial showed a highly significant weight reduction. However, fenfluramine was withdrawn from the market worldwide on September 15, 1997, because of heart valve damage . Combination treatment of orlistat and sibutramine, which had been approved only for long-term use, did not induce any further weight loss [53]. Because none of the single-agent drugs that have been approved or appear close to approval have consistently been able to achieve a weight loss of more than approximately 10% of body weight , several other combinations of existing drugs are now under development and may be the next therapeutic option for treatment of obesity.

Serotonin receptor activation:

Lorcaserin is a selective serotonin 2C (5HT2c) receptor agonist that was anticipated to recapitulate the weight loss effects of fenfluramine without its adverse cardiac effects.51 Lorcaserin 10mg BID was FDA-approved in 2012 on the basis of two large randomized, placebo-controlled trials in nondiabetic patients (BLOOM,31 n=3182, 50% attrition; BLOSSOM,32 n=4004, 45% attrition) along with a third, smaller trial in adults with type 2 diabetes (BLOOM-DM,30 n=603, 34% attrition). In these trials, participants received low-intensity nutritional and exercise counseling. Lorcaserin decreased body weight modestly, by about 3.2 kg (~3.2% of initial body weight) more than placebo.29 However, significantly more patients treated with lorcaserin 10mg bid than placebo lost ≥5% (BLOOM: 47 vs. 20%, BLOSSOM: 47 vs. 25%, BLOOM-DM: 37 vs. 16%) or ≥10% (BLOOM: 23 vs. 8%, BLOSSOM: 23 vs. 10%, BLOOM-DM: 16 vs. 4%) of their initial weight. Reduction in body weight below baseline in the one study31 with data from participants who took lorcaserin for 2 years had average weight loss of 5.6 kg, versus 2.4 kg among placebo-treated participants. Blood pressure, total cholesterol, LDL-cholesterol, and triglycerides also decreased significantly more in lorcaserin-treated participants.52 Among patients with diabetes, lorcaserin treatment led to lower body weight and improved glycated hemoglobin concentrations.30 Adverse effects include headache, nausea, fatigue, and dizziness.52 Although neither incidence of valvulopathy nor hypertension was statistically greater during lorcaserin than placebo treatment, both were numerically somewhat more prevalent and the FDA has requested that a post-approval trial to assess the long-term cardiovascular effects of lorcaserin be conducted.5