BCGP / pharmacokinetics/pharmacodynamics

Acidic drugs are primarily bind to albumin (highly protein bound). Drugs that are highly protein/plasma bound tend to stay in the blood longer, resulting in a lower volume of distribution. Drugs that primarily distribute into tissue have a high volume of distribution.

Basic drugs are less protein bound and therefore readily distribute into tissue, resulting in a higher volume of distribution. These drugs often stay for longer periods of time in organs and tissues, often leading to higher concentrations, narrower therapeutic index and decreased clearance.

C0 = Dose/Vd C0 = 1500mg/67.5L = 22.2 mg/L

-T>MIC: the pharmacodynamics outcome that is correlated with efficacy for time dependent drugs; increased bacterial killing is based on the percentage of time the concentration exceeds the MIC. Drugs reach a saturable killing rate, therefore, increasing drug concentrations more will not affect the bacterial activity. Example of drugs: Penicillins, cephalosporings, monobactmas, clindamycin, macrolides, linezolid, tetracyclines.
-Peak/MIC: the pharmacodynamics outcome that is correlated with efficacy for concentration depend drugs. The rate and extend of killing of bacteria will increase with increased drug concentrations relative to the MIC. Administer higher doses with a decreased frequency of administration. Examples of drugs: aminoglycosides, floroquinolones, ketolide, metronidazole, oritavancin.
-AUC/MIC: the pharmacodynamics outcome that is correlated with efficacy for concentration depend drugs. It measures the AUC relative to the MIC of the organisms. Administer higher doses with a decreased frequency of administration. Example of drugs: floroquinolones, macrolides, tetracyclines, vancomycin.

-T>MIC: the pharmacodynamics outcome that is correlated with efficacy for time dependent drugs; increased bacterial killing is based on the percentage of time the concentration exceeds the MIC. Drugs reach a saturable killing rate, therefore, increasing drug concentrations more will not affect the bacterial activity. Example of drugs: Penicillins, cephalosporings, monobactmas, clindamycin, macrolides, linezolid, tetracyclines.
-Peak/MIC: the pharmacodynamics outcome that is correlated with efficacy for concentration depend drugs. The rate and extend of killing of bacteria will increase with increased drug concentrations relative to the MIC. Administer higher doses with a decreased frequency of administration. Examples of drugs: aminoglycosides, floroquinolones, ketolide, metronidazole, oritavancin.
-AUC/MIC: the pharmacodynamics outcome that is correlated with efficacy for concentration depend drugs. It measures the AUC relative to the MIC of the organisms. Administer higher doses with a decreased frequency of administration. Example of drugs: floroquinolones, macrolides, tetracyclines, vancomycin.

F = (AUC PO)/(AUC IV) x (Dose IV)/(Dose PO) F = 1/1 x 25/100 = 0.25 X 100% = 25%

-T>MIC: the pharmacodynamics outcome that is correlated with efficacy for time dependent drugs; increased bacterial killing is based on the percentage of time the concentration exceeds the MIC. Drugs reach a saturable killing rate, therefore, increasing drug concentrations more will not affect the bacterial activity. Example of drugs: Penicillins, cephalosporings, monobactmas, clindamycin, macrolides, linezolid, tetracyclines.
-Peak/MIC: the pharmacodynamics outcome that is correlated with efficacy for concentration depend drugs. The rate and extend of killing of bacteria will increase with increased drug concentrations relative to the MIC. Administer higher doses with a decreased frequency of administration. Examples of drugs: aminoglycosides, floroquinolones, ketolide, metronidazole, oritavancin.
-AUC/MIC: the pharmacodynamics outcome that is correlated with efficacy for concentration depend drugs. It measures the AUC relative to the MIC of the organisms. Administer higher doses with a decreased frequency of administration. Example of drugs: floroquinolones, macrolides, tetracyclines, tigecycline, vancomycin.

Cmax = Dose/Vd Cmax = 1000mg/24.5L = 40.8 mg/L

Ke = 0.693/(t1/2 ) = 0.14 h-1 C = Cmax x e-ke x t = 40.8 x e-0.14 x 12 = 7.6 mg/L

C0 = Dose/Vd = 2000mg/18L= 111 mg/L

k= 0.693/(t1/2 )= = 0.693/(2 )= 0.345
Fraction remaining after 1 half life (2 hours) = e^(-kt)= e – 0.345 x 2= 0.50
Amount remaining after 1 half life (2 hours) = 0.50 x 111mg/mL = 55.5 mg/mL
Fraction remaining after 2 half lives (4 hours) = e^(-kt)= e – 0.345 x4 = 0.25
Amount remaining after 2 half lives (4 hours) = 0.25 x 111 mg/mL = 27.75 mg/mL
Fraction remaining after 3 half lives (6 hours) = e^(-kt)= e – 0.345 x6 = 0.125
Amount remaining after 3 half lives (6 hours) = 0.125 x 111 mg/mL = 13.875 mg/mL
Fraction remaining after 4 half lives (8 hours) = e^(-kt)= e – 0.345x8 = 0.0625
Amount remaining after 4 half lives (8 hours) = 0.0625 x 111 mg/mL = 6.93 mg/mL
It will take 4 half lives for cefepime to reach a concentration of 6.93 mg/mL Since the MIC of Cefepime is 8, it will take approximately 8 hours for cefepime to reach a concentration of 6.93 mg/mL, which is a blood concentration below MIC.

T>MIC = ln ( Dose/(Vd x MIC) ) x (t1/2)/ln⁡〖(2)〗 x 100/DI
T>MIC = ln ( (1000 mg)/(18 L x 8) ) x (2 hours)/ln⁡〖(2)〗 x 100/(12 hours)
T>MIC = 46.7%

-T>MIC: the pharmacodynamics outcome that is correlated with efficacy for time dependent drugs; increased bacterial killing is based on the percentage of time the concentration exceeds the MIC. Drugs reach a saturable killing rate, therefore, increasing drug concentrations more will not affect the bacterial activity. Example of drugs: Penicillins, cephalosporings, monobactmas, clindamycin, macrolides, linezolid, tetracyclines.
-Peak/MIC: the pharmacodynamics outcome that is correlated with efficacy for concentration depend drugs. The rate and extend of killing of bacteria will increase with increased drug concentrations relative to the MIC. Administer higher doses with a decreased frequency of administration. Examples of drugs: aminoglycosides, floroquinolones, ketolide, metronidazole, oritavancin.
-AUC/MIC: the pharmacodynamics outcome that is correlated with efficacy for concentration depend drugs. It measures the AUC relative to the MIC of the organisms. Administer higher doses with a decreased frequency of administration. Example of drugs: floroquinolones, macrolides, tetracyclines, vancomycin.

t1/2 = (0.693 x Vd)/CL
t1/2 = (0.693 x 700mL/kg x67kg)/(120mL/min)
= 270 minutes = 4.5 h

Ke= ln⁡〖C1-ln⁡C2 〗/(t2-t1)
Ke= ln⁡〖(24.5)-ln⁡〖(14.5)〗 〗/(37-32) = 0.104
T1/2= 0.693/0.104 = 6.66 h = 7h

F = (AUC PO)/(AUC IV) x (Dose IV)/(Dose PO)
F = 1/1 x 50/100 = 0.5 X 100% = 50%

Ke= ln⁡〖C1-ln⁡C2 〗/(t2-t1)
Ke= ln⁡〖(6.5 mg/L)-ln⁡〖(1.2 mg/L)〗 〗/((14-9) ) = 0.34 h-1
T1/2= 0.693/0.34 = 2.1 h

-T>MIC: the pharmacodynamics outcome that is correlated with efficacy for time dependent drugs; increased bacterial killing is based on the percentage of time the concentration exceeds the MIC. Drugs reach a saturable killing rate, therefore, increasing drug concentrations more will not affect the bacterial activity. Example of drugs: Penicillins, cephalosporings, monobactmas, clindamycin, macrolides, linezolid, tetracyclines.
-Peak/MIC: the pharmacodynamics outcome that is correlated with efficacy for concentration depend drugs. The rate and extend of killing of bacteria will increase with increased drug concentrations relative to the MIC. Administer higher doses with a decreased frequency of administration. Examples of drugs: aminoglycosides, floroquinolones, ketolide, metronidazole, oritavancin.
-AUC/MIC: the pharmacodynamics outcome that is correlated with efficacy for concentration depend drugs. It measures the AUC relative to the MIC of the organisms. Administer higher doses with a decreased frequency of administration. Example of drugs: floroquinolones, macrolides, tetracyclines, vancomycin.

There is a drug interaction between levofloxacin and amiodarone, which may increase the risk of QT prolongation. Levofloxacin is associated with QT prolongation and rarely torsades de pointes. Amiodarone also has a risk of QT prolongation and torsades de pointes. This drug interaction is possible for days to weeks after amiodarone is discontinued because amiodarone has a long half-life. There is also a drug interaction with furosemide and amiodarone. Caution must be used because loop diuretics can lower potassium and magnesium levels, which can cause amiodarone to not work effectively, but patient is on electrolyte replacement protocol and on it for short duration. Reference: Gold Standard, Inc. Levofloxacin. Clinical Pharmacology [database online]. Available at: https://www.clinicalpharmacology-ip.com/Forms/Monograph/monograph.aspx?cpnum=746&sec=moninte&t=0. Accessed: May 18, 2016.
Gold Standard, Inc. Amiodarone. Clinical Pharmacology [database online]. Available at: https://www.clinicalpharmacology-ip.com/Forms/Monograph/monograph.aspx?cpnum=25&sec=moninte&t=0. Accessed: May 18, 2016.

Answer A. With aging, blood pressure and total peripheral resistance increase, however, a decrease in cardiac output is seen. A progressive decline in baroreceptor sensitivity is a characteristic feature of human aging as is a decrease in Beta-adrenergic receptor sensitivity.
Reference:
1. Martin WH 3rd e. Effects of aging, gender, and physical training on peripheral vascular function. - PubMed - NCBI. Ncbinlmnihgov. 2016. Available at: https://www.ncbi.nlm.nih.gov/pubmed/1860209. Accessed October 12, 2016.
2. O'Mahony D e. Reduced baroreflex sensitivity in elderly humans is not due to efferent autonomic dysfunction. - PubMed - NCBI. Ncbinlmnihgov. 2016. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10600664. Accessed October 12, 2016.
3. Ferrara N, Komici K, Corbi G et al. β-adrenergic receptor responsiveness in aging heart and clinical implications. Frontiers in Physiology. 2014;4. doi:10.3389/fphys.2013.00396.

Answer: A. There is a progressive reduction in total body water and lean body mass that occurs and which results in a relative increase in body fat. Renal mass decreases with age and reflects the reduction in nephrons. Both renal plasma flow and as well as glomerular filtration rate decline with age.
Reference:
1. Mangoni AJackson S. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. British Journal of Clinical Pharmacology. 2003;57(1):6-14. doi:10.1046/j.1365-2125.2003.02007.x.
2. Summary of the Updated American Geriatrics Society/British Geriatrics Society clinical practice guideline for prevention of falls in older persons. J Am Geriatr Soc 2011;59:148-57.


Answer D. Expiratory flow rates decrease with aging and typically show changes in the flow-volume curves. Other age-related changes that occur in the lungs include weakening of the respiratory muscles as well as a decrease in lung measures of lung function such as vital capacity, which is the maximum amount of air that can be breathed out following a maximum inhalation.
Reference:
1. Janssens J, Pache J, Nicod L. Physiological changes in respiratory function associated with ageing. European Respiratory Journal. 1999;13(1):197-205. Available at: http://erj.ersjournals.com/content/13/1/197.long. Accessed October 13, 2016.
2. System E. Effects of Aging on the Respiratory System. Merck Manuals Consumer Version. 2016. Available at: https://www.merckmanuals.com/home/lung-and-airway-disorders/biology-of-the-lungs-and-airways/effects-of-aging-on-the-respiratory-system. Accessed October 13, 2016.

Answer B. Aging has been associated with various GI changes such as: a decrease in splanchnic blood flow, delayed gastric emptying, and an increase in gastric pH.
Reference:
1. Mangoni AJackson S. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. British Journal of Clinical Pharmacology. 2003;57(1):6-14. doi:10.1046/j.1365-2125.2003.02007.x.

Answer D. Blood flow to the liver may be reduced with aging by 25-47% and dermal thickness, vascularity, and cellularity also decreases with age. There is a progressive reduction in total body water and lean body mass that occurs and which results in a relative increase in body fat.
Reference:
1. Mangoni AJackson S. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. British Journal of Clinical Pharmacology. 2003;57(1):6-14. doi:10.1046/j.1365-2125.2003.02007.x.
2. Summary of the Updated American Geriatrics Society/British Geriatrics Society clinical practice guideline for prevention of falls in older persons. J Am Geriatr Soc 2011;59:148-57.


Answer D. Pharmacokinetic changes in the elderly such as an increase in volume of distribution of lipid soluble drugs, results in prolonged elimination half-life of these agents. Thus, polar drugs that are mainly water-soluble tend to have smaller volumes of distribution, resulting in higher serum levels in older patients. Serum albumin (binds to acidic drugs) decrease with age, resulting in an increased free fraction in plasma of high protein bound acidic drugs.
Reference:
1. Mangoni AJackson S. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. British Journal of Clinical Pharmacology. 2003;57(1):6-14. doi:10.1046/j.1365-2125.2003.02007.x.
2. Summary of the Updated American Geriatrics Society/British Geriatrics Society clinical practice guideline for prevention of falls in older persons. J Am Geriatr Soc 2011;59:148-57.


Answer D. Hepatic metabolism includes phase 1 reactions (oxidation, reduction and hydroxylation) and phase 2 reactions (conjugation with glucuronate, sulphate or acetate). Phase 1 reactions, are reduced during the aging process, probably due to a combination of reduced hepatic blood flow (35% reduction in hepatic blood flow in the elderly) and reduced hepatic volume. Thus, drug metabolism, particularly first-pass metabolism (e.g. propranolol, labetalol, verapamil, metoclopramide, opioids) may be considerably reduced in elderly people, which in return may increase their drug concentrations.
Reference:
1. Hughes. Prescribing for the elderly patient: why do we need to exercise caution?. British Journal of Clinical Pharmacology. 2002;46(6):531-533. doi:10.1046/j.1365-2125.1998.00842.x.
2. Summary of the Updated American Geriatrics Society/British Geriatrics Society clinical practice guideline for prevention of falls in older persons. J Am Geriatr Soc 2011;59:148-57.


Answer B. The main effect of an increased volume of distribution is a prolongation of half-life. An increase VD and half-life have been observed for agents such as diazepam. Although, in general, the volume of distribution of most benzodiazepines tends to increase with age, for reason that are not clear, the VD of alprazolam (short half-life BZD) specifically decreases in elderly men but remains unchanged in elderly women. Triazolam is also considered to have a short half-life, compared to diazepam (highly lipophilic). Phase 2 reactions usually involve conjugation of phase 1 metabolites and appear to be unchanged by the ageing process although they may be impaired in some frail elderly people, an example of this would be lorazepam (no accumulation due to inactive metabolites.)
Reference:
1. Mangoni AJackson S. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. British Journal of Clinical Pharmacology. 2003;57(1):6-14. doi:10.1046/j.1365-2125.2003.02007.x.
2. Summary of the Updated American Geriatrics Society/British Geriatrics Society clinical practice guideline for prevention of falls in older persons. J Am Geriatr Soc 2011;59:148-57.


Answer D. Lithium, cimetidine, and digoxin distribution in elderly is influenced by physiologic change related to body composition, particularly total body water. There is a decrease in total body water with advancing age, which results in a lower volume of water per kilogram of body weight. So the same dose of these agents in an older person would have less water for them to distribute into, resulting in a higher serum lithium concentration.
Reference:
1. Mohandas E, Rajmohan V. Lithium use in special populations. Indian Journal of Psychiatry. 2007;49(3):211. doi:10.4103/0019-5545.37325.
2. Hughes. Prescribing for the elderly patient: why do we need to exercise caution?. British Journal of Clinical Pharmacology. 2002;46(6):531-533. doi:10.1046/j.1365-2125.1998.00842.x.

Answer D. An unbiased Cockcroft-Gault creatinine clearance can be calculated using actual body weight in underweight patients and ideal body weight in patients of normal weight. Using ABW(0.4) for overweight, obese, and morbidly obese patients appears to be the least biased and most accurate method for calculating their Cockcroft-Gault creatinine clearance. In addition, the common practice of rounding or replacing low Serum Creatinine values with an arbitrary value of 1.0 mg/dl for use in the CG equation should be avoided. Rounding S(c) (r) in patients with low S(c) (r) did not improve accuracy or bias of the creatinine clearance calculations.
Reference:
1. Dowling T, Wang E, Ferrucci L, Sorkin J. Glomerular Filtration Rate Equations Overestimate Creatinine Clearance in Older Individuals Enrolled in the Baltimore Longitudinal Study on Aging: Impact on Renal Drug Dosing. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2013;33(9):912-921. doi:10.1002/phar.1282.
2. Winter MA e. Impact of various body weights and serum creatinine concentrations on the bias and accuracy of the Cockcroft-Gault equation. - PubMed - NCBI. Ncbinlmnihgov. 2016. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22576791. Accessed October 13, 2016.