Geriatric drug therapy. By Linda Farho, Pharm.D

Lecture outline

• Pharmacokinetics recall: Absorption, Distribution, Metabolism, Elimination. Bioavailability.
• Effects of Aging on: absorption, metabolism, volume of distribution and the kidney.
• Estimating GFR in the Elderly.
• Determining creatinine clearance.
• Pharmacodynamics.
• Concepts related to an optimal pharmacotherapy.
• Consequences of overprescribing.
• Adverse drug events (ADE): most common medications, Beers criteria, patient risk factors for ADE.
• Drug – drug interactions (DDI).
• Drug – disease interactions.
• Principles of prescribing in the elderly.
• Preventing polypharmacy.
• Enhancing medication adherence.
• Clinical cases.

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Clinical Pharmacological Issues in the Elderly. By Charles A. Cefalu, MD

Lecture outline

• Factors related to adverse drug reactions.
• Changes of aging: liver, renal clearance, CNS.
• Normal physiological changes in the organ systems.
• Pharmaceutical agents that require hepatic metabolism.
• The cytochrome system.
• Drugs eliminated in the kidneys requiring dosage adjustment.
• Aminoglycoside dosing in the elderly with impaired renal function.
• Practical rule of thumb for dose adjustment.
• Anticholinergic agents.
• Clinical conditions that necessitate dosage adjustment in the elderly.
• Anorexia and aging.
• Screening for potential toxicity of prescription drugs: H2 blockers, beta blockers.
• Innapropriate drugs: anticholinergics, indomethacin, propxyphene, trimethobenzamide and many others.

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The Bagful of Pills: Polypharmacy in the Elderly. By Oana Marcu, DO

Lecture outline

• Definitions: polypharmacy, adverse drug reaction.
• Economic consequences.
• Geriatric prescription principles.
• High risk medications in the elderly: Beers and Canadian criteria as consensus data.
• High risk medications: analgesics (NSAIDs, narcotics, muscle relaxants) and narrow therapeutic index (digoxin, phenytoin, warfarin, theophylline, lithium) cardiovascular (antihypertensives, calcium channel blockers, propanolol, diuretics – see indications and mechanism of action- ), psychotropics (TCAs, antipsychotics, benzodiazepines , sedatives).
• Avoiding polypharmacy: adjust the dose, review regimen regularly, educate.
• Personal Health Records.
• Clinical cases.

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Polypharmacy in the Elderly. By Rosemary D. Laird, MD

Lecture outline

• Overview of polypharmacy.
• The brown Bag.
• Medications and the elderly.
• Polypharmacy and the non-adherence.
• Adverse drug reactions.
• The role of the PCP.
• Prescribing pearls.

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Recommended reading

• Pocket Guide: Pharmacokinetics Made Easy (2009)
• Basic Clinical Pharmacokinetics (2009)
• Concepts in Clinical Pharmacokinetics (2010)
• Clinical Pharmacokinetics, 4th Edition (2008)

• Aspirin is a weak acid (pKa 3.4).
• Acidic drugs in an acidic environment (like gastric lumen) are most likely to be in their neutral form ( non-ionized )
• Non-ionized drugs are more lipid soluble. Hence, they can be readily absorbed
• Since aspirin is a weak acid and gastric pH is an acidic environment,  it can be readily absorbed.
• Bloodstream has a pH of around 7.4, therefore aspirin tends to be ionized. This prevents the drug from diffusing back to the stomach.

Source: University of Rhode Island Pharmacy Animations

Now, watch again the video paying attention to the following details.

Non-ionized form a at the gastric lumen. It has 8 white spheres.

.

.

.

.

Ionized form of aspirin, in the bloodstream. It has 7 white spheres, this means that it has lost a proton.

Deprotonated form =  ionized = non-lipid soluble.

Now,since the drug is ionized it can’t diffuse back to the stomach and remains in the bloodstream.

This is ion trapping!

.

Recommended reading

• First pass metabolism
• Patients in whom oral administration should be avoided
• P-glycoprotein (P-gp)
• Relevance of drug distribution in compartments
• Context specific half life
• Cytochrome 450
• Pharmacogenetics

Pharmacotherapy in critical care: pharmacokinetics

Recommended pharmacokinetics reading

First, a video that analyzes the factors that affect drug distribution: protein binding, molecular weight and lipid solubility.

Authors: Nelson Caetano, Dr. Jef Bratberg. University of Rhode Island

A transcript of the explanatory text:

Unbound drug passes freely through blood vessels and is distributed into the rest of the body. Protein bound drug is trapped within the vessel and is therefore unable to reach its intended sight of action.

Small drug molecules can freely diffuse out of the blood vessel while large drug molecules are confined to the plasma. Heparin is a good example of a drug like this.

Lipid solubility of a drug is a major component in determining its distribution, particularly on the brain. The blood brain barrier prevents the crossing of polarized molecules from capillaries to brain neurons.

The slides below are part of a lecture I give about pharmacokinetics. I chose the slides that explain the meaning of the different values of volume of distribution.

A drug that has a volume of distribution near the plasma volume (e.g. 5 liters) is a drug distributed mainly in the intravascular space. A drug with a very high volume of distribution ( hundreds of liters) should guide us to think that is a drug that bind very strongly to a particular tissue.

Important Pharmacokinetic Parameters

• Clearance (model independent)
• Relationship between Clearance and Volume of Distribution
• Rates and orders of reactions
• Apparent Volume of Distribution (one compartment)

Dosing Calculations

• Loading Dose (LD)
• Maintenance Dose Rate (MDR)
• Maintenance Dose

Download study aid for pharmacokinetics

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Note: the words underlined don’t mean right answer but link to another page.

6 – Pharmacokinetics: Drug Metabolism
1.1) Which of the following locations is the most likely for finding a free, unaltered drug?
a) Urine
b) Feces
c) Breast milk
d) Fat
e) Sweat

1.2) Most drugs are active in their ____ form and inactive in their ____ form.
a) Non-polar; Polar
b) Polar; Non-polar
c) Water-soluble; Lipid-soluble
d) Lipid-insoluble; Water-insoluble
e) Neutral; Neutral
2.1) Drug biotransformation phase I makes drugs ____ polar for metabolism and phase II
makes drugs ____ polar for excretion.
a) More; More
b) More; Less
c) Less; More
d) Less; Less
2.2) Which of the following is NOT a phase II substrate?
a) Glucuronic acid
b) Sulfuric acid
c) Acetic acid
d) Amino acids
e) Alcohol
3) Which of the following reactions is phase II and NOT phase I?
a) Oxidations
b) Reductions
c) Conjugations
d) Deaminations
e) Hydrolyses
4) Which of the following metabolically active tissues is the principle organ for drug
metabolism?
a) Skin
b) Kidneys
c) Lungs
d) Liver
e) GI Tract
5.1) Damage at which of the following locations would most affect the goals of phase II
biotransformation?
a) Skin
b) Kidneys
c) Lungs
d) Liver
e) GI Tract
Match the biotransformation reaction with the drug:
5.2) Hydroxylation of aromatic ring to increase polarity a) Codeine
5.3) N-dealkylation b) Morphine
5.4) Sulfoxidation c) Thioridazine
5.5) O-dealkylation d) Nicotine
5.6) N-oxidation e) Phenobarbitol
5.7) Side chain oxidation with -OH to increase polarity f) Pentobarbitol
5.8) Conversion to glutathione and reactive intermediate g) Acetaminophen
6.1) What is the goal of the P450 system (microsomes pinched off from endoplasmic
reticulum)?
a) Metabolism of substances
b) Detoxification of substances
c) Increasing pH of compartments containing substances
d) Decreasing pH of compartments containing substances
e) A & B
6.2) Regarding the microsomal drug metabolizing system, a patient with late stage
alcoholism and liver damage would have more ETOH available due to which of the
following concepts?
a) Increased induction
b) Decreased induction
c) Increased inhibition
d) Decreased inhibition
6.3) Regarding the microsomal drug metabolizing system, a patient who is a chronic user
of barbiturates would need more drug to produce the same effects due to which of the
following concepts?
a) Increased induction
b) Decreased induction
c) Increased inhibition
d) Decreased inhibition
6.4) Which of the following are the drugs that induce CYP 1A2 and the drugs that have
their metabolism induced by 1A2?
a) Carbamazepine & phenobarbitol; Theophyline & warfarin
b) Phenobarbitol & phenytoin ; Phenytoin & warfarin
c) Carbamazepine & phenytoin; Warfarin
d) Carbamazepine; Cyclosporine
6.5) Which of the following are the drugs that inhibit CYP 1A2 and the drugs that have
their metabolism inhibited by 1A2?
a) SSRIs; Phenytoin & warfarin
b) Amiodarone & cimetidine; Phenytoin & warfarin
c) Cimetidine, erythromycin, & grapefruit juice; Theophyline & warfarin
d) Cimetidine & erythromycin; Cyclosporine
6.6) Which of the following groups of people is the least likely to have biotransformation
effects due to altered hepatic function?

a) Infants

b) Adults

c) Elderly

d) Chronic alcoholics

e) Acetaminophen overdoses

6.7) In what location does amino acid conjugation of glycine (e.g. salicyclic acid) take

place?

a) Microsomal

b) Cytosol

c) Mitochondria

6.8) Where does acetylation conjugation (e.g. isoniazid) and sulfate conjugation (e.g.

acetaminophen) take place?

a) Microsomal

b) Cytosol

c) Mitochondria

6.9) Where does glucuronide conjucation (e.g. digoxin, bilirubin) take place?

a) Microsomal

b) Cytosol

c) Mitochondria

6.10) What is a result of conjugation of isoniazid via N-acetylation?

a) Detoxification of liver

b) Detoxification of kidneys

c) Detoxification of blood

d) Detoxification of urine

e) Hepatotoxicity

7 – Pharmacokinetics: Principles of Eliminations
1.1) One liter contains 1,000 mg of a drug. After one hour, 900 mg of the drug remains.
What is the clearance?
a) 100 mL
b) 100 mL/hr
c) 1 mg/ml
d) 100 mg
e) 1 mg/sec
1.2) To maintain a drug concentration at steady state, the dosing rate should equal the
elimination rate. Which of the following is true? (CL = Drug Clearance)
a) Dosing rate = CL + target concentration
b) Dosing rate = CL – target concentration
c) Dosing rate = CL * target concentration
d) Dosing rate = CL / target concentration
1.3) Which of the following is most useful in determining the rate of elimination of a
drug, in general?
a) Drug concentration in urine (renal elimination)
b) Drug concentration in stool (bilary elimination)
c) Drug concentration in blood
d) Drug concentration in brain
e) Drug oxidation rate
2.1) For first-order drug elimination, half life t(1/2) is ____ at two places on the curve
and a constant ____ is lost per unit time.
a) Equal; Amount
b) Equal; Percentage
c) Not equal; Amount
d) Not equal; Percentage
2.2) For first-order drug elimination, given the half-life equation of t(1/2) = (0.693 * Vd)
/ CL, how many half-lives would be necessary to reach steady state (≈95%) without a
loading dose?
a) 1 to 2
b) 2 to 3
c) 3 to 4
d) 4 to 5
e) 5 to 6
2.3) Which of the following is NOT a drug exhibiting zero-order elimination kinetics?
a) Aspirin
b) Morphine
c) Phenytoin
d) ETOH
2.4) For zero-order drug elimination, half-life t(1/2) is ____ at two places on the curve
and a constant ____ is lost per unit time.
a) Equal; Amount
b) Equal; Percentage
c) Not equal; Amount
d) Not equal; Percentage
2.5) If a drug with a 2-hour half life is given with an initial dose of 8 mcg/ml, assuming
first-order kinetics, how much drug will be left at 6 hours?
a) 8 mcg/ml
b) 4 mcg/ml
c) 2 mcg/ml
d) 1 mcg/ml
e) 0.5 mcg/ml
3.1) What are the units for steady-state concentration (Css), or infusion rate over
clearance?
a) mg/min
b) ml/min
c) mg/ml
d) ml/mg
e) min/mg
3.2) What percentage of the steady-state drug concentration is achieved at 3.3 * t(1/2)?
a) 10%
b) 25%
c) 50%
d) 75%
e) 90%

4.1) Increasing the rate of infusion changes the time necessary to reach the steady-state
concentration.
a) True
b) False
4.2) An injection of two units of a drug once-daily (qd) will yield the same steady-state
concentration as an injection of one unit of a drug twice-daily (bid).
a) True
b) False
5.1) Which of the following drugs would most likely need a loading dose to help reach
therapeutic levels?
a) Acetaminophen, t(1/2) = 2 h
b) Aspirin, t(1/2) = 15 m
c) Tetracycline, t(1/2) = 11 h
d) Digitoxin, t(1/2) = 161 h
e) Adenosine, t(1/2) = 10 s
5.2) A target concentration of 7.5 mg/L of theophylline is required for a 60 kg patient.
What is the loading dose, given the following: Vd = 0.5 L/kg, Cl = 0.04 L/kg/hr, t(1/2) =
9.3 hr?
a) 0.5 L/kg * 60 kg * 7.5 mg/L = 225 mg/h, infusion
b) 0.5 L/kg * 60 kg * 7.5 mg/L = 225 mg, bolus
c) 0.04 L/kg/hr * 60 kg * 7.5 mg/L = 18 mg/h, infusion
d) 0.04 L/kg/hr * 60 kg * 7.5 mg/L = 18 mg, bolus
5.3) A target concentration of 7.5 mg/L of theophylline is required for a 60 kg patient.
What is the steady state maintenance dose, given the following: Vd = 0.5 L/kg, Cl = 0.04
L/kg/hr, t(1/2) = 9.3 hr?
a) 0.5 L/kg * 60 kg * 7.5 mg/L = 225 mg/h, infusion
b) 0.5 L/kg * 60 kg * 7.5 mg/L = 225 mg, bolus
c) 0.04 L/kg/hr * 60 kg * 7.5 mg/L = 18 mg/h, infusion
d) 0.04 L/kg/hr * 60 kg * 7.5 mg/L = 18 mg, bolus

Complete PDF file with answers

More USMLE pharmacology questions

Recommended pharmacokinetics reading

Pharmacokinetics: Half-Life

The period of time required for the concentration or amount of drug in the body to be reduced to exactly one-half of a given concentration or amount. The given concentration or amount need not be the maximum observed during the course of the experiment, or the concentration or amount present at the beginning of an experiment, since the half-life is completely independent of the concentration or amount chosen as the “starting point “. Half-lives can be computed and interpreted legitimately only when concentration or amount varies with time according to the law appropriate to the kinetics of a first order reaction: the common logarithm of the concentration or amount is related linearly to time, e.g.:

log C=a+bt

where C is concentration at time t, a (in logarithmic units) is the intercept of the line with the ordinate, and b (which has a negative sign) is the slope of the line. The parameters of the equation can be estimated from the plot of experimental values of log C and t. The half-life can be computed simply by dividing the slope of the curve into 0.301, the difference between the logarithm of a number (C) and the logarithm of number half as large (C/2); the symbol for half-life is t1/2.

The half-life of a drug in plasma or serum is frequently taken as indicating the persistence of the drug in its volume of distribution; this interpretation may be incorrect unless the material can move freely and rapidly from one fluid compartment of the body to another, and is not bound or stored in one or another tissue. The term “biological half-life” should not be used instead of the specific terms “plasma half-life” or “serum half-life”. The tissue for which the half-life of a drug is determined should always be specified, e.g., “serum half-life”; the half-life of a drug in muscle, kidney, etc., or in the whole organism can be determined. Drug half-lives are frequently based on the results of chemical analyses, i.e., the results of the reaction of a reagent with a specific chemical group of a drug molecule; it should be remembered that detection of the group per se does not necessarily imply its continuous existence as part of a biologically active drug molecule.

A drug molecule that leaves the plasma may have any of several fates: it can be destroyed in the blood; it can be eliminated from the body; or it can be translocated to a body fluid compartment other than the intravascular to be stored, biotransformed, or to exert its pharmacodynamic effects.

When the plot of log plasma or serum concentration (during the period of its decline) against time is composed of two straight line segments, the inference may be made that two first order processes are involved in the distribution and biotransformation and elimination of the drug. The earlier phase – represented by the line segment of greater slope – is termed the distributive phase, and corresponds to the period during which translocation of the drug to its ultimate volume of distribution occurs and is the dominant process; the later phase – represented by the line of lesser slope – is termed the eliminative phase, and corresponds to the period when biotransformation and elimination of drug are dominant processes. For two-phase systems, three phase systems, etc., half-lives of the drugs in the various phases can be determined only after more sophisticated analysis of the data than that described above.

The copyright of the text is hold by Trustees of Boston University. Permission has been granted for its use in this website.

Recommended pharmacokinetics reading

• Pocket Guide: Pharmacokinetics Made Easy (2009)
• Basic Clinical Pharmacokinetics (2009)
• Concepts in Clinical Pharmacokinetics (2010)
• Clinical Pharmacokinetics, 4th Edition (2008)

ka:

The “absorption rate constant” for a drug administered by a route other than the intravenous. The rate of absorption of a drug absorbed from its site of application according to first-order kinetics. ka is determined directly, or indirectly, as the slope of the linear relationship between the logarithm of the amount un absorbed and t, when natural logarithms, i.e. logarithms to the base e, are used. The half-time for absorption is computed as 0.693/ka, i.e. ln 2/ka.

The copyright of the text is hold by Trustees of Boston University. Permission has been granted for its use in this blog.

Recommended pharmacokinetics reading