Dr. Eyad

Preface:

Lippincott Illustrated Reviews-Pharmacology is a wide-spread book with simple language and figures, making it a useful book for the students of Medicine, Nursing, and Pharmacology. However, the book includes many scientific and graphical mistakes that should be made note of.

In this brief book I will be highlighting some mistakes in the current (sixth) edition of Lippincott Pharmacology. I will mention the page number, with a photo of the location of the mistake and why it is mistake, then the correction.

Some mistakes simply contradict a very well-known established scientific fact, in which case I may not mention references for the correction. For other mistakes, a reference or more for correction is mentioned. This book includes a total of 37 corrections, ten of which are considered relatively minor corrections, for which reason I put them at the end.

I hope both instructors and students will make use of this booklet for more authentic teaching and learning.

Eyad Qunaibi

PhD in Pharmacology from University of Houston, TX, USA

Associate Professor in Pharmacology at Jarash University, Jordan

February, 2017


Correction 1: Page 3:

 

Figure 1-01

 

In the comparison of IM vs. IV midazolam (Fig 1.3), there is a couple of issues:

  1. The IV curve should reach zero concentration (as in the dashed red line I added), intersecting with the IM curve. The way it is drawn originally in your figure shows as if IV injections give sustained levels as IM ones, which is not the case.
  2. The bioavailability after the IM injection (compared with the IV inj.) should be higher than shown in your fig. Bioavailability of 5 mg IM midazolam is somewhat between 87% and 100%. See:

with focus on the phrase (bioavailability was 1.0 for both drugs) meaning midazolam and diazepam.

with focus on the sentence (The absolute bioavailability of intramuscular midazolam was calculated in 11 patients as 87 +/- 18%).

Therefore, the alternative I suggest should look something like this figure:

Figure 2-02

 

Note a higher IM bioavailability than fig 1.3 and intersection of IV with IM curves.


Correction 2: Page 4:

Figure 3-05

Nasal inhalation is not a suitable title. It should be (Nasal preparations) or (Nasal spray and inhalation) for example. This is because the term ‘nasal inhalation’ means a preparation applied in the nose with the purpose of having it ‘inhaled’ to the respiratory system, which applies to inhaled anesthetics.

The very first example mentioned (oxymetazoline) is a nasal decongestant and its preparation is described as (nasal spray) and is never described as ‘inhalation’. Desmopressin preparation is usually described as spray rather than inhalation. Mometazone furoate preparation is described as either spray or inhalation.

However, I reemphasize that the preparation of oxymetazoline is never described as inhalation because it is not meant to be inhaled but to act locally as a decongestant.


Correction 3: Page 5:

Figure 7-07

Patients do not need to regulate dose with inhalation devices. They are in fact called
‘metered dose’ devices. This point can be omitted with the next disadvantage below it
becoming:
(Some patients may have difficulty using inhalers, leading to variable dose).


Correction 4: Page 7:

Figure 8-08

It is confusing to include both weak acids and weak bases in the same figure. Notice that the figure included B and BH+, both of which were assigned for weak bases in Fig 1.7 in Lippincott. A pKa of 6.5 is for a weak acid, not a weak base.

Correction: the representation for a weak base should be separated from that of the weak acid, or it should be mentioned in the text that opposite predominance of protonated vs. deprotonated forms applies to weak base on the two sides of a pKa higher than 7 without including this in the figure.


Corrections 5: Page 7:

Fugure 9-09

At the arrow in the above text image, the phrase ‘per area’ should be added so that the sentence becomes: ‘The intestines receive much more blood flow than the stomach per area’…to make it clear that it is not the larger surface area of intestine we talk about here, because this last factor is already detailed in the next point (i.e. point 3. Total surface area available for absorption).


Correction 6: Page 9:

Under the title (E. Therapeutic equivalence) we read these sentences:

image013

These sentences are contradictory with the sentence under the title (D. Bioequivalence). This is because: “two drugs that are bioequivalent” -as in the second sentence of the note above- necessarily achieve the two conditions for therapeutic equivalence that are mentioned in the first sentence of the note (i.e. similarity in “maximum serum drug concentration and the time required to reach peak concentration”), because these two bioequivalent drugs “show comparable bioavailability and similar times to achieve peak blood concentrations” as defined under (D. Bioequivalence). So, the conclusion “two drugs that are bioequivalent may not be therapeutically equivalent” is inconsistent with the sentences above.

In fact, therapeutic equivalence requires factors other than “max serum drug concentration and the time required to reach peak concentration”, which are the conditions of bioequivalence. Look at the FDA Orange Book: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm079068.htm#tecode, with focus on the title (Therapeutic equivalence).


Correction 7: Page 10:

image015

First of all, extracellular fluid includes blood, and this is what Lippincott itself mentions in page 11 under the title (b. Extracellular fluid):

image017

In addition, it is meant to say that many drugs accumulate inside cells, not in tissues, because tissues involve their interstitial fluid.

In the figure below, I show the concept of drug accumulation inside cells compared with interstitial fluid and plasma:

image019

So, the sentence should be: Many drugs accumulate in cells, leading to higher concentrations in cells than in the interstitial fluid and blood.


Correction 8: Page 12:

image021

Instead of “is lipophilic” it should be (has enough lipophilicity), because ethanol is mentioned at the end of the paragraph as an example, and ethanol is generally hydrophilic in deed, not lipophilic. So, (enough lipophilicity) is more accurate to describe ethanol.


Correction 9: Page 12:

image023

This part of the sentence (and extend the duration of action) should be omitted because the relationship between half-life and duration of action is complex and not always proportional. For example, binding of a drug to the intracellular proteins or fats out of the site of action increases volume of distribution and t1/2 of that drug but decreases duration of its action because it decreases its concentration at the site of action below effective concentration (propofol as an example).

In addition, saying “any factor that increases Vd” may make the student think Vd can be manipulated, while in deed it is constant for a given drug.

If it was meant that the innate properties of a drug which increase its Vd also increase t1/2 then the sentence should read: (drugs with higher Vd have longer t1/2).

If, on the other hand, the disease states that can increase Vd of a drug are what the sentence is talking about, then the correlation is also complex. For example, being obese can increase the Vd of lipophilic drugs but is not known to increase its duration of action. Diseases that decrease plasma proteins not only increase distribution to extravascular compartments, but also increase delivery of the drug to the elimination organs.

In brief, the phrase (and extend the duration of action) should be omitted.


Correction 10: Page 13:

image025

The underlined sentence is misleading because it makes the student think Clearance is equal to the amount of drug cleared, while it is the volume of blood from which the drug is cleared per unit time regardless of the amount of drug cleared.

One may argue that clearance is used to estimate the amount of drug cleared. However, clearance itself is not correctly defined anywhere in this chapter, making this sentence more problematic because a student would simply think it is “the amount of drug cleared”, which is in fact a common mistake among students!

CL is unique (constant) for a particular drug and a particular patient. Being constant means that it remains the same over a broad range of plasma concentrations (corresponding to a broad range of amounts of drug cleared).


Correction 11: Page 17:

image027

Just the opposite is the case! Incompletely developed tubular secretory mechanism causes retention of certain drugs in the arterioles (vascular compartment) not the glomerular filtrate (tubular compartment). This is because secretory mechanisms cause secretion from blood into tubules, not reabsorption from tubules into blood. See the figure below for illustration:

image029

image031


Correction 12: Page 17:

image033

It is confusing to use clearance interchangeably with excretion. Same is said about using eliminating interchangeably with excreting.

Clearance involves both processes of metabolism and excretion.

Also: Elimination involves both processes of metabolism and excretion.

Therefore, it is more accurate to say:

‘Excretion by other routes’….’Drug excretion may also occur’…..drug-metabolizing and drug-excreting organs’.


Correction 13: Page 20:

image035

The highlighted sentence gives the wrong impression that changing the dosing frequency changes “the rate at which the steady state is approached’ without affecting Css value, especially that the sentence is mentioned under the title (Effect of dosing frequency). The sentence should be: Dosing frequency changes neither Css magnitude, nor the rate of achieving Css.


Correction 14: Page 21:

Steady-state concentration is almost achieved in 2 t1/2s in Fig. 1.25 in Lippincott, while it should be achieved in about 4-5 t1/2s (see correction 15).

The interval for t1/2 should be narrowed.

image037


Correction 15: Page 22:

image039

The t1/2 is disproportional with the time to achieve steady state concentration in Fig. 1.26 in Lippincott. In page 19 it is mentioned that “a drug reaches steady state in about four to five half-lives”.

In 2 t1/2s only 75% of the steady state concentration should be achieved, while a much higher concentration is achieved in this figure. The same mistake has occurred in the curves after increasing and decreasing the doses.

A correction can be made by halving the magnitude of elimination t1/2 indicated at the left extreme of the x-axis.


Correction 16: Page 23:

image041

This wording makes the student think that the listed reactions are all truly phase II reactions and that the question is about which of them makes the metabolite readily excretable. While, in reality, all of them, except glucuronidation, are phase I reactions. The question needs to be as follows:

(While of the following is a phase II metabolic reaction that makes phase I metabolites readily excretable in urine?).


Correction 17: Page 29:

image043

β-Receptors are not a good example for low spare receptor percentage because this is, at least, controversial. Other references mention just the opposite:

“Several studies have indicated that in humans and experimental animals, about 90% of β adrenoceptors in the heart are spare receptors.” (Katzung and Trevor’s Pharmacology Examination and Board Review, 11th edition p.22)

“Thus, adrenaline can elicit the maximum cardiac inotropic response even when 90% of the cardiac β1 adrenergic receptors are occupied by relatively irreversible antagonists. This indicates that the cardiac tissue possesses a large number of spare beta, receptors.” (Pharmacology and Pharmacotherapeutics, 24th Edition, 2015, p. 34)


Correction 18: Page 33:

image045

In Fig 2.11 in Lippincott, the sentence in the rectangle is false and it should be:

In this example, approximately 12% of maximal receptor activity is shown basally (constitutively, without stimulation).

The two sentences are not the same although they may seem so at first glance.

The original sentence is false because it is based on the wrong assumption that an unoccupied basally-active receptor has the same activity as a full agonist-occupied receptor. This abolishes the whole concept of intrinsic activity and coupling efficiency!

In page 31 of the book it is stated that: “Efficacy is dependent on the number of drug–receptor complexes formed and the intrinsic activity of the drug (its ability to activate the receptor and cause a cellular response).”

So, an unoccupied receptor does not have the same ability to couple to signaling cascade as the full agonist-occupied receptor.

Assume we are taking about GPCRs. Several constitutive (basally active) receptors have the ability to activate G-protein that sums up to the ability of one agonist-occupied receptor to do so.

Let’s give numerical explanation: assume we have a GPCR system without agonist activation. Basal activity means that these receptors will couple to and activate G-protein (say Gs) constitutively, let’s say at a rate of one Gs per second for each receptor. Assume you add an agonist with intrinsic activity of activating the receptor to couple to 100 Gs per second. This means that 100 unoccupied receptors gave the activity of one agonist-stimulated receptor.

The activity of unoccupied receptors can by no means equate that of an agonist-occupied one because this nullifies the concept of intrinsic activity that makes the agonist ‘agonist’.

Therefore, the sentence needs to be changed to:

In this example, approximately 12% of maximal receptor activity is shown basally (constitutively, without stimulation).

This basal activity is contributed to by ALL unoccupied receptors, not by 12% of them.


Corrections 19: Page 35:

image048

In Fig 2.14 of Lippincot, the dashed vertical line should be transferred to the indicated location. The whole idea of this line is to show that there is no intersection (overlapping) between the two curves (Therapeutic and adverse) unlike warfarin, where the intersection occurs and is denoted by the line. The whole idea is that all patients can benefit from the desired effect at suitable concentrations without having unwanted adverse effect.


Correction 20: Page 56:

image049

Nitric oxide does not stimulate protein kinase G production, it stimulates cGMP production, which in turn stimulates protein kinase G, leading to hyperpolarization and smooth muscle relaxation.

In the following figure, I illustrate the concept further:

image051


Correction 21: Page 67:

image053

The underlined part of the sentence is confusing because it makes one think we are talking about receptors of the type shown in the figure below:

image055

…which is not the case. Therefore, the sentence should be:

“This effect results from blockade of the inhibitory M1 receptors (autoreceptors) on the prejunctional membranes that normally limit ACh release” (as in Katzung Basic and Clinical Pharmacology). The word ‘inhibitory’ should be used to describe the receptors, not the neurons.

It becomes clear for the student then that the receptor we are talking about is the one highlighted with an arrow in the figure below (originally Fig 4.3 page 53 in Lippincott):

image057


Correction 22: Page 81:

image059

One concludes from this paragraph that down-regulation is one mechanism of desensitization, which is not the case!

In fact, the mechanism of desensitization is the one mentioned in the third point (an inability to couple to G protein…). Downregulation is different and includes a decrease in the total number of cell-surface receptors as mentioned in page 29 under the title (Desensitization and down-regulation of receptors).

All three processes are mechanisms for tolerance to drugs.

Therefore, the paragraph should become:

Prolonged exposure to the catecholamines reduces the responsiveness of target systems to these catecholamines. Three mechanisms have been suggested to explain this phenomenon:

  • Sequestration of receptors.
  • Downregulation of receptors.
  • Desensitization of receptors, that is an inability of receptors to couple to G protein

Correction 23: Page 86:

image061

The highlighted sentence has long been an outdated obsolete belief, contradictory to what has been stated in other references:

(Norepinephrine is the preferred initial vasopressor agent for hemodynamic support. Norepinephrine achieves greater hemodynamic response than dopamine and is less likely to cause tachydysrhythmias) (Pharmacotherapy: A Pathophysiological Approach. Joseph DiPiro et al, 9th edition, 2014).

(Norepinephrine, in contrast to earlier recommendations, is an effective agent in septic and cardiogenic shock when used properly. Dobutamine and dopamine are also used.  Unfortunately, the arrhythmogenic effects of these drugs may be dose-limiting.) (Katzung and Trevor’s Pharmacology Examination and Board Review, 10th edition p.279).

“Tachydysrhythmias are common due to the release of endogenous norepinephrine by dopamine entering the sympathetic nerve terminal. For this reason, it is no longer considered first-line therapy for septic shock” (Pharmacotherapy: A Pathophysiological Approach. Joseph DiPiro et al, 9th edition, 2014).


Correction 24: Page 98:

image063

The highlighted sentence is, according to most guidelines, an outdated obsolete belief that has been contradicted by evidence-based research since a long time. Cardioselective beta-blockers are considered safe in patients with respiratory diseases and recommendations are now against depriving these patients from the benefits of cardioselective beta-blockers whenever they have concomitant diseases requiring their use.

See the following references for example:

(β-Blockers, especially nonselective agents, have been generally avoided for patients with hypertension and reactive airway disease (asthma or chronic obstructive pulmonary disease [COPD] with a reversible obstructive component) due to a fear of inducing bronchospasm.80 This precaution is more of a myth than a fact. Data suggest that cardioselective β-blockers can safely be used in patients with asthma or COPD.81 Therefore, cardioselective β-blockers should be used to treat a compelling indication (i.e., post-MI, coronary disease, or heart failure) for patients with reactive airway disease (Pharmacotherapy: A Pathophysiological Approach. Joseph DiPiro et al, 9th edition, 2014).

See also: Global Strategy for Asthma Management and Prevention (2016 update, with the following statement existing in the 2015 report as well):

(If cardioselective beta-blockers are indicated for acute coronary events, asthma is not an absolute contra-indication, but the relative risks/benefits should be considered) (http://ginasthma.org/wp-content/uploads/2016/04/GINA-2016-main-report_tracked.pdf accessed on January, the 24th, 2017).

In fact, even Up To Date database, which follows to Wolters Kluwer, to which Lippincott Pharmacology also follows, clearly states that:

“However, beta blockers appear to be safe in patients with COPD and indeed may reduce mortality and exacerbations”!

(http://www.uptodate.com/contents/treatment-of-hypertension-in-asthma-and-copd accessed on Jan, the 24th, 2017).

See also example this evidence-based report:

http://www.medscape.com/viewarticle/464040_4

With a focus on the conclusion:

“The findings from these meta-analyses are consistent with other studies that have shown that the use of cardioselective β blockers in patients with COPD and concomitant cardiovascular disease is well tolerated. One study on survivors of myocardial infarction included 46,000 patients with concomitant asthma or COPD and showed a significant reduction in total mortality for those treated with β blockers compared with those who were not. This indicated that when β blockers are withheld from patients with obstructive airway disease, the mortality benefits associated with these medications are also withheld.”

See also this meta-analysis done in 2002:

http://www.ncbi.nlm.nih.gov/pubmed/?term=Cardioselective+beta-blockers+in+patients+with+reactive+airway+disease%3A+a+meta-analysis.

With a focus on the conclusion:

“Given their demonstrated benefit in such conditions as heart failure, cardiac arrhythmias, and hypertension, cardioselective beta-blockers should not be withheld from patients with mild to moderate reactive airway disease.”

See also this paper published recently (Nov, 2015) in bmj with the title (Cardioselective β blockers are safe to use in asthma):

http://www.bmj.com/content/351/bmj.h6328.long

Therefore, the sentence needs to be adjusted to something like:

(Cardioselective beta-blockers can be used in patients with asthma or COPD for the treatment of concomitant diseases requiring their use.)


Correction 25: Page 115:

image065

In Figure 8.11 of Lippincott, the underlined phrase gives the wrong impression that dopamine agonists themselves delay motor complications while in deed they themselves cause these complications, but later than levodopa. The sentence should be:

(Initiation of therapy with dopamine agonists delays motor complications).

Also, if you refer to the studies from which these figures were reproduced, you will find that levodopa was finally added to the dopamine agonist after the 4 or 5-year monotherapy with the agonist. This is another reason why the sentence should be: (dopamine agonists delays motor complications).


Correction 26: Page 123:

image067

REM is the abbreviation of rapid eye movement. Non-rapid eye movement sleep is abbreviated as NREM sleep.

In fact, benzodiazepines, which are the subject of this sentence, do not increase REM, but NREM sleep.

“Benzodiazepines enhance sleep duration and reduce arousals. [35]Exposure increases stage 2 sleep while decreasing REM and stages 3 and 4 sleep.” (http://www.medscape.com/viewarticle/410827_6 accessed on Jan, the 24th, 2017).


Correction 27: Page 220:

image069

Addiction does not “lead to” dependence or tolerance. Psychological dependence is simply termed addiction.

“The older term “physical (physiologic) dependence” is now generally denoted as ependence, whereas “psychological dependence” is more simply called addiction.” (Katzung and Trevor’s Pharmacology Examination and Board Review, 10th edition p.279).


Correction 28: Page 420:

image071

Peak onset is not a correct term. We should either say: ‘peak effect’ or ‘onset of action’. What was meant here is: peak effect. In fact, the onset of action of α1-adrenergic antagonists occurs within hours, but it is the peak effect that need weeks. See:

http://www.medscape.com/viewarticle/458899_6

with focus on: ” Onset of action for these agents occurs within hours, but peak effect is reached in two to four weeks. ”


 

Minor Corrections

Minor correction 1: Page 5:

image073

In figure 1.10 of Lippincott, drug concentration after IV injection is not started from zero although in figure 1.3 page 3 it is. This is confusing for students. The same pattern should betted be used for both.

This is in addition to the two corrections added on the figure:

  1. Adding (%) to the equation
  2. Rewarding ‘Drug IV given’

Minor correction 2: Page 8: under the title (4. Contact time at the absorption surface):

image075

‘delays’ is not appropriate with ‘rate’. It should be either: Decreases the rate of absorption  Or:  Delays the absorption.


Minor correction 3: Page 9:

image077

Paradoxical is an adjective that describes a paradox, something with two meanings that don’t make sense together. It is used with unexpected phenomena. A well-known example has been positive effects of beta-blockers in heart failure before understanding its mechanisms ”partially’.

Since reasoning is given for poor absorption of very lipophilic drugs, ‘Paradoxically’ should better be omitted.


Minor correction 4: Page 13:

image079

Km has not been defined anywhere in the chapter with more than being ‘the Michaelis constant’, which does not explain to the student the concept behind it. It needs to be defined as follows:

Km is the substrate concentration at half maximal velocity.


Minor correction 5: Page 16:

image081

This sentence can be misunderstood that reabsorption is one means of drug elimination, while it is just the opposite. I suggest the following alternative: A drug passes through several processes in the kidney before elimination: glomerular filtration, active tubular secretion, and passive tubular reabsorption.


Minor correction 6: Page 18:

Under the title (B. Clinical situations resulting in changes in the drug half-life):

image083

Should be: (less frequent dosing.) or: (longer dosing intervals).

 

THE END

 

Categories: Pharmacology

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