Download A Clinically-oriented Approach To Teaching Medical

A Clinically‐oriented Approach To Teaching Medical Pharmacology
Dale Quest, Associate Professor of Pharmacology
Department of Medical Education, Paul L. Foster School
of Medicine
Texas Tech University Health Sciences Center
El Paso, TX 79905.
ASPET Pharmacology Division Symposium medical education is changing
• In the past, pharmacology courses were often taught in the second undergraduate year of a medical school curriculum. • Those courses focused on content; mostly on the major uses, mechanism of action, side effects, contraindications and pharmacokinetics of structural or therapeutic categories of drugs. Are basic pharmacology courses relevant to physician education? • Pharmacology provides a foundation for therapeutics, but little attention and almost no integrative strategies go beyond an assumption that pharmacology, as taught in the pre‐clinical phase, translates as a useful basis for therapeutics in subsequent phases of clinical training and practice.
• Many other factors influence therapeutic choices: evidence from clinical trials, a persuasive pharmaceutical industry, continuing professional learning (CME), clinical practice guidelines (some more evidence‐based or biased than others), dogmatic practice patterns, and role models who are not necessarily good examples.
• To what extent do prescribers bring the concepts and principles of pharmacology they learned in the first two years of med school to bear on therapeutic decision‐making? Today, • integrated digital clinical decision‐making support suites are advancing to the point that an iPhone delivers more useful pharmacology than professors have traditionally taught from textbooks. • Students have immediate access to detailed, regularly updated peer‐reviewed evidence that ties complete pharmacological profiles including approved and unapproved uses, standard and trade names, mechanisms of action, pharmacodynamics, pharmacokinetics, individualized analysis of drug interactions, incompatibilities, nature and frequencies of adverse effects, dose adjustment, toxicology, together with clinical practice guidelines and key dental, medical, surgical, pediatric references... fear and failure to evolve our teaching beyond Year 2:
• Some basic science educators are intimidated by the idea of anticipating the clinical importance of pharmacology as a basis for therapeutics, and cannot see themselves remaining involved beyond Year 2 to guide reflection and build on the basic science underpinnings relating diseases and pharmacologic interventions
• basic pharmacologists’ role in medical education will fade if the pre‐
clinical foundation in basic pharmacology as it is currently packaged has little influence on the quality of physician practice
• pharmacology professors, rather than ‘signing off’ at the end of Year 2 might transcend redundancy in medical education if we can more effectively link basic and clinical sciences from day 1 of Year 1 through to the end of Year 4.
• the undergraduate medical school curriculum is one of the first challenges and a key driver for success in enabling healthcare decision‐
making through clinical support and knowledge management. • Students will henceforth need to develop basic competency with digital clinical decision‐making support suites before they move into the clerkships. Pharmacology courses can play a key role in enabling the generation of practitioners going forward, to bring the weight of medical science to bear on decision making at the patient‐practitioner interface with electronic support. • Pharmacology and pathology are bridging disciplines linking the basic sciences to clinical practice (diagnostic reasoning and clinical decision‐
making). • On the premise that all physicians prescribe drug therapy for the diagnosis, prevention and treatment of disease, and that pharmacology should be taught in the context that it will be used, it is rational to teach pharmacology and pathophysiology in tandem. • A teaching/learning process initiated at the University of Saskatchewan is being adapted to help medical students experience the clinical relevance of pharmacology across the integrated four‐year curriculum of the new Paul L. Foster School of Medicine.
The process as illustrated in the next slide begins when:
• medical students identify the pathophysiological mechanisms of medical conditions for which the mechanisms of disease are well enough understood to provide rational drug targets. – It is particularly relevant for students to begin to incorporate
the use of an evidence‐based electronic clinical decision‐
making support suite such as Lexi‐Comp™, Micromedex™, Clinical Pharmacology™, or Epocrates Premium™
(see Clauson KA, Polen HH, Marsh WA. Clinical decision support tools: performance on personal assistant versus online drug information
databases. Pharmacotherapy 2007;27(12):1651‐8.). – Suites that include resources such as Harrison’s Practice, ABX, Current Dx & Tx, that explain the mechanisms of the disease condition are particularly useful. Online or hardcopy textbooks may be used, but patient‐practitioner interface Figure 1 the process:
• the next challenge for students is to propose mechanisms of drug action to counter the mechanisms of disease activity. – An Excel spreadsheet is used to develop a ‘Student Formulary’ of prototype drugs that includes a column of drug activities – students use the ‘sort’ and ‘find’ functions of the Excel application. • In a separate column associated with a desired drug mechanism of action there will be the name of a prototype, • and in another column are examples of other potentially useful therapeutic choices that share the same mechanism of action.
• with the prototype drug as default, students are then asked to compare the prototype against other therapeutic choices using S.T.E.P.S.(Safety—Toleration—Efficacy—Price—
Simplicity) analysis • S.T.E.P.S. is an approach similar to the ‘compare drugs’ function in the Micromedex™ database; and finally, students use an electronic clinical decision‐making support suite to rationalize their drug choices in light of potential for drug‐
drug interactions and co‐morbidities before writing a ‘preliminary prescription’. Duplicate prescription pads facilitate using the preliminary prescription as a challenge for individual students, – who can then be tasked to defend and revise their drug choices within small groups; • the members of small groups can subsequently present and debate drug choices made by other small groups in a Team‐Based Learning fashion.
The following slides illustrate the process with ‘drugs for pheochromocytoma’ as an example
HYPERTENSION
Unit 6, beginning of Year 2 of the PLFSOM integrated scheme‐inductive curriculum, if a patient presents with hypertension, students learn “what to ask”, “what to look for” and “what investigations” are appropriate to reason through this scheme and arrive at “pheochromocytoma” as a diagnosis
HYPERTENSION
TRUE
PRIMARY
MISLABELLED
Secondary
Volume
dependent
Renal
)
Parenchymal
Adrenal
Cortical
Hormones &
Chemicals
Angiotensin II
↑ SVR
↑ CO + ↑ SVR
Obesity
Pheochromocytoma
Other ↑ SVR
Pharmacology usually follows the other SPM sessions, so students will already understand what is meant by increased systemic vascular resistance (↑SVR) from the Physiology SPM session, and will know quite a bit about the pathophysiology of pheochromocytoma from the Pathology SPM session.
REYNOLDS, Cecille A.
DOB: 14APR73 123 Somewhere, CA 90210
ID: 37 y.o. woman is a homemaker, mother of two high school students and wife of a federal police officer. HPI: 18 month history of sudden, seemingly unprovoked episodes of anxiety accompanied by “pounding”
headaches, palpitations, sweating, tremor, chest tightening, blurred vision and usually nausea. Symptoms generally subside rapidly, although headaches persist for hours. Treatment for panic disorder was initiated following referral to psychiatry, but she has since been diagnosed with pheochromocytoma. First, define the mechanisms of disease, then propose mechanisms by which drugs might counteract the disease.
Mechanisms of Disease
Pheochromocytoma is a rare catecholamine‐secreting tumor. Because of excessive autonomous secretion of catecholamines, a pheochromocytoma can precipitate life‐threatening hypertension and cardiac arrhythmias.
students should thus review the synthesis and receptor‐mediated effects of catecholamines: CT contrast scan: arrow shows a 5 cm right adrenal mass. fractionated plasma free metanephrines and 24‐hr urine markers of catecholamine excess were markedly elevated.
Objectives:
challenge students to learn and apply pharmacological concepts and principles in the context of managing a medical condition:
The general topic: hypertension, secondary
The condition: pathological increase in systemic vascular resistance in the case of pheochromosytoma Mechanism of disease: autonomous surges of catecholamines (dopamine, norepinephrine and epinephrine)
Pharmacological concepts: manipulation of sympathetics
• synthesis of catecholamines: substrates and enzymes
• receptors: alpha‐1, alpha‐2, beta‐1, beta‐2
• agonists
• antagonists:
• competitive
• non‐competitive
Pharmacological principles:
• a competitive antagonist will reduce the apparent potency of an agonist
• a non‐competitive antagonist will reduce the efficacy of an agonist
tyrosine hydroxylase (TH) is the rate‐limiting step in the biosynthetic pathway for catecholamines. Ref: Dluhy RG, Williams JE. Endocrine hypertension. In Larsen PR, Kronenberg HM, Melmed S, Polonsky KS [Eds]. Williams Textbook of Endocrinology, 10th Ed. Philadelphia: WB Saunders, 2003:555. key:
AADC: aromatic L‐amino acid decarboxylase; DBH: dopamine β‐hydroxylase; PNMT: phenylethanolamine N‐methyltransferase (expressed only in chromaffin tissues)
epinephrine
Ç
(phenylethanolamine N‐methyltransferase)
only within chromaffin cells
Ç
ξ α1 receptors
•vasoconstriction
•sweating, piloerection
•glycogenolysis ξ α2 receptors
•vasoconstriction
•Èinsulin secretion
ξ β1 receptors
•Ç force and rate of cardiac contraction
•Çrenin secretion
(tyrosine hydroxylase
tyrosine
presynaptic and chromaffin cells
ξ β2 receptors
•vasodilation
•bronchial smooth muscle relaxation
•glycogenolysis
presynaptic receptor effects
“Concepts?”
“Principles?”
• Concepts are the abstract ideas we attach to words. – provides a common understanding of what is encompassed within the definition (e.g., drugs contain a known quantity of pure active substance) – provides a set of criteria to distinguish the concept from other ideas (e.g., distinguish drugs from nutrients , natural products and nutriceuticals)
• Principles state relationships between concepts; enable us to explain and predict.
combining concepts into pharmacological principles
Combine 4 basic pharmacology concepts:
– agonists: An agonist is a drug which activates a receptor and thereby elicits a response : i.e., has affinity + intrinsic activity
– antagonists: An antagonist is a drug which competes for the same receptors, but does not activate the receptor (i.e., has affinity but no intrinsic activity)
– potency: concentration of agonist that elicits half‐maximal response
– efficacy: the maximum response that can be elicited by an agonist
into a useful pharmacological principle: • The presence of an antagonist will reduce the apparent potency of an agonist
– increasing the concentration of agonist will overcome the effects of a competitive antagonist – but a non‐competitive antagonist will not be surmounted by increasing the concentration of agonist This dose-response curve shows how competitive antagonists cause
a parallel rightward shift in the apparent potency of an agonist
without changing the maximum effect that can be achieved with a
higher dose of the agonist:
A noncompetitive antagonist can’t be pushed off the receptor, so the
maximum effect is weaker no matter how much agonist is added.
the process with ‘drugs to manage pheochromocytoma’ as the example disease condition:
the student ‘prototype Formulary’ is sorted by drug mechanism…
There are several handheld clinical decision‐making support suites to choose from, e.g., Thomson ClinicalXpert suite running on the Pocket PC platform, and Lexi‐Comp running on the Palm and iPhone platforms Tap on <Disease> begin to type “phe…”,
and ‘pheochromocytoma –
acute’ appears.
Tap on that entry and a pulldown menu lets you jump to what background on the Dx you wish to access: Hx, PE, investigations, DDx, and Tx.
Let’s see what treatments are used to treat acute pheochromocytoma.
Was phenoxybenzamine
one of the prototype drugs that you chose from the Formulary on the basis of its mechanism of action?
Is this why you chose phenoxybenzamine to treat Mrs. Reynolds?
Propranolol is another prototype you might have selected because its mechanism of action will address the effects of excessive catecholamine release at a different type of receptor.
In a Formulary column to the right of propranolol, you might have noticed that several other beta adrenergic receptor antagonists are available. S.T.E.P.S. analysis would be a useful way to compare therapeutic differences side‐by‐side to see if they have a potential therapeutic advantage over the default prototype drug.
How does esmolol differ from propranolol?
Might the difference confer an advantage or disadvantage in Mrs. Reynold’s situation? S.T.E.P.S.:
metyrosine
phenoxybenzamine
Safety
blocks catecholamine synthesis (dopamine), thus extrapyramidal effects (EPSEs) are common, may potentiate adverse effects of dopamine antagonists and Parkinson’s Disease S&S
long lasting (offset ~3 days) noncompetitive alpha adrenergic antagonism; can produce profound postural hypotension with reflex tachycardia
short‐acting (off‐set 2‐4 hrs) competitive alpha adrenergic antagonism; can produce profound postural hypotension with reflex tachycardia
potential to induce refractory asthma attack, heart block, bradycardia. hypotension; withdrawal tachycardia and hypertension
Toleration
CNS depression (↓ mental alertness); >10%) ; EPSEs diarrhea ≤ 10% , N&V
nasal congestion, xerostomia
miosis, nasal congestion
miosis, nasal congestion
CNS depression (↓
mental alertness); Efficacy
endogenous catecholamine synthesis reduced by 35%‐
80% at maintenance doses of 1‐4g/day.
titrated to achieve insurmountable alpha adrenergic antagonism
STAT dose in hypertensive emergency; titrated to achieve insurmountable alpha antagonism
titrated to inhibiit tachycardia, palpitations, sweating, tremor duing catecholamine surges
Price
250 mg – 1g q6h x 7‐14 days 100 x 250 mg capsules costs $1,935.00 [Aton Pharma] Cost of therapy ranges $542 to $4,335 depending on dose and duration
20 mg BID – 40 mg TID x 7‐
14 days; 30 x 10 mg capsules costs $214.00 . Cost of therapy ranges $100 to $1,198 depending on dose and duration
1‐5 mg TID x 7‐14 days 60 x 1, 2 or 5 mg caps costs $18, $23, or $34.00 Cost of therapy ranges $7 to $24 depending on dose and duration
30‐60 mg daily
7‐14 days ; 30 x 60 mg tabs costs ~ $131; Cost of therapy ranges $15 to $60 depending on dose and duration
Orally bioavailable and kinetics suitable for titration with or without food. oral or intravenous administration. oral dosing
oral or intravenous administration. www.
drugstore.com
Simplicity
prazocin
propranolol
• students can be asked to write an individual prescription
• take their individual prescription to their small groups to explain/defend/revise
• the small groups pool their collective reasoning to reach consensus on the most rational approach
• separate small groups compare and discuss their treatment choices • the professor can explain the evidence and rationale for current best practice How does this approach differ from how you already teach medical pharmacology?
• What are the relative pros and cons of this method?
How could you implement this, or a variation of this at your institution?