Академический Документы
Профессиональный Документы
Культура Документы
for
Medical Students
A USMLE Step 1 & 2 Review
(Practice Q&A included)
phase III: large sample sizes, often double-blinded RCT; comparative (new
drug vs. placebo or standard of care) to establish safety and efficacy
need to consider dosing route if drugs are meant to cross these barriers
# of Half-Lives 1 2 3 4 5
% of Steady State Conc. 50 75 75 90 96.9
special situations
use a loading dose for drugs w a long half-life and when there is
clinical need to rapidly achieve therapeutic levels (e.g. amiodarone,
digoxin, phenytoin)
use continuous infusion for drugs w very short half-life and when
there is need for a long-term effect and multiple or frequently
repeated doses are too inconvenient (e.g. nitroprusside, insulin,
unfractionated heparin)
Marc Imhotep Cray, M.D. 44
Steady state of a drug displaying first-order kinetics
Steady state of a drug w t1/2 of 3 h
It takes about 15 h (5 x t1/2) to reach steady state .
non-competitive antagonism
o antagonist binds to an alternate site near agonist binding site,
producing allosteric effects that change ability of agonist to bind (e.g.
organophosphates irreversibly bind acetylcholinesterase)
Marc Imhotep Cray, M.D. 59
Mechanism of agonists and antagonists
Agonist Binding
Antagonist Binding
3) Non-competitive irreversible binding
Safety
LD (lethal dose): dose of a drug needed to cause death in
50
TI (TD50/ED50) is a measure of margin of Drug A has a much narrower TI than Drug B. Dose of
safety of a given drug Drug A required to achieve a 100% therapeutic
response will be toxic in 50% of patients
For Drug B, this is only 10%
66
Therapeutic Drug Monitoring
definition: using serum drug concentration data to optimize
drug , e.g.→ dose adjustment, monitor compliance
serum drug samples are usually taken when drug has reached steady
state (after approx. 5 half-lives)
TDM is often used for drugs that have:
narrow TIs
unpredictable dose-response relationships
significant consequences assoc. w therapeutic failure or toxicity, and
wide inter-patient PK variability
NE action is terminated by
reuptake at presynaptic membrane
diffusion from synaptic cleft, and
degradation at monoamine oxidase (MAO) and catechol-O-methyl
transferase (COMT)
Marc Imhotep Cray, M.D. 81
Parasympathetic Nervous System
blood vessels, adrenals, sweat glands, spleen capsule, and
adrenal medulla do NOT have parasympathetic innervation
Le T., Bhushan V. First Aid for the USMLE Step 1 2017. New York, NY: M-H. 2017.
Marc Imhotep Cray, M.D. 84
Direct Effects of Autonomic Innervation on
Cardiorespiratory System
Organ Sympathetic NS Parasympathetic NS
Receptor Action Receptor Action
Heart
1. Sinoatrial β1 ↑ HR M ↓conduction
2.Atrioventricular node β1 ↑ conduction M ↓ conduction
3. Atria β1 ↑ contractility M ↓ conduction
4. Ventricles β1 ↑ contractility M ↓ HR
Blood Vessels
1. Skin, splanchnic α1, β2 Constriction M Dilatation
2. Skeletal muscle α Constriction M Dilatation
3. Coronary β2 (lg m) Dilatation M Dilatation
α1, β2 Constriction M Dilatation
β2 Dilatation M Dilatation
Lungs
1. Bronchiolar sm. Mm. β2 Relaxation M Constriction
2. Bronchiolar glands α1, β2 ↑secretion M Stimulation
Practice Questions (with answers and explanations sheet) for this presentation.
For more scientific background on the topics presented in this review see:
Cray M (2015). General Principles of Pharmacology (UNIT 1, pgs. 10-29). In:
Integrated Scientific and Clinical Pharmacology: A Course Syllabus and Digital
Guidebook for Medical Students (MS1 & MS2)
Reference texts in e-Book sub-folder of Dr. Cray’s Pharmacology & Therapeutics cloud
• Goodman and Gilman’s The Pharmacological Basis of Therapeutics. Brunton LL,
Chabner BA , Knollmann BC (Eds.) ; McGraw-Hill 12th ed. 2011.
• Basic and Clinical Pharmacology, Katzung, Masters, Trevor; McGraw-Hill 12th ed. 2012
• Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition,
Sanders 2014.
Marc Imhotep Cray, M.D. 87
General References
1. Hennessy S, Flockhart DA. The need for translational research on drug-drug
interactions. Clin Pharm Ther. 2012;91:771-773.
2. Lesko LJ, Zheng S, Schmidt S. Systems approaches in risk assessment. Clin Pharm Ther.
2013;93: 413-424.
3. Kaddurah-Daouk R, Weinshilboum RM. Pharmacometabolomics: implications for
clinical pharmacology and systems pharmacology. Clin Pharmacol Ther. 2014;95:154-167.
4. White RW, Harpaz R, Shah NH, et al. Toward enhanced pharmacovigilance using
patient-generated data on the internet. Clin Pharmacol Ther. 2014;96:239-246.
5. Johnson JA, Cavallari LH. Pharmacogenetics and cardiovascular disease: implications for
personalized medicine. Pharmacol Rev. 2013;65:987-1009.
6. Wang L, McLeod HL, Weinshilboum RM. Genomics and drug response. N Engl J Med.
2011; 364:1144-1153.
7. Wheeler HE, Maitland ML, Dolan ME, et al. Cancer pharmacogenomics: strategies and
challenges. Nat Rev Genet. 2013;14:23-34.