Clinical Pharmacology
Pharmacokinetics and
Pharmacodynamics Synopsis
Companion: Pharmacokinetics and Marc Imhotep Cray, M.D.
Pharmacokinetics Synopsis Notes BMS / CK-CS Teacher
http://www.imhotepvirtualmedsch.com/
Fundamental Principles of Pharmacology
PHARMACOKINETICS (PK)
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Drug Biodisposition
Permeation:
Drug permeation is dependent on:
Solubility
Concentration gradient
Surface area and vascularity
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Fundamental Principles of Pharmacology
Clinical Correlate:
Gut bacteria metabolize lactulose to
lactic acid, acidifying the fecal masses
and causing ammonia to become
ammonium. Useful in Tx of hepatic
encephalopathy.
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Fundamental Principles of Pharmacology
Bioavailability (f)
lntravascular dose
Plasma Drug Concentration
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Fundamental Principles of Pharmacology
First-Pass Effect
Bioavailability (f) and First-Pass Metabolism
DISTRIBUTION
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Fundamental Principles of Pharmacology
Redistribution
Biotransformation of Drugs
Biotransformation Classification
There are two broad types of biotransformation,
called phase I and phase II.
Phase I (Non-Synthetic Metabolism)
• Definition: modification of the drug molecule via oxidation,
reduction, or hydrolysis.
a) Microsomal Phase I Metabolism
Cytochrome P450 isozymes
Localized in the smooth endoplasmic reticulum(SER)
microsomal fraction of cells (especially liver, but also GI tract,
lungs, and kidney)
- P450s have an absolute requirement for molecular oxygen
and NADPH
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Fundamental Principles of Pharmacology
Monoamine oxidases
Metabolism of endogenous amine neurotransmitters
(dopamine, norepinephrine, and serotonin)
Alcohol metabolism
Alcohols are metabolized to aldehydes and then to
acids by dehydrogenases
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Fundamental Principles of Pharmacology
Phase II Biotransformation
Synthetic Metabolism
• Definition: Conjugation with endogenous compounds
via the activity of transferases
• May follow phase I or occur directly
• Types of conjugation (3):
Glucuronidation
- Inducible
- May undergo enterohepatic cycling (Drug:
Glucuronide intestinal bacterial glucuronidases free
drug)
Reduced activity in neonates
Examples: morphine and chloramphenicol
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Elimination
Concerns processes involved in elimination of drugs from
body (and/ or plasma) and their kinetic characteristics.
The major modes of drug elimination are:
• Biotransformation to inactive metabolites
• Excretion via the kidney
• Excretion via other modes, including bile duct, lungs,
and sweat
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Fundamental Principles of Pharmacology
Graphic Analysis:
Example of a graphic analysis of t1/2
Renal Elimination
• Rate of elimination=
glomerular filtration rate (GFR) + active secretion -
reabsorption (active or passive)
• Filtration is a nonsaturable linear function. Ionized and
nonionized forms of drugs are filtered, but protein-bound
drug molecules are not
• Clearance (Cl):
- Definition: volume of blood cleared of drug per unit of time
- Cl is constant in first-order kinetics
- Cl = GFR when there is no reabsorption or secretion and no
plasma protein binding
- Protein-bound drug is not cleared; Cl = free fraction x GFR
NB/Bridge to Renal Physiology: lnulin clearance is used to estimate GFR
because it is not reabsorbed or secreted. A normal GFR is close to 120 ml/min. 24
Fundamental Principles of Pharmacology
Rate of Infusion
All have the same time to plateau
Increases in plasma levels of same
drug infused at five different rates
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Fundamental Principles of Pharmacology
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Fundamental Principles of Pharmacology
PK Equations
Single-Dose Equations Abbreviations:
(1) Volume of distribution (Vd)
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Fundamental Principles of Pharmacology
PHARMACODYNAMICS (PD)
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Fundamental Principles of Pharmacology
PD Definitions
Pharmacodynamics relates to drugs binding to receptors and
their effects
• Agonist:
A drug is called an agonist when binding to the receptor
results in a response.
• Antagonist:
A drug is called an antagonist when binding to the receptor is
not associated with a response
The drug has an effect only by preventing an agonist from
binding to the receptor.
• Affinity:
ability of drug to bind to receptor, shown by proximity of
curve to the y axis (if curves are parallel); nearer the y axis,
the greater the affinity
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Fundamental Principles of Pharmacology
PD Definitions
• Potency: shows relative doses of two or more agonists to
produce same magnitude of effect. Shown by proximity of
respective curves to the y axis (if the curves do not cross)
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Fundamental Principles of Pharmacology
Bridge to Biochemistry
Definitions:
Affinity: how well a drug and a receptor
recognize each other Affinity is inversely related
to the Kd of the drug
Notice the analogy to the Km value used in
enzyme kinetic studies
Comparison of D-R Curves for Two Drugs Acting on the Same (left panel) and on
Different (right panel) Receptors
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Fundamental Principles of Pharmacology
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Fundamental Principles of Pharmacology
Noncompetitive antagonists:
° Cause a nonparallel shift to right
° Can be only partially reversed by dose of the agonist
0 Appear to efficacy of the agonist
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Fundamental Principles of Pharmacology
SIGNALING MECHANISMS:
Types of Drug Responsive Signaling Mechanisms
• Binding of an agonist drug to its receptor activates an effector or
signaling mechanism
• Several different types of drug-responsive signaling mechanisms
are known:
1. Intracellular Receptors
2. Membrane Receptors Directly Coupled to Ion Channels
3. Receptors Linked Via Coupling Proteins to Intracellular Effectors
Gs proteins, Gi proteins, Gq proteins
4. Cyclic GMP and Nitric Oxide Signaling
5. Receptors That Function as Enzymes or Transporters
6. Receptors That Function as Transmembrane Enzymes
7. Receptors for Cytokines
See GPCRs-Signal Transduction Toolkit (& Other Receptor Mechanisms)
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Fundamental Principles of Pharmacology
1. Intracellular Receptors
Receptors for steroids Binding of hormones or drugs to such
receptors releases regulatory proteins that permit activation (and in
some cases dimerization) of hormone-receptor complex
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Fundamental Principles of Pharmacology
GPCR (2)
Gs proteins
• Binding of agonists to receptors linked to G5 proteins increases
cAMP production
• Such receptors include those for catecholamines (beta),
dopamine (D1 ), glucagon, histamine (H2), prostacyclin, and
some serotonin subtypes
Gi proteins
• Binding of agonists to receptors linked to Gi proteins decreases
cAMP production
• Such receptors include adrenoreceptors (alpha2), ACh (M2),
dopamine (D2 subtypes), and several opioid and serotonin
subtypes
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Fundamental Principles of Pharmacology
GPCR(3)
Gq proteins
• Other receptor systems are coupled via GTP-binding proteins
(Gq), which activate phospholipase C releases second
messengers inositol triphosphate (IP3) and diacylglycerol (DAG)
from the membrane phospholipid phosphatidylinositol
bisphosphate (PIP2)
The IP3 induces release of Ca2+ from the sarcoplasmic reticulum
(SR), which, together with DAG, activates protein kinase C
Protein kinase C serves then to phosphorylate a set of tissue-
specific substrate enzymes, usually not phosphorylated by
protein kinase A, and thereby affects their activity
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Fundamental Principles of Pharmacology
From: Tao etal. First Aid for the USMLE Step 1 2015, pg. 248
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Additional reading:
Drug Discovery and Clinical Trials-Wiki articles
Drug Discovery and Development: Understanding the R&D Process
(A innovation.org PDF)
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Fundamental Principles of Pharmacology
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Further study:
Digital Guidebook: Unit 1 string (Pgs. 10-29)
PK video mini-lectures, tutorials and textbook
GPCRs-Signal Transduction Toolkit (& Other Receptor Mechanisms)
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THE END
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Sources:
Davis. Kaplan USMLE Step 1 Pharmacology Lecture Notes, 2013
Gleason. Déjà Review: Pharmacology, 2010
Rosenfeld. BRS Pharmacology, 2013
Tao. First Aid for the USMLE Step 1 2015
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