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PH01-
Pharmacodynamics and pharmacokinetics
!"
Pharmacodynamics and
Pharmacokinetics
Matthew B. Wilkinson, PhD, M4
#$%&'"()&*)"(+,$$-"$."#/0)+)&/"
PH01-
Enzyme kinetics 1
2
Enzyme kinetics
Vmax = maximum reaction velocity for a given amount of enzyme
• Proportional to enzyme concentration
Michaelis-Menten plot
Substrate concentration [S] (mM)
Kaplan Biochemistry 2011: Figures I-8-4
FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228
ME 3e: 55
PH01-
Enzyme kinetics 2
3
Enzyme kinetics
Michaelis constant (Km): Substrate concentration required to reach half Vmax =
• High Km ! low affinity
• Low Km ! high affinity
Michaelis-Menten plot
Substrate concentration [S] (mM)
1
affinity
Kaplan Biochemistry 2011: Figures I-8-4
FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228
ME 3e: 55
PH01-
Enzyme kinetics 3
4
Enzyme kinetics
Michaelis constant (Km): Substrate concentration required to reach half Vmax =
Vmax = maximum reaction velocity for a given amount of enzyme
Kaplan Biochemistry 2011: Figure: I-8-5
1
affinity
• High Km ! low affinity
• Low Km ! high affinity
• Proportional to enzyme concentration
Lineweaver-Burk plot
FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228
ME 3e: 55
PH01-
• Resemble substrate, bind at active site
• Increasing substrate concentration can overcome inhibition
• Decrease potency
Enzyme inhibitors 1
Competitive inhibitors
Non-competitive inhibitors
• Typically bind at allosteric site, not near active site
• Cannot be overcome with increased substrate concentration
• Decrease efficacy
Enzyme Enzyme
Active site
Substrate
Competitive inhibitor Non-competitive inhibitor
5
Enzyme inhibitors
Allosteric site
FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228
ME 3e: 55
PH01-
Enzyme inhibitors 2
Competitive Non-competitive
Resemble substrate Yes No
Overcome with "substrate
concentration
Yes No
Bind active site Yes No
Vmax No effect #
Km " No effect
Pharmacodynamics #Potency #Efficacy
Graphs cross? Yes No
Competitive vs. Non-competitive inhibitors
1 / (velocity)
1 / (substrate concentration)
Lineweaver-Burk plot
Non-competitive
Competitive
No inhibitor
6
Enzyme inhibitors
FA 2012: 258.1 • FA 2011: 232.1 • FA 2010: 228
ME 3e: 55
PH01-
Volume of distribution
Volume of distribution, Vd = total amount of drug in body
[drug]plasma
Low Vd (4-8 L)
Mid Vd (12-14 L)
High Vd (>total body water)
Vd of plasma protein bound drugs are altered in liver and kidney disease
• Hepatic disease: ! synthesis of plasma proteins
• Renal diseases: Plasma proteins (and bound drugs) are excreted in the urine
mostly in blood
mostly extracellular fluid
distributed in all tissues, non-fluid compartments (fat)
(liters)
7
Volume of distribution
FA 2012: 259.1 • FA 2011: 232.2 • FA 2010: 228
ME 3e: 166
PH01-
Drug clearance
Clearance (CI) =
Rate of drug elimination
Plasma drug concentration
= Vd x ke
• Clearance refers to the volume of blood totally cleared of drug per unit time
• Units:
• Rate of drug elimination: (mass)/(units of time)
• Plasma drug concentration: (mass)/(volume of plasma)
• Elimination rate constant (ke): t-1
• Renal clearance:
• Clearance:
• Equals glomerular filtration rate (GFR) when there is no reabsorption,
secretion, or plasma protein binding
• Inulin and creatinine clearance are used to estimate GFR
• Protein-bound drugs are not cleared
• Clearance = (free fraction) x GFR
8
Drug clearance
FA 2012: 259.1 • FA 2011: 232.2 • FA 2010: 228
ME 3e: 166
PH01-
Drug half-life
• A1$%&'"$."21/")'"'*3/4".$5"*&"*1$%&'"$."05%6")&"',/"7$08"'$"+,*&6/"78"$&/",*-."
• Half-life relates to both a decrease in plasma concentration via
elimination or an increase in plasma concentration via drug infusion
• Steady state is reached in 4-5 half-lives with continuous infusion
t1/2 =
0.7 x Vd
Clearance
n t1/2
[drug]
1 t1/2 2 t1/2 3 t1/2 4 t1/2 5 t1/2
50 % 75 % 87.5 % 93.75 % 96.9 %
9
Drug half-life
FA 2012: 259.1 • FA 2011: 232.2 • FA 2010: 228
ME 3e: 166
"
PH01-
Loading and maintenance doses
Loading dose
Bioavailability (F)
• Fraction of administered drug that reaches systemic circulation
• Some drugs fail to be absorbed, or are metabolized before reaching circulation
Maintenance dose
• Large initial dose given to fill up Vd
• Can increase plasma concentration in less than 4-5 half-lives
LD =
Vd x Cp
F
MD =
Cl x Cp
F
• Given to maintain constant blood plasma levels
• Lowered if hepatic/renal function is impaired
F = 1 for IV infusion
Cp blood plasma conc.
Cl clearance
F bioavailability
10
Loading and maintenance doses
FA 2012: 259.2 • FA 2011: 233.1 • FA 2010: 229
ME 3e: 167
PH01-
Drug elimination
Zero order elimination
First order elimination
• Constant amount of drug eliminated with time
• Phenytoin, aspirin, ethanol
• Constant fraction of drug eliminated with time
• Most drugs follow first-order kinetics
100 mg ! 90 mg ! 80 mg ! 70 mg ! !
100 mg ! 50 mg ! 25 mg ! 12.5 mg ! !
11
Drug elimination
FA 2012: 260.1 • FA 2011: 233.2 • FA 2010: 229
ME 3e: 166
PH01-
Renal excretion
• Both ionized (I) and nonionized (N) forms
are filtered
• Only non-ionized forms are actively
secreted or reabsorbed
• Ionized forms of drug are “trapped” in
filtrate
• Drugs that are weak acids:
• Barbiturates, methotrexate, aspirin,
• Drugs that are weak bases:
• Amphetamines
Kaplan Pharmacology 2011: Figure I-1-3
12
Renal excretion
PERMEATION
• Drug permeation is dependent on:
– Solubility. Ability to diffuse through lipid bilayers (lipid solubility) most drugs; however, water solubility can influence permeation phases.
– Concentration gradient. Diffusion down a concentration gradient—unionized drug forms contribute to the concentration gradient.
– Surface area and vascularity. Important with regard to absorption the systemic circulation. The larger the surface area and the the better is the absorption of the drug.
• Ionization
– Many drugs are weak acids or weak bases and can exist in either ionized forms in an equilibrium, depending on the pH of the the pKa (the pH at which the molecule is 50% ionized and – Only the nonionized (uncharged) form of a drug crosses biomembranes.
– The ionized form is better renally excreted because it is water Weak Acid R–COOH R–COO– + (crosses membranes) (better cleared)
Weak Base R–NH+
3 R–NH2 + H+
(better cleared) (crosses membranes)
80
Form
weak
base
In A Nutshell
For Weak Acids and Weak
Bases
Ionized = Water soluble
Nonionized = Lipid soluble
Clinical Correlate
Gut bacteria metabolize
lactulose to lactic acid,
Draft Not for Distribution
PERMEATION
• Drug permeation is dependent on:
– Solubility. Ability to diffuse through lipid bilayers (lipid solubility) is important for
most drugs; however, water solubility can influence permeation through aqueous
phases.
– Concentration gradient. Diffusion down a concentration gradient—only free,
unionized drug forms contribute to the concentration gradient.
– Surface area and vascularity. Important with regard to absorption of drugs into
the systemic circulation. The larger the surface area and the greater the vascularity,
the better is the absorption of the drug.
• Ionization
– Many drugs are weak acids or weak bases and can exist in either nonionized or
ionized forms in an equilibrium, depending on the pH of the environment and
the pKa (the pH at which the molecule is 50% ionized and 50% nonionized)
– Only the nonionized (uncharged) form of a drug crosses biomembranes.
– The ionized form is better renally excreted because it is water soluble.
Weak Acid R–COOH R–COO– + H+
(crosses membranes) (better cleared)
Weak Base R–NH+
3 R–NH2 + H+
(better cleared) (crosses membranes)
80
60
Nonionized Form
Renal Clearance weak
base
In A Nutshell
For Weak Acids and Weak
Bases
Ionized = Water soluble
Nonionized = Lipid soluble
Clinical Correlate
Gut bacteria metabolize
lactulose to lactic acid,
acidifying the fecal masses and
Draft Not for Distribution
PERMEATION
• Drug permeation is dependent on:
– Solubility. Ability to diffuse through lipid bilayers (lipid solubility) is important for
most drugs; however, water solubility can influence permeation through aqueous
phases.
– Concentration gradient. Diffusion down a concentration gradient—only free,
unionized drug forms contribute to the concentration gradient.
– Surface area and vascularity. Important with regard to absorption of drugs into
the systemic circulation. The larger the surface area and the greater the vascularity,
the better is the absorption of the drug.
• Ionization
– Many drugs are weak acids or weak bases and can exist in either nonionized or
ionized forms in an equilibrium, depending on the pH of the environment and
the pKa (the pH at which the molecule is 50% ionized and 50% nonionized)
– Only the nonionized (uncharged) form of a drug crosses biomembranes.
– The ionized form is better renally excreted because it is water soluble.
Weak Acid R–COOH R–COO– + H+
(crosses membranes) (better cleared)
Weak Base R–NH+
3 R–NH2 + H+
(better cleared) (crosses membranes)
80
Form
Renal weak
base
Nutshell
Weak Acids and Weak
Ionized = Water soluble
Nonionized = Lipid soluble
Clinical Correlate
bacteria metabolize
lactulose to lactic acid,
Draft Not for Distribution
PERMEATION
• Drug permeation is dependent on:
– Solubility. Ability to diffuse through lipid bilayers (lipid solubility) is important for
most drugs; however, water solubility can influence permeation through aqueous
phases.
– Concentration gradient. Diffusion down a concentration gradient—only free,
unionized drug forms contribute to the concentration gradient.
– Surface area and vascularity. Important with regard to absorption of drugs into
the systemic circulation. The larger the surface area and the greater the vascularity,
the better is the absorption of the drug.
• Ionization
– Many drugs are weak acids or weak bases and can exist in either nonionized or
ionized forms in an equilibrium, depending on the pH of the environment and
the pKa (the pH at which the molecule is 50% ionized and 50% nonionized)
– Only the nonionized (uncharged) form of a drug crosses biomembranes.
– The ionized form is better renally excreted because it is water soluble.
Weak Acid R–COOH R–COO– + H+
(crosses membranes) (better cleared)
Weak Base R–NH+
3 R–NH2 + H+
(better cleared) (crosses membranes)
80
Form
Renal Clearance weak
base
In A Nutshell
For Weak Acids and Weak
Bases
Ionized = Water soluble
Nonionized = Lipid soluble
Clinical Correlate
Gut bacteria metabolize
lactulose to lactic acid,
Draft Not 9
9
:" ;"
:" ;"
Weak Acid"
PERMEATION
• Drug permeation is dependent on:
– Solubility. Ability to diffuse through lipid bilayers (lipid solubility) is important for
most drugs; however, water solubility can influence permeation through aqueous
phases.
– Concentration gradient. Diffusion down a concentration gradient—only free,
unionized drug forms contribute to the concentration gradient.
– Surface area and vascularity. Important with regard to absorption of drugs into
the systemic circulation. The larger the surface area and the greater the vascularity,
the better is the absorption of the drug.
• Ionization
– Many drugs are weak acids or weak bases and can exist in either nonionized or
ionized forms in an equilibrium, depending on the pH of the environment and
the pKa (the pH at which the molecule is 50% ionized and 50% nonionized)
– Only the nonionized (uncharged) form of a drug crosses biomembranes.
– The ionized form is better renally excreted because it is water soluble.
Weak Acid R–COOH R–COO– + H+
(crosses membranes) (better cleared)
Weak Base R–R–NH2 + H+
(better crosses membranes)
80
Form
Renal weak
base
In A Nutshell
For Weak Acids and Weak
Bases
Ionized = Water soluble
Nonionized = Lipid soluble
Clinical Correlate
Gut bacteria metabolize
lactulose to lactic acid,
Draft Not for Distribution
FA 2012: 260.2 • FA 2011: 233.3 • FA 2010: 229
ME 3e: 166
PH01-
Biotransformation 1
• Occurs in the liver
• Conversion of lipid soluble drugs into water soluble metabolites " # renal excretion
• Two forms of drug metabolism: Phase 1 and 2
Phase I:
• Three mechanisms of metabolization: Oxydation, reduction, and hydrolysis
• Cytochrome P450 enzymes:
• Located in smooth endoplasmic reticulum of the liver (to lesser extent GI, lungs, kidneys
• Require O2 and NADP
• Mechanisms of cytochrome P450 enzyme metabolism:
• Reduction
• Oxidation
• Hydroxylation and dealkylation
13
Biotransformation
FA 2012 260 • FA 2011: 233.4 • FA 2010: 229.4
ME 3e: 167
PH01-
Cytochrome P-450 interactions
Inducers Inhibitors
Quinidine HIV protease inhibitors
Barbiturates Isoniazid (INH)
St. John’s wort Sulfonamides
Phenytoin Cimetidine
Rifampin Ketoconazole
Griseofulvin Grapefruit juice
Carbamazepine Omeprazole
Chronic alcohol use Chloramphenicol
Glucocorticoids Marcolides
Ritonavir
14
Cytochrome P-450 interactions
FA2012 273 • FA 2011: 245.2 • FA 2010: 241.2
ME 3e: 167
PH01-
Biotransformation 2
Phase I Metabolism
• Leads to polar, water-soluble metabolites
• Non-cytochrome P450 enzyme metabolism
• Mechanisms of metabolism:
• Hydrolysis: Addition of H20 to drugs to assist metabolism
• Esterase
• Amiidase
• Monoamine oxidase: Metabolizes amines
• Endogenous amines: Dopamine, norepinephrine, serotonin
• Exogenous amines: Tyramine
• Alcohol metabolism
15
Biotransformation
FA 2012 260 • FA 2011: 233.4 • FA 2010: 229.4
ME 3e: 167
PH01-
Biotransformation 3
Phase II Metabolism
• Conjugation of functional groups to a drug
• Converts polar molecules to inactive molecules " # renal excretion
• Mechanisms of metabolism:
• Acetylation
• Glucuronidation
• Sulfation
• Methylation
• Glutathione conjugation
16
Biotransformation
FA 2012 260 • FA 2011: 233.4 • FA 2010: 229.4
ME 3e: 167
PH01-
Potency vs. efficacy 1
Potency: measure of how much drug required to give desired effect
typically expressed as EC50 - concentration that gives 50% of max. response
Efficacy: maximal effect that a drug can produce
Kaplan Pharmacology 2011: Figure I-2-2
B = full agonist
A = partial agonist (low efficacy) with high potency
C = partial agonist with low potency
17
Potency vs. efficacy
FA 2012: 261.1 • FA 2011: 233.5 • FA 2010: 229
ME 3e: 168
PH01-
Potency vs. efficacy 2
log [drug]
% Response
log [drug]
% Response
Competitive Antagonists
Non-competitive Antagonists
Efficacy
Potency
Potency: #
Efficacy: no effect
Potency: no effect
Efficacy: #
Partial Agonist
Acts at same site as agonist, but lower efficacy
Can have higher or lower potency than agonist
Full agonist
<" =" Partial agonist
>"
18
Potency vs. efficacy
FA 2012: 261.2 • FA 2011: 234.1 • FA 2010: 230
ME 3e: 168
PH01-
Physiologic antagonists
Substrate that produces opposite effect of an agonist, but acts through different
receptor/pathway
Example:
Bronchoconstriction Bronchodilation
Muscarinic
Agonist
"-adrenergic
Agonist
19
Physiologic antagonists
FA 2012: n/a • FA 2011: 234.2 • FA 2010: n/a
ME 3e: n/a
PH01-
Therapeutic index
Measure of drug safety. Higher therapeutic index indicates safer drug.
TI =
median dose that produces toxic or lethal effect
median dose required to produce therapeutic effect
=
LD50
ED50
LD - lethal dose
ED - effective dose
Kaplan Pharmacology 2011: Figure I-2-5
20
Therapeutic index
FA 2012: 261.3 • FA 2011: 234.3 • FA 2010: 230
ME 3e: 168
PH02-
Sympathetic and parasympathetic nervous systems
1
Sympathetic and Parasympathetic
Nervous Systems
Matthew B. Wilkinson, PhD, M4
!"#$%&'($)(&'*+"",&"-&!./(*($.&
PH02-
Autonomic nervous system
Kaplan Pharmacology 2011: Figure II-1-1
*
2
Autonomic nervous system
Parasympathetic
Sympathetic *
Thoracolumbar
,
Sympathetic fibers release dopamine to activate renal vascular smooth
muscle via D1 receptors!
FA 2012: 262.1 • FA 2011: 235.1 • FA 2010: 231
ME 3e: 186
PH02-
Acetylcholine receptors
Nicotinic ACh receptors (nAChRs)
Muscarinic ACh receptors (mAChRs)
Ligand-gated Na+/K+ channels
NN: autonomic
Nm: somatic muscular (neuromuscular junction)
G protein-coupled receptor
M1 M2 M3 M4 M5
Autonomic
Nervous
System
CNS
3
Acetylcholine receptors
FA 2012: 262.2 • FA 2011: 235.2 • FA 2010: 231
ME 3e: 189
PH02-
G protein-coupled receptor
0)1,)$&2+)34)*","56&7899:&;(5#3.&<=7=>&
Gs / Gi Gq
4
G protein-coupled receptor
FA 2012: 263.1 • FA 2011: 236.1 • FA 2010: 232
ME 3e: 169
PH02-
GPCR physiology
Class Receptor Functions
q !1 vascular smooth muscle contraction, pupillary dilation (mydriasis), intestinal and bladder
sphincter contraction
i !2 !sympathetic release, !insulin release
s "1 "heart rate and contractility, "renin release
s "2 vasodilation, bronchodilation, !uterine tone
q M1 CNS, gastric parietal cells
i M2 !heart rate, !atrial contractility
q M3 stimulates glandular secretions (sweat, gastric acid), "gut peristalsis, pupillary sphincter
muscle contraction (miosis), ciliary muscle contraction (accommodation)
s D1 renal vascular smooth muscle relaxation
i D2 !sympathetic release
q H1 "sinus and bronchial mucus production, bronchiole constriction, itching/pain
s H2 "gastric acid secretion
q V1 vascular smooth muscle contraction
s V2 "water reabsorption in collecting tubules of kidneys
5
GPCR physiology
FA 2012: 263.1 • FA 2011: 236.1 • FA 2010: 232
ME 3e: 187
PH02-
Cholinergic nerve terminal
Kaplan Pharmacology 2011: Figure II-2-1
Hemicholinium
Botulinum Vesamicol
Toxin
6
Cholinergic nerve terminal
FA 2012: 264.1 • FA 2011: 237.1 • FA 2010: 233
ME 3e: 189
PH02-
Metyrosine
Reserpine
Guanethidine
Amphetamines
Cocaine
TCAs
Amphetamines
Adrenergic nerve terminal
Kaplan Pharmacology 2011: Figure II-3-1
7
Adrenergic nerve terminal
FA 2012: 264.1 • FA 2011: 237.1 • FA 2010: 233
ME 3e: 192
PH02-
Cholinomimetics
Cholinomimetic Drugs (parasympathomimetics)
Bethanechol
Muscarinic agonist. Longer acting than ACh (resistant to esterase).
Treatment of ileus and urinary retention (Bowels and Bladder)
Carbachol
Muscarinic/nicotinic agonist. Applied to eye to cause contraction of
ciliary muscle, relief of open-angle glaucoma. Also constricts pupil
Pilocarpine
Muscarinic agonist. Stimulates tears, sweat, saliva. Constricts pupil
and ciliary muscle. Also used for acute glaucoma
Methacholine
Muscarinic agonist. Causes bronchoconstriction when inhaled.
Used for asthma challenge test
8
Cholinomimetics
FA 2012: 265.1 • FA 2011: 238.1 • FA 2010: 234
ME 3e: 189
PH02-
Anticholinesterases
Anticholinesterases (indirect cholinomimetics)
Neostigmine Quaternary amine (no entry into CNS). Treatment of ileus, urinary
retention, and myasthenia gravis. Post-operative reversal of
neuromuscular junction blockade
Pyridostigmine Quaternary amine. Treatment of myasthenia gravis
Edrophonium Very short acting (10-20 mins.) Diagnosis of myasthenia gravis
Physostigmine Tertiary amine (can enter CNS). Treatment of glaucoma. Antidote
for atropine toxicity
Echothiophate Treatment of glaucoma
9
Anticholinesterases
FA 2012: 265.1 • FA 2011: 238.1 • FA 2010: 234
ME 3e: 190
PH02-
Cholinesterase inhibitor poisoning
10
Cholinesterase inhibitor poisoning
Cholinesterase inhibitor poisoning (high systemic acetylcholine)
Symptoms: Diarrhea
Urination
Miosis
Bronchoconstriction
Bradycardia
Excitation (skeletal muscle and CNS)
Lacrimation
Salivation
Sweating
Treatment:
Atropine (muscarinic antagonist)
Pralidoxime a.k.a 2PAM (regenerates cholinesterase)
FA 2012: 265.2 • FA 2011: 238.2 • FA 2010: 234
ME 3e: 191
PH02-
Muscarinic receptor antagonists
11
Muscarinic receptor antagonists
Classic example: Atropine
• Tertiary amine ! can enter the CNS
• Effects: the opposite of DUMBBELSS
• ! Epithelial secretions
• Mydriasis, cycloplegia
• Hyperthermia
• Vasodilation
Muscarinic receptor antagonists:
• Tachycardia
• Sedation
• Urinary retention
• Constipation
50
Pharmacologic effects
• Atropine effects in order of increasing dose are:
– Decreased secretions (salivary, bronchiolar, sweat)
– Mydriasis and cycloplegia
– Hyperthermia (with resulting vasodilation)
– Tachycardia
– Sedation
– Urinary retention and constipation
– Behavioral excitation and hallucinations
• Other classes of drugs with antimuscarinic pharmacology:
– Antihistamines
– Tricyclic antidepressants
– Antipsychotics
– Quinidine
– Amantadine
– Meperidine
• Treatment of acute intoxication:
– Symptomatic ± physostigmine
Table II-2-6. Clinical Uses and/or Characteristics of M Blockers
Drug Clinical Uses and/or Characteristics
Atropine Antispasmodic, antisecretory, management of AChE inhibitor OD,
antidiarrheal, ophthalmology (but long action)
Tropicamide Ophthalmology (topical)
Ipratropium Asthma and COPD (inhalational)—no CNS entry, no change in
mucus viscosity
Scopolamine Used in motion sickness, causes sedation and short-term memory block
Benztropine, Lipid-soluble (CNS entry) used in parkinsonism and in acute
trihexyphenidyl extrapyramidal symptoms induced by antipsychotics
NICOTINIC RECEPTOR ANTAGONISTS
Ganglion Blocking Agents
• Drugs: hexamethonium and mecamylamine
• Reduce the predominant autonomic tone (see Table II-2-7)
• Prevent baroreceptor reflex changes in heart rate (see Figure II-2-4)
• Most are no longer available clinically because of toxicities (rarely, mecamylamine in
hypertension)
Bridge to Physiology
ANS Dominance
For effector tissues with dual
innervation, PANS is dominant.
These include the SA and AV
nodes of the heart, the pupil,
GI and GU muscles, and
sphincters. SANS is dominant
only in terms of vascular tone
and thermoregulatory sweat
glands.
Draft Not for Distribution
Kaplan Pharmacology 2010: Table II-2-6
FA 2012: 266.1 • FA 2011: 239.2 • FA 2010: 235
ME 3e: 190
PH02-
Nicotinic antagonists
12
Nicotinic antagonists
Hexamethonium (nicotinic antagonist)
Used to prevent vagal reflexes due to sympathetic stimulation
Example: can be used to prevent reflex bradycardia caused by increased
blood pressure due to increased norepinephrine
Excess hexamethonium can cause orthostatic hypotension, blurred vision,
constipation
FA 2012: n/a • FA 2011: 239.3 • FA 2010: 235
ME 3e: 189
PH02-
Direct sympathomimetics 1
13
Direct sympathomimetics
Epinephrine:
• Function:
• !," agonist
• Low doses selective for "1 receptors
• Clinical usage:
• Treatment for anaphylaxis, open-angle glaucoma, asthma, hypotension
• Prolongs the effect of local anesthesia
• Adverse effects:
• "systolic blood pressure + !diastolic blood pressure = widened pulse pressure
Norepinephrine:
• Function:
• Mainly !-receptor agonist, but has some "-receptor activity
• Clinical usage:
• Treatment of hypotension
• Adverse effects:
• Splanchnic vasoconstriction and !renal perfusion
• "systolic blood pressure + "diastolic blood pressure = little/no change in pulse pressure
• Reflexive decrease in heart rate
FA 2012: 266.3 • FA 2011: 240.1 • FA 2010: 236
ME 3e: 193
PH02-
Direct sympathomimetics 2
Isoproterenol "1 "2 agonist. Treatment for AV conduction block. !diastolic BP (this
effect induces a reflexive "heart rate)
Dopamine D1 = D2 > " > ! agonist. Inotropic and chronotropic.
Treatment for shock, especially with heart failure
Dobutamine "1> "2 agonist. Inotropic. Treatment of heart failure. Used in cardiac
stress test
Ritodrine "2 agonist. Reduces premature uterine contractions
Metaproterenol
Albuterol
Salmeterol
Terbutaline
Selective "2 agonists ("2>"1). Treatment of asthma
Acute: metaproterenol and albuterol
Long-acting: salmeterol
Direct sympathomimetics
14
Direct sympathomimetics
FA 2012: 266.3 • FA 2011: 240.1 • FA 2010: 236
ME 3e: 193
PH02-
Indirect sympathomimetics
Amphetamine Induces catecholamine release from terminals. Treatment for
narcolepsy, obesity, and ADHD.
Ephedrine Induces catecholamine release. Treatment for nasal congestion, urinary
incontinence, hypotension.
Cocaine Inhibits reuptake of catecholamines. Vasoconstriction, local anesthetic.
Tyramine Similar mechanism to amphetamines, cleared by MAO
(MAO inhibitors can cause hypertension, especially with tyramine-rich
foods such as wine and cheese).
Indirect sympathomimetics
15
Indirect sympathomimetics
FA 2012: 267.1 • FA 2011: 240.1 • FA 2010: 236
ME 3e: 194
PH02-
Sympathoplegics
Clonidine:
• Agonists of central !2-adrenergic receptors which decreases sympathetic outflow
!-methyldopa:
• Used to treat hypertension by decreasing sympathetic tone
16
Sympathoplegics
FA 2012: 267.2 • FA 2011: 241.1 • FA 2010: 237
ME 3e: 193
PH02-
Alpha-blockers
Non-selective (!1 and !2)
!1-selective
!2-selective
Phenoxybenzamine (irreversible)
Phentolamine (reversible)
Treatment of pheochromocytoma. Also used to treat
Raynaud’s syndrome
Prazosin
Terazosin
Doxazosin (longest acting)
Treatment of hypertension, urinary retention (BPH).
May cause orthostatic hypotension
(usually taken at bedtime)
Mirtazapine Treatment of depression. Can cause sedation, increased
serum cholesterol, and increased appetite
17
Alpha-blockers
FA 2012: 268.1 • FA 2011: 241.2 • FA 2010: 237
ME 3e: 193
PH02-
Beta-blockers 1
Non-selective ("1 and "2)
"1-selective
Partial "-agonists
Pindolol
Acebutolol
Metoprolol
Atenolol
Betaxolol
Esmolol (very short acting)
Propranolol (migraines)
Timolol (glaucoma)
Nadolol
Pindolol
Mixed ! and " blockers
Carvedilol
Labetalol
18
Beta-blockers
FA 2012: 269.1 • FA 2011: 242.1 • FA 2010: 238
ME 3e: 193
PH02-
Beta-blockers 2
Treatments for:
19
Beta-blockers
Side effects:
• Exacerbation of asthma
• Impotence
• Bradycardia
• AV blockade
• Sedation
• Decreased glucagon secretion
FA 2012: 269.1 • FA 2011: 242.1 • FA 2010: 238
ME 3e: 193
PH03-
Sympathetic and parasympathetic nervous systems
1
Toxicology and Adverse
Reaction
Matthew B. Wilkinson, PhD, M4
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PH03-
Antidotes 1
Drug Antidote
Acetaminophen N-acetylcysteine
Salicylates Sodium bicarbonate to alkalinize urine, dialysis
Antidotes
FA 2012: 270.1 • FA 2011: 243.1 • FA 2010: 239 2
ME 3e: 172
PH03-
Antidotes 2
Drug Antidote
Anticholinesterases
Organophosphates
(insecticides)
Atropine, 2-PAM (pralidoxime)
Anticholinergics Physostigmine
3
Antidotes
FA 2012: 270.1 • FA 2011: 243.1 • FA 2010: 239
ME 3e: 172
PH03-
Antidotes 3
Drug Antidote
!-blockers Glucagon to increase inotropy and chronotropy of heart
Digitalis Anti-digitalis Fab fragments. Normalize serum electrolytes, especially K+,
then lidocaine, magnesium
4
Antidotes
FA 2012: 270.1 • FA 2011: 243.1 • FA 2010: 239
ME 3e: 172
PH03-
Antidotes 4
Drug Antidote
Iron Deferoxamine (de-Fe-roxamine)
Lead Ca-EDTA (chelator), dimercaprol, succimer, penicillamine
Arsenic, mercury, gold Dimercaprol, succimer
Copper, arsenic, gold Penicillamine
5
Antidotes
FA 2012: 270.1 • FA 2011: 243.1 • FA 2010: 239
ME 3e: 171
PH03-
Antidotes 5
Drug Antidote
Cyanide Nitrite, hydroxocobalamin, thiosulfate
Methemoglobin Methylene blue, vitamin C
Carbon monoxide 100% O2 (hyperbaric chamber)
6
Antidotes
FA 2012: 270.1 • FA 2011: 243.1 • FA 2010: 239
ME 3e: 172
PH03-
Antidotes 6
Drug Antidote
Methanol, ethylene glycol Ethanol, fomepizol
Opioids Naloxone, naltrexone
Benzodiazepines Flumazenil
Tricyclic antidepressants
(TCAs)
NaHCO3 (intravenous alkalinization), adjunctively treat for
seizure, hyperthermia, and arrhythmia
7
Antidotes
FA 2012: 270.1 • FA 2011: 243.1 • FA 2010: 239
ME 3e: 172
PH03-
Antidotes 7
Drug Antidote
Heparin Protamine
Warfarin (coumadin) Vitamin K, fresh frozen plasma
(restore factors II, VII, IX, X, and Proteins C, S)
tPA, streptokinase Aminocaproic acid
Theophylline !-blocker
8
Antidotes
FA 2012: 270.1 • FA 2011: 243.1 • FA 2010: 239
ME 3e: 172
PH03-
Adverse effects: cardiovascular reactions
Side effect Causal agent
Atropine-like (anti-cholinergic) symptoms TCAs, anti-histamines
Dilated cardiomyopathy Doxorubicin, daunorubicin
Coronary vasospasm Cocaine, sumatriptan
Cutaneous flushing
Vancomycin, Adenosine, Niacin,
Ca-channel blockers (VANC)
Torsades de pointes
Class III (sotalol) and Class IA (quinidine)
antiarrythmics, cisapride (update: removed
from the US market because of arrhythmias)
Treat with magnesium
Dilated cardiomyopathy
Dr. Edwin P. Ewing, Jr., commons.wikimedia.org
Used with permission.
9
Cardiovascular reactions
FA 2012: 271.1 • FA 2011: 244.1 • FA 2010: 240
ME 3e: 170
PH03-
Adverse effects: hematologic reactions
Side effect Causal agent
Agranulocytosis Clozapine, carbamazepine, colchicine, propylthiouracil, dapsone,
methimazole
Aplastic anemia Chloramphenicol, benzene, NSAIDs, felbamate
Hemolytic anemia
(Coombs-positive)
Methyldopa
Gray baby syndrome Chloramphenicol
G6PD-deficient hemolytic
anemia
Isoniazid (INH), sulfa drugs, aspirin, ibuprofen, nitrofurantoin,
primaquin
Megaloblastic anemia
(hypersegmented neutrophils)
Methotrexate, sulfa drugs, phenytoin
Thrombosis Oral contraceptives (higher risk with smoking)
Hypersegmented Neutrophils
Bobjgalindo, commons.wikimedia.org
Used with permission.
10
Hematologic reactions
FA 2012: 271.1 • FA 2011: 244.1 • FA 2010: 240
ME 3e: 170
PH03-
Adverse effects: respiratory reactions
Side effect Causal agent
Cough ACE-inhibitors (use angiotensin-receptor blockers instead)
Pulmonary fibrosis Bleomycin, amiodarone, busulfan
11
Respiratory reactions
FA 2012: 271.1 • FA 2011: 244.1 • FA 2010: 240
ME 3e: 170
PH03-
Adverse effects: GI reactions
Side effect Causal agent
Hepatitis Isoniazid (INH)
Cholestatic hepatitis Macrolide antibiotics (azithromycin, clarithromycin)
Hepatic necrosis Halothane, valproic acid, acetaminophen,
Amanita phalloides (mushroom)
Pseudomembranous
colitis
Clindamycin, ampicillin, cephalosporins
Pancreatitis Azathioprine, sulfonamides, valproic acid, methyldopa,
furosemide, corticosteroids, sulindac, tetracycline, didanosine,
estrogens, 6-mercaptopurine, pentamidine, 5-aminosalicyclic
acid compounds, octreotide
Pseudomembranous colitis, endoscopy
Bijan Zendeh, commons.wikimedia.org
Used with permission.
12
GI reactions
FA 2012: 271.1 • FA 2011: 244.1 • FA 2010: 240
ME 3e: 170
PH03-
Adverse effects: reproductive/endocrine reactions
Side effect Causal agent
Adrenocortical insufficiency Glucocorticoid withdrawal, etomidate
Gynecomastia Spironolactone, digitalis, cimetidine, alcohol, estrogens,
ketoconazole
Hot flashes Tamoxifen, clomiphene
Hypothyroidism Lithium, amiodarone
13
Reproductive/endocrine reactions
FA 2012: 271.1 • FA 2011: 244.1 • FA 2010: 240
ME 3e: 170
PH03-
Adverse effects: musculoskeletal/connective tissue reactions
Side effect Causal agent
Gingival hyperplasia Phenytoin
Gout Furosemide, thiazides
Osteoporosis Corticosteroids, heparin
Photosensitivity Sulfonamides, Amiodarone, Tetracyclines,
Fluoroquinolones
Rash
(Stevens-Johnson syndrome)
Sulfa drugs, penicillin, carbamazepine, allopurinol
Lupus-like syndrome Hydralazine, INH, procainamide, phenytoin
Tendon rupture Fluoroquinolones
Stevens-Johnson syndrome
Dr. Thomas Habif, commons.wikimedia.org
Used with permission.
14
Musculoskeletal/connective tissue reactions
FA 2012: 272.1 • FA 2011: 245.1 • FA 2010: 241
ME 3e: 170
PH03-
Adverse effects: renal/GU reactions
Side effect Causal agent
Fanconi’s syndrome Expired tetracycline
Interstitial nephritis Methicillin, NSAIDs
Hemorrhagic cystitis Cyclophosphamide
15
Renal/GU reactions
FA 2012: 272.1 • FA 2011: 245.1 • FA 2010: 241
ME 3e: 170
PH03-
Adverse effects: neurologic reactions
Side effect Causal agent
Cinchonism Quinidine, quinine
Diabetes insipidus Lithium, demeclocycline
Seizures Bupropion, imipenem/cilastatin, INH
Parkinson-like syndrome Haloperidol, chlorpromazine, reserpine,
metoclopramide
Tardive dyskinesia Typical antipsychotics
16
Neurologic reactions
FA 2012: 272.1 • FA 2011: 245.1 • FA 2010: 241
ME 3e: 170
PH03-
Adverse effects: multi-organ reactions
Side effect Causal agent
Disulfiram-like reaction Metronidazole, procarbazine, sulfonylureas, cephalosporins
Nephrotoxicity / neurotoxicity Polymxyins
Nephrotoxicity / ototoxicity Aminoglycosides, vancomycin, loop diuretics, cisplatin
17
Multi-organ reactions
FA 2012: 272.1 • FA 2011: 245.1 • FA 2010: 241
ME 3e: 170
PH03-
Cytochrome P-450 interactions
Inducers Inhibitors
Quinidine HIV protease inhibitors
Barbiturates Isoniazid (INH)
St. John’s wort Sulfonamides
Phenytoin Cimetidine
Rifampin Ketoconazole
Griseofulvin Grapefruit juice
Carbamazepine Omeprazole
Chronic alcohol use Chloramphenicol
Glucocorticoids Marcolides
18
Cytochrome P-450 interactions
FA 2012: 273.1 • FA 2011: 245.2 • FA 2010: 241
ME 3e: 167
PH03-
Alcohol metabolism
Kaplan Pharmacology 2011: Figure IV-2-1
19
Alcohol metabolism
Treatment (both): Ethanol, Fomepizole, or in severe cases, dialysis!
FA 2012: n/a • FA 2011: 246.1 • FA 2010: 242
ME 3e: 13
PH03-
Sulfa drugs
• Any drugs that contain a sulfonamide group
• Allergies to these drugs are common
Edgar181,
commons.wikimedia.org
Used with permission
Symptoms: Sulfonamide group
• Pruritic rash
• Fever
• Stevens-Johnson syndrome
• Hemolytic anemia
• Thrombocytopenia
• Agranulocytosis
• Urticaria (hives)
Drugs:
• Sulfonamide antibiotics
• TMP-SMX
• Acetazolamide
• Furosemide
• Thiazides
• Sulfasalazine
• Celecoxib
• Probenecid
20
Sulfa drugs
FA 2012: 273.2 • FA 2011: 246.2 • FA 2010: 242
ME 3e: n/a
PH03-
Common drug name endings
-afil erectile dysfunction
drugs
-ane inhalational anesthetics
-azepam benzodiazepines
-azine phenothiazine
-azole antifungals
-barbital barbiturates
-caine local anesthetics
-cillin penicillins
-cycline antibiotics, protein
synthesis inhibitors
-etine SSRIs
-ipramine tricyclic antidepressants
-navir protease inhibitors
-olol ! antagonist
-operidol butyrophenone (neuroleptic)
-oxin cardiac glycoside (inotropic)
-phylline methylxanthines
-pril ACE inhibitor
-terol !2 agonist
-tidine H2 antagonist
-triptan 5-HT1B/1D agonists (migraine)
-triptyline TCAs
-tropin pituitary hormone
-sartan angiotensin receptor blockers
-zolam benzodiazepine
-zosin "1 antagonist
21
Common drug name endings
FA 2012: 274.1 • FA 2011: 247.1 • FA 2010: 243
ME 3e: n/a
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