Kaplan_TopicEssentials_Pharmacology.pdf

1
QBank Integrated Plan
PHARM FUNDAMENTALS
PHARMACOKINETICS
IONIZATION AND PERMEATION
JOSHUA D. BROOKS, Ph.D.
Associate Director of Preclinical Academics, Kaplan Medical
Instructor of Pharmacology and Biochemistry
1
Ionization of Drugs
• Many drugs are weak acids or weak bases – this means they can
be bound to a proton (H+) or not depending on the environment.
• Protonation depends on:
• pH of the environment (can change)
• pKa of the drug (based on drug structure, does not change)
• When pH (environment) = pKa (drug), drug is 50% charged
• TIP: Think of pKa as the pH where the H+ is removed
2

2
A patient is admitted for treatment of drug overdose. It is observed
that when the urine pH is acidic, the renal clearance of the drug is
greater than the GFR. When the urine pH is alkaline, the clearance is
less than the GFR. The drug is probably a:
A. Strong acid
B. Strong base
C. Weak acid
D. Weak base
3
A patient is admitted for treatment of drug overdose. It is observed
that when the urine pH is acidic, the renal clearance of the drug is
greater than the GFR. When the urine pH is alkaline, the clearance is
less than the GFR. The drug is probably a:
A. Strong acid
B. Strong base
C. Weak acid
D. Weak base
4

3
Ionization of Weak Acids
WEAK ACIDS: pKa
R–COOH
Non-ionized (uncharged)
Absorbable (lipid-soluble)
R–COO– + H+
Ionized (charged)
Trapped (water-soluble)
Acids to remember – Aspirin, warfarin, penicillin, cephalosporins, loop
diuretics, thiazide diuretics
5
Ionization of Weak Bases
WEAK BASES:
R–NH+
Ionized (charged)
Trapped (water-soluble)
R–N + H+
Non-ionized (uncharged)
Absorbable (lipid-soluble)
Bases to remember – morphine, local anesthetics, PCP, amphetamine
à NARCOTICS!
HINT #1: If drug and
environment similar:
Non-ionized (absorb!)
HINT #2: If drug and
environment different:
Ionized (trap!)
pKa
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PHARM FUNDAMENTALS
PHARMACOKINETICS
ABSORPTION & ELIMINATION
7
Plasma Level of Drugs
a
b
s
o
r
p
t
i
o
n
elimination
minimum effective
concentration
onset of
activity
time to peak
tmax
Time
[Plasma
drug]
peak level
C max
curve
shows
some
extra-
vascular
route
first seeing
drug effect
duration of action
lag
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5
Elimination
• Major modes of drug elimination are:
• Biotransformation to inactive metabolites
• Excretion via the kidney
• Excretion via other modes including bile duct, lungs, sweat
• Elimination half-life (t1/2) = time to eliminate 50% of a given
amount (or to decrease plasma level to 50% of a former level)
9
First-Order Kinetics
• A constant fraction (not amount) is eliminated per unit time
• 80mg 40mg 20 mg 10mg 5mg
• Rate of elimination is dependent of plasma concentration
• Most drugs follow first-order elimination rates, and t1/2 is a
constant for these drugs
4h 4h 4h 4h
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6
Upon overdose, drug levels were measured over time and found to
decrease in the following fashion:
2hr 2hr 2hr
5000mg à 4500mg à 4000mg à 3500mg
Which drug below was most likely taken?
A. Amitriptyline
B. Aspirin
C. Atenolol
D. Levofloxacin
E. Lisinopril
11
Upon overdose, drug levels were measured over time and found to
decrease in the following fashion:
2hr 2hr 2hr
5000mg à 4500mg à 4000mg à 3500mg
Which drug below was most likely taken?
A. Amitriptyline
B. Aspirin
C. Atenolol
D. Levofloxacin
E. Lisinopril
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7
Zero Order Kinetics
• A constant amount (not fraction) is eliminated per unit time
• 80mg 70mg 60mg 50mg 40mg
• Rate of elimination is independent of plasma concentration
• These drugs have no fixed half-life
• Examples:
• Phenytoin at high therapeutic doses
• Ethanol except at low blood levels
• Aspirin at toxic doses
4h 4h 4h 4h
HINT:
Zero PEAs for me
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PHARM FUNDAMENTALS
PHARMACOKINETICS
DISTRIBUTION
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8
Volume of Distribution
• A theoretical number that correlates IV dose of a drug with plasma
level at zero time
• BOARD VERSION: dose = Vd * C0
• C0 – concentration at injection (amount in blood)
• Vd – amount in tissues (amount distributed)
Vd =
Dose
C0
15
• Stuck in blood? Low Vd
• Ionized (trapped) drugs stay in the blood compartment
• Many drugs bind plasma proteins (like albumin) for transport;
equilibrium exists between bound and free drug
• Stuck in tissue? High Vd
• Many drugs will leave the blood for tissues but then bind
proteins in the tissue and stay there
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9
A patient on warfarin is given trimethoprim-
sulfamethoxazole therapy for a recurring UTI. Which of the following
actions should the physician take to maintain adequate
anticoagulation?
A. Begin therapy with vitamin K
B. Increase the dosage of warfarin
C. Make no changes to the dosage of warfarin
D. Decrease the dosage of warfarin
E. Stop the warfarin and change to low-dose aspirin
17
A patient on warfarin is given trimethoprim-
sulfamethoxazole therapy for a recurring UTI. Which of the following
actions should the physician take to maintain adequate
anticoagulation?
A. Begin therapy with vitamin K
B. Increase the dosage of warfarin
C. Make no changes to the dosage of warfarin
D. Decrease the dosage of warfarin
E. Stop the warfarin and change to low-dose aspirin
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10
• Competition between drugs for protein-binding sites will affect
distribution as well
• Drugs with low Vd may compete for plasma-protein binding and
increase the “free fraction” more free drug = more activity!
DRUG-DRUG INTERACTION: Plasma protein displacement
Warfarin (displaced by other low Vd drugs like sulfonamides)
Drug + Protein Drug-Protein Complex
(Active, free) (Inactive, bound)
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• Competition between drugs for protein-binding sites will affect
distribution as well
• Drugs with high Vd values may compete for protein binding and
increase the “free fraction” increased displacement.
DRUG-DRUG INTERACTION: Drugs displaced from tissue proteins
Digoxin (Displaced by other high Vd drugs like quinidine)
Drug + Protein Drug-Protein Complex
(Active, free) (Inactive, bound)
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PHARM FUNDAMENTALS
PHARMACOKINETICS
PHASE I METABOLISM – CYP450s
21
Examples of Cytochrome P450s
CYP450 Substrates Tested Inducers Tested Inhibitors
1A2
Theophylline
Acetaminophen
Smoking
Quinolones
Macrolides
2A6
Many CV & CNS
drugs
Phenobarbital
Haloperidol
Quinidine
Some SSRIs
3A4
Majority of
prescribed
drugs
General
inducers
General inhibitors
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12
A patient taking a statin is admitted to the hospital for muscle pain,
fatigue and dark urine. Evaluation reveals that he is in acute renal
failure. The addition of which of the following medications is most
likely to have precipitated this patient’s condition?
A. Erythromycin
B. Phenobarbital
C. Rifampin
D. Griseofulvin
E. Phenytoin
F. St. John’s Wort
23
A patient taking a statin is admitted to the hospital for muscle pain,
fatigue and dark urine. Evaluation reveals that he is in acute renal
failure. The addition of which of the following medications is most
likely to have precipitated this patient’s condition?
A. Erythromycin
B. Phenobarbital
C. Rifampin
D. Griseofulvin
E. Phenytoin
F. St. John’s Wort
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General Inducers of CYP450 3A4
• Anticonvulsants (barbituates, phenytoin, carbamazepine)
• Antibiotics (rifampin)
• Chronic alcohol & smoking
• St. John’s Wort
ASSUMPTION: Drug metabolism turns drug off
TAKEAWAY: Inducers will lower activity of other drugs
COMMON 3A4 SUBSTRATES : Warfarin, oral contraceptives
(metabolize fast à stop working)
EXCEPTION: Acetaminophen
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General Inhibitors of CYP450 3A4
• Acute alcohol
• Antiulcer meds (cimetidine, omeprazole)
• Antimicrobials (the macrolide erythromycin, ketoconazole,
chloramphenicol, protease inhibitor: ritonavir)
ASSUMPTION: Drug metabolism turns drug off
TAKEAWAY: Inhibitors will increase activity of other drugs
COMMON 3A4 SUBSTRATES : Warfarin, theophylline, statins
(metabolize slowly à substrate builds up à drug toxicity)
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PHARM FUNDAMENTALS
PHARMACOKINETICS
METABOLISM – PHASE I METABOLISM
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Phase I Metabolism Definition
• Phase I: modification of drug through oxidation, reduction, and
hydrolysis
• Examples: Cytochrome P450s, cholinesterases, monoamine
oxidases, alcohol metabolism
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Phase I Metabolism – Monoamine oxidase
• Metabolize amine neurotransmitters
• Endogenous: dopamine, NE, and serotonin
• Exogenous: tyramine (found in dried meats, dried fruits, aged
cheeses, wines, chocolate, beers)
TYRAMINE: Should be metabolized by MAOA in the gut when ingested.
SIDE EFFECT: MAO inhibitors + a diet high in tyramine
Tyramine absorbed à NE displaced/released à hypertensive crisis
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Phase I Metabolism – Alcohol Metabolism
• Caused by oxidation/reduction and the use of dehydrogenases
• Alcohols aldehydes acid
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16
A homeless middle-aged male patient presents in the emergency
room in a state of intoxication. He complains that his vision is blurred
and that it is “like being in a snowstorm.” His breath smells a bit like
an anatomy lab. The most likely cause of this patient’s intoxicated
state is the ingestion of
A. Ethanol
B. Ethylene glycol
C. Isopropanol
D. Methanol
31
A homeless middle-aged male patient presents in the emergency
room in a state of intoxication. He complains that his vision is blurred
and that it is “like being in a snowstorm.” His breath smells a bit like
an anatomy lab. The most likely cause of this patient’s intoxicated
state is the ingestion of
A. Ethanol
B. Ethylene glycol
C. Isopropanol
D. Methanol
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17
Phase I Metabolism – Ethylene Glycol & Methanol
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PHARM FUNDAMENTALS
PHARMACOKINETICS
METABOLISM – PHASE II METABOLISM
34

18
Phase II Metabolism Definition
• Phase II: Conjugation with endogenous compounds using
enzymes called transferases
• Examples: Glucuronidation, acetylation, glutathione
conjugation
35
A patient presents to her physician for a follow-up after taking
hydralazine for the past several months. She complains of a rash and
muscle pains. Upon replacing the drug, the symptoms eventually
disappear. Which of the following enzymes in this patient contributed
to this problem?
A. Cytochrome P450s
B. Glucuronsyltransferase
C. Monoamine oxidase
D. N-acetyltransferase
E. Pseudocholinesterase
36

19
A patient presents to her physician for a follow-up after taking
hydralazine for the past several months. She complains of a rash and
muscle pains. Upon replacing the drug, the symptoms eventually
disappear. Which of the following enzymes in this patient contributed
to this problem?
A. Cytochrome P450s
B. Glucuronsyltransferase
C. Monoamine oxidase
D. N-acetyltransferase
E. Pseudocholinesterase
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Phase II Metabolism – Glucuronidation
• Localized in the smooth endoplasmic reticulum of cells
• Reduced activity in neonates
• Inducible by barbiturates
PATH: Deficiencies in glucuronyl-transferase (UGT)
• Crigler-Najjar Type 1 = no detectable UGT
• Crigler-Najjar Type 2 = Less than 10% of UGT
• Gilbert Syndrome = Low affinity UGT
RELEVANCE OF BARBS? Diagnose Crigler-Najjar Type 1 vs. 2
PATH: Gray Baby syndrome
↑ unconjguated chloramphenicol due to lack of enzymes
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Phase II Metabolism – Acetylation
• Genotypic variation; fast and slow acetylators
• Drug-induced systemic lupus erythematosus by slow acetylators
when taking:
• hydralazine
• procainamide
• isoniazid (INH)
TESTING NOTE: drug- and non-drug SLE
à butterfly malar rash; + ANA
drug-induced SLE only à anti-histone
antibodies
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PHARM FUNDAMENTALS
PHARMACOKINETICS
EQUATIONS
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21
A narcotics addict is brought to the emergency room in a deep coma.
His friends stated he took a large dose of morphine 6 hours earlier. A
blood analysis shows a blood level of 0.25 mg/L. Morphine has a Vd of
200 L and a half-life of 3 hours. How much morphine did the patient
inject?
A. 25 mg
B. 50 mg
C. 100 mg
D. 200 mg
41
A narcotics addict is brought to the emergency room in a deep coma.
His friends stated he took a large dose of morphine 6 hours earlier. A
blood analysis shows a blood level of 0.25 mg/L. Morphine has a Vd of
200 L and a half-life of 3 hours. How much morphine did the patient
inject?
A. 25 mg
B. 50 mg
C. 100 mg
D. 200 mg
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Equation 1: Single-Dose Equation
• Loading dose (LD):
LD = Vd × Cp
f
EXAMPLE Q: A narcotics addict is brought to the emergency room in a deep
coma. His friends stated he took a large dose of morphine 6 hours earlier. A
blood analysis shows a blood level of 0.25 mg/L. Morphine has a Vd of 200 L
and a half-life of 3 hours. How much morphine did the patient inject?
43
A 29-year-old man is brought to the emergency department 20
minutes after being involved in a motor vehicle collision. Treatment
with a continuous infusion of morphine at a dose of 0.5 mg/min is
begun. The half-life of morphine is 1.9 hours, and its volume of
distribution (Vd) is 230 L. The clearance (CL) for morphine is 30 L/h.
What will the concentration at steady state be?
A. 0.1 mg/L
B. 0.16 mg/L
C. 1 mg/L
D. 1.6 mg/L
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23
A 29-year-old man is brought to the emergency department 20
minutes after being involved in a motor vehicle collision. Treatment
with a continuous infusion of morphine at a dose of 0.5 mg/min is
begun. The half-life of morphine is 1.9 hours, and its volume of
distribution (Vd) is 230 L. The clearance (CL) for morphine is 30 L/h.
What will the concentration at steady state be?
A. 0.1 mg/L
B. 0.16 mg/L
C. 1 mg/L
D. 1.6 mg/L
45
Equation 2: Multiple-Dose Equation
• Maintenance dose (MD):
MD = Cl × Css × τ
f
EXAMPLE Q: A 29-year-old man is brought to the emergency department 20
minutes after being involved in a collision. Treatment with a continuous
infusion of morphine at a dose of 0.5 mg/min is begun. The half-life of
morphine is 1.9 hours, and its volume of distribution is 230 L. The clearance
for morphine is 30 L/h. What will the concentration at steady state be?
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PHARM FUNDAMENTALS
PHARMACODYNAMICS
DEFINITIONS
47
Definition 1: Affinity
Affinity compares the amount of drugs that causes the same relative
response when both drugs bind the on same receptor
• Lower [drug] à drug binds better à higher affinity
48

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Definition 2: Potency
Potency compares the amount of drugs that causes the same
relative response when both drugs cause the same effect (no matter
which receptors are used)
• Lower [drug] à less drug to elicit similar response à higher
potency
49
Definition 3: Efficacy
Efficacy compares the maximal effect elicited by a drug no matter
how much drug was needed
• Larger maximal effect à stronger agonist at receptor à higher
efficacy
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Graded-Dose Response Curves
Affinity?
Potency?
Efficacy?
A > B
A > B
A = B
19
Affinity?
Potency?
Efficacy?
????
X > Y
X > Y
Biological
effect
Biological
effect
51
PHARM FUNDAMENTALS
PHARMACODYNAMICS
TYPES OF ANTAGONISM
52

27
Anti-muscarinic drugs are implicated in the treatment of beta-blocker
induced-asthma. What term below best describes this effect?
A. Chemical antagonist
B. Noncompetitive antagonist
C. Partial agonist
D. Pharmacological antagonist
E. Physiologic antagonist
53
Anti-muscarinic drugs are implicated in the treatment of beta-blocker
induced-asthma. What term below best describes this effect?
A. Chemical antagonist
B. Noncompetitive antagonist
C. Partial agonist
D. Pharmacological antagonist
E. Physiologic antagonist
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Pharmacological Antagonists
Competitive (bind same site on same receptor):
• Cause a parallel RIGHT shift in the D-R curve for agonists
• Appear to ¯ the apparent affinity of the agonist
55
Pharmacological Antagonists
Noncompetitive (bind different site on same receptor):
• Always eventually causes shift down (turns off receptors)
• Appears to ¯ the efficacy of the agonist
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29
Pharmacological Potentiators
Potentiators (bind different site on same receptor):
• No affect alone; only act to increase response to other ligand
• Appears to potency of agonist (same effect with less substrate)
57
Non-Pharmacological Antagonism
Physiologic antagonism (different receptors):
• Two agonists with opposing physiological actions antagonize each
other using two different receptors.
EX: Using a muscarinic antagonist for beta-blocker induced asthma
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30
Non-Pharmacological Antagonism
Chemical antagonism (no receptors):
• Formation of a complex between drug and another compound, no
receptor used
EX: Treating rheumatoid arthritis with infliximab
EX: Treating heparin overdose with protamine sulfate
59
PHARM FUNDAMENTALS
PHARMACODYNAMICS
SIGNALING – cAMP and Ca2+
60

31
An agent applied to human cells is believed to activate G-protein
dependent phospholipase C. Which of the following intracellular
substances is most likely to increase immediately after exposure to
this agent.
A. cAMP
B. Ca2+
C. Cl-
D. Gq
E. cGMP
61
An agent applied to human cells is believed to activate G-protein
dependent phospholipase C. Which of the following intracellular
substances is most likely to increase immediately after exposure to
this agent.
A. cAMP
B. Ca2+
C. Cl-
D. Gq
E. cGMP
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32
G-Protein Mediated Signaling: cAMP
Gs protein activation leads to increased cyclic adenosine
monophosphate (cAMP)
• Tested receptors: adrenoreceptors (β), dopamine (D1),
vasopressin in kidney (V2), histamine (H2), and glucagon
MICRO: Cholera toxin and heat-labile ETEC toxins target and activate
Gs in enterocytes à more PKA à more Cl- secretion à diarrhea
63
G-Protein Mediated Signaling: cAMP
Gi protein activation leads to decreased cyclic adenosine
monophosphate (cAMP)
• Tested receptors: adrenoreceptors (α2), muscarinic (M2)
dopamine (D2), serotonin (5HT1) and opioid (μ, κ, δ).
MICRO: Pertussis toxin targets and inactivates Gi à more cAMP à
more PKA activity.
HINT: If you’d inhibit me, I’d get MAD2.
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G-Protein Mediated Signaling: Ca2+
Gq protein activation leads to increased Ca2+ mobilization
• Tested receptors: adrenoreceptors (α1), muscarinic (M1, M3),
angiotensin II, vasopressin in vasculature (V1), & serotonin (5HT2)
HINT: Smooth muscle and Gq
Mobilize Ca2+ in muscle —”Q”strict
HINT: Odd muscarinics and
alpha = Gq
65
PHARM FUNDAMENTALS
PHARMACODYNAMICS
SIGNALING – cGMP & Tyrosine Kinases
66

34
A patient takes nitroglycerin for angina. Which of the following best
explains the biochemical mechanism of action of the angina
medication?
A. Activation of a Gq protein
B. Activation of a Gs protein
C. Activation of a Gi protein
D. Activation of a membrane-bound guanylyl cyclase enzyme
E. Activation of a cell soluble guanylyl cyclase enzyme
67
A patient takes nitroglycerin for angina. Which of the following best
explains the biochemical mechanism of action of the angina
medication?
A. Activation of a Gq protein
B. Activation of a Gs protein
C. Activation of a Gi protein
D. Activation of a membrane-bound guanylyl cyclase enzyme
E. Activation of a cell soluble guanylyl cyclase enzyme
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35
Non-G-Protein Mediated Signaling: cGMP
• Nitric oxide (NO) is synthesized in endothelial cells and diffuses into
smooth muscle, activating soluble (intracellular) guanylate cyclase
which makes cyclic guanosine monophosphate (cGMP).
• Atrial natriuretic factor (ANF) activates a membrane receptor
guanylate cyclase
EX: Soluble Activators
Nitroglycerin (for angina)
EX: Membrane Activators
Nesiritide (for CHF)
69
Non-G-Protein Mediated Signaling: Tyrosine Kinases
Membrane tyrosine kinases:
• These receptors mediate the first steps in signaling by insulin and
growth factors (including EGF and PDGF).
• They bind the hormone with an extracellular domain, and binding
causes dimerization of receptors.
• The membrane receptors autophosphorylate on tyrosine residues
to mediated a downstream cascade.
70

36
Non-G-Protein Mediated Signaling: Tyrosine Kinases
Non-membrane tyrosine kinases:
• Cytoplasmic janus activated kinases (JAKs) are activated
downstream of “-poietins,” immunomodulators, prolactin, and
growth hormone signaling.
• JAKs phosphorylate signal transducers and activators of
transcription (STATs) which cross the nuclear membrane to change
gene expression.
71
PHARM FUNDAMENTALS
AUTONOMIC NERVOUS SYSTEM
INTRODUCTION
72

37
Which of the following nervous outputs is noradrenergic?
A. Sympathetic output to adrenals
B. Sympathetic output to sweat glands
C. Sympathetic output to the bladder
D. Parasympathetic output to the heart
E. Parasympathetic output to the bronchi
73
Which of the following nervous outputs is noradrenergic?
A. Sympathetic output to adrenals
B. Sympathetic output to sweat glands
C. Sympathetic output to the bladder
D. Parasympathetic output to the heart
E. Parasympathetic output to the bronchi
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38
Anatomy of the ANS
PANS:
Rest and Digest
SANS:
Fight or Flight
Thermoregulation
PHYSIOLOGY:
ACh at post-ganglionic
target causes secretion
à PANS & SANS!
75
Anatomy of the ANS Neuronal NE:
Fast onset,
short duration
Hormonal Epi:
Slower onset,
longer duration
Adrenal gland as
a ganglion
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39
Epinephrine vs. Norepinephrine Effects
Cell 1
S
A
N
S
NE
Blood
EPI EPI EPI EPI
β
Cell 2
β
β
β
77
Anatomy of the ANS
Smooth & Cardiac
Muscle:
Muscarinic
(M agonist, ↑ ACh)
SOMATIC:
Motor neurons
Skeletal Muscle:
Nicotinic muscle
(NM agonist, ↑ ACh)
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40
PHARM FUNDAMENTALS
REFLEX RESPONSE
79
A patient receives a powerful arteriolar vasodilator that does not act
on adrenoreceptors or muscarinic receptors. Which of the following
effects will be observed if no other drugs are used?
A. Tachycardia and increased cardiac contractility
B. Decreased mean arterial pressure and decreased cardiac
contractility
C. Decreased mean arterial pressure and increased salt and water
excretion in the kidney
D. No change in mean arterial pressure and decreased cardiac
contractility
80

41
A patient receives a powerful arteriolar vasodilator that does not act
on adrenoreceptors or muscarinic receptors. Which of the following
effects will be observed if no other drugs are used?
A. Tachycardia and increased cardiac contractility
B. Decreased mean arterial pressure and decreased cardiac
contractility
C. Decreased mean arterial pressure and increased salt and water
excretion in the kidney
D. No change in mean arterial pressure and decreased cardiac
contractility.
81
Autonomic Feedback Loop
Give a vasoconstrictor,
raise patient’s BP.
M2
β1
β1
α1
↑ Ach
↓ NE
REFLEX:
Wants to
lower BP
HINT:
Whatever
your drug
does to
BP, the
system
does the
opposite
to HR
TAKEAWAY:
Vasoconstrict &
cause reflex
bradycardia (PANS)
WHAT ABOUT A VASODILATOR? Vasodilate & cause
reflex tachycardia (SANS)
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42
Inhibiting an ANS Reflex
M2
NN
Ach Ach
PANS
β1
NN
Ach NE
SANS
Ganglion blocker
Ganglion blocker Muscarinic blocker
Beta blocker
83
PHARM FUNDAMENTALS
CHOLINERGIC NERVE TERMINALS
84

43
Drugs of the Cholinergic Neuroeffector Junction
1. Hemicholinium
2. Botulinum toxin
3. Acetylcholinesterase
inhibitors
4. Receptor agonists
and antagonists
NOTE: Direct vs. Indirect-acting drugs
• Direct drugs act on receptor of cell
• Indirect drugs act at nerve terminal or
synapse to increase/inhibit signal
Indirect
Direct
85
Which of the following is an expected effect of a therapeutic dose of a
drug that blocks muscarinic-3 receptors?
A. Decreased cAMP in cardiac muscle
B. Decreased DAG in salivary gland tissue
C. Increased IP3 in intestinal smooth muscle
D. Increased sodium influx into the skeletal muscle end plate
86

44
Which of the following is an expected effect of a therapeutic dose of a
drug that blocks muscarinic-3 receptors?
A. Decreased cAMP in cardiac muscle
B. Decreased DAG in salivary gland tissue
C. Increased IP3 in intestinal smooth muscle
D. Increased sodium influx into the skeletal muscle end plate
87
Receptor G-protein Downstream Signal
M1 and M3 Gq coupled ↑ phospholipase C à ↑ IP3, DAG, Ca2+
M2 Gi coupled ¯ adenylyl cyclase à cAMP
NN and NM No 2nd
messengers
activation (opening) of Na+/K+
channels (depolarization)
Cholinergic Receptor Mechanisms
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45
PHARM FUNDAMENTALS
CHOLINERGIC RECEPTOR EFFECTS
89
Target Direct Agonist Effect
Sphincter Muscle (eye) Contraction—miosis
Ciliary Muscle (eye)
Contraction—accommodation for near
vision
Innervated Muscarinic
Receptors and their Activity
Miosis, accommodation
(near vision)
Direct agonist (M) AChE Inhibitor (↑ACh)
Miosis, accommodation
(near vision)
Antagonist
Mydriasis, cycloplegia
(far vision)
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46
SA node (heart) ¯ HR—negative chronotropy
AV node (heart)
¯ Conduction velocity—negative
dromotropy
Bradycardia
Bradycardia
Antagonist
Tachycardia
More Innervated Muscarinic
91
Bronchioles (lung) Contraction – bronchospasm
Glands (lung) Secretion
Bronchospasms,
secretions
Bronchospasms,
secretions
Antagonist
Bronchodilation,
less secretion
Innervated Muscarinic
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47
Stomach ↑ Motility—cramps
Glands (GI) Secretion
Intestine Contraction—diarrhea, involuntary defecation
Bladder
Contraction (detrusor), relaxation
(trigone/sphincter), voiding, urinary incontinence
Sphincters
Relaxation, except lower esophageal, which
contracts
Glands Secretion—sweat, salivation, and lacrimation
More Innervated Muscarinic Receptors and their
Activity
Direct agonists and acetylcholinesterase inhibitors are almost
identical – all of these receptors are innervated.
93
An overdose of muscarinic agonist carbachol but not an overdose of
acetylcholinesterase inhibitor neostigmine could cause the following:
A. Miosis
B. Cholinergic crisis
C. Hypotension
D. Bronchoconstriction
E. Sweating
94

48
An overdose of muscarinic agonist carbachol but not an overdose of
acetylcholinesterase inhibitor neostigmine could cause the following:
A. Miosis
C. Hypotension
E. Sweating
95
Endothelium
(blood vessels)
Dilation (activation of endothelial nitric oxide
synthase—eNOS).
↑ NO production à
vasodilation, ↓ BP
No endothelial effect
(no BP change)
Antagonist
No endothelial
effect (no BP
change)
TIP #1: Muscarinic agonist (direct) vs. AChE inhibitor (indirect)?
Check blood pressure – only the muscarinic agonist will vasodilate.
Non-Innervated Muscarinic
96

49
An overdose of acetylcholinesterase inhibitor neostigmine but not an
overdose of muscarinic agonist carbachol could cause the following:
A. Miosis
C. Hypotension
E. Sweating
97
An overdose of acetylcholinesterase inhibitor neostigmine but not an
overdose of muscarinic agonist carbachol could cause the following:
A. Miosis
C. Hypotension
E. Sweating
98

50
Target Receptor Effect of Agonist
Adrenal medulla NN Secretion of epinephrine and NE
Autonomic
ganglia
NN Stimulation— depend on PANS / SANS
innervation and dominance
Neuromuscular
junction
NM Stimulation—twitch/ hyperactivity of
skeletal muscle
No muscarinic receptor on skeletal
muscle à no effect.
Direct muscarinic agonist AChE Inhibitor (↑ACh)
More ACh at NMJ à skeletal
muscle contraction
TIP #2: Muscarinic agonist (direct) vs. AChE inhibitor (indirect)?
Check skeletal muscle – only the AchE inhibitor has stimulates.
Nicotinic Receptors and their
Activity
99
PHARM FUNDAMENTALS
MUSCARINIC ACTIVATION
100

51
Which of the following is the best drug for distinguishing between
myasthenic crisis (insufficient therapy) and cholinergic crisis (excessive
therapy)?
A. Atropine
B. Donepezil
C. Edrophonium
D. Physostigmine
E. Pralidoxime
101
Which of the following is the best drug for distinguishing between
myasthenic crisis (insufficient therapy) and cholinergic crisis (excessive
therapy)?
A. Atropine
B. Donepezil
C. Edrophonium
D. Physostigmine
E. Pralidoxime
102

52
Drug Clinical Uses
Acetylcholine Short half-life—no clinical use
Bethanechol Rx—ileus (postop/neurogenic) urinary
retention (contracts detrusor smooth
muscle à ↑ emptying)
Methacholine Dx—bronchial hyperreactivity
Pilocarpine,
Cevimeline
Rx—glaucoma (pilcocarpine), xerostomia
Direct Acting Muscarinic
Agonists
NAMING: Muscarinic agonists
“-chol”
PATH: Sjogren’s syndrome
Tx: pilocarpine, cevimeline
103
Drug Clinical Uses
Edrophonium Dx—myasthenia; used to differentiate myasthenia
from cholinergic crisis
Physostigmine Rx—glaucoma; antidote in atropine overdose
Neostigmine,
pyridostigmine
Rx—ileus, urinary retention, myasthenia, reversal
of non-depolarizing NM blockers
Donepezil,
Rivastigmine,
Galantamine
Rx—Alzheimer disease
Indirect Acting
Acetylcholinesterase Inhibitors
NAMING: Acetycholinesterase inhibitors – “-stigmine”
PATH: Alzheimer’s—Loss of ACh neurons in
Meynert’s nucleus
104

53
Important Notes about
Acetylcholinesterase Inhibitors
• Physostigmine is a tertiary amine; it crosses the blood-brain
barrier
• Neostigmine and pyridostimgine are quaternary amines; they
cannot cross the blood brain barrier
• Edrophonium can be used to diagnose myasthenia, but
neostigmine or pyridostigmine are used to treat
105
Toxicity of Excess Muscarinic Activation
• Diarrhea
• Urination
• Miosis
• Bradycardia
• Bronchoconstriction
• Emesis
• Lacrimation
• Salivation
• Sweating
HINT: DUMBBELSS (excessive muscarinic activity) – too much
muscarinic agonist or too much AChE inhibitor!
HINT: Too much anti-muscarinic drug? Anti-DUMBBELSS!
106

54
PHARM FUNDAMENTALS
MUSCARINIC ANTAGONISTS
107
A patient presents to the physician with a dilated right eye and
complains that she could not read the lunch menu with the same eye.
Which of the following drugs is most likely responsible for her
symptoms?
A. Bethanechol
B. Physostigmine
C. Pilocarpine
D. Scopolamine
E. Timolol
108

55
A patient presents to the physician with a dilated right eye and
complains that she could not read the lunch menu with the same eye.
Which of the following drugs is most likely responsible for her
symptoms?
A. Bethanechol
B. Physostigmine
C. Pilocarpine
D. Scopolamine
E. Timolol
109
Muscarinic Antagonist Effects
• Decreased secretions
• Mydriasis and cycloplegia
• Hyperthermia (with resulting vasodilation)
• Tachycardia
• Sedation
• Urinary retention and constipation
• Behavioral: excitation and hallucination
HIGH YIELD SIGNS OF ANTIMUSCARINIC OVERDOSE:
Hot, dry, red, dilated pupils, tachycardia
110

56
Drug Clinical Uses
Atropine Antispasmodic, antisecretory, management of
AChE inhibitor OD, antidiarrheal, ophthalmology
(long action)
Tropicamide Ophthalmology (topical)
Ipratropium,
Tiotropium
Asthma and COPD (inhalational)—no CNS entry, no
change in mucus viscosity
Scopolamine Used in motion sickness, causes sedation
Selected Muscarinic Antagonists
NAMING: Muscarinic antagonists – “-trop-” or “-scop”
111
Drug Clinical Uses
Benztropine,
Trihexyphenidyl
Lipid-soluble (CNS entry) used in parkinsonism and
in acute EPS induced by antipsychotics
Oxybutynin,
Tolterodine
Urge incontinence à relax detrusor smooth
muscle; ↓ overactivity
Selected Muscarinic Antagonists
PATH: Parkinson’s à DA loss à excess ACh signal à resting tremors
Tx: benztropine/trihexyphenidyl
PLANT TO NOTE: Jimsonweed – gardener’s mydriasis
Contains atropine, scopolamine, and hyoscyamine
112

57
Selected Drugs with Anti-
Muscarinic Side Effects
• 1st generation anti-histamines (diphenhydramine, etc.)
• Anti-psychotics
• Tricyclic antidepressants
• Quinidine
• Meperidine
113
PHARM FUNDAMENTALS
ADRENERGIC NERVE TERMINALS
114

58
Drugs of the Adrenergic
Neuroeffector Junction
1. MAO Inhibitors
2. Releasers
3. Reuptake blockers
4. α2 agonists and
antagonists
5. Agonists and
antagonists of α1
and β1 receptors
Indirect
Direct
115
A man suffers internal bleeding that causes his blood pressure to
decrease. This causes a sympathetic response in his arteriolar smooth
muscle. What intracellular second messenger will be activated in
these cells?
A. Increase in cAMP
B. Decrease in cAMP
C. Increase in IP3
D. Decrease in IP3
E. Increased in cGMP
116

59
A man suffers internal bleeding that causes his blood pressure to
decrease. This causes a sympathetic response in his arteriolar smooth
muscle. What intracellular second messenger will be activated in
these cells?
A. Increase in cAMP
B. Decrease in cAMP
C. Increase in IP3
D. Decrease in IP3
E. Increased in cGMP
117
Receptor G-protein Downstream Signal
a1 Gq coupled ↑ phospholipase C à ↑ IP3, DAG, Ca2+
a2 Gi coupled ¯ adenylyl cyclase à ¯ cAMP
b1, b2, b3, D1 Gs coupled ↑ adenylyl cyclase à ↑ cAMP
Adrenergic Receptor Mechanisms
118

60
PHARM FUNDAMENTALS
ADRENERGIC RECEPTOR EFFECTS
119
Eye: radial (dilator)
muscle
Contraction: mydriasis
Arterioles (skin, viscera) Contraction: ↑ TPR,
↑diastolic pressure, ↑ afterload
Veins Contraction: ↑ venous return,
↑ preload
Bladder trigone and
sphincter and prostatic
urethra
Contraction: urinary retention
Liver ↑ glycogenolysis
Alpha-1 Receptors
120

61
Prejunctional nerve
terminals
↓ transmitter release and NE synthesis
Platelets Aggregation
Pancreas ↓ insulin secretion
Eye ↓ aqueous humor production
Alpha-2 Receptors
121
SA node ↑ HR (positive chronotropy)
AV node ↑ Conduction velocity (positive dromotropy)
Atrial and ventricular
muscle
↑ Force of contraction (positive inotropy),
conduction velocity, CO, and oxygen
consumption
His-Purkinje ↑ Automaticity & conduction velocity
Kidney ↑Renin release
Beta-1 Receptors
122

62
Blood vessels (all)
Vasodilation: ↓TPR, ↓ diastolic
pressure, ↓ afterload
Uterus Relaxation
Bronchioles (lungs) Dilation
Skeletal muscle ↑ glycogenolysis: contractility
Liver ↑ glycogenolysis
Pancreas ↑ insulin secretion
Eye ↑ aqueous humor production
Beta-2 Receptors
DUAL EFFECTS OF EPINEPRHINE :
Low epi? β dominates (↓ BP). High epi? α dominates (↑BP).
Physiologic dose? α dominates.
123
Receptor Target/Effect
Dopamine 1
Vasodilation: in kidney
↑ RBF
↑ GFR
↑ Na+ secretion
Beta-3
Relaxation of the detrusor muscle of the
bladder relaxation
Other Receptors
DRUG: Mirabegron (treat symptoms of overactive bladder)
DRUG: Fenoldopam (D1 agonist) – Hypertensive emergencies;
only dilator to work at kidney; causes natriuresis
124

63
Receptor G-protein Downstream signal
a1 Gq coupled ↑ phospholipase C à ↑ IP3, DAG, Ca2+
a2 Gi coupled ¯ adenylyl cyclase à ¯ cAMP
b1, b2, b3, D1 Gs coupled ↑ adenylyl cyclase à ↑ cAMP
Adrenergic Receptor
Mechanisms
125
PHARM FUNDAMENTALS
ADRENERGIC AGONISTS
126

64
Selective Alpha Agonists
Alpha-1: Phenylephrine
• ↑ Mean blood pressure via vasoconstriction
• ↑ BP may elicit a reflex bradycardia
• Primary uses: nasal decongestant and ophthalmologic use
(mydriasis without cycloplegia); hypotensive states
Alpha-2: methyldopa and clonidine
• Stimulate pre-junction receptors in the CNS to decrease
sympathetic outflow.
• Primary use: mild to moderate hypertension (HTN)
127
Selective Beta Agonists
Beta-1: Dobutamine
• Primary use: congestive heart failure
Beta-2: Salmeterol, albuterol, metaproterenol, terbutaline
• Primary use: asthma
• Tertbutaline is used for premature labor
β2 on lungs: bronchodilation
β2 on uterus: relaxation
128

65
Non-selective Beta Agonists
Isoproterenol
• Original primary uses: bronchospasm, heart block, and
bradyarrhythmia
• Side effects:
• Flushing
• Angina
• Arrhythmias
Not used anymore;
just seen in CV questions
129
PHARM FUNDAMENTALS
ADRENERGIC ANTAGONISTS
130

66
Selective Alpha Antagonists
Alpha-1: Prazosin, doxazosin, terazosin, tamsulosin
• Primary uses: hypertension, benign prosthetic hyperplasia
Alpha-2: mirtazapine
• Primary use: anti-depressant
TAMSULOSIN: Not as active in vasculature, targets a1a
MIRTAZAPINE AS AN ANTI-DEPRESSANT:
a2 antagonist: Block negative feedback à ↑ NT synthesis/release
131
Non-selective Alpha Antagonists
• Phentolamine, competitive (Use: MAO inhibitor + tyramine)
• Phenoxybenzamine, noncompetitive (Use:
pheochromocytoma)
132

67
Beta Antagonists
• b1 blockade:
• ¯ HR, ¯ SV, ¯ CO, possible AV block
• ¯ Renin release (this is the major way b blockers ↓ BP)
• b2 blockade:
• ↑ TGs, LDLs
• ¯ Aqueous humor production
• May cause problems with:
• Asthma: bronchospasm, block β2
• Vasospastics: vasospasms, block β2
• Diabetics inhibit HR changes, block β1
decreased insulin, block β2
133
Selected Beta Antagonists
Drugs b1-Selective ISA Sedation Blood Lipids
Acebutolol + ++ + –
Atenolol + – – ↑↑
Metoprolol + – + ↑↑
Pindolol – ++ + –
Propranolol – – +++ ↑↑
Timolol – – ++ ↑↑
DRUG NAMING: Beta blockers
‘”-olol” drugs
NAMING: Blockers selectivity
A-M ”-olol”: β1 selective
N-Z ”-olol”: Non-selective
134

68
Selected Beta Antagonists
Drugs b1-Selective ISA Sedation Blood Lipids
Acebutolol + ++ + –
Atenolol + – – ↑↑
Metoprolol + – + ↑↑
Pindolol – ++ + –
Propranolol – – +++ ↑↑
Timolol – – ++ ↑↑
DRUG USAGE: Beta blockers selectivity
A-M ”-olol”: better for asthmatics, diabetics, & vasospastics
(less β2 block – less side effect)
135

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