Pharmacology

Pharmacology
from the ancient Greek word for drug pharmakon
A Frieze from the
Palace of
King Sargon II
(8 th Century BC)
1600 BC Earliest written document that
mentions drugs is found in the
Egyptian Medical Papyrus
460-377 BC Hippocrates Ethics of Medicine and
the cause of disease was due to an
imbalance of humors
Mandrake
Flowers
Poppy plants
(opium)
Poppy
Capsules

57 AD Dioscorides - Materia Medica over 500 plants and
remedies
130-201 Galen - Theory of disease
1493-1541 Paracelsus – Grandfather of Pharmacology, “All
things are poisons…..depends upon the dose”
1805 Serturner – Isolated Morphine
1909 Ehrlich - Chemotherapy
1935 Domagk – discover first sulfonamide
1950’s Beyer – development of thiazides & others
Pharmacology
The study of substances (drugs) on living systems
Pharmacokinetics deals with the absorption, distribution, biotransformation and
excretion of drugs
Pharmacodynamics deals with the study of the biochemical and physiological
effects of drugs and their mechanism of action
Toxicology deals with adverse effects of drugs and chemicals
Pharmacotherapeutics the use of drugs in the prevention and treatment of
disease
Virtually all drugs produce more than one effect yet one effect that
predominates over a particular dose range is referred to the therapeutic
window.
1960/70’s
development of Propanolol and Cimetidine
Drugs are used to prevent, diagnose and/or treat disease. Drugs modify
physiological processes-they DO NOT create new processes or effects
General Drug Mechanism
Drugs are used to correct defects in physiology
Deficiency of some essential component – replacement therapy
Most Drugs act at Receptors to produce and effect
In order for drugs to interact “bind” with receptors they should have:
-Shape
-Size
-Charge
-Atomic Composition
Affinity
Excess Action of some normal or even essential ingredient –
chemical antagonist or exogenous substances
The Physiochemical Environment of the specific part of the body
may be altered by a drug – “nonspecific”

Dose Response
Lock & Key Theory of
Drug Receptor Interaction
Drug-Receptor
Complex
+ -
Drug
-
+
Receptor
Lock & Key Theory of
Drug Receptor Interaction
Drug Receptor - Affinity
How well a drug binds to a receptor is dictated
by the affinity of the drug for the receptor
Drug-Receptor
Complex
Dynamic
Drug
D + R
k +1
k -1
DR
+ -
-
+
Receptor
(Dissociation Constant)
K A = k-1
k +1
Low K A =
High Affinity

Receptors
The majority of all Receptors are proteins
Receptors bind with drugs & bring about
change in cell function
Evidence for Receptors
1. Extreme Potency/Efficacy of Drugs
2. Chemical Selectivity (i.e., similar molecules
produce similar effects)
Evidence for Receptors
1. Extreme Potency/Efficacy of Some Drugs
2. Chemical Selectivity (i.e., similar molecules
produce similar effects)
3. Stereoselectivity

L-Epinephrine
D-Epinephrine
L-Epinephrine
D-Epinephrine
OH
H
H
CH 3
OH
OH
H
CH 3
OH C C N
OH
H
H
OH C C N
H
H
H
Stereo-Selectivity
OH
H
H
CH 3
OH
OH
H
CH 3
OH C C N
OH C C N
OH
H
H
H
H
H
Intracellular Effects
Evidence for Receptors
Targets for Drug Action
1. Extreme Potency/Efficacy of Some Drugs
2. Chemical Selectivity (i.e., similar molecules
produce similar effects)
3. Stereoselectivity
4. Competitive Antagonists
5. Cloning and Expression of Receptors

Drug
G-protein Coupled Receptors
Drug
NT
NT
AC
GDP
G-protein Coupled Receptors
G-protein Coupled Receptors
NT
GIRK
NT
K +
GIRK
AC
AC
NT NT
NT NT
βγ
α βγ
GDP
α
GTP
K +
GTP
GDP

G-protein Coupled Receptors
G-protein Coupled Receptors
NT
K +
NT
K +
AC
AC
NT NT
K +
NT NT
α
GTP
cAMP
K +
α
GTP
ATP
GDP
GDP
amplification
PKA
cREB
G-protein Coupled Receptors
NT
AC
NT NT
α
GDP
GTP
P
βγ
PDE
cAMP
5’AMP
amplification
PKA
cREB

G q -protein Coupled Receptors
Cont. G q -protein Coupled Receptors
G q Coupling
(G q -protein)
CAM
kinase
Ca 2+
Ca 2+
PKC
PIP 2
PLC
IP3
DAG

Tyrosine Kinase Receptors
Kinase
cascade
2 nd Messenger linked Receptors (metabotropic)

Dose Response Curves
Dose Response Curves
Propionylcholine
100 Acetylcholine
Acetylcholine
100
% Response
75
50
25
Propionylcholine
75
50
25
0
0.0 0.2 0.4 0.6 0.8 1.0
Dose ( μg/ml)
arithmetic scale
0
0.001 0.01 1.0 10.0
Dose ( μg/ml)
logarithmic scale
% Response
100
75
50
25
Relevant Data on a Dose
Response Curve
80%
20%
Three Different Types of Dose
Response Curves
0
0.001 0.01 1.0 10.0
Log Dose (ug/ml)
ED 50 = 0.05ug (x- intercept)

Quantal Dose Response Curve
Graded Dose Response Curve
100
100
# Responding
75
50
25
Variable:
Dose
Constant:
Time
Response
% Response
75
50
25
Variable:
Dose
Response
Constant:
Time
0
0.001 0.01 1.0 10.0
0
0.001 0.01 1.0 10.0
Log Dose ( μg/ml)
Log Dose ( μg/ml)
Time Action Curve
Potency vs. Efficacy
% Response
100
80
60
40
20
1 mg/kg
3 mg/kg
10 mg/kg
Variable:
Dose
Response
Time
% Response
100
75
50
25
0
Efficacy A
B
Potency
0.001 0.01 1.0 10.0
C
0
0 15 30 45 60 75 90 105 120
Log Dose (ug/ml)
Time (min)

Dose Response Curves
Dose Response Curves
% Response
100
75
50
25
0
Partial Agonist
B
C
A
Full Agonist
Antagonist
Potency: Left/Right shift of the dose response curve,
Amount of drug required to produce a response
Efficacy: The height of the dose response curve,
-25
D
Inverse Agonist
Ability of a drug to induce a maximal response
0.001 0.01 1.0 10.0
Log Dose (ug/ml)
Dose Response Curves
Does and Antagonist have Affinity
Does and Antagonist have Efficacy
Does and Antagonist have Potency
YES
NO
YES
Which has higher Efficacy
Partial agonist
Full agonist
Partial agonist
Which has higher Potency
Full agonist
Can’t tell without looking at a DRC

Shift in Potency
No loss of Efficacy
Competitive Antagonist
Shift in Potency
loss of Efficacy
Drugs Often Result in
Several Biological
Responses

Drugs Produce More Than One Effect
Drugs Produce More Than One Effect
% Response
100
75
50
25
constipation
antitusive
analgesia
resp. depression
death
% Response
100
75
50
25
Therapeutic Index “window”
LD 50
ED 50
=
50
2
= 25
analgesia
death
0
0.001 0.01 1.0 10.0
100.0 1000.0
0
0.001 0.01 1.0 10.0
100.0 1000.0
Log Morphine (mg/kg)
ED 50 (2mg/kg)
LD 50 (50mg/kg)
Log Morphine (mg/kg)
Response According to Age Sex Health
% Response
100
80
60
40
20
Teenager Female Lance Armstrong
Middle Male Todd Vanderah Age
Elderly Dick Cheney
0
1 3 10 30 100 300
Log [Drug]

Review
Agonists: Affinity, Selectivity, Potency and Efficacy
Antagonists: Affinity, Selectivity & Potency
Competitive Antagonists: Decrease Potency
Non-Competitive Antagonists: Decrease Potency
Decrease Efficacy
Drugs often produce more than one effect
Drug Response depends on the tissue it acts on
Review
Categories of Receptors
- Ion Channels (ionotropic)
-Enzymes
- Transporters
-2 nd Messenger Receptors
- Nuclear Receptors
- Kinase receptors
-G-proteins
Activation of
G-proteins
Leads to
G αs
G αi
G αq
Decrease cAMP and PKA activity
Activate the Kinase Cascade
Increase cAMP and PKA activity
PLA 2
Tyrosine Kinase Receptors
Adenylate Cyclase
Increase Arachidonic Acid Release
Increase IP3 and DAG
Increase PKC and CAM kinase activity
Decrease IP3 and DAG

Pain and Opioid Mechanisms
Pain
• Most common reason for seeking medical care
• Everyone experiences pain…30% of Americans will
suffer from chronic pain
• Treatment of pain improves outcome;
• Chronic pain is itself a disease which can and should
be treated.
Congenital Insensitivity to Pain

C & Aδ Fibers
Pain Pathways
Somatosensory
Cortex
Thalamus
From
Brain
To
Brain
Spinal
Cord
Neural Steps in the Processing of Pain Signals
1. Transduction - Noxious stimuli → electrical signals
2. Transmission - Neural events from the periphery to the
cortex
3. Modulation - Nervous system can selectively inhibit or
enhance pain signals
4. Perception - subjective interpretation by the cortex
Sensory component
Affective component
Nociceptive Transmission Pathway
Sensory
Receptor Periphery CNS
Nociceptors:
• C-polymodal
small, non-myelinated
• Aδ-mechanical
thermal
Medium, thinly-myelinated
Spinal
cord
DRG
Thalamus

C-Polymodal Nociceptors
Pressure
Nociceptors (C & Aδ fibers)
Free nerve endings that do NOT adapt
Heat
Respond to many modalities
Action Physical: heat, cold, force
Potentials Chemical: capsaicin, protons, bradykinin, ATP, PGE 2
Found Heat throughout body:
Stimuli
skin, muscle, joint, viscera, bone
48 ºC
Chemical
Some are unresponsive “silent”
only respond after injury or inflammation
TRPV1 receptor
ion channel
Na +
Ca +2
outer
Inner
Heat
Activation
Peripheral Nociceptor Activation
↓pH
Receptor Potential
Prostaglandins (PG)
K +
Bradykinin (BK)
Capsaicin
Used to identify nociceptors
Trigger Zone

Peripheral Nociceptor Activation
“Axon Reflex”
Peripheral Nociceptor Activation
“Recruitment of Surrounding Nociceptors”
H
mast cell
PG SP
H
PG
SP
PG
SP
PG
platelet
BK
Neuronal recruitment
Trigger Zone
Peripheral Nociceptor Activation
“Actions of Pain Relievers”
Sensitized Nociceptors
Allodynia
Hyperalgesia
Opioids
Neuronal recruitment
H
PG
SP
PG
Opioids
1) Opioids act to hyperpolarize the nociceptor
2) Opioids act to reduce inflammatory mediators
From immune cells (also the site of NSAIDs)
Subjective Pain Intensity
6
5
4
3
2
1
41 43 45 47 49
Stimulus Temperature ( o C)
After
injury
Naive

C and Aδ Nociceptor Mediated Pain
C-fiber
Touch fibers
DRG
Dorsal
Columns
Spinothalamic
Tract
Periphery
Spinal Cord
Pain Fibers
Aδ fiber
Lisauer’s tract
I
Pain
intensity
First
pain
Second
pain
laminae
II
IV
V
Time
Ventral
Roots
Burn
Spinothalamic
Projection to
Thalamus
Opioids Inhibit Noxious Input
Nociceptive
Input
Flare
ENK
Ca ++
Substantia
gelatinosa
Spinal
Cord
μ Opioid Receptors
Pain Transmitters:
Glutamate
Substance P
Dorsal Horn,
Spinal Cord
EPSP

Spinothalamic
Projection to
Thalamus
Opioids Inhibit Noxious Input
ENK
Morphine / Fentanyl
Nociceptive
Input
Ca ++ Conductance
Substantia
gelatinosa
K + efflux (hyperpolarize)
Afferent Pathways
Underlying The Sensation
of Pain
MIDBRAIN
MEDULLA
THALAMUS
STT
Activation of μ
Opioid Receptors
Morphine / Fentanyl
Pain Transmitters:
Substance P
Glutamate
CGRP
K + efflux (hyperpolarize)
DRG
Glutamate
Substance P
2º
SPINAL CORD
Descending
Pain
Pathways
To thalamus
Rostral
midbrain
From hypothalamus,
amygdala, cortex
Periaqueductal
gray
Descending Modulation of Spinal Nociceptive Input
Opioid Disinhibition
PAG
CP/RM
GABA A
CL -
GABA
Caudal Pons
Rostral Medulla
Nucleus
Raphe magnus
From pain
nociceptors
Dorsolateralfuniculus
(DLF)
(Hyperpolarize)

Descending Modulation of Spinal Nociceptive Input
PAG
Opioid Disinhibition
Morphine
(Hyperpolarize)
CP/RM
Release
5HT & NE
Enk/End
GABA A
CL -
(Hyperpolarize)
X
GABA
release
GABA
K +
DLF
PAG
CP/RM
Release
Enkephalins / Endorphins
Serotonin / Norepinephrine
Opioid Receptors
• Three cloned opioid receptors
– mu, delta and kappa
• Opioid receptors are coupled to the G i /G o class of
G-protein coupled receptors
• Opioid agonist cause inhibition of adenylyl cyclase
and decrease cAMP formation
• Selective agonists:
– Fentanyl
– Morphine
– Meperidine
• Selective antagonists:
– β-FNA
N
OH
μ Opioid Receptor
Mu
• Most of the currently available opioids work
through the mu opioid receptor
HO
O
N
H
O
O
O

δ Opioid Receptor
κ Opioid Receptor
• Selective agonists:
– DPDPE
– SNC80
– Deltorphin II
• Selective antagonist:
– Naltrindole
• Selective agonists:
– Butorphanol
– Ketocyclazocine
• Selective antagonist:
– nor-BNI
N
OH
N
OH
N
HO
HO
O
N
H
HO
O
N
H
O
OH
Mammalian Endogenous Opioid Peptides
Opioid Receptor Pharmacology
Precursor Endogenous peptide Amino acid sequence
Pro-opiomelanocortin β-Endorphin YGGFMTSEKSQTPLVTLFKNAIIKNAYKKGE
Pro-enkephalin [Met]enkephalin YGGFM
[Leu]enkephalin
YGGFL
YGGFMRF
YGGFMRGL
Metorphamide
YGGFMRRV-NH2
Pro-dynorphin Dynorphin A YGGFLRRIRPKLKWDNQ
Dynorphin A(1-8)
YGGFLRRI
Dynorphin B
YGGFLRRQFKVVT
α-neoendorphin
YGGFLRKYPK
β-neoendorphin
YGGFLRKYP
Pro-nociceptin / OFQ Nociceptin FGGFTGARKSARKLANQ
Pro-endomorphin* Endomorphin-1 YPWF-NH2
Endomorphin-2
YPFF-NH2
•Different pharmacological effects are mediated by
the different receptors
CNS
CNS
Gut
CNS
CNS
CNS
CNS
Pharmacological Effects of Opioid Receptor
Activation
Effect Mu (μ) Delta (δ) Kappa (κ)
Analgesia +++ +++ +
Respiratory Depression +++ 0 +
Constipation +++ + 0
Prolactin Release +++ 0 +
Euphoria +++ 0
Dependence Potential +++ + 0
Dysphoria + +++
*Presumed to exist, awaiting discovery

Main Effects of Opioids at Therapeutic Doses
Physical Dependence
Desirable Undesirable Mixed Desirability
Analgesia Nausea, vomiting Sedation
Relief of anxiety Urinary retention Euphoria
Dysphoria
Cough suppression
Mental clouding ↓ Bowel motility
Tolerance
Drug dependence syndrome
Respiratory depression
Postoperative ileus
Biliary spasm
• Prolonged exposure to an opioid agonist can
produce adaptations at the cellular and systems
levels which oppose the drug effect
– the patient has become physically dependent on the
drug
• physical dependence does not equal addiction!!!
• The discontinuation or sudden reduction in drug
levels, or the administration of an antagonist, can
lead to a withdrawal syndrome
Symptoms and Signs of Opioid Withdrawal
Addiction Liability
Symptoms
restlessness
irritability
increased sensitivity to pain
nausea
abdominal cramps
myalgia
dysphoria
insominia
anxiety
drug craving
Signs
pupillary dilation
sweating
tachycardia
vomiting
diarrhea
hypertension
yawning
fever
rhinorrhea
piloerection
• Studies in the 1920s and 1950s were influential in
setting opioid analgesia policy in the later part of
the 20 th century
– chronic opioid therapy leads to addiction
– Kathleen Foley quote
• These studies had methodological flaws and more
recent reports have suggested that the risk of
iatrogenic opioid addiction is very low
– the incidence of addiction in chronic pain patients
parallels the lifetime prevalence rates in the general
population (Fishbain et al., 1992)

Addiction Liability
Dopaminergic Disinhibition
VTA
Mesolimbic & Mesocortical
Dopaminergic Pathway
Mesolimbic & Mesocortical
Dopaminergic Pathway
Dopamine
Release
GABA A
CL -
(Hyperpolarize)
GABA A
CL -
(Hyperpolarize)
(Hyperpolarize)
Morphine
X
GABA
release
GABA
GABA
K +
Respiratory Depression
• Respiratory depression is the most lifethreatening
of the side-effects associated with
opioid analgesics
– major cause of fatal opioid overdoses
• Opioid receptors are located on chemoreceptors
and ventral respiratory group neurons in the
medulla
– diminished sensitivity to changes in O 2 and CO 2 levels
– changes in tidal volume and frequency of respiration
Constipation
• One of the biggest concerns with chronic opioid
administration is severe constipation
– occurs in almost all patients receiving chronic opioids
• In many cases, constipation is the primary reason
for the patient discontinuing opioid therapy
– development of opioid antagonists that do not cross
the blood-brain barrier
Oral
Peristalsis Produced by Coordinated
Contraction and Relaxation of Muscle Coats
Longitudinal muscle
*****
*****
Bolus
*****
*****
Myenteric plexus
(Auerbach’s)
***** *****
***** *****
Anal
Contracted
Relaxed
Circular muscle
Submucous plexus
(Meissner’s)

Opioids and Intestinal Motility
Segmenting Contractions
Normal
Reduced Contractions
{
Diarrhea
Propulsive Contractions
Segmenting Contractions
Opioids
Loperamide (Imodium)
Normal
Flow
Increased
Flow
Increased
Flow
Decreased
Flow
Drug Interactions
• Many other CNS depressants can act in an additive or
synergistic manner with opioid analgesics
– benzodiazepines
–barbiturates
–alcohol
– antipsychotics
• MAO inhibitors with opioids may produce hyperpyrexic
coma and hypertension
– especially with meperidine
• Stimulants have sometimes been used to counteract the
CNS depressant effects of opioids
Morphine
Methadone
• Prototypical mu opioid agonist
– still isolated from raw opium
• Multiple preparations available
–parenteral
– oral and sustained release (MS Contin)
–rectal
• Indicated for moderate to severe pain
• Full opioid agonist
– efficacy similar to morphine
– good oral bioavailability
– long half-life and duration of action
• The compound has antagonist actions at the
NMDA receptor complex
– decreased development of tolerance and physical
dependence
– role in treatment of neuropathic pain
• Used in the treatment of heroin addiction

Fentanyl and Analogues
Meperidine
• Relatively selective mu opioid agonists
– typically more potent than morphine
– shorter duration of action (e.g., remifentanil)
– high efficacy compounds
• Fentanyl can be given by various routes
– transdermal patch
– fentanyl lozenge (lollipop)
• Moderate efficacy opioid agonist
– used for moderate pain
• The compound has antimuscarinic effects
– cardiovascular effects possible
– limited constriction of the pupil
• Accumulation of metabolite (normeperidine) can
produce seizures
– caution with high doses and in patients with renal
insufficiency
Codeine
Oxycodone
• Codeine is a weak opioid analgesic
– has limited affinity for opioid receptors
– considered a prodrug
• Needs to be demethylated to morphine
– approximately 10% of Caucasians lack the cytochrome
P450 isozyme (CYP 2D6)
– these patients will get no relief from even high doses
of codeine
• Opioid agonist with moderate efficacy
• Recent controversy with this drug
– sustained release preparation-OxyContin
– pellets can be crushed and a solution injected
• Purdue Pharma has tried to reformulate the
compound with naloxone
– oral administration would still be effective
– parenteral administration would result in blockade of
opioid actions

Propoxyphene
Diphenoxylate/Loperamide
• Very weak opioid agonist
– used in combination with aspirin and
acetaminophen
• Limited clinical utility
• Diphenoxylate is a weak opioid agonist with low
abuse liability
– atropine added as a combination product for
treatment of diarrhea and to discourage abuse
• Loperamide is a weak opioid agonist that does not
readily cross the blood-brain barrier
– low abuse liability
– common OTC antidiarrheal medication
Mixed Opioid Agonists/Antagonists
Tramadol
• These compounds are characterized by different
actions on each of the opioid receptors
–nalbuphine-kappa agonist/mu antagonist
–buprenorphine-partial mu agonist
– pentazocine-kappa agonist, weak mu agonist
• These agents are contraindicated in opioid
dependent patients
– severe withdrawal syndrome may develop
• Novel analgesic action
– weak mu opioid agonist
– blocks reuptake of serotonin
– blocks reuptake of norepinephrine
• Marketed as a compound with efficacy similar to
codeine with less side-effects
– no addiction liability
– less GI effects
– efficacy in neuropathic pain states
–expensive

Naloxone
Naltrexone
• Prototypical opioid antagonist
• Used to treat opioid overdose
– low oral bioavailability
– short duration of action
• Will precipitate a severe withdrawal syndrome in
opioid dependent patients
• New evidence suggests that this compound has
inverse agonist actions in opioid dependent states
– increase in withdrawal symptoms
• Prototypical opioid antagonist
• Used to treat heroin addicts
– good oral bioavailability
– long duration of action
• New evidence suggests that this compound has
inverse agonist actions in opioid dependent states
– role in patient compliance
• Approved for the treatment of alcoholism
– decreases binge type drinking
Conclusions
Tucson, Arizona Pain Group
• Pain is mediated by nociceptors and perceived by the
brain.
• Multiple sites where opioids work to relieve pain.
• Opioids produce multiple effects.
• Opioids are abused for their euphoric effects by
indirectly causing an increase in dopamine release.