Transcript IVG. Well-established Second Messengers Ca++

IVG. Well-established Second Messengers
cAMP
Second messenger: Cyclic AMP
1. cAMP is 2nd messenger - released into cytoplasm due to
1st messenger (hormone) binding; a number of others in
eukaryotic cells
2. 2nd messengers can activate many cell activities leading to
large-scale, coordinated response
cAMP
IVG. Well-established Second Messengers
mediates such hormonal responses as:
the mobilization of stored energy
Beta*the breakdown of carbohydrates in the liver
adrenergic
catecholamines
*the breakdown of triglycerides in fat cells
increased rate and strength of heart muscle
contraction
the conservation of water by the kidneys
cAMP inducing agent=vasopressin
Ca++ homeostasis
cAMP inducing agent = parathyroid hormone
many many other responses mediated by cAMP
cAMP
IVG. Well-established Second Messengers
Agonist binding
AC
Activation of Gs
and stimulation of
the effector
Adenylyl Cyclase
(AC)
ATP
Conversion of ATP to
cyclic AMP (cAMP) by
AC.
cAMP
Reg= regulatory region
Cat= catalytic region
Cat
Cat
Reg
Reg
cAMP-dependent protein kinase
[CAMP kinase]
cAMP
IVG. Well-established Second Messengers
Agonist binding
AC
ATP
Binding of cAMP to
Reg sites releases
the cat regions
which can
phosphorylate
proteins.
cAMP
P
Substrate
Cellular Response
Cat
ATP
Cat
Reg
cAMP
Reg
cAMP
Substrate
cAMP-dependent protein kinase
[CAMP kinase]
cAMP
IVG. Well-established Second Messengers
P
Substrate
Cellular Response
Can include any of these:
*Enzyme activation
*Protein synthesis
*Muscle relaxation
*Nerve stimulation
*Hormone secretion
cAMP
IVG. Well-established Second Messengers
When the agonist stimulus
Agonist dissociates
stops, the intracellular
actions of cAMP are
terminated by three
mechanisms (1-3).
AC
1
GTP
hydrolysis
3
P
Substrate
Phosphatases
P
X
Phosphorylated
substrate
generated by
CAMP kinase is
de-phosphorylated
Substrate
Diminished cellular response
ATP
X
cAMP
2
5’-AMP
Cyclic nucleotide
phosphodiesterases
CAMP kinase activation is inhibited
Re-establishment of the tetramer
Cat Reg
Cat Reg
cAMP
IVG. Well-established Second Messengers
Agonist dissociates
AC
GTP
hydrolysis
ATP
X
Cyclic nucleotide
phosphodiesterases
cAMP
5’-AMP
FYI
What would you expect the effect of
caffeine on cAMP levels to be?
How about on CAMP kinase?
Caffeine
Theophylline
Other methylxanthines
Act as competitive
inhibitors of
phosphodiesterases
cAMP
IVG. Well-established Second Messengers
Different cells express different types of substrates for
CAMP kinase, which helps explain some of the tissuespecific effects:
In Liver
Phosphorylase Kinase
Activated by phosphorylation
CAMP
ATP
P
Phosphorylase Kinase
Glucose released
from glycogen
CAMP
Glycogen Synthase
ATP
P
Glycogen Synthase
Inhibition of
inactivated by phosphorylation
glycogen synthesis
IVG.
Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Another well-studied 2nd messenger system involves receptormediated stimulation of phosphoinositide hydrolysis.
Some of the agonists, hormones and growth factors that trigger
this pathway bind to G-protein coupled receptors (Gqcoupled)
Receptor
acetylcholine (muscarinic)
alpha1-adrenergic
platelet activating factor
serotonin (5-HT 1C and 5-HT 2)
2nd messenger
Ca++
&
phosphoinositides
IVG.
Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Inositiol-Phosphate Pathway
A. Ligand binding activates G protein
B. G protein activates phospholipase C (PLC)
C. PLC hydrolyzes phosphatidyl inositol 4,5 bis-phosphate
to diacylglycerol (DAG) and inositol 1,4,5 tris-phosphate
(IP3) - both second messengers
1. IP3 goes to ER where it stimulates the release of calcium and activates protein kinases
2. DAG stays in membrane where it binds and
activates protein kinase C (PKC)
IVG.
Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Agonist binding
DAG
PLC PIP2
Gq protein
stimulation
IP3
PLC family that produces two second messengers,
diacylglycerol (DAG) and inositol 1,4,5-triphosphate
(IP3) by hydrolyzing the membrane lipid
phosphatidylinositol 4,5-bisphosphate (PIP2).
IVG.
Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Agonist binding
DAG
PLC PIP2
Gq protein
stimulation
IP3
Ca++ Ca++
Ca++
IP3 goes to ER where it stimulates release of
calcium activates protein kinases
Ca++
IVG.
Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Agonist binding
DAG
PLC PIP2
Gq protein
stimulation
ER
IP3
Ca++ Ca++
Ca++
Released Ca++ binds to
calmodulin.
Calmodulin
Ca++
Ca++
Ca++
Ca++
release
IVG.
Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Agonist binding
DAG
PLC PIP2
ER
IP3
Calmodulin becomes
activated and
stimulates signaling Ca++
Ca++
through calcium/
Calmodulin
calmodulin
dependent protein
kinases
Calcium/Calmodulin-Dependent
Protein Kinase
Ca++ Ca++
Ca++
Ca++
Ca++
Ca++
Ca++
release
IVG.
Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Agonist binding
DAG
PLC PIP2
ER
IP3
Ca++ Ca++
Inactive
Active P
Ca++
Ca++
Ca++
Calmodulin
Calcium/Calmodulin-Dependent
Protein Kinase
Ca++
Ca++
Ca++
Ca++
release
IVG.
Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Ca++
Ca++
Calmodulin
Calcium/Calmodulin-Dependent
Protein Kinase
active
Substrate
ATP
P
Substrate
Cellular Response
IVG.
Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Agonist binding
DAG
PLC PIP2
Gq protein
stimulation
IP3
Meanwhile, DAG stays in membrane where it
binds and activates protein kinase C (PKC)
PKC
inactive
IVG.
Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Agonist binding
DAG
PLC PIP2
Gq protein
stimulation
IP3
PKC
Substrate
active ATP,
Ca++
P
Substrate
Activated PKC will phosphorylate certain
substrates involved in cellular response.
Cellular Response
IVG.
Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
In addition to general calcium/calmodulin-dependent protein
kinases that can phosphorylate a wide variety of substrates,
Different cell types may contain one or more
specialized Calcium/calmodulin-dependent protein
kinases with limited substrate specificity
(eg. myosin light chain kinase).
At least nine different types of PKC have been characterized.
IVG.
Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Multiple mechanisms exist to terminate signaling by this PLC
pathway:
IP3 is rapidly dephosphorylated by phosphatases
DAG is either
phosphorylated and converted back to into
phospholipids
or
deacylated to yield arachidonic acid
Ca++ is actively removed from the cytoplasm by calcium ion
pumps (into ER)
These and other nonreceptor elements of the calciumphosphoinositide signaling pathway are now becoming
targets for drug development.
cGMP
IVG.
Well-established Second Messengers
cGMP (cyclic guanosine-3’,5’-monophosphate) has established
signaling roles in only a few cell types.
In intestinal mucosa and vascular smooth muscle, cGMP-based
signal transduction is initiated when:
GTP
*ligand binds to extracellular domain of receptor
*ligand binding stimulates intracellular guanylyl cyclase
activity
*cGMP activates cGMP-dependent protein kinases
Guanylyl cyclase
Substrates get
cGMP
cGMP-dependent protein kinase
phosphorylated
cGMP-dependent protein kinase
IVG.
Well-established Second Messengers
cGMP
Increased cGMP
Atrial natriuretic factor
Binds its receptor
ANFR
GTP
GCactivity
cGMP
cGMP accumulation
NO
The lipid-soluble gas
nitric oxide (NO) is
GTP
Guanylyl
released by nearby
cyclase
vascular endothelial cells
cGMP
And direct activates the
enzyme. Several vasodilator drugs mimic NO cGMP accumulation
IVH. Phosphorylation: a Common Theme
*Reversible phosphorylation is involved in almost all
2nd messenger systems.
*Phosphorylation plays a key role in every step of
signaling:
Regulation of receptors
(eg. autophosphoryltion; desensitization)
Regulation of kinases and kinase-substrates
modulating cellular responses
IVH. Phosphorylation: a Common Theme
Think of phosphorylation as a molecular ‘memory’
phosphorylation records the memory
dephosphorylation erases the memory,
often taking longer than is required for
dissociation of ligand
Lastly,
cAMP, Ca++ and other 2nd messengers can use the
presence or absence of kinases or kinase substrates
to produce different effects in different cell types.
V.
Receptor Classes and Drug Development
Receptor Subtypes
Evidence for receptor subtypes arose because agonists
that supposedly mimicked the same neurotransmitter had
radically different postsynaptic effects at different sites.
For example, although both smooth and striated muscle
contain acetylcholine receptors, nicotine exerts potent
agonistic effects on striated muscle, yet is nearly
ineffective on smooth muscle.
Similarly, muscarine exerts potent agonistic effects on
smooth muscle, yet is much less effective on striated
muscle. Thus acetylcholine receptors come in at
least two varieties, nicotinic and muscarinic.
V.
Receptor Classes and Drug Development
The same chemical can act on completely different
receptor classes:
Acetylcholine
activates nicotinic acetylcholine receptors
*Ligand-gated ion channel
activates muscarinic acetylcholine receptors
*G-protein coupled receptor (Gq)
Each receptor class usually includes multiple subtypes of
receptor, often with significantly different signaling or
regulatory properties.
V.
Receptor Classes and Drug Development
The same chemical can act on completely different
receptor classes:
Norepinephrine
activates many structurally-related receptors
beta-adrenergic
G protein-coupled, Gs; increased heart rate
alpha1-adrenergic
G protein-coupled, Gq; vasoconstriction
alpha2-adrenergic
G-protein coupled, Gi;
opening of K+ channels; decreased heart rate
V.
Receptor Classes and Drug Development
The existence of multiple receptor classes and
subtypes for the same ligand has opened up
opportunities fro drug development:
Propranolol, a selective antagonist of beta-adrenergic
receptors
can reduce heart rate without preventing the
sympathetic nervous system from inducing
vasoconstriction
(because it acts at beta-adrenergic and not alpha)
(alpha mediates vasoconstriction)
V.
Receptor Classes and Drug Development
Drug selectivity may apply to structurally identical receptors
expressed in different cells
for example:
the drug tamoxifen acts as an
*antagonist on estrogen receptors in mammary tissue
(useful as treatment in breast cancer)
*agonist on estrogen receptors in bone.
(may help against osteoporosis)
*partial agonist on estrogen receptors in the uterus
(stimulates endometrial cell proliferation)
V.
Receptor Classes and Drug Development
Drug selectivity may apply to structurally identical receptors
expressed in different cells
WHY?
different cell types express different accessory
proteins which interact with steroid receptors
and change the functional effects of drugreceptor interaction.
V.
Receptor Classes and Drug Development
NEW DRUG DEVELOPMENT
not confined to agents that act on receptors
clinically useful agents might be developed
that act selectively on specific:
G proteins
kinases
phosphatases
or the enzymes that degrade 2nd
messengers
VI.
Relationship Between Drug Dose and Clinical Response
When faced with a patient who needs treatment:
*variety of possible drugs
which one will drug will produce a maximal
benefit?
what kind of dosing regimen is required?
The prescriber must understand:
*how drug-receptor interactions underlie the relations
between dose and response in patients
*are there known variations in responsiveness to the
drug? Toxic side effects?
EFFECT
(% of maximum)
VIA. Dose and Response in Patients
Graded Dose-Response Curves
show effects on a continuous scale and the intensity
of the effect is proportional to the dose.
(what we’ve been discussing thus far)
Log concentration
VIA. Dose and Response in Patients
Graded Dose-Response Curves
When choosing among drugs and determining appropriate
doses of drug, it is important to consider each drug’s
potency and maximal efficacy.
100%
Response
Potency
refers to the concentration
EC50 or dose ED50 of drug
required to produce 50% of
that particular drug’s maximal
effect.
A
B
50%
Log [Drug]
Which is more potent?
EC50 EC50
A lower dose needed to elicit 50% max response
VIA.
Dose and Response in Patients
A
B
Response
100%
C
50%
25%
Log [Drug]
EC50
EC50
EC50
NOTE: Drug C acts as a partial agonist.
Which is more potent?
C lower dose
needed to elicit 50%
of a particular drug’s
max response
Potency
refers to the
concentration EC50
or dose ED50 of
drug required to
produce 50% of
that particular
drug’s maximal
effect.
VIA.
Dose and Response in Patients
Efficacy
In this example, the
maximal efficacy of
drug C is less than
the maximal
efficacies of drugs A
and B.
Drugs A and B have
the same efficacy.
B
100%
Response
the measure of an
effect produced by a
drug.
A
C
50%
25%
Log [Drug]
ED50
ED50
ED50
VIA.
Dose and Response in Patients
Efficacy
depends on factors such as:
route of administration
absorption
distribution throughout the body
clearance from the blood or the site of action
VIA. Dose and
Response in Patients
Extremely steep dose response curves may have important
clinical consequences if the upper portion of the curve
represents an undesirable extent of response (eg. coma
caused by a sedative-hypnotic).
EFFECT
(Sedation)
Shape of Dose-Response Curves
coma
Undesirable
sleep
More desirable
Log [Drug]
Steep dose-response curves can also be produced by a
receptor-effector system in which most receptors must be
occupied before any effect is seen.
VIA. Dose and
Response in Patients
Graded dose-reponse curves are limited in their application to
clinical decision making:
Quantal Dose-Effect Curves
*impossible to use them if pharmacologic response is
an ‘either-or’ event (a quantal event)
prevention of: convulsions, arrhythmias, death
*clinical relevance of a graded dose response curve in
a single patient may be limited in its application to
other patients
potential variability among patients in
*severity of disease
*responsiveness to drug
VIA.
These problems may be
avoided by:
determining the dose of
drug required to produce an
effect of specific magnitude
in large numbers of patients
(or animals) and then
plotting the cumulative
frequency distribution of
responders vs. the log dose.
Patients tend to respond to
drugs in a distribution
similar to a Gaussian normal
curve.
Dose and Response in Patients
100
Percent of Individuals Responding
To Treatment (eg. for headache)
Quantal Dose-Effect
Curves
50
Dose at which
50% of
patients exhibit
the specified
quantal effect
Log [Drug]
ED50
VIA.
Dose and Response in Patients
Quantal Dose-Effect Curves
Quantal dose-effect curves may also be used to generate
information regarding the margin of safety.
Toxic effects of a drug on humans or animals can also be
assessed by plotting the cumulative frequency distribution
of responders vs. the log dose.
As for the therapeutic effects, potentially toxic effects of
drugs display a distribution similar to a Gaussian normal
curve in people or animals.
In order for a drug to have a high margin of safety in
patients or animals, therapeutic effects should be observed
at lower doses than toxic effects.
VIA.
Percent of Individuals Responding
100
Cumulative
percent of
patients exhibiting
therapeutic effect
50
Dose and Response in Patients
Cumulative
percent of
patients exhibiting
toxic effect
Therapeutic effects and
toxic effects do not
overlap
Dose at which
50% of
patients exhibit
the specified
quantal effect
ED50
Dose at which
50% of
patients exhibit
a toxic effect
TD50
Log [Drug]
Quantal curve of a hypothetical drug that provides relief for headaches.
VIA.
Percent of Individuals Responding
100
50
Cumulative
percent of
patients
exhibiting
therapeutic
effect
Dose at which
50% of patients
exhibit the
specified quantal
effect
ED50
Dose and Response in Patients
Therapeutic
effects and toxic
effects slightly
overlap
Cumulative
percent of
patients
exhibiting
toxic effect
Dose at which
50% of
patients exhibit
a toxic effect
TD50
Log [Drug]
Quantal curve of a second drug that provides relief for headaches.
VIA.
Percent of Individuals Responding
100
50
Cumulative
percent of
patients
exhibiting
therapeutic
effect
Dose at which
50% of patients
exhibit the
specified quantal
effect
ED50
Dose and Response in Patients
Cumulative
percent of
patients
exhibiting
toxic effect
Dose at which
50% of
patients exhibit
a toxic effect
Therapeutic
effects and toxic
significantly
overlap
TD50
Log [Drug]
Quantal curve of a third drug that provides relief for headaches.
Percent of Individuals Responding
VIA.
Dose and Response in Patients
No overlap in the quantal
dose-response curve is
highly desired (to avoid
unwanted toxic effects),
but not always possible.
100
50
ED50
TD50
The margin of safety
of a drug will depend
on the ratio between
Log [Drug] ED50 and TD50.
The therapeutic index is defined as the ratio of
TD50
------ED50
What can be said of a drug’s safety if
this ratio is equal or close to 1?
VIA. Dose and Response in Patients
The therapeutic index (TI) of a drug in humans is
almost never known
most studies involving obvious toxicity are halted
toxicity studies in animals are used to estimate
a drug’s therapeutic index.
In summary,
Both graded and quantal dose-effect curves provide
information concerning the potency and selectivity of
drugs.
The graded dose-response curve indicates the maximal
efficacy of a drug.
The quantal dose-effect curve indicates the potential
variability of responsiveness among patients.
VIB.
Variation in Drug Responsiveness
Individuals may vary in responsiveness to a drug.
Responses include:
idiosyncratic
an unusual response very rarely observed in
most patients
hypo-responsive
drug effect is smaller than expected
hyper-responsive
drug effect is larger than expected
VIB.
Variation in Drug Responsiveness
Individuals may vary in responsiveness to a drug.
Responses include:
tolerance
responsiveness decreases as a consequence of
continued drug administration
tachyphylaxis
responsiveness diminishes rapidly after
administration of the drug
When these effects occur, the dose should be modified or the
drug itself changed.
VIB.
Variation in Drug Responsiveness
Individuals may vary in responsiveness to a drug.
FACTORS to be considered in variable drug responses:
age
body size
sex
disease state
simultaneous administration of other drugs
Four general mechanisms may contribute to variations in
drug responsiveness.
variable drug response may be caused by more than
one of these mechanisms
NOT COVERED IN LECTURE... PLEASE READ
VIB.
Variation in Drug Responsiveness
1. alteration in concentration of drug that reaches the receptor
*rate of drug absorption
*altered drug distribution in body compartments
*altered drug metabolizing enzymes
repeated measurements of drug concentrations in blood
during the course of treatment are often helpful in
dealing with the variability of clinical response caused
by pharmacokinetic differences among individuals.
NOT COVERED IN LECTURE... PLEASE READ
VIB.
Variation in Drug Responsiveness
2. variation in concentration of an endogenous receptor ligand
example:
saralasin, a weak partial agonist of angiotensin
receptors
this agent will lower blood pressure in patients with
hypertension and lots of angiotensin
in patients with low levels of angiotensin, this agent will
elevate blood pressure
NOT COVERED IN LECTURE... PLEASE READ
VIB.
Variation in Drug Responsiveness
3. alterations in number or function of receptors
*increases or decreases in the number of receptor sites
likely to account for much of the variability in
response to SOME drugs among individuals
(particularly drugs that act at receptors for
hormones, catecholamines, neurotransmitters)
Not rigorously established in humans.. BUT:
eg. thyroid hormone increases the number of betaadrenergic receptors in rat heart muscle and
cardiac sensitivity to catecholamines.
tachycardia has been observed in patients with
overactive
glands.
NOT thyroid
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PLEASE READ
VIB.
Variation in Drug Responsiveness
3. alterations in number or function of receptors
in some cases, the agonist can induce a ‘down- regulation’
of its own receptor
eg.
receptor internalization and degradation >>> synthesis
in other cases,
an antagonist may increase the # of receptors in a cell or
tissue by preventing down-regulation. When the
antagonist is withdrawn, the elevated number of
receptors can produce an exaggerated response to
physiological concentrations of the a agonist.
NOT COVERED IN LECTURE... PLEASE READ
VIB.
Variation in Drug Responsiveness
3. alterations in number or function of receptors
Withdrawal symptoms can often occur when
administration of an agonist is discontinued.
the # of receptors which has been decreased by
drug-induced down-regulation is too low for
endogenous agonist to produce effective
stimulation.
For example,
clonidine
an agonist of the alpha2-adrenergic receptor
whose activity reduces blood pressure
Can produce hypertensive crisis if withdrawn abruptly,
probably because the drug
down-regulates
alpha2 receptors.
NOT COVERED
IN LECTURE... PLEASE READ
VIB.
Variation in Drug Responsiveness
3. alterations in number or function of receptors
Various therapeutic strategies can be used to address
receptor-specific changes in drug responsiveness:
*tolerance may require increasing the dose or
substituting a different drug
*the down- or up- regulation of receptors may make it
dangerous to discontinue certain drugs abruptly.
the patient may have to be weaned slowly from
the drug and watched carefully for signs of
withdrawal.
NOT COVERED IN LECTURE... PLEASE READ
VIB.
Variation in Drug Responsiveness
4. changes in components of response distal to receptor
Although drugs act through receptors, drug response depends
on
the functional integrity of biochemical processes in the
responding cell and physiologic regulation by interacting
organ systems.
CHANGES IN POSTRECEPTOR PROCESSES represent the
largest and most important class of mechanisms that
cause variations in drug responses.
NOT COVERED IN LECTURE... PLEASE READ
VIB.
Variation in Drug Responsiveness
4. changes in components of response distal to receptor
Characteristics that may limit the clinical response:
age and general health of the patient
severity and pathophysiologic mechanism of the disease
wrong diagnosis (e.g.)
congestive heart failure will not respond to
agents that increase myocardial contractility
if the pathophysiologic mechanism is
unrecognized stenosis of the mitral valve
rather than myocardial insufficiency.
NOT COVERED IN LECTURE... PLEASE READ
VIB.
Variation in Drug Responsiveness
4. changes in components of response distal to receptor
Unsatisfactory therapeutic response can often be traced to
compensatory mechanisms in the patient that respond to and
oppose the beneficial effects of the drug.
For example,
tolerance to an antihypertensive vasodilator agent
may be due to compensatory increases in
sympathetic nervous response as well as fluid
retention by the kidney.
The patient in which something like this is occurring
may require additional drugs to achieve a useful
therapeutic response.
NOT COVERED IN LECTURE... PLEASE READ
VII.
Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
Drugs are classified according to their primary effect
BUT no drug causes only a single, specific effect!
It is more appropriate to say that drugs are selective, rather
than specific, in their actions and receptor affinities.
that is, they bind one or a few types of receptor more
tightly than any other receptors.
VII.
Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
Selectivity can be measured by:
*comparing binding affinities of a drug to different
receptors
*comparing EC50 values for different effects of a drug
Two types of drug effects:
Beneficial (Therapeutic)
Toxic (side effect)
VII.
Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
Beneficial and toxic effects mediated by the same
receptor-effector mechanism:
Direct pharmacologic extension of the therapeutic actions
eg. bleeding caused by excess anticoagulant therapy
(the dose makes the poison)
HOW to deal with this?
judicious management of dose can avoid toxicity
(along with careful patient monitoring)
not administering the drug at all
(use of an alternate drug)
VII.
Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
Beneficial and toxic effects mediated by the same
receptor-effector mechanism:
In some instances, a drug is clearly necessary and beneficial but
produces unacceptable toxicity at doses that yield benefit.
(in such cases, addition of another drug may be possible)
eg.
prazosin, an alpha1-adrenergic receptor antagonist
acts on receptors in vascular smooth muscle to reduce
blood pressure
as a consequence, patients may suffer postural
hypotension when standing (sudden drop in BP when
standing)
VII.
Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
Beneficial and toxic effects mediated by the same
receptor-effector mechanism:
as a consequence, patients may suffer postural
hypotension when standing (sudden drop in BP when
standing)
Appropriate management?
In addition to alpha1 receptors, BP is regulated by
changes in blood volume and tone of arterial smooth
muscle.
Giving a diuretic and a vasodilator may allow the dose of
prazosin to be lowered with relief of postural hypotension
and continued control of blood pressure.
VII.
Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
Beneficial and toxic effects mediated by the same
receptor-effector mechanism:
Receptor
Receptor
DRUG
DRUG
eg. vascular smooth muscle; prazosin
Toxic
Therapeutic
Occur within the same tissue
VII.
Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
Beneficial and toxic effects mediated by the same
receptor-effector mechanism:
Postural hypotension:
While at rest, quadrupeds have a distinct orthostatic advantage
over bipedal humans because their blood reservoirs (mostly
veins) are at a similar level as the brain and heart. In contrast,
a human in the act of standing has approximately 750
mL of thoracic blood abruptly translocated downward.
Standing fills venous blood reservoirs below the heart, removes
venous return from the heart, and reduces cerebral perfusion
because of the hydrostatic change in BP. In contrast, more than
70% of a dog's vascular capacitance is situated at or above
cardiac level, and the dog's brain is at a similar level.
VII.
Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
Beneficial and toxic effects mediated by the same receptor-effector
mechanism:
Postural hypotension (cont):
Upright posture in humans, therefore, is a fundamental stressor.
Upright posture requires rapid and effective circulatory and
neurologic compensations to maintain BP, cerebral blood flow,
and consciousness. Without these compensatory mechanisms,
the brain's precarious position well above the neutral cardiac
point (roughly at the right atrium) and the presence of large
venous reservoirs below the neutral point would cause BP to
decrease rapidly because of gravitational pooling of blood within
the dependent veins; cerebral ischemia and loss of
consciousness would follow rapidly. Once consciousness and
postural tone are lost, the resultant fall would render a person
recumbent, remobilizing the blood and restoring consciousness.
Evolution apparently has dictated a trade-off between manual
dexterity and orthostatic competence. http://www.emedicine.com/ped/topic2860.htm
VII.
Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
Beneficial and toxic effects mediated by identical
receptors but in different tissues or by different effector
pathways:
Many drugs produce their desired effects and toxic effects by
acting at the same receptor
digitalis glycosides (inhibit Na+/K+ ATPase)
augment cardiac contractility
BUT also
cardiac arrhythmias, g.i. effects, vision
methotrexate
inhibition of dihydrofolate reductase
death of tumor cells BUT also,
death of healthy cells
VII.
Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
Beneficial and toxic effects mediated by identical
receptors but in different tissues or by different effector
pathways:
Therapeutic strategies to avoid these toxicities?
*drug should ALWAYS be administered at the lowest
dose that produces acceptable benefit
(complete abolition of symptoms may not be achieved)
*adjunctive drugs that act through different receptor
mechanisms may allow lowering the dose of the first drug,
decreasing its toxicity.
*specifically placing the drug in parts of the body where it will
have reduced toxicity (eg. infusion of drug into a tumor)
VII.
Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
Beneficial and toxic effects mediated by identical
receptors but in different tissues or by different effector
pathways:
Receptor
Receptor
DRUG
DRUG
eg. digitalis; therapeutic in
cardiac contractility; toxic
effects in gastrointestinal
tract and eye
Toxic
Tissue 2
Therapeutic
Tissue 1
VII.
Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs
Beneficial and toxic effects mediated by different types
of receptors:
New drugs are emerging with improved receptor selectivity.
DRUG
DRUG
Receptor
1
Receptor
2
eg. alpha and beta-adrenergic agonists
Receptor
1
DRUG
Receptor
2
DRUG