IVG. Well-established Second Messengers
cAMPSecond 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
IVG. Well-established Second Messengers cAMP
mediates such hormonal responses as:
the mobilization of stored energy*the breakdown of carbohydrates in the liver*the breakdown of triglycerides in fat cells
increased rate and strength of heart muscle contraction
the conservation of water by the kidneyscAMP inducing agent=vasopressin
Ca++ homeostasiscAMP inducing agent = parathyroid hormone
many many other responses mediated by cAMP
Beta-adrenergic catecholamines
IVG. Well-established Second Messengers cAMP
GTP
Agonist binding
AC
Activation of Gs and stimulation of the effector Adenylyl Cyclase (AC)
ATP
cAMP
Conversion of ATP to cyclic AMP (cAMP) by AC.
Cat
CatReg
Reg
cAMP-dependent protein kinase[CAMP kinase]
Reg= regulatory regionCat= catalytic region
IVG. Well-established Second Messengers cAMP
GTP
Agonist binding
ACATP
cAMP
Cat
Reg
Reg
cAMP-dependent protein kinase[CAMP kinase]
cAMP
cAMP
Binding of cAMP to Reg sites releases the cat regions which can phosphorylate proteins.
SubstrateSubstratePATP
Cellular Response Cat
IVG. Well-established Second Messengers cAMP
SubstrateP
Cellular Response
Can include any of these:
*Enzyme activation*Protein synthesis*Muscle relaxation*Nerve stimulation*Hormone secretion
IVG. Well-established Second Messengers cAMP
When the agonist stimulus stops, the intracellular actions of cAMP are terminated by three mechanisms (1-3).
GTP
Agonist dissociates
ACATP
cAMP
GDP
GTP hydrolysis
5’-AMP
Cyclic nucleotide phosphodiesterases
X X
CAMP kinase activation is inhibitedRe-establishment of the tetramer
SubstrateP
SubstrateP
Phosphatases
Diminished cellular responseCatCat Reg
Reg
Phosphorylated substrate generated by CAMP kinase is de-phosphorylated
1 2
3
IVG. Well-established Second Messengers cAMP
GTP
Agonist dissociates
ACATP
cAMP
GDP
GTP hydrolysis
5’-AMP
Cyclic nucleotide phosphodiesterases
X
FYICaffeineTheophyllineOther methylxanthines
Act as competitive inhibitors ofphosphodiesterases
What would you expect the effect ofcaffeine on cAMP levels to be?
How about on CAMP kinase?
IVG. Well-established Second Messengers cAMP
Different cells express different types of substrates for CAMP kinase, which helps explain some of the tissue-specific effects:
CAMPPhosphorylase KinasePhosphorylase Kinase
ATP
P
Glucose released from glycogen
Glycogen Synthase
CAMP
ATPGlycogen Synthase
P
Inhibition of glycogen synthesis
In LiverActivated by phosphorylation
inactivated by phosphorylation
IVG. Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Another well-studied 2nd messenger system involves receptor-mediated stimulation of phosphoinositide hydrolysis.
Some of the agonists, hormones and growth factors that trigger this pathway bind to G-protein coupled receptors (Gq-coupled)
Receptoracetylcholine (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 PhosphoinositidesInositiol-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
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).
GTP
Agonist binding
PLC PIP2DAG
IP3Gq proteinstimulation
IVG. Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
IP3 goes to ER where it stimulates release of calcium activates protein kinases
GTP
Agonist binding
PLC PIP2DAG
IP3Gq proteinstimulation
Ca++ Ca++
Ca++Ca++
IVG. Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Released Ca++ binds to calmodulin.
GTP
Agonist binding
PLC PIP2DAG
IP3Gq proteinstimulation
Ca++ Ca++
Ca++Ca++
Ca++Ca++
Ca++ release
ER
Calmodulin
Calmodulin
IVG. Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Calmodulin becomes activated and stimulates signaling through calcium/ calmodulin dependent protein kinases
GTP
Agonist binding
PLC PIP2DAG
IP3Ca++ Ca++
Ca++Ca++Ca++Ca++
Ca++ release
ER
Ca++Ca++Calcium/Calmodulin-Dependent
Protein Kinase
Calmodulin
IVG. Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
GTP
Agonist binding
PLC PIP2DAG
IP3Ca++ Ca++
Ca++Ca++Ca++Ca++
Ca++ release
ER
Ca++Ca++Calcium/Calmodulin-Dependent
Protein Kinase
InactiveActive P
Calmodulin
IVG. Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
Ca++Ca++
Calcium/Calmodulin-Dependent Protein Kinase
Substrate Substrate
P
ATP
Cellular Response
active
IVG. Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
GTP
Agonist binding
PLC PIP2DAG
IP3Gq proteinstimulation
Meanwhile, DAG stays in membrane where it binds and activates protein kinase C (PKC)
PKCinactive
IVG. Well-established Second Messengers
Ca++ (Calcium) and Phosphoinositides
GTP
Agonist binding
PLC PIP2DAG
IP3Gq proteinstimulation
Activated PKC will phosphorylate certain substrates involved in cellular response.
PKCactive
Substrate
Substrate
P
ATP,Ca++
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 PhosphoinositidesMultiple 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
ordeacylated to yield arachidonic acid
Ca++ is actively removed from the cytoplasm by calcium ion pumps (into ER)
These and other nonreceptor elements of the calcium-phosphoinositide signaling pathway are now becoming targets for drug development.
IVG. Well-established Second Messengers
cGMP
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:
*ligand binds to extracellular domain of receptor*ligand binding stimulates intracellular guanylyl
cyclase activity*cGMP activates cGMP-dependent protein kinases
GTP cGMPGuanylyl cyclase
cGMP-dependent protein kinasecGMP-dependent protein kinase
Substrates get phosphorylated
IVG. Well-established Second Messengers
cGMP
Increased cGMP
ANF-R
GCactivity
Atrial natriuretic factorBinds its receptor
GTP
cGMP
cGMP accumulation
Guanylyl cyclase
NOGTP
cGMP
cGMP accumulation
The lipid-soluble gas nitric oxide (NO) is released by nearbyvascular endothelial cellsAnd direct activates the enzyme.
Several vasodilator drugs mimic NO
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 SubtypesEvidence 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:
Acetylcholineactivates 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:
Norepinephrineactivates many structurally-related receptors
beta-adrenergicG protein-coupled, Gs; increased heart rate
alpha1-adrenergicG protein-coupled, Gq; vasoconstriction
alpha2-adrenergicG-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 drug- receptor interaction.
V. Receptor Classes and Drug Development
NEW DRUG DEVELOPMENTnot 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?
VIA. Dose and Response in PatientsGraded 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)
EFF
EC
T(%
of
maxim
um
)
Log concentration
Which is more potent?A lower dose needed to elicit 50% max response
VIA. Dose and Response in PatientsGraded 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.
A BPotencyrefers to the concentration EC50 or dose ED50 of drug required to produce 50% of that particular drug’s maximal effect.
Resp
onse
100%
50%
Log [Drug]
EC50 EC50
VIA. Dose and Response in Patients
A BR
esp
on
se
100%
50%
Log [Drug]
EC50 EC50
Which is more potent?C lower dose needed to elicit 50% of a particular drug’s max response 25% Potencyrefers to the concentration EC50 or dose ED50 of drug required to produce 50% of that particular drug’s maximal effect.
C
EC50
NOTE: Drug C acts as a partial agonist.
VIA. Dose and Response in PatientsEfficacy
the measure of an effect produced by a drug.
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.
A B
Resp
on
se
100%
50%
Log [Drug]
ED50 ED50
25%
C
ED50
VIA. Dose and Response in PatientsEfficacy
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
Shape of Dose-Response Curves
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).
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.
EFF
EC
T(S
ed
ati
on
)
Log [Drug]
More desirablesleep
coma Undesirable
VIA. Dose and Response in Patients
Quantal Dose-Effect Curves
Graded dose-reponse curves are limited in their application to clinical decision making:
*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. Dose and Response in PatientsQuantal Dose-Effect Curves
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.
Perc
en
t of
Ind
ivid
uals
Resp
on
din
gTo T
reatm
en
t (e
g.
for
head
ach
e) 100
Log [Drug]
50
ED50
Dose at which 50% of patients exhibit the specified quantal effect
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. Dose and Response in PatientsPerc
en
t of
Ind
ivid
uals
Resp
on
din
g 100
Log [Drug]
50
TD50
Dose at which 50% of patients exhibit a toxic effect
ED50
Dose at which 50% of patients exhibit the specified quantal effect
Cumulative percent of patients exhibiting therapeutic effect
Cumulative percent of patients exhibiting toxic effect
Quantal curve of a hypothetical drug that provides relief for headaches.
Therapeutic effects and toxic effects do not overlap
VIA. Dose and Response in PatientsPerc
en
t of
Ind
ivid
uals
Resp
on
din
g 100
Log [Drug]
50
TD50
Dose at which 50% of patients exhibit a toxic effect
ED50
Dose at which 50% of patients exhibit the specified quantal effect
Cumulative percent of patients exhibiting therapeutic effect
Cumulative percent of patients exhibiting toxic effect
Quantal curve of a second drug that provides relief for headaches.
Therapeutic effects and toxic effects slightly overlap
VIA. Dose and Response in PatientsPerc
en
t of
Ind
ivid
uals
Resp
on
din
g 100
Log [Drug]
50
TD50
Dose at which 50% of patients exhibit a toxic effect
ED50
Dose at which 50% of patients exhibit the specified quantal effect
Cumulative percent of patients exhibiting therapeutic effect
Cumulative percent of patients exhibiting toxic effect
Quantal curve of a third drug that provides relief for headaches.
Therapeutic effects and toxic significantly overlap
VIA. Dose and Response in Patients
Perc
ent
of
Indiv
iduals
Resp
ondin
gNo overlap in the quantal dose-response curve is highly desired (to avoid unwanted toxic effects), but not always possible.
The margin of safety of a drug will depend on the ratio between ED50 and TD50.
100
Log [Drug]
50
TD50ED50
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 PatientsThe 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-responsivedrug effect is smaller than expected
hyper-responsivedrug 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
tachyphylaxisresponsiveness diminishes rapidly after
administration of the drug
When these effects occur, the dose should be modified or the drug itself changed.
NOT COVERED IN LECTURE... PLEASE REANOT COVERED IN LECTURE... PLEASE READD
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 REANOT COVERED IN LECTURE... PLEASE READD
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 REANOT COVERED IN LECTURE... PLEASE READD
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 REANOT COVERED IN LECTURE... PLEASE READD
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 beta- adrenergic receptors in rat heart muscle and cardiac sensitivity to catecholamines.
tachycardia has been observed in patients with overactive thyroid glands.
NOT COVERED IN LECTURE... PLEASE REANOT COVERED IN LECTURE... PLEASE READD
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 REANOT COVERED IN LECTURE... PLEASE READD
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,
clonidinean 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 REANOT COVERED IN LECTURE... PLEASE READD
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 REANOT COVERED IN LECTURE... PLEASE READD
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 REANOT COVERED IN LECTURE... PLEASE READD
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 REANOT COVERED IN LECTURE... PLEASE READD
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.
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:
DRUG
Receptor
DRUG
Receptor
ToxicTherapeutic
Occur within the same tissue
eg. vascular smooth muscle; prazosin
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 contractilityBUT alsocardiac arrhythmias, g.i. effects, vision
methotrexateinhibition 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:
DRUG
Receptor
DRUG
Receptor
ToxicTherapeuticTissue 1
Tissue 2
eg. digitalis; therapeutic in cardiac contractility; toxic effects in gastrointestinal tract and eye
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
Receptor1 DRUG
Receptor1
Response 1
Receptor2
DRUG
Receptor2
DRUGResponse 2
eg. alpha and beta-adrenergic agonists