Download Sympathomimetic Drugs

Sympathomimetic Drugs
Dumrongsak Pekthong
M.Sc.(Pharmacology)
Wording
• Adrenergic agonists
• Adrenomimetic drugs
• Adrenoceptor agonists
• Sympathomimetic drugs
Outline
A. Review of sympathetic activation
B. Introduction
C. Types and subtypes of adrenoceptors
D. Mechanism of action
E. Classification of sympathomimetic drugs
F. Mode of action
Outline
G. Chemistry, SAR and Pharmacokinetics
H. Organ system effects
I. Clinical application of sympathomimetics
J. Adverse effects of sympathomimetics
K. Drug interactions
Objectives
1. List tissues that contain sig. No. of alpha receptors of the a1 or
a2 type and b1 or b2 receptors.
2. Describe the major organ system effects of a pure alpha agonist, a
pure beta agonist, and a mixed alpha and beta agonist. Give
examples of each type of drug.
Objectives
3. Describe a clinical situation in which the effects
of an indirect sympathomimetic would differ
from those of a direct agonist.
4. List the major clinical applications of the
adrenoceptor agonists.
Suggested Reading
 Katzung BG. Basic & clinical pharmacology.
8th ed., 2001.
 Katzung BG, Trevor AJ. Examination &board
review pharmacology. 5th ed. 1998.
 Goodman&Gilman. Basic pharmacology. 9th
ed., 1996.
 Pharmacology, Lippincott’s Illustrated Reviews
1992.
A. Review of Sympathetic Activation
• ‘Fight’ or ‘Flight’ on Stress
• Heart
– HR, contractility, conduction velocity
• Vessels (arterioles)
– Skin, cutaneous, visceral : constrict
– Skeletal muscle, coronary: dilate
A. Review of Sympathetic Activation
• Vessels (Vein): constrict
• Eye
– Radial muscle, iris: contract
– Ciliary muscle: relax for far vision
• Lung
– Tracheal and bronchial muscle: relax
A. Review of Sympathetic Activation
• Stomach and intestine
– Motility and tone
– Sphincters : contraction
– Secretion (intestine): inhibition
• Urinary bladder
– Detrusor or bladder wall: relax
– Trigone, sphincter: constrict
A. Review of Sympathetic Activation
• Posterior pituitary: ADH secretion
• Liver: glycogenolysis, gluconeogenesis
• Pancreatic b cells
---stimulate insulin release
• Skeletal muscle
– contractility, glycogenolysis, K+ uptake
A. Review of Sympathetic Activation
• Fat cells: lipolysis
• Uterus
– non-pregnant: relax
• Sweat gland : secretion
• Hair : piloerection
B. Introduction
• The effects of adrenomimetic drugs are similar
to sympathetic activation.
• But why each adrenomimetic drug can produce
different responses?
• The differences in affinity to adrenoceptor
subtypes are responsible for different responses.
C. Types and subtypes of adrenoceptors
• Adrenergic receptors locate on smooth muscle,
cardiac muscle, exocrine glands, endocrine
glands and on nerve terminals.
• the transmitter in all adrenergic neurons was
NE
• When NE and Epi interacted with an
adrenoceptor, in some tissues the response was
excitatory while in other tissues it was inhibitory
C. Types and subtypes of adrenoceptors
• Two subtypes of adrenoceptors (a and b)
 a - excitatory in most tissues
(except - intestinal smooth muscle)
 b - inhibitory in most tissues
(except - heart)
C. Types and subtypes of adrenoceptors
Rank Order of Potency
1. a receptors Epi > NE >> Iso
2. b receptors Iso > Epi > NE
Type of adrenoceptor
 a 1,a 2
b 1,b 2,b 3
 DA1, DA2
C. Types and subtypes of adrenoceptors
 a1 type
:Phenylephrine, methoxamine
 a1A, a1B a1D
 a2 type
 a2A
 a2B , a2C
:Clonidine, BHT920
:Oxymetazoline
C. Types and subtypes of adrenoceptors
 b type :Isoproterenol
 b1
 b2
 b3
:Dobutamine
:Procaterol, terbutaline
:BRL37344
 Peripheral Dopamine (DA) type
 DA1
 DA2
:Fenoldopam
:Bromocriptine
:Dopamine
C. Types and subtypes of adrenoceptors
• Generally
a 1 ---Contraction of smooth muscle
b 2 ---Relaxation of smooth muscle
b 1 ---Stimulation in heart
a 2 ---Inhibition, for GI tract ---Relaxation
D. Mech. of action of Adrenomimetic drugs
 a 1 via coupling protein Gq
 a 2 via coupling protein Gi
 b 1, b 2 , b 3 via coupling protein Gs
Ca 2+
Phosphatidylinositol
a1 -Agonist 4, 5-diphosphate
a1
Cell Membrane
Gq
Phospholipase C
SR
IP
3
Ca 2+
Ca 2+ -dependent protein kinase
DAG
Protein kinase C
a2 - Agonist
a2
Cell Membrane
AC
ATP
Gi
cAMP
Enzyme-PO4
AC= Adenylyl cyclase
No biological effect
b -Agonist
b - receptor
Cell Membrane
AC
Gs
ATP
cAMP
Enzyme-PO4
AC= Adenylyl cyclase
Biological effect
Mech. of action of Dopamine
DA1 type
–
cAMP
DA2 type
–
cAMP
Central Dopamine Receptor -different effect
– D1-like:
D1A, D1B, D5
– D2-like:
D2, D3, D4
Ca2+ channels
Vascular smooth muscle
Ca2+ (intracellular)
Calmodulin
ATP
Ca2+ -calmodulin complex
cAMP
b 2 agonists
Proteinkinase A
MLCK*
Myosin light chain
(Myosin-LC)
Myosin-LC kinase (MLCK)
Myosin-LC- PO4
MLCK-(PO4)2
Myosin-LC
Actin
Contraction
Relaxation
b1-Agonist
b1-receptor
2+
Ca
Vagus
M
Gs
AC
ATP
Gi
kinase
cAMP
Ca 2+
Heart rate
Contraction Conduction
Heart
E. Classification of Sympathomimetics
• By chemistry
– Catecholamines
– Non-catecholamines
• By mode of action
– direct acting
– indirect acting
• By selectivity (to types of receptor)
E. Classification of Sympathomimetics
I. Catecholamines (CAs)
II. Non-catecholamines
A. Direct acting
• classified by alpha, beta receptor subtypes
• a 1 -selective, a 2 -selective, nonselective
• b 1 -selective, b 2 -selective , nonselective
B. Indirect acting
-Releasers
- Reuptake inhibitors
F. Mode of action
I. Direct acting
– bind to receptor directly
II. Indirect acting
– cause the release of stored catecholamines
– inhibit reuptake of catecholamines by nerve
terminals (uptake 1)
• increase transmitter in synapse
List of Adrenomimetic Drugs
A. General agonists
– Direct (a 1 , a 2 , b 1 , b 2 )
: Epinephrine*, Ephedrine
– Indirect, releasers:
: Tyramine*, Amphetamine, Ephedrine
– Indirect, uptake inhibitors
: Cocaine*, Tricyclic antidepressants (TCAs)
List of Adrenomimetic Drugs
B. Selective agonists
a 1 , a 2 , b 1 : Norepinephrine*
a 1 > a 2 :
Phenylephrine*,
methoxamine, metaraminol, midodrine
a 2 > a 1
:Clonidine*, methylnorepinephrine,
apraclonidine, brimonidine
b 1 = b 2 : Isoproterenol*
List of Adrenomimetic Drugs
B. Selective agonists
 b 1 > b 2 : Dobutamine*
 b 2 > b 1 : Terbutaline*, albuterol,
metaproterenol, ritodrine
 Dopamine agonist: Dopamine*,
bromocriptine
G. Chemistry, SAR and Pharmacokinetics
OH (para)
OH (meta)
C
b
C
a
Catechol
Ethylamine
N
Chemical structure of parent compound of
Catecholamines
Structure-Activity Relationship (SAR) of
Adrenomimetics
• Responsible for
– different receptor selecitvity of
sympathomimetics
– different distribution of drugs -->
different actions
– different duration
Pharmacokinetic differences between CAs
and NonCAs
Catecholamines
– cannot be given orally
– short half-life, short duration
– not cross blood-brain barrier (BBB)
reasons: due to having catechol group
– Rapid destruction by MAO and COMT
– MAO, COMT locate at gut wall, liver
– High polarity
Pharmacokinetics of sympathomimetics
Drug
Oral activity
Duration
Epinephrine
No
minutes
Norepinephrine
No
minutes
Isoproterenol
Poor
minutes
Dopamine
No
minutes
Dobutamine
No
minutes
Catecholamines
Pharmacokinetics of sympathomimetics
Other sympathomimetics
Drug
Oral activity
Duration
Amphetamine,
Yes
Hours
Ephedrine
Yes
Hours
Phenylephrine
Poor
Hours
Albuterol,
Yes
Hours
metaproterenol, terbutaline
Pharmacokinetics of sympathomimetics
Other sympathomimetics
Drug
Oxymetazoline,
Oral activity
Duration
Yes
Hours
No
Minutes to
Hours
xylometazoline
Cocaine
H. Organ System Effects
1. Vascular system
2. Heart
3. Net cardiovascular actions
4. Bronchi
5. Eye
6. Gastrointestinal tract (GI tract)
7. Genitourinary tract (GTU tract)
8. Metabolic and hormonal effects
9. Central nervous system (CNS)
1. Vascular system effects
A. a 1 agonists
– eg, phenylephrine (pure alpha agonist)
– constrict skin, cutaneous,
visceral(splanchnic), pulmonary, renal blood
vessels
– constrict veins
– consequently a rise in BP and an increase in
peripheral vascular resistance (PVR or TPR)
– Often evoke a compensatory reflex
bradycardia
1. Vascular system effects
B. b 2 agonists
– eg, terbutaline (pure beta agonist)
– dilate arterioles in skeletal muscle, coronary
arteries
– consequently reduce PVR and BP.
– [Voluntary muscle ----> tremor (b 2)]
– Low dose of Epi: Beta2 activation is dominant.
1. Vascular system effects
C. a 2 agonists
– eg, clonidine (antihypertensive drugs)
– when given orally, reduce sympathetic
outflow from CNS and consequently
decrease BP
– cause vasocontriction when given IV or
topically (nasal spray)
1. Vascular system effects
D. Dopamine agonists (eg, dopamine)
• DA1 receptor
– locate at smooth muscle of renal,
coronary, cerebral, mesenteric arteries
• relaxation
– tubule of kidney
• inhibit Na+/K+ ATPase pump
• --> natriuresis, diuresis
Dopamine
• Low dose (0.5-2 mcg/kg/min): activate
Dopamine receptors
• Intermediate dose(2-10): activate Beta
receptors
• High dose(>10): activate Alpha receptor
• Very useful in treatment of renal failure
associated with shock (low to moderate
dose)
Distribution and Effect of Peripheral
Dopamine DA2 Receptor
DA2 group
: locate at presynaptic adrenergic nerve
endings, sympathetic ganglia --inh NE
release
: adrenal cortex ---inh AII-mediated
aldosterone secretion
: pituitary gland---inh prolactin release
: emetic center of medulla---emesis
2. Cardiac effects
b agonists
• eg, isoproterenol
• predominantly b 1 receptor(also b 2 )
• activation of which produces an increase in
– the rate of cardiac pacemakers (normal and
abnormal)
– force of contractions
– AV node conduction velocity
3. Net cardiovascular actions
a and b 1 agonists
– eg, norepinephrine
– may cause a reflex increase in vagal
outflow (due to BP increase) --> reflex
bradycardia
– This reflex often dominates any direct
beta effects on the heart rate.
3. Net cardiovascular actions
a and b 1 agonists (cont’d)
• If reflex is blocked (eg, by ganglion
blockers), NE can cause tachycardia (b 1 )
Pure alpha agonists
• eg, phenylephrine
• will routinely slow heart rate via the
baroreceptor reflex
3. Net cardiovascular actions
Pure beta agonists
– eg, isoproterenol
– almost always increases the heart rate
Net effect on Blood Pressure
• Diastolic blood pressure (DBP) is affected
mainly by PVR and HR
• Alpha and b 1 receptors have the greatest
effects on PVR
3. Net cardiovascular actions
Net effect on Blood Pressure (cont’d)
• Systolic blood pressure (SBP) = DBP +
pulse pressure (PP)
• Pulse pressure is determined mainly by
stroke volume (SV), which is influenced by
b 1 receptors (and venous return)
• Cardiac output (CO) = HR x SV
• So, alpha and beta selectivity determine
SBP, DBP and PP
Effect of NE to intact CVS
Mean arterial pressure
(MAP) = DBP + 1/3 of
(SBP-DBP)
a 1 ,a 2 ,b 1
Effect of Epi to intact CVS
a 1 ,a 2 ,b 1,b 2
Effect of Iso to intact CVS
b 1,b 2
Effect of DA to intact CVS
• DA1, Beta1
• Moderate Dose
Effect of Catecholamines to intact CVS
4. Respiratory System
b 2 agonists
– eg, terbutaline
– produce relaxation of tracheal
and bronchial muscle
5. Eye
• Radial muscle, iris (pupillary dilator)
– contraction (a 1) --> mydriasis
– topical phenylephrine and similar alpha agonists
– accommodation is not significantly affected
– outflow of aqueous humor may be facilitated
--> reduce intraocular pressure (IOP)
• Ciliary muscle: relaxation for far vision (b 2)
6. Gastrointestinal tract
• alpha and beta receptors locate on smooth
muscle and on neurons of enteric nervous
system
• Stomach and intestine
– Motility and tone: (a 2 ,b 2)
– Sphincters : contraction (a 1)
– Secretion (intestine): inhibition (a 2)
: inhibit salt and water secretion
7. Genitourinary tract
• Urinary bladder
– Detrusor or bladder wall: relax (b 2)
– Trigone, sphincter, prostate gland:
constrict (a 1 )
• Uterus
– non-pregnant: relax (b 2)
– pregnant:
contract(a 1 ), relax (b 2)
8. Metabolic and hormonal effects
• Kidney
– renin release (b 1)
• Pancreatic b cells
– inhibit insulin release (a 2 )
– stimulate insuline release (b 2)
• Glycogenolysis in liver and skeletal
muscle (b 2)
8. Metabolic and hormonal effects
• Glucose out of liver associated with
initially hyperkalemia, then transport
into skeletal muscle resulting in a later
hyperkalemia.
• Lipolysis (b 3) : break down of
triglycerides (TGs) into free fatty
acids(FFAs) --> increase lactate from
lipid metabolism
9. CNS effects
• Catecholamines do not produce CNS effects
• eg, Amphetamine have stimulant effects on
CNS
• Beginning with mild alerting or reduction of
fatigue
• Progressing to anorexia, euphoria, and
insomnia
• CNS effects probably represent the release of
dopamine in certain dopaminergic tracts
• Very high doses lead to marked anxiety or
aggressiveness, paranoid, and sometimes
convulsions
I. Clinical Application of Sympathomimetics
1. Cardiovascular system
2. Respiratory system
3. Anaphylaxis
4. Eye
5. Genitourinary tract
6. CNS
7. Additional uses
1. Cardiovascular application
A. Increase blood flow
– acute heart failure (b 1), decrease PVR through
partial b 2 effect: Dobutamine
– cardiogenic shock from MI, CHF or septic shock
: Dopamine
B. Reduce blood flow and increase BP
– Surgery : prolong action of local anesthetics (a 1)
– hypotension, during spinal anesthesia (a 1) : NE
– congestion (a 2) : oxymetazoline
1. Cardiovascular application (cont’d)
• Shock due to septicemia or myocardial
infarction is usually made worse by
vasoconstrictors
• chronic orthostatic hypotension due to
inadequate sympathetic tone: midodrine (a 1)
C. Cardiac application
– paroxysmal atrial tachycardia (a 1)
– complete heart block or cardiac arrest (b 1)
: Epi or Iso
2. Respiratory application
• Especially selective b 2 agonists are drug of
choice in treatment of acute asthmatic
bronchoconstriction (Epi and Iso also)
• Emphysema, bronchitis
3. Anaphylaxis
• Epinephrine is drug of choice for immediate
treatment of anaphylactic shock (a 1 ,b 1, b 2)
• sometimes supplemented with antihistamines
and corticosteroids
4. Ophthalmic Application
• Alpha agonists, especially phenylephrine, often
used topically to
– produce mydriasis, eg, ophthalmologic exam
– reduce the conjunctival itching and congestion
caused by irritation or allergy
– do not cause cycloplegia (paralysis of
accommodation)
• Epi and prodrug, dipivefrin, sometimes used for
glaucoma. Phenylephrine also
5. Genitourinary Tract Application
• Beta2 agonists (ritodrine, terbutaline) used
in premature labor, but cardiac stimulant
effect may be hazardous to both mother and
fetus.
• Ephedrine (long-acting)
: sometimes used to improve urinary
continence in children with enuresis and
in the elderly (contract trigone, prostate
of bladder)
6. CNS Application
• Amphetamine: widely used and abused
• Legitimate indication: narcolepsy,
attention deficit hyperkinetic syndrome,
weight reduction
• Metabolism effect (b 2, b 3 ) and anorexant
effect
• Misuse or abuse for deferring sleep, for
mood-elevating, euphoria-producing action
7. Additional uses
Central a 2 agonists
– hypertension
– menopausal hot flushes
– narcotics, alcohol, smoking withdrawal
J. ADRs of Sympathomimetics
Catecholamines
– little CNS toxicity
– high dose: excessive vasoconstriction,
cardiac arrhythmias, MI, pulmonary edema
or hemorrhage, tissue necrosis.
Other sympathomimetics
• Phenylisopropylamines
– mild to severe CNS toxicity depending on
dosage
– small dose: nervousness, anorexia, insomnia
J. ADRs of Sympathomimetics
• Phenylpropylamines (PPA)
– higher dose: anxiety, aggressiveness,
paranoid, convulsion
• Peripherally acting agents: predictable toxicity
- a 1 agonists: hypertension, bradycardia
(reflex)
– b 1 agonists: palpitation, sinus tachycardia,
serious arrhythmias
– b 2 agonists: skeletal muscle tremor
J. ADRs of Sympathomimetics
• No drug are perfectly selective; at high dose,
selectivity will decrease.
• Cocaine:
- special importance: drug of abuse
- cardiac arrhythmias or infarction and
convulsions
K. Drug interaction
Tyramine --MAO inhibitors
 tyramine not a drug, found in many foods
 tyramine is rapidly metabolized by MAO.
 MAO inhibitors increase the stores of
catecholamines in vesicles.
 Tyramine is a releaser of catecholamines
 may occur hypertensive crisis due to
massive levels of NE
K. Drug interaction
Reuptake inhibitors -- Direct acting sympathomimetics
 eg, Cocaine vs NE
 when cocaine is given before NE -- intensify the
effects of NE
Epinephrine reversal
Beta blockers -- Sympathomimetics
 Can you predict the resulting effects ?
Thank you for your attention