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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 - PowerPoint PPT Presentation
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SympathomimetSympathomimetic Drugsic Drugs
Dumrongsak Dumrongsak PekthongPekthong
M.Sc.M.Sc.(Pharmacology)(Pharmacology)
Wording•Adrenergic agonists
•Adrenomimetic drugs
•Adrenoceptor agonists
•Sympathomimetic drugs
OutlineA. Review of sympathetic activationB. IntroductionC. Types and subtypes of
adrenoceptorsD. Mechanism of actionE. Classification of
sympathomimetic drugsF. Mode of action
OutlineG. Chemistry, SAR and
PharmacokineticsH. Organ system effectsI. Clinical application of
sympathomimeticsJ. Adverse effects of
sympathomimeticsK. Drug interactions
Objectives1. List tissues that contain sig. No.
of alpha receptors of the or type and or 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.
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.
Objectives
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
•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 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
A. Review of Sympathetic Activation
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
• Two subtypes of adrenoceptors ( and )
- excitatory in most tissues
(except - intestinal smooth muscle)
- inhibitory in most tissues
(except - heart)
C. Types and subtypes of adrenoceptors
Rank Order of Potency
receptors Epi > NE >> Iso
receptors Iso > Epi > NE
Type of adrenoceptor
, , , DA1, DA2
C. Types and subtypes of adrenoceptors
type :Phenylephrine, methoxamine
D
type :Clonidine, BHT920
:Oxymetazoline
C
C. Types and subtypes of adrenoceptors
type :Isoproterenol
:Dobutamine
:Procaterol, terbutaline
:BRL37344
Peripheral Dopamine (DA) type :Dopamine
DA1 :Fenoldopam
DA2 :Bromocriptine
C. Types and subtypes of adrenoceptors
•Generally ---Contraction of smooth muscle
---Relaxation of smooth muscle
---Stimulation in heart
---Inhibition, for GI tract ---Relaxation
C. Types and subtypes of adrenoceptors
D. Mech. of action of Adrenomimetic drugs
via coupling protein Gq
via coupling protein Gi
, , via coupling protein Gs
Cell Membrane
Ca 2+
Ca 2+
Ca 2+ -dependent protein kinase
SR
Phospholipase CI
P3
DAG
Phosphatidylinositol 4, 5-diphosphate
-Agonist
Protein kinase C
Gq
Cell MembraneAC Gi
Agonist
ATP
cAMPcAMP
No biological effect
Enzyme-PO4
AC= Adenylyl cyclase
Cell Membrane- receptor
-Agonist
ACGs
ATP
cAMPcAMP
Biological effect
Enzyme-PO4
AC= Adenylyl cyclase
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+ channelsCa2+
(intracellular)
CaCa2+2+ - -calmodulin calmodulin complexcomplex
Calmodulin
ATP
cAcAMPMP
MLCMLCK*K*
MLCK-MLCK-(PO(PO44))22
Myosin light chain (Myosin-LC)
Myosin-LC- PO4
Myosin-LC
Actin
Vascular smooth muscle
Contraction Relaxation
Myosin-LC kinase (MLCK)
agonists
Proteinkinase A
M
ACGs Gi
-receptor
-Agonist
kinaseAT
P
Ca 2+
Ca 2+
Heart rate ConductionContraction
Vagus
HeartHeart
cAMPcAMP
E. Classification of Sympathomimetics• By chemistry–Catecholamines
–Non-catecholamines
• By mode of action– direct acting
– indirect acting
• By selectivity (to types of receptor)
I. Catecholamines (CAs)
II. Non-catecholamines
A. Direct acting• classified by alpha, beta receptor subtypes
• -selective, -selective, nonselective
• -selective -selective , nonselective
B. Indirect acting-Releasers - Reuptake inhibitors
E. Classification of Sympathomimetics
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
DrugsA. General agonists
– Direct ( , , , )
: Epinephrine*, Ephedrine– Indirect, releasers:
: Tyramine*, Amphetamine, Ephedrine– Indirect, uptake inhibitors
: Cocaine*, Tricyclic antidepressants (TCAs)
List of Adrenomimetic
DrugsB. Selective agonists
, , : Norepinephrine*
> : Phenylephrine*,
methoxamine, metaraminol, midodrine
> :Clonidine*, methylnorepinephrine,
apraclonidine, brimonidine
= : Isoproterenol*
List of Adrenomimetic
DrugsB. Selective agonists
> : Dobutamine*
> : Terbutaline*, albuterol,
metaproterenol, ritodrine
Dopamine agonist: Dopamine*, bromocriptine
G. Chemistry, SAR and
Pharmacokinetics
Chemical structure of parent compound of Catecholamines
OH (para)
OH (meta)
C
C
N
Catechol
Ethylamine
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
Catecholamines
Epinephrine No minutes
Norepinephrine No minutes
Isoproterenol Poor minutes
Dopamine No minutes
Dobutamine No minutes
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 Oral activity Duration
Oxymetazoline, Yes Hours
xylometazoline
Cocaine No Minutes to Hours
Pharmacokinetics of sympathomimetics
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. 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. agonists– eg, terbutaline (pure beta agonist)
– dilate arterioles in skeletal muscle, coronary arteries
– consequently reduce PVR and BP.
– [Voluntary muscle ----> tremor ()]
–Low dose of Epi: Beta2 activation is dominant.
1. Vascular system effects
C. 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
agonists
• eg, isoproterenol
• predominantly receptor(also )
• 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
and 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
and agonists (cont’d)
• If reflex is blocked (eg, by ganglion blockers), NE can cause tachycardia ( )
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 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 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)
, ,
Effect of Epi to intact CVS
, , ,
Effect of Iso to intact CVS
,
Effect of DA to intact CVS
• DA1, Beta1
• Moderate Dose
Effect of Catecholamines to intact CVS
4. Respiratory System
agonists
–eg, terbutaline– produce relaxation of tracheal
and bronchial muscle
5. Eye
• Radial muscle, iris (pupillary dilator)
– contraction () --> 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 ()
6. Gastrointestinal tract
• alpha and beta receptors locate on smooth muscle and on neurons of enteric nervous system
• Stomach and intestine
– Motility and tone: (,)
– Sphincters : contraction ()
– Secretion (intestine): inhibition () : inhibit salt and water secretion
7. Genitourinary tract
• Urinary bladder
– Detrusor or bladder wall: relax ()
– Trigone, sphincter, prostate gland: constrict ()
• Uterus
– non-pregnant: relax ()
– pregnant: contract(), relax ()
8. Metabolic and hormonal effects
• Kidney
– renin release ()
• Pancreatic cells – inhibit insulin release ()
– stimulate insuline release ()
• Glycogenolysis in liver and skeletal
muscle ()
8. Metabolic and hormonal effects
• Glucose out of liver associated with initially hyperkalemia, then transport into skeletal muscle resulting in a later hyperkalemia.
• Lipolysis () : 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 I. Clinical Application of Sympathomimeticsof 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 (), decrease PVR through
partial effect: Dobutamine
– cardiogenic shock from MI, CHF or septic shock : Dopamine
B. Reduce blood flow and increase BP
– Surgery : prolong action of local anesthetics (
– hypotension, during spinal anesthesia (
– congestion ( : 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 ()
C. Cardiac application– paroxysmal atrial tachycardia (
– complete heart block or cardiac arrest ()
: Epi or Iso
2. Respiratory application
• Especially selective 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 ( ,)
• 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 ( ) and
anorexant effect
• Misuse or abuse for deferring sleep, for mood-elevating, euphoria-producing action
7. Additional uses
Central 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
agonists: hypertension, bradycardia (reflex)
– agonists: palpitation, sinus tachycardia,
serious arrhythmias
– 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