sympathomimetic drugs dumrongsak pekthong m.sc.(pharmacology)

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


•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

• Two subtypes of adrenoceptors ( and )

- excitatory in most tissues

(except - intestinal smooth muscle)

- inhibitory in most tissues

(except - heart)


Rank Order of Potency

receptors Epi > NE >> Iso

receptors Iso > Epi > NE

Type of adrenoceptor

, , , DA1, DA2


type :Phenylephrine, methoxamine

D

type :Clonidine, BHT920

:Oxymetazoline

C


type :Isoproterenol

:Dobutamine

:Procaterol, terbutaline

:BRL37344

Peripheral Dopamine (DA) type :Dopamine

DA1 :Fenoldopam

DA2 :Bromocriptine


•Generally ---Contraction of smooth muscle

---Relaxation of smooth muscle

---Stimulation in heart

---Inhibition, for GI tract ---Relaxation


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)


DrugsB. Selective agonists

, , : Norepinephrine*

> : Phenylephrine*,

methoxamine, metaraminol, midodrine

> :Clonidine*, methylnorepinephrine,

apraclonidine, brimonidine

= : Isoproterenol*


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


Amphetamine, Yes Hours

Ephedrine Yes Hours

Phenylephrine Poor Hours

Albuterol, Yes Hours

metaproterenol, terbutaline


Other sympathomimetics


Oxymetazoline, Yes Hours

xylometazoline

Cocaine No Minutes to Hours


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


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.


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)


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


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.


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


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


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 ()


• Kidney

– renin release ()

• Pancreatic cells – inhibit insulin release ()

– stimulate insuline release ()

• Glycogenolysis in liver and skeletal

muscle ()


• 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

sympathomimetic drugs dumrongsak pekthong m.sc.(pharmacology)

Documents

adrenoceptor subtypes

constricteyeradial muscle

cardiac muscle

constrictskeletal muscle

contractciliary muscle

bronchial muscle

alpha receptors

subtypes of adrenoceptorsd