ADRENERGIC AGONISTS & ANTAGONISTS

DR SINDHU K

MVSC SCHOLAR,

DEPT OF VPT,

COVAS, POOKODE.

AGONISTS CLASSIFICATION DIRECT ACTING Selective (phenylephrine, dobutamine)

Non-selective (oxymetazoline, NE, Isoproterenol)

MIXED ACTING ephedrine

INDIRECT ACTING Releasing agents ( amphetamine)

Uptake inhibitors (cocaine)

MAO & COMT inhibitors (entacapone)

Alpha -1 adrenergic receptor agonists

1. phenylephrine 2. methoxamine 3. midodrine

Phenylephrine direct acting non-catecholamine powerful alpha 1 agonist/CNS MOA : activation of alpha1 adrenoceptors vascular smooth M = VC peripheral VC = systolic & diastolic BP blood supply renal, splanchnic & skin but coronary blood flow I/O pressure mydriasis

Clinical indications

Critical care unit spinal/epidural anesthesia elevates BP (reflux bradycardia negligable) = beneficial tachycardic condition/ cardiomyopathy as pressor agent maintenance of blood pressoAs midriatic agent pupil dilation

Doses Pressor agent

Dogs @ 1-3 microgram/kg/min

Cats @ 0.1mg/kg SC

Horses @ 5mg (total) IV 2.5% ophthalmic solution as mydriatic agent 10% solution

Methoxamine selective alpha1 receptor agonist & similar in structure/action to phenylephrine causes dose related systolic & diastolic BP peripheral vascular resistance & VC hypertension associated with bradycardia + activation of vagus

Clinical indications 1. pressor agent treatment of hypotension

2. to relieve attacks of paroxysmal supraventricular tachycardia

Dogs & cats @ 0.04 – 0.08 mg/kg IV

Cattle & horses @ 0.1 - 0.2 mg/kg IM, once day

Midodrine orally effective prodrug desglymidodrine selectively stimulates alpha adrenoceptors of vascular smooth M & causes vasoconstriction. treatment of autonomic insufficiency & postural hypotension.

Alpha -2 adrenergic receptor agonists

1. clonidine 2. xylazine 3. guanfacine & guanabenz

Clonidine

Imidazoline derivative predominantly utilized in human medicine for hypertension & tachycardia before the research & development, it was given with out the prescription to cure diseases

MOA: (prototype of alpha-2) Direct acting rapid IV inj transient raise BP activation of post-junctional alpha 2 receptors Brain alpha 2 receptors especially medulla oblongata inhibits NE central sympathetic outflow In periphery activation of pre-junctional alpha 2 receptors suppress release of NE peripheral vasodilation. On Central I-R of brain activation pre-synaptic alpha2 receptors hypotensive effect (no transient hypertensive effect)

Clinical indications + dosesIn human medicine = Antihypertensive drug De-addiction therapy for narcotics, tobacco & chronic alchoholismIn Veterinary medicine

As Sedative & Analgesic

1. sheep @ 0.006 mg/kg IV

2. horses @ 0.025 mg/kg IV

Xylazine Alpha 2 adrenoceptor agonist structurally similar clonidineUsed as Central sedative analgesic + muscle relaxant property MOA : stimulation action on central alpha 2 receptors sedation+analgesia

: on CVS peripheral alpha2 action initial peripheral resistance +

BP followed by long duration of lowered BP(central action)

Clinical indications sedation in dogs, cats & horses. preanesthetic sedative prior to inhalant anesthesia, injectable. as sedative prior to local, regional & epidural anesthesia. As general anesthesia with ketamine.

Doses

dogs & cats @ 1-3 mg/kg IM horses @ 0.6 -1 mg/kg IV pigs @ 0.5 – 3 mg/kg IMSheep & goats @ 0.1 – 0.2 mg/kg IM Cattle @ 0.05-0.03 mg/kg IM

Selective alpha 2 receptor agonists.1. guanfacine

2. guanabenz

3. detomidine

4. apraclonidine

5. tizanide

6. lofexidine

Beta -1 adrenoceptor agonists

1. Dobutamine 2. Denopamine 3. Xamoterol 4. Prenalterol

Dobutamine

Synthetic direct acting catecholamine + selective beta1 adrenergic action L - isomer potent alpha 1 agonist pressor effect D – isomer potent alpha 1 antagonist blocks l isomer D isomer 10 times more potent beta 1 agonist than l isomer

MOA + clinical application DOSE dependant response @ 2.5-15 microgram/kg/min IV infusion significant change in HR, +++ inotropic +++ chronotropic , peripheral resistance. @ very high doses > 20 microgram/kg/min HR increases clinically used as inotropic agent in Rx of CHF in Dogs @ 5 – 20 microgram/kg/min IV infusion Equine anesthesia to maintain mean BP prevents hypotension induced myopathy = (complication of equine anesthesia) Horses @ 1 – 5 microgram/kg/min, IV infusion

Denopamine oral cardioselective drug MOA : selective binding to the beta1 adrenergic receptors in heart cardiac M contractibility increased enhanced cardiac output in +ion = potential to dilate coronary blood vessels clinically used to Rx angina & CHF

Beta-2 adrenoceptor agonists

1. Terbutaline 2. Clenbuterol 3. Salbutamol 4. Salmeterol 5. Pirbuterol 6. Isoetarine 7. Orciprinaline

Terbutaline

selective beta 2 adrenoceptor agonist found in bronchial, vascular & uterine smooth M Relaxation. effective when taken orally, S/C, inhalation. horse poor oral absorption resorcinol ring (not substrate MAO)

MOA +CLINICAL INDICATION stimulates production of cAMP activation of adenylate cyclase inhibit release of inflammatory mediators mast cells stimulation of beta2 receptors bronchodilation bronchial secretion increases + bronchial clearance by ciliary action. mucolytic activity applied therapeutically as a fast acting bronchodilator & relief from profuse nasal secretion. cats limited use Bcoz cardiac stimulant actionHorses after parenteral inj = sweating & CNS excitation.

Doses Dogs @ 1.25 – 5 mg/kg, PO, TID. Cats @ 0.1 mg/kg PO BID Horses @ 0.002 -0.005 mg/kg IV dose may be adjusted as required @ 2-4 mg/kg by inhalation using nebulizer

Clenbuterol Direct acting beta 2 receptor agonist stimulation of beta 2 receptors in respiratory tract + ciliary beating of respiratory mucosal cells increases mucolytic action its primarily approved for Horses as a BRONCHODILATOR in the management of airways obstruction COPD

@ dose rate of 0.8 microgram/kg BID if no response then

@ 0.16 microg/kg

@ 0.24 microg/kg

@ 0.32 microg/kg

Salbutamol highly selective beta 2 adrenergic agonist B2 >>B1 pharmacological + therapeutic indication similar to terbutaline bronchodilator effect with minimal cardiac stimulationUsed principally in Dogs & Cats bronchial Smooth M to alleviate bronchospasm / cough Dogs @ 0.02 – 0.05 mg/kg PO 3-4 times daily

Salmeterol Long acting selective beta2 adrenergic agonistHigher lipophilicity prolonged pulmonary residence timeSalmeterol 10 folds potent than salbutamolHorses improves pulmonary function 55% with in 60 min of aerosol administration + long duration of action = 8 hours horses @ 0.5 – 1 microgram/kg by aerosol inhalation.

ANTI-ADRENERGIC DRUG/ SYMPATHOLYTICS

Alpha receptor antagonists.Non selective

Eg: phenoxybenzamine, phentolamine.

Alpha-1 selective

Eg: prazocin, terazocin, urapidil etc.

Alpha-2 selective

Eg: yohimbine.

NON SELECTIVE ALPHA ADRENERGIC RECEPTORS ANTAGONISTS

1. HALOALKYLAMINE DERIVATIVES/ ALKYLATING AGENTS – phenoxybenzamine , dibenamine

2. IMIDAZOLINE DERIVATIVES – tolazoline, phentolamine

3. ERGOT DERIVATIVES – ergotamine , dihydroxyergotamine

Phenoxybenzamine Haloalkylamine derivative binds to a1/a2 R inhibits activation mediated by endogenous catecholamines.blocks both alpha 1 & alpha 2 adrenoceptors non competitive block irreversible block.Progressive decrease in peripheral resistance, tachycardia, relaxation of nictating membrane, blocks pupillary dilatation, relaxation of urinary sphincter, increases insulin secreation. Used in the treatment of hypertension caused by pheochromocytoma

DALE’S EPINEPHRINE REVERSAL PHENOMENA

DOSES

For Rx of reflux dyssinergia in Dogs @ 0.25 – 0.5 mg/kg, PO, BIDFor hypertension associated with phaeochromocytoma Dogs @ 0.2 – 1.5 mg/kg PO BID

TOLAZOLINE

Imidazole derivative Direct vasodilator & cardiac stimulant actionAlso blocks 5HT receptors + histamine like actionIn veterinary medicine used primarily as Antidote to xylazine overdose in dogs & cats @ 4 mg/kg slow IV

ERGOT ALKALOIDS Are the 1st adrenergic blocking drugs discovered with which Henry Dale demonstrated the vasomotor reversal phenomenon.Therapeutic use mainly to stimulate contraction of uterus post – partum & to relieve the pain of migraine in human medicine.

SELECTIVE ALPHA-1 ADRENERGIC RECEPTOR ANTAGONISTS.

1. QUINALZOLINE DERIVATIVES – prazosin, terazocin

2. INDOLE DERIVATIVES – indoramin

3. MISCELLANEOUS – urapidil, ketanserin

Prazocin Hcl

Prototype of selective Alpha-1 adrenergic R antagonistsExtremly potent & highly selective alph-1 receptor blocking drugAlpha-1 Receptor (1000folds) >>>> Alpha-2 ReceptorPharmacological effect peripheral vascular resistance & BPIn dogs for Rx systemic hypertension/pulmonary hypertension

< 15 kg BW @ 1 mg total dose, PO, TID

> 15 kg BW @ 2 mg total dose, PO, TID

Therapeutic application in human medicine

Terazocin structural analogue of prazocin mainly used for the Rx of BPH-Benign Prostatic Hyperplasia ( BP by peripheral vasodilation)

It is often considered the drug of choice for men with hypertension & prostate enlargement. Indoramin indole derivative & competitive alpha1 R antagonist occasionally used in human beings for the Rx of hypertension & BPH. Prazocin primarily used in humans for the management of hypertension.

Miscellaneous drugs Urapidil acts both as an alpha1 adrenoceptor antagonist & an 5HT1A receptor agonist

Ketanserin blocks alpha1 adrenoceptors, serotonin 5HT2A & 5HT2C receptors & histamine H1 receptors.

The exact role of these drugs in Rx of hypertension & other conditions remains to be determined.

SELECTIVE ALPHA-2 ADRENRGIC RECEPTOR ANTAGONISTS.

YOHIMBINE Indolealkylamine alkaloid obtained naturally from west African evergreen tree = Pausinystalia yohimbe Rx of xylazine & medetomedine reversal

Dogs & Cats @ 0.1 mg/kg, slow IV. Rx of xylazine induced emesis

Dogs & Cats @ 0.25 – 0.5 mg/kg IM SC BID

Atipamezole Synthetic selective alpha-2 adrenoceptor blocking drug primarily used as a reversal drug for Medetomidine & dexmedetomidine induced adverse effects.Acts by competitively blocking alpha2 receptors in CNS & periphery.

Clinical indications:

I. For Amitraz poisoning all species @ dose rate 0.05mg/kg, IV

II. For medetomidine & other alpha2 agonist reversal

Dogs @ 5 times the previous asministered dose of medetomidine,IM.

Cats @ 2.5 times the previously administered dose of medetomididne , IM.

BETA ADRENERGIC RECEPTOR ANTAGONISTS NON SELECTIVE

{1st Generation}

propranolol, nadolol, pindolol, timolol, sotalol

{3rd Generation}

carvedilol, carteolol, labetalol, bucindololSELECTIVE

{2nd Generation}beta 1 : metoprolol, atenolol, esmolol, acebutolol

{3rd Generation}beta 2 : betaxolol, celiprolol, nebivolol

Non-selective beta adrenergic receptor antagonists.

Propranolol Prototype of nonselective B receptor blockers.Interacts with both B1 & B2 receptors.Lacks sympathomimetic activity.Powerful local anesthetic action.Partial agonist @ serotonin 5HT1B receptors.

Clinical indication + doses Negative inotropic & negative chronotropic effects.Peripheral vasoconstriction. Bronchoconstriction.

Used as Antiarrhythmic drug

Dogs @ 0.1 mg/kg IM TID

Horses @ 175 mg/kg total dose PO

Cats @ 2.5 mg/kg total dose PO

Selective beta adrenergic receptor antagonists.

METAPROLOL prototype of selective B1 adrenergic receptor (cardioselective) Potency to block cardiac stimulation action >>> propranolol.Effectively used for supraventricular Tachycardia, premature ventricular contraction & V. hypertrophy.Dogs @ 5-50 mg total dose PO BID/TIDCats @ 2 – 15 mg total dose PO TID

LABETALOL mixed alpha & beta adrenoceptor blockerPrimarily used in Human medicine for Rx of hypertension In veterinary medicine pheochromocytoma & clonidine withdrawal hypertensionDogs @ 0.2 – 0.4 mg/kg PO once daily following titrating dose to twice daily.

Atenolol Devoid of intrinsic sympathomimetic & membrane stabilizing activity.It is used mainly as anti-arrhythmic drug.Clinical indication:

I. For cardiac conditions Dogs @ 6.5-25mg total dose, PO, BID/TID Cats @ 6.5-12.5mg total dose, PO, SID

II. For hypertension Dogs & Cats @ 2 mg/kg, PO, SID

Esmolol An ultra short acting cardioselective beta1 adrenoceptor blocker.It is devoid of intrinsic sympathomimetic & membrane stabilizing action.Esmolol is very useful for the investigation & immediate therapy for tachycardias.It is particularly useful in critical ill patients where adverse effects of bradycardia, heart failure/hypotension which may require rapid withdrawl of drug.For investigation, esmolol may be used as a test drug to indicate whether beta blocker therapy is warranted as an antiarrhythmic agent or not??

Dogs & Cats @ 0.5-1 mg/kg, slow IV as loading dose followed by 0.05 -0.2 mg/kg/min IV infusion.

ButaxamineSelective beta-2 adrenergic receptor antagonist.Blocks vasodilator & bronchial smooth muscle

inhibitory effect of isoprenaline which are mediated through B2 receptors.Primarily used in research where B receptor blockade is studied with other effects of drug.Butaxamine is not clinically used because blockade of B2 adrenergic receptor has no therapeutic application.

ALPHA & BETA ADRENERGIC RECEPTOR ANTAGONISTS.

I. LABETALOL

II. CARVEDILOL

LABETALOLMixed alpha & beta adrenoceptor blocker.Primarily used in human beings for Rx hypertension & Phaeochromocytoma , clonidine withdrawl hypertension

and in geriatric patients.

Carvedilol Mixed alpha & beta adrenoceptor antagonist which blocks B1, B2 & A1 receptors also possess antioxidant, antiproliferative & membrane stabilizing effects.Undergoes Firstpass metabolism & t1/2 = 1.5 hrs.Therapeutic indication: Hypertension (A1 antagonism)

Tachyarrhythmias ( B1 antagonism)

MI & CHF (antioxidant/antiproliferative effect).

Dogs @ 0.2-0.4 mg/kg, PO, once daily, followed by titrating dose to twice daily.Contraindicated in dehydrated/hypotensive/asthmatic animals.Adverse effect in dogs bradycardia, hypotension, bronchoconstriction.

LETS HAVE RECALL OF WHAT WE LEARNT TILL NOW !!!

References.GOODMAN & GILMAN`S The pharmacological basis of therapeutics, 11th edition.HS SANDHU Essentials of veterinary pharmacology and toxicology, 2nd edition. H RICHARD ADAMS Veterinary pharmacology and therapeutics, 8th edition. Jim E Riviere & Mark G Papich, Veterinary Pharmacology and Therapeutics, 9th edition. google images.