CATECHOLAMINES &NON CATECHOLAMINES.

.PRESENTED BYDR SINDHU K

MVSC SCHOLAR,

DEPT OF VPT, COVAS.

`

Autonomic drugs Drugs that exerts pharmacological effects simulating activation, intensification or inhibition of either the sympathetic/parasympathetic nervous system have been historically referred to as autonomic drugs.

classification sympathomimetic sympatholytic parasympathomimetic parasympatholytic

Classifications sympathomimetic adrenergic adrenomimetic sympatholytic receptor blocking effects neuronal blocking effects parasympathomimetic cholinergic cholinomimetic parasympatholytic receptor blocking effects neuronal blocking effects

Adrenergic nerves are

not required for their

effect.

CATECHOLAMINES

Activate receptor

of effector cells

catecholamines

Direct acting sympatho

mimetic amines

catecholamines

CATECHOLAMINES Norepinephrine – alpha agonist property Epinephrine – mixed acting (alpha & beta agonist) Isoproterenol – selective beta agonist Dopamine – immediate precursor of NE

ADRENERGIC/SYMPATHOMIMETIC DRUGS

Amine substances that causes physiologic response similar to those evoked by the endogenous adrenergic mediators viz Epinephrine & Norepinephrine are known as ADRENERGIC DRUGS SYMPATHOMIMETIC = pharmacologic effect mimic sympathetic nervous system clinically relevant adrenergic agonist

pharmacological action.

receptor activation.

`

Adrenoceptors / adrenergic receptors

• adrenoceptors are macro molecular structure localized on/within the surface membrane of cells innervated by adrenergic neurons • basic physiological function is to recognize & interact with endogenous adrenergic mediators viz : Adr, Noradr.• adrenergic receptors are membrane bound G protein coupled receptors which functions primarily by increasing / decreasing the intracellular production of secondary messengers cAMP, IP3, DAG.

Organs Alpha action Beta actionArterioles & veins Vasoconstriction = rise in BP Vasodilation = fall in BP

Heart Arrhythmia @ higher dose Positive inotropic, positive chronotropic

Radial muscle of iris Mydriasis aqueous secretion

Relaxation of ciliary muscles aqueous secretion

Urinary bladder contraction relaxation

Uterus contraction Relaxation

Splenic capsule Contraction Relaxation

Insulin Secretion inhibited Augumented insulin Glucagon Secretion

Epinephrine secreted by adrenal medulla & neuro -effector transmitter of adrenergic drugs.

`

Pharmacological effect cardiovascular system vascular smooth muscle : alpha = vasoconstriction -> mesenteric arteries -> mucus membrane -> renal beds -> cutaneous : beta = vasodilation -> skeletal muscle -> coronary blood vessel -> liver

Blood pressure Norepinephrine -> dose related increase in systolic & diastolic BP Epinephrine -> potent vasopressor agent

Heart Iso >>> Epi > Norepi

Smooth muscles & uterus Alpha receptors causes contraction -> release of intracellular Ca++

activation of IP3

Contraction

Beta receptors -> Relaxation

Metabolic effectsCarbohydrate metabolism glycogenolysis in liver release of glucagon & release of insulin Lipid metabolism -> raises concentration of free fatty acids in blood -> stimulates beta receptors of adipose tissues -> activates adenylate cyclase -> cAMP stimulates lipase for hydrolysis of triacylglycerols -> free fatty acids & glycerol

Pharmacokinetics orally not effective -> rapid metabolism by MAO & COMT rapidly absorbed after IM injection for immediate effects I/V

on inhalation action restricted to respiratory tract (local action)

Clinical indications

Drug of choice for treatment of Type 1 hypersensitivity reactionIn critical conditions = drowning, suffocation, shock, electrocutionBcoz of vasoconstriction property used in combination with local anestheticsSevere respiratory distress like acute asthma & anaphylactic shock (B.dilator)In opthalmology as 2% epinephrine solution

Doses for hypersensitivity reactionSmall animals @ 5-20 microg/kg, IV, SC, IM @ 50 microg/kg endotracheally (feline asthma)Large animals @ 20 micrig/kg IM & 5-10 microg/kg IV for cardiac resucscitation (asystole/cardiac arrest)Small animals @ 10-20 microg/kg IV @ 100 – 200 microg/kg endotracheallyLarge animals @ 20 microg/kg SC, IV, I/tracheally.

Norepinephrine Noradrenaline released by the mammalian post ganglionic sympathetic NS NA constitutes 10-20% of catecholamine content adrenal medulla NA affects large area of brain -> mainly Alertness & Arosal. Levo form >> dextro form NE differs from Epi only by lacking the methyl substitution in amino group chemically 1-B (3,4 – dihydroxy phenyl) alpha - aminoethanol

Pharmacological effects Blood vessel -> Vasoconstriction BP -> dose related increase in systolic & diastolic BP heart -> potent myocardial stimulant Smooth Muscles -> Relaxation of intestinal SM = retention of ingesta Metabolic effect -> hyperglycemia

PharmacokineticsIneffective when given orallypoorly absorbed from S/C siteinactivated by MAO & COMT4-16 % administered drug excreted in urine

Clinical indicationsI. NE has limited use but therapeutically

important in INTENSIVE CARE UNIT II. in patients with critical hypotension

(vasodilatory shock viz septic shock & neurogenic shock )

III. in the treatment of BP, NE is administered by I/V infusion dose titrated to pressor response.

IV. Major limitation in clinical application = NE reduces blood supply to kidneys

Doses All species @ 0.1 – 0.2 microgram/kg/min IV infusion in 5% dextrose or 5% dextrose saline solution but never use NS solution alone. infusion of NE should be reduced gradually, avoiding abrupt withdrawl.

Isoprenaline/isoproterenolDirect acting synthetic CA’s with chemical name d, 1- B(3,4-dihydroxyphenyl)-alpha-isopropyl aminoethanol Hcl.It was commonly used to treat ASTHMA before the clinical applications of beta receptors were discovered. Iso predominantly stimulates B1 & B2 adrenoceptors and has no alpha activity @ therapeutic levels.

Pharmacological effects1. CARDIOVASCULAR SYSTEM>decreased pheripheral resistance (relaxation of skeletal muscles)>markedly decreases diastolic pressure with moderately increase in systolic pressure>most potent cardiac stimulant +++chronotropic +++inotropic

GITPotent INHIBITORY effect

RESPIRATORY EFFECTS>potent BRONCHODILATOR.

>inhibits the antigen mediated release of histamine & other mediators of inflammation.

>often used clinically to dilate bronchiolar airways during episode of allergic reactions.

Clinical indications + Doses for Sinoatrial arrest, Sinus Bradycardia, Complete AV blockDogs & Cats @ 0.4 mg (total dose) in 250 ml of 5% dextrose slow IV infusion.

for bronchoconstriction/feline asthmaDogs @ 0.1 – 0.2 mg (total dose) IM or SC 4 times a day.Cats @ 0.2mg (total dose) in 100 ml of 5% dextrose slow IV infusion to effect, TID

Horses @ 0.4 microgram/kg in normal saline, slow IV.

DOPAMINE 3,4-dihydroxy phenyl ethylamineEndogenous CA’s = immediate precursor of NE as central NT in the basal ganglia & the adrenal medulla.PERIPHERY -> synthesized in renal epithelium diuretic/natriuretic. is an important adrenergic & dopaminergic agonist used in ICU = maintain HR/BP

Pharmacological effect MOA mixed adrenergic action -> direct (alpha & beta) -> indirect (release of NE) dopaminergic actions (D1, D2 receptors)

Cardiovascular system @ low I/V dose = 0.5 – 2 microgram/kg/min RENAL DOSE acts on vascular D1 dopaminergic receptors & dilates renal, mesenteric, coronary vascular bed.@ intermediate dose = 2 – 10 microgram/kg/min RENAL&CARDIAC DOSEStimulates renal D1 receptors + activates beta adrenergic receptors on heart -> release of NE ++inotropic effect, systolic BP@ high dose = > 10 microgram/kg/min PRESSOR DOSEActivates vascular alpa1 adrenoceptors VC, elevated BP negate the dopaminergic effect.

Clinical indication + dosesAdjunctive therapy of acute cardiac failure All species @ 1 – 10 microgram/kg/min, IV infusion in NSAdjunctive therapy for oliguric renal failure All species @ 2 – 5 microgram/kg/min, IV infusion with diureticsTreatment of severe hypotension/shock All species @ 1 – 20 microgram/kg/min, IV infusion

NONCATECHOLAMINES 3-4 DIHYDROXYBENZENE max potency

many drugs without catechol nucleus exerts similar effect = noncatecholamines1. Ephedrine2. Amfetamine3. Methyl phenidate4. Pseudoephedrine5. Phenyl Propanol Amine6. oxymetazoline

EPHEDRINE mixed acting alkaloid isolated from Chinese shrub Ma huang levo isomer = more active

used as stimulant, nasal decongestant, bronchodilator, to promote urinary incontenance in small animals.

MOA sympathomimetic action = direct activation of alpha/beta receptors= release of endogenous NE action in CNS limited bcoz crosses BBB weakly & not very efficiently. repeated doses causes TACHYPHYLAXIS (depletes the neuronal pool of NE)

Doses 1. For bronchoconstriction Dogs @ 1-2 mg/kg, PO, BID Cats @ 2-5 mg/kg, PO, BID 2. Urinary incontinence Dogs & Cats @ 2-4mg/kg PO TID 3. As Pressor agent Dogs @ 0.5-0.75 mg/kg, IV,IM, SC 4. As decongestant 1-1.5% solution.

PSEUDO EPHIDRINE stereo-isomer of ephedrine pharmacological effect = Ephedrine in veterinary medicine it is used orally as decongestant symptomatic relief in URT inf cats allergic rhinitisDogs @ 15-50 mg (total) PO TIDCats @ 2-4 mg/kg PO BID

. .

AMPHETAMINE

synthetic sympathomimetic powerful CNS stimulant action + alpha/beta adrenergic action powerful psycho stimulant drug + potent drug of abuse & drug dependency.

Pharmacological effectsRelease of several NT’S = NE, Dopamine, serotonin from storage vesicle @ their respective nerve terminals.Peripheral effectsCentral effects{stimulates entire CS axis, cortex, brain stem, medulla high alertness, decreasd fatigue, mood elevation, euphoria, decreased appetite}CNS stimulant = drug of abuse = athletics & race horses improve physical performance

METAMPHETAMINE In humans causes amphetamine psychosis resembles paranoid schizophrenic attacks like hallucinations & paranoid delusions, loss of weight tolerance to central action toxic effects of amphetamine pharmacokinetic+pharmacodynamics recovery = rapid after withdrawal of drug but chronic conditions precipitate as psychosis in veterinary medicine limited use

METHYL PHENIDATE Racemic mixture of a psychostimulant drug with structural resemblance to amphetamine MOA - dopamine level & NE in brain through reuptake inhibition of MAO transporters. approved clinically for Rx of attention deficient hyper activity syndrome, psychiatric disorder, obsessive compulsive disorders in humans

PHENYL PROPANOL AMINENon catecholamine sympathomimetic agent Pharmacological action = EphedrineIn veterinary medicine used as decongestant, mild bronchodilator For the treatment of urethral sphincter hypotonus.Dogs & cats @ 1-2 mg/kg PO TIB

OXYMETAZOLINEDirect acting noncatecholamine MOA : non selectively agonizes alpha1 & alpha2 adrenergic receptors : vascular alpha1 adrenergic receptors VasoConstriction. : local application stimulation of endothelial post synaptic alpha2 receptors VC (on systemic circulation) : In contrast ~ centrally mediated inhibition of sympathetic tone via pre-synaptic alpha2 receptors vasodilation.

Clinical indicationsTopically as decongestant Rhinitis & conjunctivitis

Discussion

Thank you

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