Adrenergic Drugs

ADRENERGIC TRANSMISSION Noradrenaline (NA) It acts as transmitter at postganglionic sympathetic sites (except sweat glands, hair follicles and some vasodilator fibres) and in certain areas of brain. Adrenaline (Adr) It is secreted by adrenal medulla.

Adrenergic receptors There are two main groups of adrenergic receptors, α and β, with several subtypes. α receptors have the subtypes α1 and α2. β receptors have the subtypes β1, β2 and β3.

α1 adrenergic receptors Smooth muscle Vessels (skin, GI system, kidney and brain) Glands Gut Liver Muscle contraction Mydriasis Vasoconstriction in the skin, mucosa etc. Gland secretion Gut relaxation but sphincter contraction Glycogenolysis

α2 adrenergic receptors Prejunctional on nerve ending Postjunctional in brain, pancreatic β cells, etc. Extrajunctional in blood vessels, platelets Negative feedback in the neuronal synapses - presynaptic inhibition of NA release Inhibition of insulin release Induction of glucagon release from the pancreas. Increased thrombocyte aggregation Vasoconstriction of veins and coronary arteries Decrease motility of smooth muscle in GIT

β1 receptors Increase heart rate Increase force of cardiac contractility Increases conduction of atrioventricular node (AV node) Renin release from juxtaglomerular cells

β2 receptor Smooth muscle relaxation, e.g. in bronchi,GI tract Relax non-pregnant uterus Relax detrusor urinae muscle of bladder wall Dilate arteries to skeletal muscle (in contrast to vasoconstriction caused by α1 and α 2 adrenoceptors). Coronary arteries have only β2 receptors. Relaxation of Bronchioles

β2 receptor

β3 receptor It is located mainly in adipose tissue and is involved in the regulation of lipolysis β3 activating drugs could theoretically be used as weight-loss agents, but are limited by the side effect of tremors.

Epinephrine (adrenaline) Epinephrine, also known as adrenaline, is a medication and hormone. As a medication it is given intravenously, by injection into a muscle, by inhalation, or by injection just under the skin. Epinephrine is normally produced by both the adrenal glands and certain neurons and plays an important role in the “fight-or-flight” response.

Norepinephrine Norepinephrine (noradrenaline) is catecholamine that functions in the human brain and body as a hormone and neurotransmitter. Norepinephrine is synthesized and released by the central nervous system and also by the sympathetic nervous system. In the sympathetic nervous system norepinephrine is used as a neurotransmitter.

Epinephrine vs Norepinephrine Adr : α1 + α2 + β1 + β2 NA : α1 + α2 + β1 but no β2 action

Comparative effects of intravenous infusion of adrenaline and noradrenaline Adr NA 1. Heart rate ↑ ↓(reflex bradycardia) 2. Cardiac output ↑↑ – 3. BP—Systolic ↑↑ ↑↑ Diastolic ↓ ↑↑ Mean ↑ ↑↑ 4. Blood flow Skin and mm ↓ ↓ Sk. muscle ↑↑ ↓ 5. Bronchial muscle ↓↓ – 6. Intestinal muscle ↓↓ - 7. Blood sugar ↑↑ –, ↑

Adrenaline action Heart Cardiac stimulation (β1), ↑ rate, force and conduction velocity Blood vessels Both vasoconstriction (α) and vasodilatation (β2) can occur . Constriction predominates in cutaneous, mucous membrane and renal arterioles. Dilatation predominates in skeletal muscles, liver and coronaries arterioles.

Adrenaline action BP Adr given by slow i.v. infusion or s.c. injection causes rise in systolic (α) but fall in diastolic (β2) BP. Mean BP generally rises. Rapid i.v. injection of Adr produces: 1) a marked increase in both systolic as well as diastolic BP. 2) The BP returns to normal within a few minutes and a secondary fall in mean BP follows.

Norepinephrine and BP It does not cause vasodilatation (no β2 action). Peripheral resistance increases consistently due to α action. NA causes only rise in systolic, diastolic and mean BP.

Adrenaline action Respiration Adr causes bronchodilatation (β2)(but not NA!) Eye Mydriasis due to contraction of radial muscles of iris (α1) The intraocular tension tends to fall. GIT Relaxation (both α and β receptors) CNS Adr produces activation of brain →restlessness, apprehension and tremor may occur. !Activation of α2 receptors in the brainstem results in decreased sympathetic outflow → fall in BP and bradycardia.

Inducations Hypotensive states (shock)/Anaphylaxis Adr is the drug of choice in anaphylactic shock (raise BP + bronchodilation) Along with local anaesthetics Duration of anaesthesia is prolonged and systemic toxicity of local anaesthetic is reduced. Local bleeding is minimised. Control of local bleeding Cardiac arrest (Adr may be used to stimulate the heart) Bronchial asthma Mydriatic

Adverse effects Tachycardia Arrhythmia Anxiety Panic attack Headache Tremor Hypertension Cerebral haemorrhage Angina Myocardial infarction

α1-adrenomimetics Phenylephrine It is an effective mydriatic and decongestant and can be used to raise the blood pressure (in hypotensive states). Methoxamine acts pharmacologically like phenylephrine. Midodrine -the treatment of postural hypotension

α2-adrenomimetics Nasal decongestant: Naphazoline Xylometazoline Oxymetazoline CNS-activating: Clonidine Guanfacine (Estulic) Tizanidine produce local vasoconstriction Regular use for long periods should be avoided because atrophic rhinitis and anosmia can occur due to persistent vasoconstriction. to treat: high blood pressure, withdrawal (from alcohol, opioids or smoking) spasms, cramping, and tightness of muscles

Mechanism of Clonidine action Clonidine → stimulate presynaptic α2-receptors in the vasomotor center → inhibiting the release of NE →decrease in sympathetic tone → lowering blood pressure. Clonidine → on the I1-receptor (imidazoline receptor), which mediates the sympatho-inhibitory actions of imidazolines to lower blood pressure.

Adverse effects of Clonidine Orthostatic hypotension (Drops in blood pressure upon standing up) Sedation Sleepiness Dizziness Fatigue Rebound effect (sudden discontinuation can cause rebound hypertension)

β1 STIMULANTS Dobutamine (in cardiogenic shock) Dopamine Cardiac stimulation ↑ rate, force and conduction velocity To treat: acute heart failure chronic heart failure in phase of cardiac decompensation cardiogenic shock ADR: Hypertension Angina Arrhythmia, including fatal arrhythmias Tachycardia Atrial fibrillation

β2 STIMULANTS Short acting (4–6 hours) : Salbutamol Terbutaline Ritodrine Long lasting (12 hours): Salmeterol Formoterol Clenbuterol the relief of bronchospasm in asthma to relax the uterine smooth muscle to delay premature labor. for prevention of asthma symptoms not for use in relieving an asthma attack (not be used to treat acute symptoms) should be used with a corticosteroid

β2 STIMULANTS Side effects Dizziness Headaches Tachycardia Arrhythmia Muscle cramps Paradoxical bronchospasm! Hypotension and collapse

β1β2-STIMULANTS Isoprenaline (isoproterenol) For the treatment of: Bradycardia heart block For asthma (rarely) ADR: Tachycardia Arrhythmia Hypotension

Sympathomimetic drugs - stimulant compounds (indirect-acting)which mimic the effects of epinephrine and norepinephrine These drugs can act through several mechanisms: Blocking breakdown of NA Blocking reuptake of NA stimulating production and release of NA. Ephedrine (found in Ephedra) Pseudoephedrine Amphetamine (Benzedrine) Phenylpropanolamine (norephedrine)

Ephedrine Ephedrine is a dangerous natural compound! Repeated injections produce tachyphylaxis. In traditional Chinese medicine, it is used as bronchodilators . Ephedrine crosses to brain and causes stimulation. Used as: A stimulant (it increases performance in athletes) Concentration aid, Appetite suppressant Weight loss (a popular supplement taken by body builders to cut down body fat before a competition). For hypotension during spinal anaesthesia /postural hypotension Bronchial asthma

Ephedrine Adverse drug reactions : Cardiovascular: tachycardia, cardiac arrhythmias, angina pectoris, vasoconstriction with hypertension Dermatological: flushing, sweating, acne vulgaris Gastrointestinal: nausea Genitourinary: decreased urination due to vasoconstriction of renal arteries Nervous system: restlessness, confusion, insomnia, mania/hallucinations, paranoia, panic, agitation Respiratory: dyspnea, pulmonary edema Miscellaneous: dizziness, headache, tremor, hyperglycemic reactions, dry mouth

Pseudoephedrine Medical uses: a stimulant (improvement in mental and physical functions ) a nasal/sinus decongestant (it reduces edema and nasal congestion/rhinitis) a wakefulness-promoting agent (treatment of sleeping disorders, excessive daytime sleepiness and narcolepsy)

Pseudoephedrine Adverse effects CNS stimulation- insomnia, nervousness, excitability, dizziness and anxiety. Tachycardia Arrhythmias Hypertension Hallucinations Seizures Systemic contact dermatitis Paranoid psychosis Stroke

Amphetamine(Adderall) Amphetamine is used to treat: Attention deficit hyperactivity disorder (ADHD) Narcolepsy (a sleep disorder) Obesity Past medical indications: Depression Nasal congestion

Amphetamine(Adderall) Hypertension Tachycardia Erectile dysfunction Loss of appetite and weight loss Seizure and tics Irritability Repetitive or obsessive behaviors Amphetamine psychosis (paranoia) Cardiogenic shock and circulatory collapse Cerebral hemorrhage Pulmonary edema and hypertension Kidney failure Addiction and Drug tolerance

Phenylpropanolamine is used as: A stimulant Decongestant Anorectic agent In Europe, PPA is still available in prescription and over-the-counter cough and cold medications.