adrenergic transmission and adrenergic drugs

what is the first step of noradrenaline synthetization?

known as the rate-limiting step. L-tyrosine, present in noradrenergic nerve terminals and also known as the precursor for vital transmitters like dopamine and norepinephrine, undergoes a hydroxylation reaction via enzyme tyrosine hydroxylase and is synthesized into dihydroxyphenylalanine, or DOPA

what is the second step of noradrenaline synthetization?

DOPA undergoes a decarboxylation reaction via DOPA decarboxylase and is turned into dopamine, which is then transported to synaptic vesicles

what is the third step of noradrenaline synthetization?

inside the synaptic vesicles, dopamine undergoes a hydroxylation reaction via dopamine β-hydroxylase and is turned into noradrenaline

where is noradrenaline stored?

in synaptic vesicles until release is required, which is done by exocytosis

what occurs when noradrenaline is released?

occurring only in the adrenal medulla, it undergoes a methylation reaction and is converted into adrenaline via enzyme phenylethanolamine N-methyl transferase

what are some ways termination of catecholamine action is done?

• by reuptake of NA by noradrenergic nerve terminal (main pathway / 70-90%) and is either restored in vesicles or broken down inside the neurone

• metabolized by monoamine oxidase (MAO) and catichol-o-methyl transferase (CAMO) and is done inside the nerve terminal. it breaks down NA after uptake

• auto-inhibitory feedback, with NA acting on presynaptic alpha-2 receptors, which decreases further NA release and acts as a negative feedback mechanism

what are adrenergic receptors (adrenoceptors)?

G-protein-coupled receptors (GPCRs) found on cell membranes that bind epinephrine and norepinephrine to regulate the sympathetic nervous system, known as the "fight-or-flight" system

what are examples of adrenergic receptors (adrenoceptors)?

α-receptors, which are divided into:

• α1

• α2

β-receptors, which are divided into:

• β1

• β2

• β3

what is the main effect of α1 activation?

• vasoconstriction

• relaxation of GIT smooth muscles

• increased (vicious) salivary secretion

• increased hepatic glycogenolysis

what is the main effect of α2 activation?

• inhibition of transmitter release NA and ACh

• platelet aggregation (aids in blood clot formation)

• contraction of vascular smooth muscles (vasoconstriction)

what is the main effect of β1 activation?

• increased cardiac rate (+ chronotropic)

• increased force of contraction (+ inotropic)

• relaxation of GIT smooth muscles

what is the main effect of β2 activation?

• bronchodilation

• vasodilation

• relaxation of visceral smooth muscles

• increased hepatic glycogenolysis

• increased muscular tremor

what is the main effect of β3 activation?

lipolysis (fat breakdown)

what are examples of direct acting non-selective (both α and β) adrenergic agonists or sympathomimetics?

• adrenaline

• noradrenaline

• dopamine

what are examples of direct acting selective adrenergic agonists or sympathomimetics?

• selective α1

• selective α2

• selective β1

• selective β2

what are examples of direct acting non-selective β adrenergic agonists or sympathomimetics?

isoprenaline

what are examples of non-direct acting adrenergic agonists or sympathomimetics?

they are drugs that affect noradrenaline release and uptake, with examples being:

• cocaine

• amphetamine

what are examples of direct acting adrenergic α- receptor antagonists, sympatholytics, or blockers?

• non-selective α- receptor antagonists

• selective α1- receptor antagonists

• selective α2- receptor antagonists

what are examples of direct acting adrenergic β- receptor antagonists, sympatholytics, or blockers?

• non-selective β-antagonists

• β1-receptor antagonists

what are examples of indirect acting adrenergic antagonists, sympatholytics, or blockers?

they are drugs that affect noradrenaline release or uptake, with examples being:

• reserpine

• guanethidine

what are examples of selective α1 agonists?

phenylephrine and methoxamine, which:

• trigger the contraction of smooth muscles besides the GIT

• cause an increase in BP due to contraction of peripheral blood vessels (vasoconstriction)

what are examples of selective α2 agonists?

clonidine, α-methyldopa and methylnoradrenaline, which:

• cause a fall in BP partly by inhibiting noradrenaline release and partly by central action

what is α-methyldopa used for?

treatment of hypertension in pregnancy

what are examples of selective β1-agonists?

dobutamine, which:

• can cause cardiac arrhythmias

• used in the treatment of heart failure associated with myocardial infarction (M.I.)

what are examples of selective β2-agonists?

salbutamol and terbutaline, which:

• are mainly used in asthma due to their bronchodilator effect

• used in pregnancy to suppress premature labor (tocolysis)

what is the clinical use of adrenaline?

considered to be an emergency drug due to being a non-selective adrenergic agonist (both α and β), it is used in:

• cardiac arrest

• acute anaphylactic shock

• prolongation of local anesthetic action

what is the clinical use of isoprenaline?

consider to be a non-selective β adrenergic agonist, it is used in symptomatic heart block

what is the clinical use of clonidine?

considered to be a selective α2- agonist, it is used to treat hypertension

what is the clinical use of selective β2-agonists?

drugs such as salbutamol, salmeterol and terbutaline, which can treat asthma via bronchodilation. salbutamol can prevent premature labor

what is the clinical use of α-methyldopa?

considered to be a selective α2-agonist, it can treat pregnancy hypertension

what is the clinical use of amphetamine?

considered to be an indirect acting adrenergic agonist, it can treat ADHD, or attention deficient hyperactivity disorder

what are some side effects of adrenergic agonists?

• heart palpitations (via β₁)

• tachycardia (via β₁)

• hypertension (via α₁)

• cardiac arrhythmias (via β₁)

• cerebral hemorrhage (via α₁)

• gangrene (via α₁)

• hyperglycemia (via β₂)

what are examples of non selective α adrenoceptor antagonists?

• phentolamine

• phenoxybenzamine

what are the effects of phentolamine?

a reversible and competitive non-selective α adrenoceptor antagonists, its effects are:

• decreased blood pressure

• can cause postural hypotension

• increased GI motility, which can trigger diarrhea

what are the effects of phenoxybenzamine?

an irreversible and non-competitive non-selective α adrenoceptor antagonists with a long duration of action (~24hrs), its effects are:

• decreased blood pressure, can cause postural hypotension

• increased cardiac output and hear rate as a reflex response

• used in management of pheochromocytoma, a rare, usually benign, tumor of the adrenal gland that causes excessive secretion of hormones (specifically epinephrine and norepinephrine)

what are examples of selective α1 adrenoceptor antagonists and what are their effects?

prazocine, doxazocine and terazocine, and their effects are:

• vasodilation

• decreased BP

• postural hypotension can occur

• decreased cardiac output which is used to lower BP

what are examples of selective α2 adrenoceptor antagonists and what are their effects?

yohimbin and idazoxan, and their effects are:

• increases release of noradrenaline and increases BP

• used as aphrodisiac as they increase arousal

what are the side effects of α adrenoceptor antagonists?

• a sudden drop in blood pressure when you go from lying or sitting down to standing up, known as postural hypotension

• nausea

• dizziness

• drowsiness

• tiredness

• weakness

what are examples of non-selective β adrenoceptor antagonists?

• propranolol

• timolol

• nadolol

what are the effects of propranolol?

non-selective β adrenoceptor antagonist, its effects are:

• decreased cardiac output, leading to bradycardia

• decreased blood pressure

• causes bronchoconstriction

• can decrease glycogenolysis, which can trigger hypoglycemia

• used to treat hypertension, glaucoma, migraine, hyperthyroidism, angina pectoris and in myocardial infarction

what are the effects of timolol and nadolol?

non-selective β adrenoceptor antagonists that are more potent than propranolol, their effects are:

• nadolol has a long duration of action (14-24 hrs)

• timolol is used topically for chronic treatment of glaucoma and in treatment of hypertension

what are examples of elective β2 adrenoceptor antagonists?

• atenolol

• acebutolol

• metoprolol

what are the effects of atenolol, acebutolol and metoprolol?

selective β1 adrenoceptor antagonists they are used for hypertensive patients who are insulin dependent or in patients with impaired pulmonary functions, as they have minimal action on β₂ receptors in bronchi, therefore, cause less bronchial constriction

why is there no selective β2 receptor antagonist?

blocking them does more harm than good. a pure β2 blocker would cause bronchoconstriction, reduced glycogenolysis and increased peripheral resistance, possibly raising BP.

what are the side effects of β adrenoceptor antagonists?

• bronchospasm (via β 2 blockage)

• heart failure (via β1 blockage)

• prolonged hypoglycemia (via β2 blockage)

• bradycardia (via β1 blockage)

• heart block (via β1 blockage)

what are examples of β-receptor antagonists with partial agonistic activity?

pindolol and acebutolol, which block β receptors but also weakly stimulate β1 and β2 receptors. their opposing actions balance each other, leading to a milder overall β-blockade, making them ideal for hypertensive patients with bradycardia and for diabetic patients with hypertension

what is an example of a non-selective α- and β-receptor blocker?

labetalol, which is useful in treating hypertensive patients where increased peripheral resistance is undesirable and in pregnancy-induced hypertension (pre-eclampsia)

cocaine

an indirect sympathomimetic, it is a local anesthetic that blocks the uptake of noradrenaline, increasing the action of adrenaline and noradrenaline. it can cause tachycardia and it increases blood pressure

amphetamine

an indirect sympathomimetic, it increases the release of noradrenaline and inhibits the reuptake

reserpine

an indirect sympatholytic, it blocks the carrier-mediated transport of noradrenaline into synaptic vesicles, thus causing depletion of NA stores in adrenergic neurons. it is used to control hypertension and has the side effect of causing depression

guanethidine

an indirect sympatholytic, it blocks the release of noradrenaline. it lowers BP in hypertensive patients, but it is no longer used clinically due to its adverse side effects (sever postural hypotension, bradycardia, nasal congestion, failure of ejaculation in males, dizziness and diarrhea)

what is the use of epinephrine / adrenaline in local anesthesia in dentistry?

they are added to lidocaine and other anesthetics since they can stimulate α1 receptors to trigger vasoconstriction at the injection site, which prolongs anesthesia, reduces bleeding and delays systemic absorption

what is the use of epinephrine / adrenaline in hemostasis in dentistry?

they can be used to control bleeding during dental surgery, once again via vasoconstriction via α1 receptors, with an example being epinephrine-infused gauze in surgical sites

what is the use of epinephrine or phenylephrine in the management of hypertension in dentistry?

they can be used to manage hypertension during sedation

what are some emergency uses of adrenergic agonists in dentistry?

• anaphylaxis management via epinephrine auto-injector (EpiPen)

• asthma attacks via β₂ agonists like albuterol or salbutamol (Ventolin)

what are examples of pressor agents (raise BP)?

• noradrenaline

• ephedrine

• dopamine

• phenylephrine

• methoxamine

• mephentermine

what are examples of bronchodilators?

• isoprenaline

• salbutamol / albuterol

• terbutaline

• salmeterol

• formoterol

• bambuterol

what are examples of CNS stimulants?

• amphetamine

• dexamphetamine

• methamphetamine

• methylphenidate

what are examples of uterine relaxants?

• ritodrine

• isoxsuprine

• salbutamol

• terbutaline

what are examples of cardiac stimulants?

• adrenaline

• isoprenaline

• dobutamine

what are examples of nasal docongestants?

• xylometazoline

• oxymetazoline

• naphazoline

• phenylephrine

• phenylpropanolamine

• pseudoephedrine

what are examples of anorectics (appetite suppressants)?

• amphetamine

• fenfluramine

• dexfenfluramine

• sibutramine