Autonomic Neurotransmission - Adrenergic transmission Flashcards
What are the steps involved in adrenergic transmission?
◦ Norepinephrine (NE) synthesis:
◦ Tyrosine → DOPA → Dopamine → Norepinephrine
◦ NE storage in synaptic vesicles
◦ Release of NE (еxocytosis) with the participation of Ca2+
◦ Binding to and activation of c- receptors
◦ Postsynaptic receptors – effect
◦ Presynaptic α2 receptors –
decrease of NE release
◦ Uptake of NE by NET or to a less
extent – diffusion
What are the possible ways to affect adrenergic transmission?
◦ Metyrosine inhibits tyrosine
hydroxylase
◦ Reserpine alkaloids inhibit vesicular monoamine transporter (VMAT)
◦ Bretylium, guanetidine inhibit NE
release
◦ Cocaine and certain antidepressant
drugs inhibit norepinephrine
transporter (NET)
◦ MAO inhibitors and COMT
inhibitors inhibit the metabolism of
NE
◦ Receptor agonists and antagonists
Which are the adrenoreceptors involved in the ANS?
- Alpha 1
- Alpha 2
- Beta 1
- Beta 2
- Beta 3
Where are alpha 1 receptors localized and what type of cellular response do they elicit?
Alpha1
Postsynaptic effector cells, especially smooth
muscle
GPCR (Gq)
↑ IP3, DAG,
Increased intracellular Ca2+
Where are alpha 2 receptors localized and what type of cellular response do they elicit?
Alpha2
Presynaptic adrenergic nerve terminals,
platelets, smooth muscle
GPCR (Gi)
Inhibition of AC, ↓ cAMP
Where are beta 1 receptors localized and what type of cellular response do they elicit?
Beta1
Postsynaptic effector cells, especially heart,
brain; presynaptic adrenergic and cholinergic
nerve terminals, juxtaglomerular apparatus of
renal tubules, ciliary body epithelium
GPCR (Gs)
Stimulation of AC, ↑ cAMP
Where are beta 2 receptors localized and what type of cellular response do they elicit?
Beta2
Postsynaptic effector cells, especially smooth
muscle
GPCR (Gs)
Stimulation of AC, ↑ cAMP
Where are beta 3 receptors localized and what type of cellular response do they elicit?
Beta3
Postsynaptic effector cells, especially lipocytes
GPCR (Gs)
Stimulation of AC, ↑ cAMP
Where are dopamine receptors localized and what type of cellular response do they elicit?
D1
(DA1)
Brain; effector tissues, especially smooth
muscle of the renal vascular bed
GPCR (Gs)
Stimulation of AC, ↑ cAMP
Which receptors are present in the eye and what action does the neurotransmitter elicit?
Receptors:
α1
β
α2
Eye:
Iris radial muscle -> Contracts
Epithelium of the ciliary
body
↑ secretion of
aqueous humor
↓ secretion of
aqueous humor
Which receptors are present in the heart and what action does the neurotransmitter elicit?
Sinoatrial node
Ectopic pacemakers
Contractility
β1
β1
β1
Accelerates
Accelerates
Increases
Which receptors are present in the blood vessels and what action does the neurotransmitter elicit?
Blood vessels:
1) Skin, splanchnic vessels
2) Skeletal muscle vessels
1) α
2) β2
1) Contracts
2) Relaxes
Which receptors are present in the bronchiolar smooth muscles and what action does the neurotransmitter elicit?
Bronchiolar smooth muscle β2
Relaxes
Which receptors are present in the GIT (smooth muscle) and what action does the neurotransmitter elicit?
Gastrointestinal tract – Smooth
muscle:
Walls
Sphincters
α2
α1
Relaxes
Contracts
Which receptors are present in the Genito-urinary tract and what action does the neurotransmitter elicit?
Genitourinary smooth muscle:
Bladder wall -> β2 = relaxes
Sphincter -> α1 = contracts
Uterus, pregnant -> β2 = relaxes
α = contracts
Prostate capsule -> α1 = contracts
Penis, seminal vesicles -> α = ejaculation
Which receptors are present in the skin and what action does the neurotransmitter elicit?
Pilomotor smooth muscle
Sweat glands
-Eccrine
-Apocrine (stress)
α
M
α
Contracts
Increases
Increases
Which receptors are present in the pancreas and what action does the neurotransmitter elicit?
Pancreas
α2 =↓ insulin
β2 =↑ insulin
Which receptors are present in the kidney and what action does the neurotransmitter elicit?
β1 ↑ renin
Which receptors are present on the mast cells and what action does the neurotransmitter elicit?
β2 ↓ Histamine
release
Which receptors are present in the presynaptic membrane in nerve endings and what action does the neurotransmitter elicit?
α2 ↓ NE release
Which receptors are present in organs with metabolic functions like the liver and fat cells and what action does the neurotransmitter elicit?
Liver -> β2, α = Gluconeogenesis
Liver -> β2, α = Glycogenolysis
Fat cells -> β3 = Lipolysis
How are the drugs affecting adrenergic transmission classified?
- Alpha adrenomimetics
- Alpha-adrenoceptor antagonists
- Beta- adrenoceptor agonists
- beta-adrenoceptor antagonists
What is a direct-acting, non-selective, alpha-adrenoceptor agonist?
Epinephrine
What is the PK of Epinephrine (direct-acting, non-selective, alpha-adrenoceptor agonist)?
◦ Orally inactive (metabolism by COMT and MAO in the GIT)
◦ Parenteral administration: SC, slow IV, locally (with local anesthetics)
◦ Short plasma half-life
What are the effects of epinephrine?
◦ Mydriasis (α1)
◦ CVS
◦ Cardiac stimulation (beta1)
◦ Vasoconstriction (α1) and vasodilation in skeletal muscles (beta2)
◦ Slight increase of mean BP (α1,beta2), sometimes decrease of diastolic BP (beta2)
◦ Respiratory system
◦ Bronchodilation (beta2)
◦ Anti-allergic effects (↓ release of histamine from mast cells) (beta2)
◦ ↑ blood glucose (beta2, α1)
◦ Hypokalemia (beta2)
What are the clinical uses of Epinephrine?
◦ In emergencies:
◦ Anaphylactic shock and other acute hypersensitivity reactions
◦ Hypoglycemic coma
◦ Status asthmaticus (acute exacerbation of asthma that remains
unresponsive to initial treatment with bronchodilators)
◦ Cardiac arrest
◦ To prolong the effect of local anesthetics
What are the adverse reactions of Epinephrine?
◦ Tachycardia, arrhythmia ◦ Increased O2 consumption by the heart ◦ Hyperglycemia ◦ Hypokalemia
What are the PK, PD, and clinical uses of norepinephrine?
PK
◦ Parenteral administration; short duration of action
PD
◦ Vasoconstriction (1)
◦ Increase of peripheral vascular resistance; an increase of systolic and diastolic BP
Clinical use
◦ In combination with local anesthetics
What are the PK and the clinical use for midodrine?
PK
◦ Oral administration
◦ Longer duration of action
Clinical use
◦ Hypotension
What is the mode of administration and adverse reactions of xylomethazoline?
Local administration in
the nose in:
◦ Rhinitis
ADR:
◦ With prolonged use: atrophic
rhinitis and anosmia (loss of
the sense of smell)
Which are the alpha 2 selective direct-acting, alpha-adrenoceptor agonists?
Systemic:
- Clonidine
- Methyldopa
Local - for treatment of glaucoma
- Brimonidine
What are the PK, PD, clinical use, and adverse reactions of Clonidine ?
PK
◦ Oral administration (Clonidine, methyldopa)
◦ By injection (Clonidine)
PD
◦ In CNS: Decrease of the sympathetic tone
◦ In the peripheral tissues: decrease the release of NE (a2)
Clinical use
◦ Hypertension
◦ Migraine prophylaxis (Clonidine)
◦ Treatment of drug dependence
ADR: ◦ Sedation, drowsiness, depression ◦ Xerostomia (Clonidine) ◦ Bradycardia, AV block(Clonidine) ◦ Rebound effect (Clonidine)
What are the PK, PD, clinical use, and adverse reactions of Methyldopa?
PK
◦ Oral administration (Clonidine, methyldopa)
◦ By injection (Clonidine)
PD
◦ In CNS: Decrease of the sympathetic tone
◦ In the peripheral tissues: decrease the release of NE (a2)
Clinical use
◦ Hypertension
◦ In pregnant women (Methyldopa)
◦ Treatment of drug dependence
ADR ◦ Sedation, drowsiness, depression ◦ Тhombocytopenia (Methyldopa) ◦ Parkinsonism (Methyldopa) ◦ Liver disorders (Methyldopa)
What are the PD and clinical use of Brimonidine?
PD
◦ In the eye: lowers
intraocular pressure
Clinical use
◦ Glaucoma
What is the PK, mechanism of action, effects, and clinical significance of amphetamine?
PK
◦ Orally active; penetrates through the BBB
Mechanism of action (indirect action):
◦ Releases NE, at high doses – dopamine and serotonin, as well
Effects:
◦ Cardio-vascular stimulation
◦ CNS:
◦ Mental stimulation and exercise; increased caution
◦ Euphoria
◦ Appetite suppression (suppression of the center of hunger)
Clinical significance - limited:
◦ Narcolepsy
◦ Attention deficit hyperactivity disorder
What are the PK, PD, adverse effects, desired effects, and clinical significance of Ephedrine?
PK ◦ Orally active ◦ Renal excretion ◦ Slower onset and longer duration of action in comparison with epinephrine: effect lasting 4-6 hours
PD
• Mechanism of action – mixed action
◦ Indirect: release of NЕ (predominantly -effects)
◦ Direct: on β-adrenergic receptors
• Effects – similar to those of epinephrine
ADR: ◦ CNS stimulation (insomnia) ◦ Tachyphylaxis – depletion of NE Clinical significance - limited: ◦ Bronchial asthma ◦ As a bronchodilator ◦ Arterial hypotension ◦ Rhinitis
What is pseudoephedrine used for?
As a component of the
solutions with a
decongestant action in
rhinitis
How are the alpha-adrenoceptor antagonists classified?
Non-selective
Selective a1
What is Nicergoline?
Non-selective (α1, α2) antagonists
Which are the alpha 1 selective alpha-adrenoceptor antagonists?
Prazosin, Doxazosin, Tamsulosin
What are the PK, PD, adverse reactions, and clinical use of Prazosin, Doxazosin, and Tamsulosin?
PK
◦ Oral administration
◦ Prazosin t1/2 = 3 h; effect – 6-8 h: 3 times daily
◦ Tamsulosin t1/2 = 9-15 h; prolonged-release tablets: once daily
◦ Doxazosin t1/2 = 22 h; once daily
PD
◦ ↓ peripheral vascular resistance (predominantly arterial vasodilation); ↓ BP
◦ ↑HDL and ↓LDL (with chronic use)
◦ Relaxation of the smooth muscle of the prostate capsule
ADR: ◦ Orthostatic hypotension; “Effect of the first dose” – prazosin ◦ Tachycardia ◦ Sexual disturbances: ↓ ejaculation ◦ Nasal congestion
Clinical use:
◦ Hypertension: prazosin, doxazosin
◦ Benign prostate hyperplasia: doxazosin, tamsulosin (tamsulosin selective α1A)
What are the PK and PD of dopamine?
PK: IV administration
PD:
• D1 receptor agonist: vasodilation of renal,
splanchnic, coronary, brain vessels
• Renal effects – used clinically to improve
the perfusion to the kidneys in situations
of oliguria
• β1 receptor agonist in the heart
• Activation of vascular α receptors (at
higher rates of infusion) vasoconstriction,
including in the renal vascular bed.
Consequently, high rates of infusion of
dopamine may mimic the actions of
epinephrine.
What is isoprenaline?
Very powerful agonist of β receptors:
• β1 – positive chrono- and inotropic
effect; ↑ cardiac output; slight ↑ systolic
BP
• β2 – vasodilation; ↓ diastolic BP
Clinical use:
• АV block
What is Dobutamine?
Synthetic catecholamine
What are the PK, PD, clinical uses, and adverse reactions of dobutamine?
PK:
• IV infusion
PD: • Relatively β1-selective • Effects: ◦ β1: Cardiac stimulation ◦ Inotropic (most pronounced, comparable to that of epinephrine) ◦ Bathmotropic effect (weaker than that of epinephrine) ◦ Weak α1 -adrenomimetic effect - in higher doses
Clinical use:
◦ Cardiogenic shock
◦ Acute heart failure
ADR:
◦ Arrhythmia
◦ ↑ O2
consumption (symptoms of angina pectoris)
What are examples of short-acting beta 2 selective beta-adrenoceptor agonists?
Salbutamol, Hexoprenaline, Clenbuterol
PK ◦ Route of administration: ◦ Inhalation (in asthma) ◦ Orally or by injection (in obstetrics and gynecology) ◦ Бъбречна екскреция ◦ t1/2 ~ 4 ч.
PD ◦ Bronchodilation ◦ Relaxation of the uterus ◦ Vasodilation in skeletal muscles ◦ Anabolic effect: ◦ Vascular effects of the compounds that should modify the nutrient flow into the muscle ◦ Beta-adrenergic-dependent enhancement of insulin action on the muscle
Clinical use
◦ Bronchial asthma attack
◦ To prevent premature labor
ADR ◦ Tachycardia ◦ Tremor ◦ Hypokalemia (increased penetration of K into the cells) ◦ Hypotension
What are examples of long-lasting beta 2 selective, beta-adrenoceptor agonists?
Salmeterol,
Formoterol
PK ◦ Route of administration: ◦ Inhalation – once daily ◦ Long duration of action (longer with Salmeterol)
PD
◦ Bronchodilation
Clinical use
◦ Bronchial asthma (chronic
use, always with GCS)
ADR
◦ Worsening of asthma if
administered alone
How are the beta-adrenoceptor antagonists classified?
- Non-selective (β1, β 2)
Propranolol
Sotalol - β1-selective (cardioselective)
Atenolol
Bisoprolol
Metoprolol - Vasodilating
Carvedilol
Nebivolol - For treatment of glaucoma
Timolol (non-selective)
Betaxolol (beta1-selective)
What are the lipid solubility, oral-bioavailability, elimination, and half-life of propranolol?
Lipid Solubility: ++
Oral bioavailability: 30%
Elimination: liver - first-pass metabolism, active metabolite
Half-life: 3-5 h
What are the lipid solubility, oral-bioavailability, elimination, and half-life of atenolol?
Lipid Solubility: -
Oral bioavailability: 40%
Elimination: renal
Half-life: 3-4 h
What are the lipid solubility, oral-bioavailability, elimination, and half-life of metoprolol?
Lipid Solubility: ++
Oral bioavailability: 50%
Elimination: liver
Half-life: 3-4 h
What are the lipid solubility, oral-bioavailability, elimination, and half-life of bisoprolol?
Lipid Solubility: ++
Oral bioavailability: 90%
Elimination: 50% in liver, 50% renal
Half-life: 9-12 h
What are the lipid solubility, oral-bioavailability, elimination, and half-life of carvedilol?
Lipid Solubility: +
Oral bioavailability: 25-35%
Elimination: liver, active metabolite
Half-life: 7-10h
What are the lipid solubility, oral-bioavailability, elimination, and half-life of nebivolol?
Lipid Solubility: +
Oral bioavailability: 12-96%
Elimination: liver
Half-life: 11-30h
What is the pharmacodynamics of Propanolol?
non-selective, local anesthetic effect
What is the pharmacodynamics of timolol?
beta-blocker used in the treatment of glaucoma
no local anesthetic effect
What is the pharmacodynamics of atenolol?
beta 1 selective beta-blocker
no local anesthetic effect
What is the pharmacodynamics of metoprolol?
beta 1 selective beta-blocker
local anesthetic effect
What is the pharmacodynamics of betaxolol?
beta 1 selective bab
weak local anesthetic effect
What is the pharmacodynamics of bisoprolol?
great beta 1 selective beta-blocker
no anesthetic effect
What is the pharmacodynamics of carvedilol?
vasodilating beta blocker
block receptors
no local anesthetic effect
What is the pharmacodynamics of nebivolol?
beta 1 selective beta-blocker
NO release (mechanism of action)
no local anesthetic effect
What are the effects of BAB on the CVS?
Effects on the CVS:
◦ Heart
◦ ↓ heart rate
◦ ↓ contractility (stroke volume)
◦ As a result of these: ↓ cardiac output; ↓ BP
◦ Blood vessels
◦ ↑ peripheral vascular resistance (nonselective)
◦ ↓ peripheral vascular resistance
(vasodilating)
◦ Kidneys
◦ ↓ renin release
What are the effects of BABs on the respiratory system?
Respiratory system:
• Bronchoconstriction (nonselective)
What are the metabolic effects of BABs?
Metabolic effects:
◦ Carbohydrate metabolism ◦ Severe hypoglycemia is possible during insulin therapy ◦ Masked hypoglycemia ◦ Insulin resistance (with chronic use)
◦ Lipid metabolism (chronic administration of non-selective BAB) ◦ ↑ VLDL ◦ ↓ HDL
What are the adverse reactions of BABs?
ADR ◦ Bronchoconstriction (in asthma, particularly nonselective) ◦ Cold extremities (β2) ◦ Nightmares, depression (in lipophilic BAB) ◦ Bradycardia, AV block ◦ Impotence (male) ◦ Rebound effect ◦ Metabolic effects (with chronic use)
What are the contraindications of BABs?
Contraindications ◦ Bronchial asthma ◦ Peripheral vascular disease ◦ AV block and bradycardia ◦ Acute heart failure
What are the drug interactions of BABs?
Drug interactions ◦ Contraindicated combination: with verapamil: both drugs ↓ heart rate and contractility ◦ Useful combinations: with nitrates or DHP calcium channel blockers: in myocardial ischemia and hypertension
What are the clinical uses of BABs?
Cardiovascular indications:
◦ Hypertension
◦ Ischemic heart disease
◦ Acute myocardial infarction – early (4-6 h after the infarction – limitation of the
infarction size, prevention of arrhythmias)
◦ Tachyarrhythmia
◦ Chronic heart failure (metoprolol, bisoprolol, carvedilol, nebivolol)
Other indications ◦ Thyrotoxicosis ◦ Tremor ◦ Migraine – prophylactically (propranolol) ◦ Glaucoma (timolol, betaxolol)
