Inotropes and vasopressors Flashcards
Define sympathomimmetics
Agents that promote the sympathetic nervous system effects by acting on adrenoreceptors or dopamine receptors.
These substances can exert their effects on adrenergic or dopamine receptors either directly or indirectly.
DIRECT sympathomimetics attach to and act directly via these receptors
INDIRECT sympathomimetics cause the release of noradrenalin to produce their effects via these receptors
Classify sympathomimmetics into Catecholamines and non-catecholamines
CATECHOLAMINES - all direct acting except dopamine Natural - Norepinephrine - Epinephrine - Dopamine (indirect)
Synthetic
- Dobutamine
- Dopexamine
- Isoproterenol
NON-CATECHOLAMINES Indirect - Metaraminol - Ephidrine - Amphetamines
Direct
- Phenylephrine
How are catecholamines synthesized?
LIVER Phenylalanine (liver) | | Phenylalanine hydroxylase | NEURONS/ADRENAL MEDULLA Tyrosine | |Tyrosine hydroxylase | DOPA (dihdroxyphenylalanine) | |DOPA decarboxylase | Dopamine | |Dopamine beta-hydroxylase | Noradrenalin | ADRENAL MEDULLA ONLY |Phenylethanolamine - N - Methytransferase | Adrenalin
Describe the structure of a catecholamine versus a benzene ring
Catechol is a benzene ring with OH groups attached at C3 and C4 of the ring.
When the above is attached to various amine side chains, it is called a catecholamine
Describe the metabolism of Noradrenalin and adrenalin. Draw the diagram including synthesis and metabolism
METABOLISM (Synthesis in previous card)
Noradrenalin ———–> Normetanephrine ——–> VMA
COMT MAO
Adrenalin —————–> Metanephrine ————–> VMA
COMT: Catechol - O - Methyltransferase
MAO: Monoamine Oxidase
What components of the autonomic nervous system ar not controlled by the hypothalamus
- GIT –> co-ordinates its own secretions locally
- Some reflex activity co-ordinated in the spinal cord
- Baroreceptor reflexes processed in medulla
Where do the parasympathetic nervous system fibres arise?
CRANIAL NERVES 3, 7, 9, 10 Eye Salivary Glands Heart Bronchi Upper GIT (to splenic flexure) Ureters
SACRAL FIBRES (S2, S3, S4)
Distal bowel
Bladder
Genitals
Summarise the effects and mechanism of the adrenoreceptors
Receptor Effect Mechanism
a1 VC Gq -> PLC -> (+)IP3 -> (+)Ca+
a2 Sed/Analg/ Gi -> (-) AC –> (-)cAMP
Inhibit SNS
(+) platelet
aggregation
B1 + inotrope Gs -> (+) AC -> (+) cAMP
+ chronotrope
B2 SM relaxation
bronchi Gs -> (+) AC -> (+) cAMP
uterus -> (+) Na/K ATPase -> enhanced Na+ / Ca+ exchange
–> decreased IC Ca
hyperpolarization
B3 Lipolysis Gs -> (+) AC -> (+) cAMP
D1 CNS (EPSEs)
PNS Renal/ Gs -> (+) AC -> (+) cAMP
mesenteric VD
D2 CNS (-) pituitary Gi -> (-) AC -> (-) cAMP
PNS (-) further
noradrenalin release
Classify positive and negative inotropes
POSITIVE INOTROPES Class 1 - Increase intracellular calcium 1. Calcium ions 2. Adrenergic Increase [cAMP] Catecholamines - Adrenalin - Noradrenalin - Dobutamine - Dopamine - Isoprenaline 3. Reduce cAMP breakdown Phosphodiesterase inhibitors - Milrenone - Theophylline 4. Glucagon (Increase cAMP via Gs and +AC) 5. Drugs reducing Na/K ATPase pump - Cardiac glycosides (digoxin) (Increased IC Na for Counter-transport with Ca --> increase IC Ca)
Class 2
- Increased sensitivity of tropomyosin to Calcium
1. Calcium Sensitizers (Levosimendan)
Class 3
- Act by a metabolic or endocrine pathways
1. Tri-iodothyronine (T3)
NEGATIVE INOTROPES
- Beta blockers
- Calcium Channel blockers (Nondihydropyridimine)
- Antiarrhythmics
- Class 1A antiarrhythmics (Quinidine, Procainamide)
- Class 1C antiarrhythmics (Flecainide)
What is the rate limiting step in catecholamine synthesis
Hydroxylation of tyrosine to DOPA (Dihydroxyphenylalanine) by tyrosine hydroxylase
tyrosine hydroxylase is only found in catecholamine containing cells (neurons)
What inhibits that rate limiting enzyme in catecholamine synthesis
Noradrenalin inhibits tyrosine hydroxylase in a negative feedback loop.
What is the name of the enzyme only found in the adrenal medulla and what is its function
PMNA
Phenylethanolamine-N-methyltransferase
Catalyses the N-methylation of adrenalin to Noradrenalin
What adrenergic receptors mediate metabolic modulation in the liver and skeletal muscle. What is the metabolic effect
LIVER
a1 and B2 –> Glycogenolysis
SKELETAL MUSCLE
B2 –> Glycogenolysis
How do catecholamines affect insulin secretion
During the stress response, catecholamines stimulate a2 receptors on pancreatic Beta islet cells to reduce insulin secretion.
Circulating adrenalin (released by the renal medulla) may also stimulate B2 adrenoreceptors on B islet cells in the pancreas
How do catecholamines affect the function of adipocytes
Catecholamines stimulate B3 receptors to cause lipolysis and thermogenesis (especially in brown fat)
Which adrenergic receptors mediate platelet aggregation
alpha 2
Stimulation of which adrenergic receptor inhibits histamine release
beta 2
What is the effect of alpha 2 stimulation on the brainstem
Inhibits SNS outflow
Adrenalin | Noradrenalin | Isoprenaline
Rank the above agents agonist potency at each receptor
alpha 1: NA > A > ISO
alpha 2: A > NA > ISO
Beta 1: ISO > NA > A
Beta 2: ISO > A > NA
Beta 3: ISO > NA = A
Where is MAO and COMT
Inside cells. this means that uptake of catecholamines is required prior to metabolism
Where is MAO found
Noradrenergic nerve terminals
Liver
Intestinal epithelium
What other substances does MAO metabolise
Dopamine
Serotonin
Classify the MAO inhibitors and list the conditions in which they are used.
Non-selective irreversible
- Phenelzine
- Isocarboxid
- Tranylcypromine
Selective reversible
1. Moclobemide
USE
- Resistant depression
- OCD
- Chronic pain syndromes
- Migraine
Where is COMT found
Absent from noradrenergic neurons
Present
- Adrenal medulla
- Other cells and tissues
What is an inotrope
Alters the force of contraction of cardiac muscle without affecting preload or afterload
Describe excitation-contraction coupling
Depolarization –> Calcium entry into the cardiac myocytes via the sarcolemma –> calcium induced calcium release from the intracellular sarcoplasmic reticulum –> increased intracellular calcium concentration. Tropomyosin is a protein complex that blocks myosin binding sites on actin, preventing cross bridge formation. Calcium binds to troponin C (on tropomyosin) and causes a conformational change in the tropomyosin so that this protein complex no longer blocks the myosin binding sites on actin. Cross bridge formation can now occur followed by the power stroke and sarcomere shortening depending on the availability of ATP.
How much calcium is contained in 10% CaCl versus Ca Gluconate
10% CaCl –> 27 mg of calcium
10% Ca Gluconate –> 9mg of calcium
What concentration is adrenalin used when combined with local anaesthetic
1:200 000
