Adrenergic Agents and Blockers Flashcards
Adrenergic Agents are drugs that mimic actions of ________ and ________ and activate the _______ nervous system.
Epinephrine & Norepinephrine; sympathetic
Adrenoreceptor that increases the heart rate:
Beta-1
Identify the correct analogy of Dobutamine isomers:
Vasodilation: Vasconstriction
a. - isomer: + isomer
b. + isomer: - isomer
[Organ System Effects and Clinical Application of Sympathomimetics - Cardiovascular System -]
b.
+ isomer: VASODILATION
- isomer: VASOCONSTRICTION
Catecholamines are derived from these amino acids:
PHENYLALANINE & TYROSINE.
Phenylalanine -> hydroxylation by the enzyme phenylalanine hydroxylase -> Tyrosine -> L-DOPA -> DOPAMINE* -> NOREPINEPHRINE* (depending on cell type) -> EPINEPHRINE*
- Catecholamines
Changes During The Flight or Fight Response of the Sympathetic Nervous System (identify if inc or dec)
BRONCHODILATION
inc
- Basta imagine mo lang ano mga changes saýo pag crunch time na for exams!
- Beta-2 Adrenoreceptor activation.
Changes During The Flight or Fight Response of the Sympathetic Nervous System (identify if inc or dec)
Saliva amount
dec
Nagddry ang mouth pag kulba or stress
Changes During The Flight or Fight Response of the Sympathetic Nervous System (identify if inc or dec)
Sphincter Muscle Tone
inc
Better urinary retention pag fight or flight response!
* Mag-iincrease lahat ng sphincter tone
Changes During The Flight or Fight Response of the Sympathetic Nervous System (identify if inc or dec)
Detrusor muscle tone
dec
Kasi pag nagcontract ang detrusor muscle ng bladder, mapapaihi ka. Better urinary retention ang nangyayari pag Fight or Flight response so dapat decreased detrusor muscle tone
Changes During The Flight or Fight Response of the Sympathetic Nervous System (identify if inc or dec)
Blood Pressure
inc
Higher blood pressure kasi mas malakas pumping ng heart for increased circulation. Basta fight or flight response, isipin mo lahat ng changes na pwedeng mgcontribute to better performance + usual manifestation of stress + energy release.
Manifestation of ULTIMATE EFFECTS during Fight or Flight response involves release of Norepinephrine from: ________ and Epinephrine is from _________
a Nerve terminals
b Adrenal Medulla
Preganglionic axons synapse on neurons close to the:
SPINAL CORD
A drug that inhibits the enzyme tyrosine hydroxylase and, therefore, catecholamine synthesis, which, as a consequence, depletes the levels of the catecholamines dopamine, adrenaline and noradrenaline in the body.
[Happens at postganglionic nerve ending
METYROSINE
Order of inhibition at postganglionic nerve ending (palabas ng nerve ending):
METYROSINE (Inhibits tyrosine -> dopamine)
RESERPINE (Inhibits dopamine -> norepinephrine)
GUANITHIDINE (inhibit the Ca2+-dependent release of norepinephrine -> impedes propagation of impulses to nerve terminals)
Adrenergic receptor that predominates in the presynaptic membrane.
Alpha-2
Location: Presynaptic adrenergic nerve terminals, platelets, lipocytes, SMOOTH MUSCLE, lower brainstem region (medulla oblongata).
Mechanism of Action: Gi, causes inhibition of adenyl cyclase, decreased cAMP (causes reverse effect of adrenergic activation) -> Therefore, Alpha-2 receptors behave like BLOCKERS!!
DIRECT or INDIRECT
Adrenergic agonists that bind directly to receptors
[Classification of Adrenergic Receptors]
DIRECT
DIRECT or INDIRECT
affects synthesis, storage, and release
[Classification of Adrenergic Receptors]
INDIRECT
The mechanism of action of this adrenergic receptor involves G-protein type Gq.
(GPCR)
Gq-> activates Phospholipase C -> formation of IP3 and DAG -> increased intracellular calcium -> metabotropic
Alpha-1
Location: Postsynaptic effector cells, heart, SMOOTH MUSCLES (e.g. BLOOD VESSELS esp arteries), GLANDS
- Basta pag Alpha receptors = Smooth Muscles.
- Para Alpha Male, ikaw pinaka-SMOOTH
- Remember na PRESYNAPTIC = Alpha-2, POSTSYNAPTIC = Alpha-1 (pero hindi lang siya ang postsynaptic adrenergic receptor)
The most clinically significant adrenergic receptor in constriction and dilatation of blood vessels.
Alpha-1
The mechanism of action of this adrenergic involves receptor Gs protein.
Gs -> stimulation of adenyl cyclase (effector) -> increased cAMP
All Beta Adrenergic Receptors
Location of this adrenergic receptor is in Postsynaptic effector cells, especially HEART, LIPOCYTES, brain, presynaptic adrenergic and cholinergic nerve terminals, JUXTAGLOMERULAR CELLS of kidney.
Beta-1 Adrenergic Receptor:
- Pag Beta-1 -> HEART
at JUXTAGLOMERULAR CELLS sa Kidney
Location of this adrenergic receptor is mainly in Postsynaptic effector cells especially LIPOCYTES.
Beta-3
*Para ma-remember, murag bilbilon ang 3, so Beta-3 = LIPOCYTES
Location of this adrenergic recepter is in Postsynaptic effector cells, especially SMOOTH MUSCLE (e.g. GI, blood vessels, lungs) and CARDIAC MUSCLE
Beta-2
*Para ma-remember, 2= 2 LUNGS. Beta-receptor na pinakarelated sa smooth muscle.
This adrenergic receptor has an opposing effect to the Alpha-1 Adrenergic Receptor
Beta-2
Alpha-1 = More VASOCONSTRICTION Beta-2 = More VASODILATION (also related to Bronchodilation)
Most important Dopamine Receptors
D1 and D2
Found in: CNS, Brain, splanchnic and renal vasculature
Dopamine Receptors that increase cAMP (Gs)
D1 & D5 (D1-like)
“1 is like an i, I for increase!”
Most important adrenergic receptor found in SMOOTH MUSCLES (stimulation will increase cAMP)
D1
Dopamine Receptor found in nerve endings
D2
Subtypes of these adrenergic receptors have the most importance for understanding efficacy and safety of novel antipsychotic drugs
Dopamine Receptors.
Dopamine Receptors are also most prominent in vertebrate CNS! Kaya siya ang pinaka-makacontribute sa brain-related drugs
Adrenoreceptor classification is based on
structure-activity relationships
Altering ligand -> change in activity
This constant serves as the “fingerprint” to identify receptors.
Kd.
- equilibrium dissociation constant
- the ratio of concentrations when equilibrium is reached in a reversible reaction (when the rate of the forward reaction equals the rate of the reverse reaction)
Decrease in Kd (equilibrium dissociation constant) would lead to Increase or Decrease in affinity of the ligand?
Increase.
Lesser dissociation, more binding.
↓Kd = ↑ affinity
TRUE or FALSE. Drugs with different affinities can
have the same potencies in eliciting a clinical effect.
FALSE. Drugs have different affinities because they have different potencies in eliciting a clinical effect
Notes on affinity regarding structure of catecholamines
Structure-activity relationships are the basis for adrenoreceptor classification. What are the important structural characteristics of the following catecholamines?
Epinephrine
Norepinephrine
Isoproterenol
Epinephrine – with methyl group
Norepinephrine - NO methyl group - “No”epinephrine
Isoproterenol – isopropyl group
TRUE or FALSE. Only little amounts is needed for ISOPROTERENOL to achieve maximal effect as compared to NOREPINEPHRINE and EPINEPHRINE
[EFFECTS OF ADRENERGIC RECEPTOR ACTIVATION > EFFECT ON FORCE OF CONTRACTION]
TRUE. ISO – more potent, same efficacy, much lower Kd
than E
ISO also has greatest affinity; E & NE – almost the same affinity
Remember: The lower the Kd, the higher the affinity, the more potent it is.
Adrenergic agonists inhibit the degradation of:
cAMP.
β and α are metabotropic receptors, meaning they increase cAMP
The most potent CATECHOLAMINE in BRONCHODILATION
[EFFECTS OF ADRENERGIC RECEPTOR ACTIVATION > EFFECT ON BRONCHODILATION]
ISOPROTERENOL
*Ang adrenergic receptor naman na nagccause ng bronchodilation ay Beta-2
ISO>E>=NE ang trend sa Effects on Contraction Adrenergic Receptor Activation.
ISO>E»NE naman sa Effects on Bronchodilation
E >= NE»_space; ISO naman sa Effect on Vasoconstriction
The response of any cell or organ to a sympathomimetic depends on the ______ and ______ of adrenergic receptors.
[CLASSIFICATION OF ACTIONS OF ADRENERGIC RECEPTORS]
DENSITY & PROPORTION
CLASSIFICATION OF ACTIONS OF ADRENERGIC RECEPTORS:
- Peripheral excitatory action
- Peripheral inhibitory action
- Cardiac excitatory action
- Metabolic action
- Endocrine actions
- Actions in the CNS
- Prejunctional actions
Identify the Adrenergic Receptor!
Dilates renal blood vessels (the receptor with most bearing)
D1
Identify the Adrenergic Receptor!
Modulates transmitter release
D2. It is found on nerve endings
Identify the Adrenergic Receptor!
Inhibition of transmitter release
Alpha-2. Remember na presynaptic siya.
Identify the Adrenergic Receptor!
Erects hair
Alpha-1. Pag smooth muscle contraction. Hair erection is due to contraction of Pilomotor smooth muscle.
Identify the Adrenergic Receptor!
Increase Renin release
Beta-1.
- Basta pag Beta-1, associated agad sa HEART CONTRACTION at JUXTAGLOMERULAR CELLS ng KIDNEYS (Hence, association with renin release.)
Identify the Adrenergic Receptor!
Activates lipolysis
Beta-3
- Remember mo lang yung bilbil ng 3
Identify the Adrenergic Receptor!
helps prevent premature labor
Beta-2
- pnemonic: It takes -2- to make B-aby.
Identify the Adrenergic Receptor!
Inhibition of lipolysis
Alpha-2
Identify the Adrenergic Receptor!
can improve urine output
D1. Remember yung effect niya na mag dilate ng renal blood vessels.
Identify the Adrenergic Receptor!
Promotes potassium uptake in skeletal muscles
Beta-2
- Pag beta-2, mostly dilation effects, so less contraction, meaning less Na and more K
Identify the Adrenergic Receptor!
stimulate phospholipase C
Alpha-1
The mechanism of action of this adrenergic receptor involves G-protein type Gq -> phospholipase C
What are the selective, direct-acting, adrenergic agonists?
α1 - Phenylephrine
α2 - Clonidine
β1 - Dobutamine
β2 - Terbutaline
What are the non-selective, direct-acting, adrenergic agonists?
α1 α2 Oxymetazoline
β1 β2 Isoproterenol
α1 α2 β1 β2 Epinephrine
α1 α2 β1 Norepinephrine
Adrenergic agonists which are Indirect-acting RELEASING AGENTS -
Amphetamine
Tyramine
- actions are dependent on the release of endogenous catecholamines; increases the release of NE from the vesicles (indirect)
Adrenergic agonists which are Indirect-acting UPTAKE INHIBITORS
Cocaine
Tricyclic Antidepressants
-> decreases re-uptake of NE (remains in the synapse, prolonging the action)
Indirect-acting Adrenergic Agonists that block the degradation of NE
MAO/COMT Inhibitors
What are the mixed-acting adrenergic agonists?
Ephedrine α1 α2 β1 β2 and releasing agent
Dopamine D1 D2 α β and releasing agent
can bind to all different kinds of receptors; both bind to the receptor and prevent reuptake of catecholamines
increased production of NE (but cannot be measured so request for urine vanilodilic acid)
PHEOCHROMOCYTOMA
TRUE or FALSE. Receptor Specificity/ Selectivity is absolute.
FALSE. Receptor Specificity/ Selectivity is RELATIVE, NOT ABSOLUTE!
- It is dependent on the amount of drug available! For example, beta-1 agonist can bind with beta-2 receptor if it is given at a higher concentration than the beta-2 agonists. Beta-2 is simply more favored.
Dopamine Effects at different blood concentrations
0.3ug/mL -> D1 -> Diuresis
0.7ug/ml -> Beta-1 -> increased heart contractility
1 ug/ml -> Alpha receptors -> increased heart rate, arrythmia
Beta-1 receptor agonist effect on cardiovascular system
Positive chronotropic effect (increased pacemaker activity, increased heart rate)
Positive inotropic effect (intrinsic contractility is increased)
Adrenergic blocker that inhibits VMAT (Vesicular Monoamine Transporter)
RESERPINE
Adrenergic blocker that Can inhibit the Ca2+-dependent release of norepinephrine
GUANITHIDINE
Symphatomimetic drug that causes myrdriasis but treats glaucoma
PHENYLEPHRINE
Drug used in the treatment of diarrhea in diabetics with autonomic neuropathy
CLONIDINE (Alpha-2 agonist)
an adrenergic agonist that is also a nasal decongestant
PHENYLEPHRINE
Beta-receptor agonist that helps relax uterine smooth muscle, used during preterm labor -
Ritodrine, Terbutaline
A mixed-acting drug that could cross BBB, has prolonged action like amphetamine, could be given orally
EPHEDRINE
Basta Blood-brain barrier -> EPHEDRINE
Agonist that could cause congestive heart failure
DOBUTAMINE
Toxicity related to this drug could lead to restlessness, tremor, anxiety, paranoid state.
AMPHETAMINE
Toxicity related to this drug could lead to convulsions, hemorrhage, arrhythmias, MI
COCAINE
prodrug converted to alpha-methylnorepinephrine. Also an alpha-2 agonist
METHYLDOPA
Selective Alpha 1 Adrenergic Antagonists
PTD
Prazosin, Terazosin, Doxazosin
SIN is antagonistic to the alpha.
Use of this alpha antagonist leads to relaxation of both arterial and venous vascular smooth muscle as well as smooth muscle in prostate
PRAZOSIN
PR-prostate - relaxation
Nonselective α1 antagonists
PHENTOLAMINE & PHENOXYBENZAMINE - PP
Beta-Blocker used for migraine
PROPRANOLOL
Beta-1 selective Adrenergic Antagonists used in patients with asthma/COPD, diabetes, peripheral vascular disease
METOPROLOL, ATENOLOL
Contraindications to Beta-Blockers
Remember na beta- receptor function ay mainly for vasodilation
- Asthma, other bronchospastic condition
- Severe bradycardia
- AV block, bradycardia-tachycardia syndrome
- Adverse Effects:
o Related to consequences of β blockade;
o Sedation, fatigue, depression (highly lipophilic
drugs), impaired exercise tolerance, insomnia,
exacerbation of peripheral vascular disease,
erectile dysfunction
Beta-blocker with longest half-life: up to 24 hours, excreted unchanged
NADOLOL
Differences in metoprolol plasma clearance is dependent on the genotype of which CYP
CYP2D6
