Block 1 Drugs Flashcards
Adrenergic receptors
Class of G protein coupled receptors that are targets of the catecholamines, especially norepinephrine and epinephrine.
Catecholamines and sympathomimetic drugs
Peripheral EXCITATOR action on some smooth muscle (blood vessels, radial muscle, glands)
Peripheral INHIBITORY action on other smooth muscle (wall of gut, bronchial tree, skeletal muscle vasculature).
What does it do in each system?
Cardiac - excitatory: increases heart rate and force of contraction
Metabolic- increases glycogenolysis (liver and muscle) and liberation of free fatty acids (adipose tissue)
Endocrine- modulates insulin secretion (decreases) and renin (increases)
CNS- respiratory stimulation, increase in wakefulness and psychomotor activity, reduction in appetite
Prejunctional actions that either inhibit or facilitate release of neurotransmitters, the inhibitor function being MOST important.
Types of sympathomimetic drugs (adrenergic agonists)
Direct acting: selective and non-selective
Mixed acting
Indirect acting: Releasing agents, uptake inhibitor, MOA inhibitors, COMT inhibitors
What are the endogenous catecholamines?
NED!
Norepinephrine
Epinephrine
Dopamine
Epinephrine (adrenalin)
Naturally occurring catecholamine, synthesized in adrenal medulla
Receptor selectivity: a1, a2, b1, b2
Cardiovascular effects: most potent vasopressor drug known (a1 receptors), but can dilate some vascular beds at low doses (b2 receptors).
With a rapid bolus IV administration, there is a rapid increase in blood pressure due to vasoconstriction (a1) and increase in heart rate (b1), contractile force (b1), and ergo cardiac output.
With slow bolus IV administration (subcutaneous perhaps) of low dose, there is an increase in heart rate and contractile force (both b1), and increase in systolic pressure (b1-mediated increase in contractility), and a DECREASE in DIASTOLIC pressure (b2- mediated dilation of skeletal muscle blood vessels) - but NO NET effect on mean blood pressure!
Respiratory effects: Powerful bronchodilation (b2)
Metabolic effects: increased glucose and free fatty acids in blood
Absorption, fate, excretion: Not effective via oral admin (too quickly metabolized by gut/liver), so must be given IV, subcut, or intramuscular by injection. Rapidly inactivated, with SHORT HALF LIFE.
Therapeutic uses: rapid relief of hypersensitivity reactions to drugs/allergens, co-admin with local anesthetics to increase duration of their action, bradyarrhythmias (this restores rhythm in patients with cardiac arrest), and ophthalmic uses (mydriatic, decreases hemorrhage, conjunctival decongestion)
Norepinephrine (Levophed)
Sympathetic neurotransmitter - endogenous catecholamine
Receptor selectivity: a1, a2, b1, and v little action on b2
Cardiovascular effects: a1 mainly, with IV infusion there is peripheral vasoconstriction (increases peripheral vascular resistance), increases BP (mean, sys, and dia), and can cause reflex bradycardia (vagally mediated) overcoming b1-mediated cardioacceleration
Absorption, fate, excretion: see epinephrine
Therapeutic uses: Used as a vasoconstrictor under certain intensive care
situations (shock, hypotension during reduced sympathetic tone)
Dopamine (intropin)
Naturally occurring neurotransmitter - endogenous catecholamine
Receptor selectivity: D1, b1, a1
Cardiovascular effects: depends on dosage, see below.
Low dose - D1 receptor effects: vasodilation of renal and mesenteric arteries- decreases peripheral resistance (D1 receptor)
Intermediate dose - combined D1 and b1 effects: increases HR, contractile force, CO, increases systolic BP with little effect on diastolic pressure (peripheral resistance is usually unchanged)
High dose - combined D1, b1, and a1 effects: cardio-stimulation and generalized vasoconstriction (increases peripheral resistance)
Therapeutic uses: Severe decompensated heart failure or shock (cardiogenic; septic), and only used in IV - dose titrated to achieve desired effect
What are the non-selective B adrenergic receptor agonists?
Isoproterenol (isuprel) and Dobutamine (dobutrex)
Non-selective B adrenergic receptor agonists
Originally played a major role in treatment of bronchoconstriction in patients with asthma or COPD (replaced by b1-selective agonist); other uses - treatment for arrhythmias (bradycardia, heart block), inotropic effect is useful to augment myocardial contractility (cardiac decompensation, heart failure, etc.)
Isoproterenol (Isuprel)
Non-selective B adrenergic receptor agonist
Receptor selectivity: b1, b2
Cardiovascular effects: decreases peripheral resistance, increases heart rate, contractile force, cardiac output, and decreases mean blood pressure.
Respiratory effects: bronchodilation
Absorption, fate, excretion: metabolized by COMT in liver and other tissues, and the duration of action is brief
Therapeutic uses: emergency use (IV admin) to stimulate heart rate during bradycardia or heart block
Dobutamine (Dobutrex)
Synthetic catecholamine - BETA 1 AGONIST
Receptor selectivity:
(-) dobutamine is a1 agonist and b agonist
(+) dobutamine is a1 antagonist and b agonist
Racemic mixture is available - overall effect is b1 agonist!
Cardiovascular effects: increased cardiac rate, contractility, and output. MINIMAL change in peripheral resistance and blood pressure.
Therapeutic uses: short half-life, administered via IV; thus it’s a short term treatment of cardiac decompensation (surgery, CHF, infarction), and cardiac stress testing for assessment of CAD
B2 Selective adrenergic agonists
Major side-effects of non-selective B adrenergic receptor agonists in the tx of asthma or COPD are caused by stimulation of b1 receptors in the heart….thus:
This led to the development of drugs with preferential affinity for b2 receptors that were designed to have oral bioavailability and a longer duration of action: relaxes bronchial smooth muscle, but also has a longer duration of action
What are the B2 selective adrenergic agonists?
Short acting B2 adrenergic agonists:
- Albuterol (Proventil/Ventolin)*
- Metaproternol (Alupent), terbutaline (brethine), levalbuterol (xopenex), and pirbuterol (maxair)
Long acting B2 adrenergic agonists:
- Salmeterol (Servent)*
- Formoterol (Foradil), Afromoterol (brovana)
Albuterol (Proventil/Ventolin)
Act mainly on B2 adrenergic receptors.
Admin mainly by inhalation or orally; short acting (3-4 hours) with RAPID onset (within 15 min).
Therapeutic use: relief of bronchoconstriction (asthma) Adverse effects (these are reduced by inhalation admin): tremor, anxiety, tachycardia
“AL is short but a RAPID runner, even though he has asthma.”
Salmeterol (Servent)
B2 adrenergic receptor agonist available ONLY FOR inhalation.
Long duration of action with inhalation (>12 hours), SLOW onset of actions (so not suitable as monotherapy for acute bronchospasm)
Major therapeutic use: COPD, moderate or severe persistent asthma (in combination with a steroid)
“SALly is a SLOW Servant because she has COPD”
A1 selective adrenergic receptor agonists
Potent vasoconstrictors due to stimulation of a1 receptors in vascular smooth muscle, which increases peripheral vascular resistance and maintains or increases BP.
Clinical utility of these drugs is limited - but have use for treating patients with HYPOTENSION (from shock, or otherwise). Some useful as nasal decongestants and for ophthalmic purposes (due to vasoconstriction)
What are the A1 selective adrenergic receptor agonists?
Phenylephrine*
Others: midodrine
Phenylephrine
Acts only on a1 adrenergic receptors - SELECTIVE
Functions: INCREASES systolic and diastolic pressure, DECREASES heart rate (reflex), and DECREASES blood flow (in most vascular beds)
Therapeutic uses:
- Ophthalmic- mydriatic, decreases hemorrhage, conjunctival decongestion
- Nasal decongestant (Neo-synephrine)- oral or nasal spray
- Use side by side with local anesthetics to increase duration of action and to decrease the dissipation of the anesthetic
- Hypotension (orthostatic hypotension, shock); IV admin
A2 selective adrenergic receptor agonists
Used for treatment of systemic hypertension; have the capacity to lower blood pressure resulting from activation of a2 receptors in the cardiovascular control centers of the CNS (such activation can SUPPRESS the OUTFLOW of sympathetic nervous system activity from the brain)
What are the a2 selective adrenergic receptor agonists?
Clonidine (catapres), Methyldopa (aldomet)
Others: guanabenz (wytensin), guanfacine (tenex)
Clonidine (Catapres)
Orally active a2 selective adrenergic agonist that directly stimulates central a2 adrenergic receptors to reduce sympathetic outflow: DECREASES peripheral resistances, heart rate, and cardiac output
Major therapeutic use: anti-hypertensive agent
Major adverse effects: dry mouth and sedation (occurs in 50% of patients), sexual dysfunction, bradycardia, edema, rebound hypertension with sudden discontinuation
“CLone = turns anything into a2”
Methyldopa (aldomet)
Orally active pro-drug; metabolized in adrenergic nerve terminals to alpha-methyldopamine and alpha-metylnorepineprhine (both of which are potent a2 receptor agonists and stimulate central a2 receptors to REDUCE SYMPATHETIC OUTFLOW) which are stored in nerve terminals and released with stimulation – thus it DECREASES peripheral resistance, heart rate, and CO.
Major therapeutic use: hypertensive
Side effects: similar to clonidine
Tyramine
Indirect-acting sympathomimetic (not a direct adrenergic receptor agonist); releases NOREPINEPHRINE from sympathetic nerves causing SYMPATHOMIMETIC actions.
Not really used as a therapeutic. Found at high levels in certain foods (fermented foods like wine, beer, cheeses and sausages = YUM- mnemonic: ty-YUM-mine). Normally metabolized to inactive products by monoamine oxidase.
Therapeutic implications: in patients taking MAO inhibitors, ingestion of food with high levels of tyramine can cause hypertensive crisis.
Amphetamine
Powerful CNS stimulant in addition to common peripheral sympathomimetic actions (i.e. cardiovascular actions and actions on smooth muscle)
Effective after oral administration- LONG HALF LIFE (several hours). The D isomer (dextroamphetamine, Dexedrines) is 3-4 x more potent than L isomer.
Releases norepinephrine and other biogenic amines (dopamine) from their storage sites in nerve terminals. In the CNS, that leads to: CNS stimulant, depresses appetite, stimulates the respiratory center (increases respiration).
Psychological dependence and tolerance develop when used chronically.
Therapeutic uses: narcolepsy, and ADHD
“AMP’d up”
Pseudoepedrine (Sudafed)
Direct a1 agonist activity with SLIGHT b2 agonist activity as well. Orally effective but LESS CNS stimulation (relative to amphetamine)
Major therapeutic use: nasal decongestant (due to a1 agonist effects), often used as a precursor to illegally synthesize METHAMPHETAMINE (meth) - new legislation in 2006 requires pharmacy to collect personal info from people who buy this and limit to 30 day supply
What are the adverse effects and toxicity of adrenergic agonists?
Throbbing headache due to potent vasoconstriction - alpha agonists
Cerebral hemorrhage due to INCREASED systemic BP - alpha agonist
Increase heart rate (palpitations) - beta agonists
Pericardial pain (angina) usually due to increased HR - beta agonists
Cardiac arrhythmias - beta agonists
Restlessness, anxiety, etc. - alpha and beta agonist
Mnemonic: TCIPCR, THE CAR IS PARKED CLOSE, RIGHT ANN?
THE CAR = ALPHA AGONIST EFFECTS = Throbbing headache, Cerebral hemorrhage
IS PARKED CLOSE = BETA AGONISTS = increased heart rate, pericardial pain, and cardiac arrhythmias
RIGHT AWAY = both = restlessness/anxiety
Adrenergic Neuron Blockers
Drugs that disrupt adrenergic neuron function by INHIBITING synthesis, storage, or release of norepinephrine. Drugs historically used as anti-hypertensive agents.
What are the types?
Guanethidine and Reserpine
Guanethidine (Ismelin) and Guanadrel (Hylorel)
Inhibit norepinephrine release and deplete neuronal amine stores. Orally active compounds used to treat several hypertension (limited use)
Guanethidine- POLAR - does not enter CNS. Long acting.
Taken into adrenergic nerves by norepinephrine transporter (NET), and replaces norepinephrine in storage vesicles (thus depleting storage supplies). Effects inhibited by TRICYCLIC ANTIDEPRESSANTS that also inhibit NET.
Side effects: numerous, limit the use - orthostatic hypotension, interferes with sexual function, diarrhea, muscle weakness, and edema
“Norepinephrine is GUAN (gone!)”
Reserpine (Serpasil)
Diffuses into adrenergic nerves- transport does not require the NET (norepinephrine transporter). Depletes nerves of neurotransmitter by inhibiting the vesicular monoamine transporter 2 (VMAT2) responsible for sequestering dopamine into storage vesicles).
Orally active compound - treats essential hypertension in combination with other drugs (RARELY used).
Can enter the brain and has CNS side effects including depression, suicidal tendencies and sedation. Other adverse effects include: diarrhea, hypotension, increased gastric acid secretion.
RES-SERPine: “REScues dopamine from working”-“SERP-ent enters your brain to make you sad suicidal”
Adrenergic Receptor Antagonists
Inhibit the interaction of norepinephrine, epinephrine, and other sympathomimetic drugs with a and b receptors.
Compounds have been developed that have different binding affinities for the various receptors: alpha (non selective, a1 selective, and a2 selective), and beta (non-selective (1st and 3rd generation), b1 (second and third generation))
