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Adrenergic Drugs 1 receptor

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Title: Adrenergic Drugs 1 receptor


1
Adrenergic Drugs (?1 receptor)
2
Adrenergic drugs (?2 receptor)
3
Adrenergic drugs (??1 receptor)
4
Adrenergic drugs (?2 receptors)
5
Adrenergic drugs (?3 receptors)
6
Adrenergic drugs (D1 receptors)
7
Adrenergic drugs (D2 receptors)
8
Adrenergic drugs receptor affinities
9
  • DA can interact with alpha or beta receptors,
    especially at higher concentrations.
  • There are specific DA receptors also DA
    receptors are especially important in the CNS and
    in renal vasculature
  • Alpha-1 receptors are post-synaptic and mainly in
    smooth muscle.
  • Alpha-2 receptors are mainly pre-synaptic located
    at nerve terminals in the CNS they may be
    located on post-synaptic membranes as well.
  • The molecular mechanisms of both alpha and beta
    receptors involve interaction of a catecholamine
    with the receptor coupled to a G protein.

10
  • Beta receptors activation of adenylyl cyclase
    (AC) and increased synthesis of cAMP via a
    stimulatory Gs protein. cAMP serves as a second
    messenger leading to specific tissue changes via
    activation of a cAMP dependent protein kinase.
  • ?1 receptors Activates phosholipase C (PLC) and
    leads to release of inositol-1,4,5-triphosphate
    (IP3) and diacylglycerol (DAG) via Gq protein.
  • ?2 receptors Inhibition of AC and decreased
    intracellular levels of cAMP via an inhibitory GI
    protein.
  • D1 receptors Stimulates an AC.
  • D2 receptors Inhibits AC and opens K channels.

11
  • Desensitization/down - regulation--tolerance,
    tachyphylaxis (rapid appearance of progressive
    decrease in response following repetitive
    administration of a pharmacologically active
    substance), or refractionaries may develop with
    exposure to catecholamines and other
    sympathomimetics. Various mechanisms have been
    invoked including phosphorylation or
    internalization of receptors and decrease in
    number of functional receptors.
  • Up-regulation/super-sensitivity--an increase in
    the number of functional receptors.

12
  • Pharmacokinetics
  • Catecholamines are quite susceptible to monoamine
    oxidase (MAO) and catechol-O-methyltransferase
    (COMT) enzymes (liver, GI tract and many tissues
    of the body) ineffective orally.
  • Rapidly taken up by active transport process in
    sympathetic post-ganglionic nerve terminals and
    other chromafin tissues--inactivated.
  • Metabolites (e.g. vanillymandelic acid - VMA) and
    free amine excreted in urine.

13
  • Pharmacodynamics Effects on Organ Systems
  • Resemble the effects of sympathetic stimulation,
    with some important differences the net effect
    depends upon the relative receptor affinity,
    intrinsic activity, and compensatory reflexes
    evoked by the direct action of the drug.
  • Note EPI is usually given as a bolus injection
    which causes it to stimulate the ?1 receptor in
    skeletal muscle and skin causing
    vaso-constriction same effect as NE.
  • PHE is a selective ? agonist.
  • ISO is a selective ? agonist, it does not
    stimulate the ? receptor.
  • NE can stimulate the ?1 receptor in the heart but
    the effect is small when compared to the
    baroreceptor reflex.
  • ISO will also set off the baroreceptor reflex but
    opposite to that of EPI BOTH INDIRECT AND
    DIRECT INFLUENCES ARE IN THE SAME DIRECTION.

14
CV Response to Sympathomimetic Amines
15
CV Response to Symapathomimetic Amines
16
CV Response to Sympathomimetic Amines
17
CV Response to Sympathomimetic Amines
18
CV Response to Sympathomimetic Amines
19
  • Notes on CV response to sympathomimetic amines
  • Since skeletal muscle has more blood volume than
    skin effects on its receptors have a greater
    effect on TPR.
  • TPR (SV)(CO)
  • MABP (TPR)(CO)
  • CO (HR)(SV), stroke volume is measured out of
    the left ventricle.
  • When BP ? you set off a baroreceptor reflex which
    ? sympathetic outflow ? contractility.
  • Skin and splanchnic vessels have more ?1 than ?2
  • Skeletal muscle has more ?2 than ?1.

20
  • Notes on CV response to sympathomimetic amines
  • NE is essentially a pure vaso-constrictor.
  • Isoproterenol is essentially a pure vaso-dilator.
  • EPI has mixed effects (? ?) depending on its
    dose and site---can dilate blood vessels in
    skeletal muscles (?2).
  • TPR increases with NE, decreases with
    isoproterenol, and usually decreases with EPI.
  • Blood Pressure EPI and NE usually increase the
    mean arterial pressure (MABP), although EPI can
    lower diastolic pressure.
  • Isoproterenol usually decreases MABP, although
    systolic pressure may rise.

21
  • CV response to sympathomimetic amines
  • All 3 drugs have cardiac stimulant properties.
  • Rate and force of conraction are DIRECT EFFECTS.
  • Any rise in BP however, elicits REFLEX SLOWING of
    the heart (NE sometimes EPI), this is an INDIRECT
    EFFECT.
  • Cardiac output INCREASED by EPI and
    isoproterenol.
  • Cardiac output is unchanged or decreased with NE
    due to vaso-constriction and indirect effects.
  • Conduction ? A-V conduction.
  • DA activates several D1 receptors in several
    vascular beds, which leads to vaso-dilation. It
    also activates ?1 receptors in the heart.
  • At low doses, peripheral resistance may decrease.
    At higher rates of infusion, DA activates
    vascular ?1 leading to vaso-constriciton,
    including the renal vascular bed.

22
  • CV response to sympathomimetic amines
  • ?2 stimulation generally results in relaxation
    e.g. bronchioles, detrusor muscle of the bladder,
    uterus and GI tract.
  • Alpha receptors ?1 receptor mediates
    contractions e.g. radial smooth muscle of the
    iris (mydriasis), sphincters of the bladder and
    GI tract.
  • Alpha-agonists that stimulate ?2 receptors
    promote relaxation of GI smmoth muscle indirectly
    by pre-synaptically reducing the release of
    acetylcholine (its an auto-receptor that acts by
    a pre-synaptic mechanism).

23
  • Sympathomimetic amines metabolic and endocrine
    effects
  • EPI (and to a lesser extent NE and ISO) elevates
    concentrations of glucose in the blood mediated
    primarily by ?2 receptors. There is ?
    glycogenolysis and gluconeogenesis due to
    stimulation of the beta receptor.
  • Insulin is inhibited by ?2 receptors and enhanced
    by ?2 receptors the predominant effect with EPI
    is inhibition with ISO its stimulation.
  • Catecholamines raise blood free fatty acid levels
    by stimulating ?3 receptors in adipocytes.
  • ?1 receptors stimulate renin secretion ??
    angiotensin II which in turn increases BP.

24
  • Sympathomimetic amines CNS
  • Catecholamines can elicit mild CNS
    stimulation--due indirectly to peripheral
    effects cannot get into the CNS.
  • Miscellaneous these drugs facilitate
    neuromuscular transmission in skeletal muscle and
    beta adrenergic effects may promote tremor (?2)
  • Lower intra-occular pressure (IOP)--EPI--?1--this
    is a paradoxical effect ? antagonist and ?
    agonist can be used for tx of glaucoma by ?
    diameter of blood vessels in the eye, ? aqueous
    humor formation.

25
  • Adverse reactions to sympathomimetic amines
  • Mainly an ext of pharmacological prop, esp
    pronounced on the heart.
  • Anxiety, forceful heart beat, palpitations, HA,
    cardiac arrhythmias.
  • NE---tissue necrosis, sloughing.
  • ISO---tremor, sweating, pallor.
  • OD TOX LIFE THREATENING increases in BP,
    cerebral hemorrhage (EPI NE) and angina
    serious cardiac arrhythmias---esp vent
    tachyarrhyth.
  • TX PROPRANOLOL PHENTOLAMINE (AGONIST).

26
  • Sympathomimetic amines clinical uses
  • CV applications hypotn states and shock
  • Cardiogenic shock DA and ISO
  • Topical hemostatic EPI---given by SC injxn _at_
    high doses causing vaso-con to ? blood loss (used
    in surgery).
  • EPI used in conjxn w local anesth to ?? systemic
    absorp, prolong action (1 200,000)
  • Anaphylaxis EPI remains the ER DOC for
    anaphylactic shock---physiologic antagonist
    (bronchial dilator).

27
Sympathomimetics clinical uses
  • Bronchial asthma EPI and ISO replaced by
    selective ?2 agonists (e.g. terbutaline)
  • Ophthalmic use EPI for glaucoma.

28
  • Other sympathomimetics
  • Ephedrine 1st orally active sympathomimetic
    introduced from the herb ma-huang by K.K. Wang
  • MOA indirect - release of catecholammines from
    storage sites in sympathetic N term some direct
    effect on ? and ? adrenergic receptors-----tachyph
    ylaxis can occur, acute tolerance develops
    rapidly due to depletion of NE.
  • Pharm efx resemble those of EPI except
    effective orally, ? duration of action, more CNS
    stimulant properties and 4.) much lower potency
    (bc does not have the catechol group)
  • Clinical uses sub for EPI, nasal decong, hypotn
    and asthma.

29
  • Adverse reactions with ephedrine
  • CV CNS effects abuse because its available in
    an herbal tea the FDA says that there is not
    enough evidence or rationale to take ephedra off
    the market.
  • It acts as a nasal decongestant by contracting
    the nasal blood vessels that have been dilated
    due to histamine. Most nasal decongestants are ?
    agonists so they do not stimulate the heart
    because it has ? rceptors.

30
  • Amphetamine (?-phenylisopropylamine)
  • MOA Indirect--release NE
  • Pharmacological effects
  • Similar to ephedrine EXCEPT more potent CNS
    stimulant properties euphorigenic effects.
  • The d isomer (i.e. dextroamphetamine--speed) is
    the most potent CNS stimulant whereas the L
    isomer has slightly greater peripheral effects.
    Methamphetamine enters the CNS even more readily
    (i.e. ice, ecstasy, MDMA)
  • Clinical uses
  • Short term use as appetite suppressant in
    conjunction with appropriate diet exercise
    efficacy diminishes with continued use. No
    evidence that long-term improvement in weight
    control can be achieved with amphetamines alone
    anorexic effect.

31
  • Amphetamine Clinical Uses
  • diet pills w sim prop, degrees of abuse
    potential
  • e.g. methamphetamine (Desoxyn) (C-II)
  • Phentermine (lonamin, phen-phen) (C-III)
  • Narcolepsy
  • Dextroamphetamine (Dexedrine)
  • Methylphenidate (Ratalin)
  • Drugs work by ? alertness and ? sleep
  • Attention deficit disorder (ADHD) in children
  • Amphetamines (i.e. dextroamphetamine
    methamphetamine, methylphenidate) paradoxical
    effect--improved attention span with poss
    improving learning--very strong ? effect in brain
    may lead to vaso-con, decrease blood flow.
  • New form longer acting, 1/ day as opposed to 3-4
    X day.

32
  • Amphetamines Adverse Reactions
  • Palpitation, angina, arrhythmias can cause death.
  • Acute tox efx sympathomimetic efx, esp CV efx,
    CNS stim--restlessness, insomnia, irritability,
    confusion, anxiety, delerium. Poss convulsions,
    coma, CVA, ? libido.
  • Chronic intoxication also includes psychotic
    reactions--paranoid shizophrenia, with possible
    hallucinations and suicidal or homicidal
    tendencies. Additional toxicities (e.g.
    pulmonary hypertension damage to heart valves)
    were subsequently identified with fenfluramine
    and dexfenfluramine, they were removed from the
    market in 1997--violence and aggression.

33
  • Other sympathomimetic agents with predominantly
    vasoconstrictor (?) activity
  • Phenylephrine (NeoOSynephrine)-pure ? agonist
  • Phenylpropanolamine
  • Imidazole derivatives (naphazoline)--mainly used
    as a vasoconstrictor nasal decongectant
    hypotension as a result of shock.
  • Principle vasocon (nasal decong hypoTN states)
  • Phenylephrine is also used as a mydriatic.
  • Phenylephrine - direcct acting ?1 selective
    agonist.
  • Phenylpropanolamine--related to ephedrine and
    amphetamine used as a nasal decongestant---warnin
    g--CV toxicity in high doses.
  • NOTE selective ? 2 adrenergic agonists (e.g.
    clondine) mainly used for HTN.

34
  • BETA RECEPTOR SELECTIVE AGONISTS
  • ?1 selective agonists Dobutamine--a syntheitc
    catecholamine related to DA. It has relative
    slectivity for ?1 receptors and used in acute
    heart failure and cardiogenic shock.
  • ?2 selective agonists
  • Terbutaline
  • Albuterol
  • All are only relatively slective for ?2
    receptors.
  • Principle uses are as bronchodilators and to
    delay premature labor (ritodrine, terbutaline) by
    relaxing the uterus.

35
  • ADRENERGIC BLOCKING AGENTS ADRENOCEPTOR
    ANTAGONIST
  • The classical alpha - adrenergic blocking
    agents (?1, ?2) include
  • Ergot alkaloids---first discovered in 1905
    variable effects and many side-effects (e.g.
    ergotamine)
  • Phentolamine (Regitine)---competitive, reversible
    antagonists--non-selective.
  • Phenoxybenzamine (Dibenzyline)---potent,
    irreversible blocking agent---non-selective.
  • Relatively selective alpha receptor blocking
    agents
  • Prazosin (Minipress) HTN
  • Yohimbine (Yohimex) Impotence, ?2 receptor.

36
  • Adrenoceptor antagonists Pharmacologic effects
  • Prevent sympathetically mediated excitatory
    responses at smooth muscle exocrine glands.
  • Net effects depend on dosage (i.e. dose
    dependent), degree of sympathoadrenal activity,
    circulating amine levels, as well as relative
    degree of slectivity.
  • CV effects
  • Blood vessels
  • vaso-dilation IF sympathetic tone is high (in
    HTN)
  • Interfere with compensatory (baroreceptor)
    reflexes ? postural reflex--causes fainting and
    syncope.
  • Block vaso-constrictor action of
    symopathomimetics.

37
  • Adrenoceptor pharmacologic effects
  • Blood pressure
  • Decreased
  • Block increase in BP caused by sympathomimetics
  • Epinephrine reversal--converts an oppressor
    response to a depressor response.
  • Heart
  • Minimal direct effects
  • Tachycardia if BP fails---reflex
  • Other effects
  • Miosis
  • Nasal stuffiness by blocking ? receptor in the
    sinuses

38
  • Adrenoceptor adverse reactions
  • Adverse reactions
  • Phentolamine----reflex cardiac stimulation due
    to enhanced NE release (via ?2 blockade) possess
    parasympathomimetic and histamine like effects
    as well tachycardia, cardiac arrhythmias,
    anginal pain, NVD, exacerbation of peptic ulcer,
    hypotension (orthostatic)
  • Phenoxybenzamine----postural hypotension, reflex
    tachycardia, nasal congestion, miosis, inhibition
    of ejaculation, sedation, nausea, weakness and
    local tissue irritation.

39
  • Adrenoceptor clinical uses
  • Pheochromocytoma---
  • CA of the adrenal medulla ? release of
    catecholamines (NE) - HTN and tachycardia
  • Pre-operative management ? HTN
  • Local vaso-con XS----phentolamine, or frostbite,
    ? blood supply to the region
  • Periph vasc dz--ltd.---Raynauds dz Ca2 channel
    blockers also effective for tx.
  • Genitourinary---phenoxybenzamine (Dibenzyline)
    prostatic hypertrophy (e.g. BPH relaxes muscle at
    base of prostrate), plastocyn also
  • Phentolamine papaverine for impotence---injxn
    inconvenient---replaced by Viagra.
  • Note selective alpha 1 blocking agents are
    effective anti-hyperTN agents w less tachycardia
    side-effects.

40
  • Beta - receptor antagonists
  • Numerous beta receptor blocking agents have been
    developed
  • Non-selective
  • Propranolol
  • Nadolol
  • Timolol
  • Pindolol
  • Sotalol
  • ?1 selective cardioselective
  • Metoprolol
  • Acebutolol
  • Atenolol
  • Esmmolol

41
Beta receptor antagonists
  • Beta receptor blocking drugs with partial
    agonistic activity intrinsic sympathomimetic
    activity (ISA)
  • Pindolol
  • Acebutolol

42
Properties of beta receptor blocking drugs
43
Properties of beta receptor blocking drugs
44
  • Pharmocokinetics of beta receptor blocking agents
  • Absorption
  • Well absorb after oral admin bioavail varies
    widely (e.g. propranolol exten 1st pass metab
    consequences---ONLY 30 IS BIOAVAILBLE)
  • Indiv varia after oral admin--must titrate dose
    individually.
  • Distribution and elimination
  • Rapidly distributed some do not readily enter
    CNS (e.g. nadolol atenolol) H2O soluble.
  • Most 1/2 lives are approximately 3-6 h
    exceptions--
  • Esmolol is shortest (10 minutes) used in the ER
    for cardiac arrhythmia
  • Nadolol is longest (up to 24 h)

45
  • Pharmacokinetics of beta receptor blocking agents
  • Distribution and elimination
  • Degree of biotransformation varies considerably
  • Propranolol, metoprolol and timolol are
    extensively metabolized in the liver.
  • Pinolol and atenolol are less completely
    metabolized
  • Nadolol is excreted unchanged in the
    urine--therefore dose must be adjusted for renal
    problems
  • Esmolol is an ester and is rapidly metabolized by
    esterases in RBCs.

46
  • Beta receptor blocking agents pharmacodynamics
  • Non-selective beta receptor blocking agents block
    sympathetically mediated
  • Cardiac acceleration-chronotropy (?1)
  • Increased myocardial contractility-inotropy (?1)
  • Vaso-dilation (?2)
  • Bronchiolar dilation (?2)
  • Hyperglycemia (?2)
  • Cardioselective beta blockers show more selective
    block of cardiac (?1) effects at lower doses
    higher doses come with other effects as well.
  • Cardiac effects
  • ? HR, contractility, ? SV and ? CO ?BP
  • ? A-V conductiondromotropy---a dromotropic
    effect deals with A-V conduction.

47
  • Beta receptor blocking agents pharmacodynamics
  • Blood pressure
  • With increased P-R interval--contr to
    anti-arrhythmia effect
  • Mechanisms of BP lowering
  • Block the release of renin (?1 mediated)
  • ? CO and TPR (?1 med), either no change or
    increased because there is no effect on ?
    receptors.
  • CNS effects
  • ? ?2 receptor ? ? sympathetic outflow.
  • Eye
  • ? IOP---paradoxical (? aqueous humor formation)
  • Other effects
  • Bronchioles constrict thus exacerbate asthma
    COPD
  • Metab efx ? glycogenolysis, ? glucagon, ?
    lipolysis hypoglycemia
  • Partial agonists pindolol and acebutolol
  • CNS stim/depress (only w drugs w hi lipid
    solub) drowsiness, fatigue and sedation.

48
  • Beta receptor blocking agents adverse reactions
  • Extensions of the pharmacological effect
  • CV ?1
  • Bradycardia
  • CHF
  • Hypotension
  • A-V block
  • Bronchioles ?2
  • Asthma wheezing
  • Bronchospasm
  • Other
  • GI----NVD
  • CNS
  • allergic

49
  • Beta receptor blocking agents clinical uses
  • HTN
  • Angina pectoris
  • Tx acute MI and prevent recurrent MI, by
    decrease work of myocardium.
  • Cardiac arrhythmias
  • Hypertrophic sub-aortic stenosis---cardiomyopathy
  • Glaucoma--topical (e.g. timolol)
  • Hyperthyroidism
  • Migraine---propranolol---prophylaxis
  • Reduce anxiety---? stage fright

50
Beta receptor blocking agents contra cxn
  • CHF
  • Cardiogenic shock
  • A-V block
  • Sinus bradycardia
  • Asthma
  • Diabetes
  • DO NOT DISCONTINUE ABRUPTLY WHEN TREATING ANGINA

51
  • Mixed aplha and beta blocking drugs
  • Labetalol
  • Non-selective beta-receptor blockade tends to
    predominate, but at higher doses, both alpha and
    beta blocking effects result. It is an effective
    anti-HTN drug produces a fall in BP with less
    tahycardia than occurs with phentolamine.
    Orrally effective.
  • Carvedilol
  • Has anti-HTN activity and is useful adjunctively
    in certain types of congestive heart failure.

52
  • Other sympathoplegic drugs anti-HTN agents
  • There are numerous sites at which drugs may act
    to alter sympathetic nervous system function and
    weaken adrenergic influences
  • Adrenoceptors on effector cells innervated by
    sympathetic post-ganglionic fibers--i.e.
    adrenergic blocking agents.
  • Sympathetic post-ganglionnic nerve terminals
  • Symapthetic ganglia
  • CNS

53
  • Adrenergc neuron blocking agents
  • Adrenergic neuron blocking agents drugs that act
    on post-gang symp N terminals to interfere w norm
    physio release of NE
  • Guanethidine---displaces NE from vesicles and
    depletes stores and also blocks the physiologic
    release of NE.
  • Consequences chemical sympathectomy
  • Transient initial sympathomimetic effect (IV)
  • Generalized sympathetic nervous system depression
  • Supersensitivity of effector cells to
    catecholamines
  • Uses severe HTN--very little use now due to
    serious side effects and drug interactions.
  • Reserpine
  • MOA impairs storage of catecholamines in
    adrenergic N term drug is metab by MAO
  • Used for mild HTN.

54
Centrally acting sympathoplegic drugs
  • Methyldopa
  • MOA decreases BP by reducing peripheral
    vascular resistance and a variable reduction in
    both heart rate and cardiac output.
  • Clonidine
  • ?2 agonist.
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