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.