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sympathomimetics

sympathomimetics

chemical properties of sympathomimetics

  • Sympathomimetics are drugs that mimic the actions of the naturally occurring catecholamines with beta-phenylethylamine being the parent compound:

(benzene ring-CH2-CH2-NH2).

  • The greatest sympathomimetic activity is when 2 C atoms separate the ring from the amino group & OH groups are on the 3,4 positions of the benzene ring making it a catecholamine.
  • When the benzene is replaced by a catechol ring (3,4-diOHbenzene), then the drug is called a catecholamine:
  • Increasing the alkyl substituent on the amino group increases beta activity (eg. isoprenaline) and if 3,5-diOH benzene as well then beta2 selectivity (eg. terbutaline, salbutamol);
  • Unsubstituted or alkyl substituted compounds are more lipid soluble as less polar & thus cross blood-brain barrier more readily (eg. ephedrine, amphetamine) but causes loss of direct peripheral sympathomimetic activity.
  • Catechol-O-methyltransferase (COMT) in GIT & liver metabolise catechol groups & thus drugs with these are not orally active.
  • Non-catecholamines are degraded by MAO, but this is inhibited if there is substitution on the alpha C atom (eg. ephedrine, amphetamine) ⇒ their half-life hours instead of minutes;
  • L-rotatory on the beta-C atom increases peripheral activity about 10 ;
  • D-rotatory on the alpha-C atom increases CNS activity (eg. d-amphetamine)

actions

Peripheral excitatory action:
  • smooth muscle blood vessels to skin, mucosa;
  • gland cells (eg. salivary, sweat) (alpha);
Peripheral inhibitory action:
  • smooth muscle GIT, bronchi, blood vessels to skeletal muscle (beta2);
Cardiac excitatory action:
  • inotropic + chronotropic (beta1);
Metabolic actions:
  • increased glycogenolysis in liver & skel. muscle;
  • liberation of FFA's from adipose tissue;
CNS actions:
  • respiratory stimulation; increased wakefulness;
  • increased psychomotor activity; decreased appetite;
Presynaptic actions:
  • either inhibitory or facilitatory effect on release of neurotransmitters - physiologically inhibitory > facilitatory

summary of sympathomimetic receptor actions

alpha 1 adrenergic:

  • Gq ⇒ inc. phospholipase C ⇒ inc. DAG + inc. IP3 ⇒ inc. [Ca]i ⇒ inc. protein kinase C ⇒ other Ca/calmod.inc.
    • ⇒ post-junctional vasc. smooth muscle ⇒ vasoconstriction;
    • ⇒ decreased arterial capacitance; increased diastolic BP; shunt blood
    • ⇒ post-jn. vascular adventitia
    • ⇒ extra-jn. vascaular intima (mainly alpha2 though)
    • ⇒ post-jn. myocardium ⇒ increased inotropy; increased arrythmias
    • ⇒ liver ⇒ glycogenolysis & gluconeogenesis ⇒ hyperglycaemia
    • ⇒ renal Na reabsorption increased via stimulating proximal tubule NHE3 and basolateral NaKATPase
    • ⇒ increased salivary secretion and salivary K+ levels
    • ⇒ genitourinary smooth muscle contraction
    • ⇒ prostate ⇒ alpha 1a contracts smooth muscle and can worsen benign prostatic hyperplasia (BPH) symptoms
    • ⇒ bladder ⇒ alpha 1a bladder neck constriction preventing retrograde ejaculation but also worsens benign prostatic hyperplasia (BPH) symptoms
    • ⇒ mitogenic response in many cells
    • CNS effects: anorexia, etc
  • NB. ischemia ⇒ decreased number of alpha1 binding sites ⇒ tolerance

alpha 2 adrenergic:

  • agonist: clonidine;
  • antagonist: Yohimbine;
  • ⇒ Gi ⇒ decreased adenylyl cyclase ⇒ decreased [cAMP]i ⇒ decreased cAMP-dep.prot.kinases;
  • ⇒ increased inward K decreased voltage-dependent calcium flow
    • ⇒ hyperpolarises cholinergic myenteric neurons ⇒ decreases GIT motility;
  • ⇒ post-jn. vasc. sm.muscle ⇒ vasoconstriction;
  • ⇒ extra-jn. vasc. intima
  • ⇒ pancreatic islets (beta cells) ⇒ decreased insulin secretion;
  • ⇒ platelet aggregation;
  • ⇒ nerve terminals ⇒ decreased release NA;

beta 1 adrenergic:

  • agonist: dobutamine;
  • ⇒ Gs ⇒ increased [cAMP] ⇒ increased cAMP-dependent protein kinase
  • ⇒ increased voltage-dependent calcium in skeletal & cardiac muscle;
  • ⇒ myocardial ⇒ increased inotropy + increased chronotropy ⇒ increased myocardial O2 demand;
  • ⇒ Purkinje fibres ⇒ increased AV nodal cond. velocity;
  • ⇒ JGM cells ⇒ increased renin secretion;

beta 2 adrenergic:

  • agonist: terbutaline; salbutamol;
  • antagonist: ICI 118551;
  • ⇒ Gs as for beta1 but ? not the Ca channel effect;
  • ⇒ bronchodilatation;
  • ⇒ peripheral vasodilatation;
  • ⇒ relaxation of genitourinary & GIT smooth muscle
  • ⇒ liver ⇒ glycogenolysis & gluconeogenesis;
  • ⇒ skeletal muscle ⇒ glycogenolysis & increased uptake K;
  • ⇒ K into cells ⇒ hypokalaemia;

beta 3 adrenergic:

  • agonist:
  • antagonist: CGP 20712A
  • ⇒ increased adenylate cyclase
  • ⇒ lipolysis in adipose tissue;
  • ⇒ relaxes detrusor muscle ⇒ increases urinary bladder capacity

Dopamine 1 receptor:

  • agonist: dopamine
  • post-synaptic ⇒ increased adenylyl cyclase ⇒ increased [cAMP]:
    • ⇒ vasodilatation (esp. renal & mesenteric)-⇒ increased GFR; increased RBF; increased Na excretion

Dopamine 2 receptor:

sympathomimetics.txt · Last modified: 2019/06/01 14:58 (external edit)