Adrenoceptor types & distribution
- covered in physiology,
- nicotinic receptors are ion channels, muscarinic are G protein mediated systems.
Benztropine, glycopyrrolate, tropicamide, tiotropium are all antimuscarinic
- alpha1 receptors –> G protein –> hydrolyses polyphosphoinositides –> IP3 +DAG –> release of Ca2+ from intracellular stores–> activation of Ca dependent protein kinases.
- Aplha 2 receptors –> also G protein –> inhibit adenyl cyclase –> decrease cAMP
- Beta 1,2, 3 receptors –> all increase adenyl cyclase activity –> increase cAMP
- Dopamine 1 – stimulates adenyl cyclase
- Dopamine 2 – inhibit adenyl cyclase – opens K channels and decrease Ca2+ influx
Selectivity – at higher concentrations the selectivity is decreased.
Adrenaline acts as a hormone whereas noradrenaline acts as neurotransmitter.
Sympathomimetic drugs increase sympathetic drive either as direct agonists(adrenaline and NA) or indirectly by decreasing reuptake(cocaine, TCA) or increasing release of catecholamines (tyramine) or decreasing breakdown of catecholamines (MAO and COMPT inhibitors). Indirect agonsist work more when there is increased sympathetic activity.
moxonidine – a2 agonist
Noradrenaline a1=a2, B1>>B2
adrenaline a1=a2, B1=b2
Blockers – terbutaline, metoprolol B2>>B1>>>>>>a
potent vasoconstrictor and positive ionotrope and chronotrope, (B2 agonism leads to skeletal blood vessel dilation –> so peripheral resistance may actually falll–> drop in DBP, but there is more alpha than beta so if you give just a nonspecific adrenoceptor agonist it will result in hypertension)
used with local anaesthetic to locally vasoconstrict to keep local anaesthetic in the region required therefore reduce dose needed
Similar to adrenaline but less B2 agonism–>increased peripheral resistance –> increase SBP and DBP. Chronotrope effect cancelled by baroreceptor reflex.
Potent B agonist so chronotrope, inotrope and potent vasodilator–> increase CO, drop DBP and small drop or small rise in SBP.
used in parkinsons disease
precursor to NA
B1 selective so increases CO without the reflex tachycardia(no vasodilation cos less B2 agonism)
used in stress test to increase cardiac work instead of exercise
Peak concentration 1-3hrs post ingestion, well absorbed orally. First pass metabilism means low oral bio availability. Large Vd. Half life 3-10hrs.
Inhibit B receptors –> negative chronotrop, reduce BP in ppl with HTN(not normal ppl with normal BP), reduce release of sympathetic renin
Acutely can increase peripheral resistance
Bronchoconstriction (esp in asthma), reduce intraocular pressure(esp in glaucoma),
Use in HTN, angina, post MI, heart failure, supraventricular and ventricular arrhythmias, glaucoma, hyperthyroidism, migarines, reduce portal vein pressure in cirrhosis.
- Non selective
- High Vd
- 30% bioavailability, dose dependent
- 3-6hr half life
- Metoprolol / Atenolol.
- b1 selective so less bronchoconstriction.
- Also prefered in diabetes(better recovery from hypoglycaemia) and PVD(avoids peripheral vasoconstriction of B2)
- 5hrs half life average
- Moderate and low lipid solubility
- Labetalol (worthy of superficial knowledge.)
- Non selective, partial agonist, reversible
- 5hr half life
- Low lipid solubility
- Hypotension with less bradycardia
- Esmolol also interesting because of short T1/2 and use in SVT.
- B1 selective
- Low lipid solubility
- 10min half life
- Use in critically ill patients and SVT, periop HTN
- Nebivolol(most B1 selective and also helps vasodilate)
Intrinsic sympathomimetic activity/partial agonist
- Less likely to cause bradycardia
Local anaesthetic action via Sodium channel blockade.
Beta blocker toxicity / overdose.
- Cool peripheries
- Vivid dreams
- Mild sedation, rarely depression
- Cardiac decompensation
- Overdose can be treated with isoprenoline or glucagon.
- Severe hypotension when taken with verapamil
- Arrhythmia from Na channel blockade
- Phentolamine/Phenoxybenzamine- a1 and a2 antagonist, 45min half life post injection, used to treat phaeochromocytoma
- Prazosin – a1 block – used for HTN and BPH
- Tamsulosin- a1 block – used for BPH
- Clinical pharmacology of alpha blockers – phaeo, HTN, Reynauds, urinary obstruction, erectile dysfunction
In general, b-blockers are more important than a-blockers, at least for the vivas.
- Tell me about the pharmacodynamics of Adrenaline.
- What are the therapeutic uses of Adrenalin
- What are the actions of noradrenaline ?
- What effects might you see in a patient who had taken amphetamines?
- What drugs have alpha blocking effects?
- Name a drug which specifically blocks a1 receptors.
- When might alpha antagonists be used ?
- What are the organ system effects of beta antagonists ?
- What agents possess b1 selectivity ?
- What agents possess intrinsic sympathomimetic activity ? What are the theoretical benefits of this
- What are the toxic effects of beta blockers ?
- What are the contra-indications to beta blockers ?
- Heart Block
- Cocaine induced ACS
- Diabetes Melitus (can slow recovery from hypoglycaemia so chose a B1 selective one)
- Electrolytes – hyperK
- What are the therapeutic uses for beta blockers ?