Pharmaceutcial Chemistry of CVS drugs III Flashcards
Arrhythmia
- Heart rhythm problems, abnormal heart rhythm, caused by different
factors
What diseases do you use beta blockers
- Hypertension
- Arrhythmia
- Angina
- MI
- CHF
What are Adrenoceptors?
- G protien coupled receptors that conotain an amine group and a catechol group (benzene with 2 alcohols)
- Small-molecule binding characteristics to be clinically significant in pharmacotherapeutics
Targets of Catecholamines
- Norepinephrine with R group of H
- Epinephrine with R group of CH3
α-receptors
- α1 = α1A, α1B, and α1D
- α2 = α2A, α2B, and α2C
β-receptors
- β1, β2, and β3 subtypes
Adrenoceptors location
- Various organs and tissues as well as on neurons of both the peripheral nervous system and central nervous system
β1 major in the heart
- All β-blockers affinity for β1 inhibit binding norepinephrine/epinephrine
- Slow heart rate/decreased myocardium contractile
β1 in kidney
- All β-blockers affinity for β1
- Decrease secretion of renin
- Decrease plasma levels of angiotensin II causing vasodialation
β2 major in CNS
- Increased sympathetic activity
- β1selective drugs can also
produce CNS side effects
β2 vascular, lungs, uterus smooth muscle
- Arterial dilation
- Bronchodilation
- Uterus muscle relaxation
β2 agonist
- Alleviating respiratory distress in
persons with asthma or used to inhibit uterine contractions in premature labour
𝛼1 stimulation of smooth muscle of the peripheral vasculature
- Constriction
causing a rise in blood pressure
α1antagonist
- Relaxation of the blood vessels and a drop in blood pressure
Extracelluar structure of Adrenoceptors
- Crystal structure of the human β2 adrenoceptor
Membrane structure of Adrenoceptors
- 7 Trans Membrane (TM) helices
Intracellular structure of Adrenoceptors
- Contains Protein G
Alcohol part alpha and beta adrenoceptor binding site
- R-enantimer is more active compared to S-enantimer forming H-bond with Asn293
Amine part alpha and beta adrenoceptor binding site
- Protonated and ionised at physiological pH. Ionic bond with Asp113
- Primay and secondary amines are better
Phenols alpha and beta adenoreceptors binding site
- H-bonds with Ser204 and
207 able to form hydrogen bonds
Catechol aromatic ring alpha and beta adrenoceptor
- Stabilising hydrophobic
interaction with Phe290
Alkyl substitution on the side chain alpha and beta adrenoreceptor binding site
- Decreases activity. Steric effect which blocks
H-bonding to the alcohol
Beta adrenoceptor Extra hydrophobic pocket
- Required for Beta receptor increasing the size of the N-alkyl substituent (CH3)
- A bulky alkyl group can fit
Pharmacological response of beta blockers
- Sympatholytic drugs
- Dependent on the drug-receptor affinity and selectivity
- Selectivity decreases at higher dose
Examples of Antagonist of β1
- Atenolol
- Metoprolol
- Bisoprolol
- Nebivolol
Examples of Antagonists of both, β1 and β2
- Propranolol
- Sotalol
- Timolol
Examples of Mixed antagonists of β1 and β2 and 𝛼1
- Carvedilol
- Labetalol
Pronethanol
- Arylethanolamines
- Withdrawn cause tumor ether
Propranolol
Aryloxypropanolamines
- Aryl
- Oxypropanol
- amino
- More potent B-blocker compared to arylethanolamines
Low energy conformation of Beta blockers
- Have overlapping critical functional groups which occupy the same approximate region of space
R absolute configuration
- Maximum effectiveness in
receptor binding, the OH group must occupy the same region in space as it does for the Catecholamines - Groups still have the same
spatial arrangements
Most beta blocker are racemic
Requirement of beta blocker
- At least one aromacic or hetroaromatic ring with hydrophobic interaction
- Hydrogen bond with either R-enantiomer arylethanolamines or s-enantiomer aryloxypropanolaminesm
- Amine forming ionic bond branched bulky N-alkyl substituents (beta antagonist require hydrophobic pocket)
- para substitutions with phenyloxypropanolamine
- Substitution on the side chain increases metabolic stability but lowers activity replace O with S or CH2 is detrimental
Lipophilic beta blockers
- Higher partion coefficient at 2.65 due to hydrocarbon naphthyl ring system
- Ability to peetrate blood brain barrier higher
- Extensive hepatic metabolism - shorter half life
Hydrophilic beta blocker
- Lower partion coefficient with LogP = 0.5
- Polar acetamide less likely to cross CNS
- ## Minimal metabolised by liver insttead cleared by kidney
Class I Antiarrhythmic Drugs
- Class based of elecrophysological effect
- Sodium channel blocker
- Affinity for Na+ channels in fast action potential tissue therefore decrease in influx of Na+
Class II Antiarrhythmic Drugs
- Beta adrenergic receptors
- Blocking norepinepherine from binding to beta receptors
- Decrease SA and AV nodes increase PR interval
- Can be selective & non-selective Esmolol and propranolol
Class III Antiarrhythmic Drugs
- Potassium channel blocker
- Block outflow of potassium increase refractory peroid of AP increase QT interval
Class IV Antiarrhythmic Drugs
- Non-dihydropyridine Ca2+ channel blockers by decreasing influx of Ca2+
- Decease slope of phase 0 prolong refractory peroid
- Decrease heart rate and prolong PR interval so longer to travel to atrial myocardium
- Verapamil and Diltiazem
Flecainide
- Sold as acetate (CH3COO-) salt which causes increase in water solubility and oral adminsitration (Amine/carboxylic acid)
- Well absorbed orally
- metabolised by CYP2D6 most elimininated renally and some via feaces
Amiodarone
- Potassium channel blocker that is lilophilic by diiodinated benzofuran derivative Long-elimination half-life cause toxicity
- HCl salt increase water
solubility/oral administration - Incomplete oral absorption
- Additive effects with CCB
Metabolite of Amiodarone
- Mono-Desethylamiodarone (May be more toxic) is metabolised to Amiodarone
- CYP2C9,CYP2D6, and CYP3A4 inhibitors inhibits the metabolism of warfarin therefore increase plasma levels and anticoagulant effect
Issues with Amiodarone vs Triiodothyronine
- Similar to triiodothyronine T3 hormone for thyroid cause hyperthyroid
- Very lithophilic drug causes risk of neurotoxicity
- Long half life cardiovascular toxicity
Counteract issues with Amiodarone to Dronedarone
Still not optimum causes mortality
- Removal of iodine groups reduce risk of thyroid issue
- reduces lipophilicity, the risks of neurotoxicity and shortens half-life significantly by Methylsulphonamide
- Associated with an increased risk of mortality
To overcome the problem of long elimination
half-life of amiodarone
- Replacing the butyl chain with ester group can undergo ester hydrolysis decrease half life
- Bulkier compound increase the steric effect for esterases and delaying inactivation
- Inactive drug
