Pharmaceutcial Chemistry of CVS drugs III

Question 1

Arrhythmia

Answer 1

• Heart rhythm problems, abnormal heart rhythm, caused by different
  factors

Question 2

What diseases do you use beta blockers

Answer 2

• Hypertension
• Arrhythmia
• Angina
• MI
• CHF

Question 3

What are Adrenoceptors?

Answer 3

• 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

Question 4

Targets of Catecholamines

Answer 4

• Norepinephrine with R group of H
• Epinephrine with R group of CH3

Question 5

α-receptors

Answer 5

• α1 = α1A, α1B, and α1D
• α2 = α2A, α2B, and α2C

Question 6

β-receptors

Answer 6

• β1, β2, and β3 subtypes

Question 7

Adrenoceptors location

Answer 7

• Various organs and tissues as well as on neurons of both the peripheral nervous system and central nervous system

Question 8

β1 major in the heart

Answer 8

• All β-blockers affinity for β1 inhibit binding norepinephrine/epinephrine
• Slow heart rate/decreased myocardium contractile

Question 9

β1 in kidney

Answer 9

• All β-blockers affinity for β1
• Decrease secretion of renin
• Decrease plasma levels of angiotensin II causing vasodialation

Question 10

β2 major in CNS

Answer 10

• Increased sympathetic activity
• β1selective drugs can also
  produce CNS side effects

Question 11

β2 vascular, lungs, uterus smooth muscle

Answer 11

• Arterial dilation
• Bronchodilation
• Uterus muscle relaxation

Question 12

β2 agonist

Answer 12

• Alleviating respiratory distress in
  persons with asthma or used to inhibit uterine contractions in premature labour

Question 13

𝛼1 stimulation of smooth muscle of the peripheral vasculature

Answer 13

• Constriction
  causing a rise in blood pressure

Question 14

α1antagonist

Answer 14

• Relaxation of the blood vessels and a drop in blood pressure

Question 15

Extracelluar structure of Adrenoceptors

Answer 15

• Crystal structure of the human β2 adrenoceptor

Question 16

Membrane structure of Adrenoceptors

Answer 16

• 7 Trans Membrane (TM) helices

Question 17

Intracellular structure of Adrenoceptors

Answer 17

• Contains Protein G

Question 18

Alcohol part alpha and beta adrenoceptor binding site

Answer 18

• R-enantimer is more active compared to S-enantimer forming H-bond with Asn293

Question 19

Amine part alpha and beta adrenoceptor binding site

Answer 19

• Protonated and ionised at physiological pH. Ionic bond with Asp113
• Primay and secondary amines are better

Question 20

Phenols alpha and beta adenoreceptors binding site

Answer 20

• H-bonds with Ser204 and
  207 able to form hydrogen bonds

Question 21

Catechol aromatic ring alpha and beta adrenoceptor

Answer 21

• Stabilising hydrophobic
  interaction with Phe290

Question 22

Alkyl substitution on the side chain alpha and beta adrenoreceptor binding site

Answer 22

• Decreases activity. Steric effect which blocks
  H-bonding to the alcohol

Question 23

Beta adrenoceptor Extra hydrophobic pocket

Answer 23

• Required for Beta receptor increasing the size of the N-alkyl substituent (CH3)
• A bulky alkyl group can fit

Question 24

Pharmacological response of beta blockers

Answer 24

• Sympatholytic drugs
• Dependent on the drug-receptor affinity and selectivity
• Selectivity decreases at higher dose

Question 25

Examples of Antagonist of β1

Answer 25

- Atenolol - Metoprolol - Bisoprolol - Nebivolol

Question 26

Examples of Antagonists of both, β1 and β2

Answer 26

- Propranolol - Sotalol - Timolol

Question 27

Examples of Mixed antagonists of β1 and β2 and 𝛼1

Answer 27

- Carvedilol - Labetalol

Question 28

Pronethanol

Answer 28

- Arylethanolamines - Withdrawn cause tumor ether

Question 29

Propranolol | Aryloxypropanolamines

Answer 29

- Aryl - Oxypropanol - amino - More potent B-blocker compared to arylethanolamines

Question 30

Low energy conformation of Beta blockers

Answer 30

- Have overlapping critical functional groups which occupy the same approximate region of space

Question 31

R absolute configuration

Answer 31

- 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

Question 32

Requirement of beta blocker

Answer 32

- 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

Question 33

Lipophilic beta blockers

Answer 33

- 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

Question 34

Hydrophilic beta blocker

Answer 34

- Lower partion coefficient with LogP = 0.5 - Polar acetamide less likely to cross CNS - Minimal metabolised by liver insttead cleared by kidney -

Question 35

Class I Antiarrhythmic Drugs

Answer 35

- Class based of elecrophysological effect - Sodium channel blocker - Affinity for Na+ channels in fast action potential tissue therefore decrease in influx of Na+

Question 36

Class II Antiarrhythmic Drugs

Answer 36

- 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

Question 37

Class III Antiarrhythmic Drugs

Answer 37

- Potassium channel blocker - Block outflow of potassium increase refractory peroid of AP increase QT interval

Question 38

Class IV Antiarrhythmic Drugs

Answer 38

- 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

Question 39

Flecainide

Answer 39

- 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

Question 40

Amiodarone

Answer 40

- 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

Question 41

Metabolite of Amiodarone

Answer 41

- 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

Question 42

Issues with Amiodarone vs Triiodothyronine

Answer 42

- Similar to triiodothyronine T3 hormone for thyroid cause hyperthyroid - Very lithophilic drug causes risk of neurotoxicity - Long half life cardiovascular toxicity

Question 43

Counteract issues with Amiodarone to Dronedarone | Still not optimum causes mortality

Answer 43

- 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

Question 44

To overcome the problem of long elimination half-life of amiodarone

Answer 44

- 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