Pharmacology

Question 1

Delivery of a drug via the respiratory system is the […] route of administration.

Answer 1

Topical

Question 2

Describe the respiratory route of administration.

Answer 2

Question 3

Respiratory Administration

• Absorption pattern
• Advantages
• Disadvantages

Answer 3

Question 4

Allbuterol is […] acting and acts on […] receptors as an […]. Its action results in relief of […] seen in conditions such as […] and […]. Its receptor targets are found in […] tissue.

Answer 4

Short

Beta 2 adrenergic

agonist

bronchospasm

asthma and COPD

smooth muscle

Question 5

Describe the role of the lungs as a route of drug excretion.

Answer 5

Blood gases are excreted by passive diffusion from the blood into the alveoli following a concentration gradient. If there is a substance in the blood that is not very soluble in blood it can readily diffuse across the membrane to be excreted in the alveoli as a gas. Volatile liquids (alcohol) are also readily excreted via the expired air. Exhlation is an exceptionto most other routes of excretion because it can be a very effective route of excretion for lipid soluble substances due to the fact that lipid soluble susbtances diffuse well across the blood/alveolar membrane.

Question 6

What are the non-respiratory functions of the lungs?

Answer 6

Question 7

How are the lungs pharmacologically active?

Answer 7

The lungs can take up, retain and metabolize and delay the release of many drugs.

Question 8

What is pulmonary extraction?

Answer 8

Refers to the transfer of a drug from the blood into the lung. The drug can then be metabolized in the lung or released unchanged back into the blood as a means to help maintain a steady state concentration of the drug. The extraction occurs in pulmonary endothelial cells. Drugs that are administered via IV are especially susceptible to this b/c they are delivered to venous blood which then goes to the right heart and the lungs before being pumped to the rest of the body. As such, the lungs hold onto a lot of drugs that are given via IV. Depending on the drug, pulmonary extraction can result in local tissue damage to the lung. If the patient is on a beta blocker (compete for drug binding sites in lungs) or has lung tissue damage this can result in decreased pulmonary extraction and potentially a toxic dose of drug being administered due to increased [drug] in the blood.

Question 9

How does the lung display endocrine function?

Answer 9

Question 10

What monoamines are inactivated by the lungs? Which are pass through unchanged?

Answer 10

Broken down

• Serotonin
• NE

Spared

• Dopamine
• Histamine
• Epi

Question 11

Which peptides are activated in the lungs?

Which peptides re inactivatd in the lungs?

Answer 11

The endothelial cells of the pulmonary circulation contain a lot of ACE which converts angiotensin I to angiotensin 2.

Bradykinin

Question 12

What prostaglandins are inactivated by the lungs?

Which pass through unchanged?

Answer 12

Inactivated

• LEFD
  
  • Leukotrienes, PGE₂, PGF₂, PGD₂

Unchanged

• PGI₂
• PGA₂

Question 13

What effect do the lungs have on circulating purines?

Answer 13

They inactivate them / degrade them

Question 14

• What is meant by a racemic mixture of a drug like epinephrine?
• Why do drug companies make racemic mixtures?
• What is the difference in potency between the two isomers?

Answer 14

• Racemic mixture contains equal amounts of both isomeric versions of epinephrine.
• Many times drugs are given in 50-50 mixtures of a drug if each isomer present has separate but different benefits, which when combined have a synergistic effect and yield better results.
• The S-isomer has a lesser effect than the R-isomer but it is longer acting. When given together you get the potency of one with the longer-lasting effects of the other.

Question 15

Racepinephrine is a racemic mixture of epinephrine. What are the advantages of Racepinephrine delivered by the respiratory route of administration?

Answer 15

The respiratory route puts the inhaled medication in a well perfused area where the drug can readily pass into the pulmonary capillaries through the relatively thin epithelial/endothelial barrier. The drug readily enters the blood stream, bypassing 1^st pass metabolism, and the lungs can act as a reservoir for the drug. If the drug is very volatile it can also be excreted through the lungs as well.

Question 16

What is the intended biological target of Racepinephrine as it relates to asthma symptoms?

Answer 16

Asthma is an irritation and constriction of the airways, commonly the bronchial passages, and production of excess mucus. Since asthma leads to bronchial constriction or narrowing of these airways, the desired therapeutic effect is the dilation of these narrowed passages. The intended biological targets of Racepinephrine, a bronchodilator, are the Beta-2 adrenergic receptors in the smooth muscle within the airways.

• • Regarding the flow-volume loops, Figure A represents James’ lung function test following the use of the inhaler while Figure B may represent his lung function test before use of the inhaler. Figure A represents a normal lung function test while Figure B has a decreased flow rate near the end of expiration, suggesting that the person may have had trouble exhaling completely (e.g., wheezing) at the end of expiration. The “scooped-out” appearance of the flow-volume loop (B) is consistent with an abnormal flow-volume loop, as seen with obstructive diseases, such as asthma. This altered appearance is due to a reduced FVC, FEV1 and FEV1/FVC ratio, which is improved by the use of bronchodilators, as seen in flow-volume loop (A).

Question 17

Explain the pulmonary mechanism of action for the desired therapeutic effect of racepinephrine.

Answer 17

Binding of the drug to Beta-2 receptors results in bronchodilation (relaxation of the smooth muscle within the airways), allowing for decreased airway resistance and an easier time breathing after the use of the inhaler.

Racepinephrine can also bind to alpha-1 adrenergic receptors of the mucosa and cause vasoconstriction. The combined effects of mucosal vasoconstriction and bronchial dilation open up the airways to relieve asthma symptoms.

Question 18

What are the risks of overuse of racepinephrine?

Answer 18

Overuse of racepinpehrine would cause continued mucosal vasoconstriction. Extensive constriction of the mucosa, while creating more space for air to flow, will reduce the irritant-fighting ability of the mucosa in normal pulmonary functioning.

Question 19

Which of the following flow-volume loops, A or B, would most resemble a lung function test following use of the inhaler? Explain your answer.

Answer 19

Figure A represents a lung function test following the use of the inhaler while Figure B may represent a lung function test before use of the inhaler. Figure A represents a normal lung function test while Figure B has a decreased flow rate near the end of expiration, suggesting that the person may have had trouble exhaling completely (e.g., wheezing) at the end of expiration. The coving of the flow-volume loop (B) is consistent with an abnormal flow-volume loop, as seen with obstructive diseases, such as asthma. This altered appearance is due to a reduced FVC, FEV1 and FEV1/FVC ratio, which is improved by the use of bronchodilators, as seen in flow-volume loop (A).

Question 20

Speculate about why repeated doses of Racepinephrine are cautioned against as it relates to its intended therapeutic effect (NOT as it relates to unintended side effects).

Answer 20

Repeated doses of Racepinephrine can lead to tolerance, which is the diminished response to a drug that occurs with repeated use. In response to prolonged stimulation, the cell can alter the receptor, internalize the receptor, and make fewer receptors, leading to decreased response over time. If the patient had a particularly bad asthma attack, due to the desensitization, they wouldn’t get the effect they really needed.

Question 21

Racepinephrine should not be used if the patient is currently taking an MAO inhibitor. Review the function of monoamine oxidase as it relates to catecholamines and explain the warning rationale for this particular combination of drugs.

Answer 21

MAO is an enzyme that degrades catecholamines, in particular Ne and Epi. Both NE and Epi are excitatory to the heart, and after they are released they are either reuptaken into presynaptic nerve terminals, reuptaken by glia, or broken down by MAO. MAO is bound to the surface membrane of mitochondria within cells, and it is abundant in noradrenergic nerve terminals.

If a patient is taking a MAO inhibitor, then they are increasing the amount of catecholamines throughout the body because they are being inhibited from degradation. Patients often take MAO inhibitors as antidepressants to increase levels of Dopamine. Since levels of catecholamines are elevated due to the inability to break them down, adding more E can increase the risk for severe HTN, which can result because of Epi’s ability to bind to beta1- and beta-2 receptors on the SA node.

Question 22

The “drug facts” for racepinephrine state that users should avoid foods or beverages that contain caffeine. Speculate about why a warning for this combination is listed in the packaging.

Answer 22

Adenosine receptors are located on presynaptic noradrenergic neurons and act to inhibit the release of NE. Caffeine is a competitive antagonist of adnosine receptors, thus causing an increase in NE leading to a stimulant effect. The increased levels of norepinephrine increase the risk for severe hypertension.

Question 23

Dietary supplements containing ephedra were banned in 2004 by the FDA, but it can still be marketed for the relief of colds and allergies. The drug facts warnings advise against using dietary supplements “containing ingredients reported or claimed to have a stimulant effect”. Why would this be a particular concern for someone taking Racepinephrine?

Answer 23

Ephedra is an herb containing ephedrine. Ephedrine has some capacity to activate various adrenergic responses, thus acting as a stimulant. Taking multiple stimulants runs the risk of hypertension because of over stimulation of adrenergic receptors.

Taking other stimulants combined with racepinephrine will also cause tachycardia, especially caffeine because it triggers such a systemic release of epinephrine. Tachycardia is of greater concern when considering possible interactions and sudden death.

Question 24

• The “drug facts” warn to stop taking Racepinephrine if experiencing a rapid heartbeat. Identify the direct target tissue for this side effect and explain the physiological reason why this might occur.
• What does this tell you about the selectivity of this drug and relate this to the dose.

Answer 24

• The direct target tissue for the side effect of rapid HR is the SA node, which possess both beta-1 and beta-2 adrenergic receptors. Stimulation of these receptors causes an increase in HR, contractility and conduction speed.
• Although the intended target of RE in this case is the lungs, it can travel throughout the body and stimulate other adrenergic receptors leading to unintended side effects. Binding to beta-2 adrenergic receptor in lungs causes broncho/vasodilation, relaxing the respective vessel. Binding to alpha-1 adrenergic receptors produces the opposite effect causing broncho/vasoconstriction. This tells us that the drug is not very selective and users should abide by the label for the dosing regimen to avoid these harmful effects

Question 25

• Why is there a warning for use of racepinephrine in a patient with high blood pressure?
• What does this tell you about the selectivity of this drug and relate this to the dose that James takes.
• Would norepinephrine (NE) be a better or worse drug alternative and why?
• Speculate as to why NE might cause reflex bradycardia (slowing of heart rate).

Answer 25

• RE can bind to alpha-1 adrenergic receptors to cause vasoconstriction and for a patient who is already hypertensive this could potentially exacerbate the problem.
• RE can also bind to beta-2 adrenergic receptors and cause vasodilation in other areas of the body and so, if the dose is maintained at a low level the beta-2 response of vasodilation might be able to balance the alpha-1 response of vasoconstriction.
• Norepinephrine (NE) is a worse alternative. Although NE is a beta-adrenergic receptor agonist, it has little effect on beta-2 receptors. As a result, NE will not help with James’s breathing, and will only increase his heart rate and blood pressure.
• NE binds to alpha-1 receptors on vascular smooth muscle –> vasoconstriction –> elevated arterial pressure stimulates baroreceptors in the carotid sinus –> CN 9 –> nucleus tractus solitarious –> slow down heart rate in order to reestablish normal BP

Question 26

As an agonist, list the receptor selectivity of Racepinephrine?

Compare the receptor selectivity of epinephrine and norepinephrine.

Regarding the receptor selectivity, what type of drug would more specifically treat asthma symptoms if delivered by inhalation?

Answer 26

• Non-selective adrenergic agonist for α and β adrenergic receptors (α₁, α₂, β₁, β₂, and β3) with preference (known as “agonist potency order”) for α2, β1, and β2 receptors and least selective for α1 and β3 receptors.
• NE most selective for α1 and β3 receptors, and least selective for β1 and β2 receptors.
• In order to treat asthma symptoms, we would want to use epinephrine because it specifically targets β2 receptors and causes smooth muscle relaxation

Question 27

Epinephrine exerts physiological effects on two different receptors in smooth muscle: β2 and α1. Describe the predicted effect of racepinephrine on smooth muscle and explain how this might impact the desired effect in the treatment of asthma.

Answer 27

At β2 receptors, Epi acts as an adrenergic agonist and causes smooth muscle relaxation (bronchodilation). At α1 receptors, it has the opposite effect - smooth muscle contraction. When α1 receptors in the airway are acted on by Epi, there is mucosal vasoconstriction and decreased subglottic edema. All of these are desired effects in improving the symptoms of asthma.

Question 28

Aziz sees an asthma specialist who prescribes an inhaler containing albuterol (beta 2 agonist) and ipratropium bromide (anticholinergic agent). Explain the mechanism by which each of these drugs can treat Aziz’s asthma symptoms.

Answer 28

Albuterol activates beta 2 adrenergic receptors, and in bronchial smooth muscle cells, promoting relaxation relieving asthma symptoms.

Basal parasympathetic tone causes bronchial smooth muscle cell constriction by actions of acetylcholine on muscarinic cholinergic receptors. Ipratropium bromide is a muscarinic receptor antagonist, which will block the stimulatory effects of acetylcholine on muscle contraction and thus promote relaxation and bronchodilation.

Question 29

Aziz returns to his pediatrician following a month on his new allbuterol/ipratropium bromide inhaler. His mother mentions that his heart seems to be racing after he receives inhaler treatment. She also mentions that he’s been unusually drowsy at times and that his mouth is often dry. Use your knowledge of cholinergic physiology to explain Aziz’s symptoms.

Answer 29

As an unintended effect of treatment, Ipratropium bromide blocks vagus release of Ach and thus activation of M2 muscarinic cholinergic receptors on cardiac pacemaker cells in the SA and AV nodes. The loss of parasympathetic tone causes elevation of heart rate by pacemaker cell excitability. Albuterol may contribute to this effect by activation of beta 2 adrenergic receptors on pacemaker cells and further increasing the rate by which pacemaker cells depolarize.

Dry mouth is a classic side effect of anticholinergic agents due to the block of parasympathetic stimulation of salivary gland secretions.

Question 30

Diuretics are commonly used to treat hypertension and congestive heart failure because they lower the effective circulating volume and result in decreased blood pressure and edema associated with heart failure, respectively. One of the potential adverse effects of some diuretics, and of epinephrine, is hypokalemia. Based on your understanding of drug-drug interactions and the resting membrane potential/leak K+ currents, speculate why drugs like epinephrine must be used cautiously in conjunction with diuretics.

Answer 30

Epinephrine-induced hypokalemia occurs via stimulation of beta-2-adrenergic receptor, which in turn activates the Na+/K+-ATPase on basolateral membrane of cells in kidney to promote subsequent K+ influx into renal cells. This can lead to hypokalemia.

Thiazide diuretics inhibit the apical Na-Cl pump in the DCT of the promoting the excretion of Na+ along with water. These drugs carry a risk of hypokalemia because they increase Na+ delivery to the distal segment of the distal tubule. Increase in the [Na+] in the distal segment of the distal tubule stimulates a sodium pump in this area to increase Na+ reabsorption in exchange for K+ and a H+. Thus, using these two drugs in conjunction can put the patient at a greater risk for developing hypokalemia.