General pharm – Types of drug interactions

Additive

• Combined effect of Drug A + Drug B is equal to the sum of their individual effects (“2+2 = 4”).
• HY USMLE example: aspirin + acetaminophen.
  • Degree of COX inhibition is the sum of both drugs individually.

Permissive

• Molecule A must be present so that Molecule B can do its job.
• HY USMLE example: cortisol is permissive of the effects of catecholamines (i.e., norepinephrine and epinephrine).
  • Alpha-1 agonism causes arteriolar vasoconstriction and an increase in BP.
  • Norepinephrine and epinephrine bind to alpha-1 receptors on arteriole endothelium.
  • Cortisol helps maintain blood pressure, not by binding to cortisol receptor where that directly increases BP; instead, cortisol upregulates alpha-1 receptors on peripheral arterioles.
  • Norepinephrine and epinephrine can now do their job.
  • Without cortisol present, there is decreased expression of alpha-1 receptors on vascular endothelium, so even if NE and E are floating around, there is insufficient alpha-1 receptor expression and BP cannot be maintained.
  • USMLE wants you to know the phrase: “cortisol is permissive of the effects of catecholamines,” where cortisol permits NE and E to do their job.
  • 43F + SLE + has surgery + intraoperatively her BP falls to 80/40; IV fluids are administered; what drug should be given? –> answer = hydrocortisone. Students always get this wrong. Patients with autoimmune disease (i.e., SLE, IBD, RA) managed with chronic corticosteroids (prednisone) will have suppression of the zona fasciculata and a decreased ability to mount a cortisol stress response during surgery or trauma –> corticosteroid in the blood is consumed –> NE and E can’t do their job –> BP falls –> give hydrocortisone (cortisol analogue) to restore alpha-1 receptor expression.

Synergistic

• Combined effect of Drug A + Drug B is greater than the sum of their individual effects (“2+2 > 4”).
• HY USMLE examples: inhibition of platelet function by clopidogrel + aspirin.
  • Clopidogrel inhibits ADP2Y12 receptor on platelets.
  • Aspirin inhibits COX.
• Ampicillin + gentamicin.
  • Ampicillin inhibits bacterial cell wall synthesis/cross-linking.
  • Gentamicin inhibits protein synthesis by inhibiting the 30S ribosomal subunit.
  • Ampicillin enables greater penetration of gentamicin into the cell.
• Gastric acid secretion (not pharmacologic but HY).
  • Acetylcholine binding to M3 receptors on parietal cells.
  • Histamine binding to H2 receptors on parietal cells.
  • Gastrin binding to gastrin receptors on parietal cells.
  • Combined effect of all three mechanisms is synergistic for gastric acid secretion.

Tachyphylaxis (tolerance)

• Desensitization after repeated/continual administration.
• HY USMLE examples: alpha-1 agonists causing rhinitis medicamentosa.
  • Alpha-1 agonism causes vasoconstriction.
  • Intranasal alpha-1 agonists (oxymetazoline, phenylephrine, midodrine) decrease blood flow through nasal mucosa, resulting in decreased inflammation. These agents are used as nasal decongestants.
  • Continual intranasal use for >4-5 days can result in decreased effect + rebound nasal congestion once stopped.
  • USMLE will ask: 16F + stuffy nose + using intranasal drug for 5 days continuously + stops using it + now has rebound nasal congestion; what drug did she use? –> answer = oxymetazoline.
• Leuprolide administered continuously for prostate cancer.
  • Leuprolide is a GnRH receptor agonist.
  • Initial effect is an increase in LH and FSH.
  • After a couple days, LH and FSH production decrease due to GnRH receptor desensitization (tachyphylaxis).
  • Should be noted that flutamide, an androgen receptor blocker, is administered concurrent to leuprolide during the first couple days in order to nullify the transient surge in LH and FSH.
• Nitrates for angina.
  • Nitrates cause upregulation of guanylyl cylcase in vascular endothelium (predominantly veins).
  • This results in increased cGMP –> increased protein kinase G activity –> dephosphorylation of myosine light-chain kinase –> relaxation of venous smooth muscle –> pooling of blood in veins –> decreased venous return to right atrium –> decreased preload –> decreased myocardial oxygen demand –> alleviation of cardiac pain.
  • Repeated use of nitrates results in diminished venodilatory effect.

Synergistic

• Combined effect of Drug A + Drug B is greater than the sum of their individual effects (“2+2 > 4”).
• HY USMLE examples: inhibition of platelet function by clopidogrel + aspirin.
  • Clopidogrel inhibits ADP2Y12 receptor on platelets.
  • Aspirin inhibits COX.
• Ampicillin + gentamicin.
  • Ampicillin inhibits bacterial cell wall synthesis/cross-linking.
  • Gentamicin inhibits protein synthesis by inhibiting the 30S ribosomal subunit.
  • Ampicillin enables greater penetration of gentamicin into the cell.
• Gastric acid secretion (not pharmacologic but HY).
  • Acetylcholine binding to M3 receptors on parietal cells.
  • Histamine binding to H2 receptors on parietal cells.
  • Gastrin binding to gastrin receptors on parietal cells.
  • Combined effect of all three mechanisms is synergistic for gastric acid secretion.

Tachyphylaxis (tolerance)

• Desensitization after repeated/continual administration.
• HY USMLE examples: alpha-1 agonists causing rhinitis medicamentosa.
  • Alpha-1 agonism causes vasoconstriction.
  • Intranasal alpha-1 agonists (oxymetazoline, phenylephrine, midodrine) decrease blood flow through nasal mucosa, resulting in decreased inflammation. These agents are used as nasal decongestants.
  • Continual intranasal use for >4-5 days can result in decreased effect + rebound nasal congestion once stopped.
  • USMLE will ask: 16F + stuffy nose + using intranasal drug for 5 days continuously + stops using it + now has rebound nasal congestion; what drug did she use? –> answer = oxymetazoline.
• Leuprolide administered continuously for prostate cancer.
  • Leuprolide is a GnRH receptor agonist.
  • Initial effect is an increase in LH and FSH.
  • After a couple days, LH and FSH production decrease due to GnRH receptor desensitization (tachyphylaxis).
  • Should be noted that flutamide, an androgen receptor blocker, is administered concurrent to leuprolide during the first couple days in order to nullify the transient surge in LH and FSH.
• Nitrates for angina.
  • Nitrates cause upregulation of guanylyl cylcase in vascular endothelium (predominantly veins).
  • This results in increased cGMP –> increased protein kinase G activity –> dephosphorylation of myosine light-chain kinase –> relaxation of venous smooth muscle –> pooling of blood in veins –> decreased venous return to right atrium –> decreased preload –> decreased myocardial oxygen demand –> alleviation of cardiac pain.
  • Repeated use of nitrates results in diminished venodilatory effect.

Synergistic

• Combined effect of Drug A + Drug B is greater than the sum of their individual effects (“2+2 > 4”).
• HY USMLE examples: inhibition of platelet function by clopidogrel + aspirin.
  • Clopidogrel inhibits ADP2Y12 receptor on platelets.
  • Aspirin inhibits COX.
• Ampicillin + gentamicin.
  • Ampicillin inhibits bacterial cell wall synthesis/cross-linking.
  • Gentamicin inhibits protein synthesis by inhibiting the 30S ribosomal subunit.
  • Ampicillin enables greater penetration of gentamicin into the cell.
• Gastric acid secretion (not pharmacologic but HY).
  • Acetylcholine binding to M3 receptors on parietal cells.
  • Histamine binding to H2 receptors on parietal cells.
  • Gastrin binding to gastrin receptors on parietal cells.
  • Combined effect of all three mechanisms is synergistic for gastric acid secretion.

Tachyphylaxis (tolerance)

• Desensitization after repeated/continual administration.
• HY USMLE examples: alpha-1 agonists causing rhinitis medicamentosa.
  • Alpha-1 agonism causes vasoconstriction.
  • Intranasal alpha-1 agonists (oxymetazoline, phenylephrine, midodrine) decrease blood flow through nasal mucosa, resulting in decreased inflammation. These agents are used as nasal decongestants.
  • Continual intranasal use for >4-5 days can result in decreased effect + rebound nasal congestion once stopped.
  • USMLE will ask: 16F + stuffy nose + using intranasal drug for 5 days continuously + stops using it + now has rebound nasal congestion; what drug did she use? –> answer = oxymetazoline.
• Leuprolide administered continuously for prostate cancer.
  • Leuprolide is a GnRH receptor agonist.
  • Initial effect is an increase in LH and FSH.
  • After a couple days, LH and FSH production decrease due to GnRH receptor desensitization (tachyphylaxis).
  • Should be noted that flutamide, an androgen receptor blocker, is administered concurrent to leuprolide during the first couple days in order to nullify the transient surge in LH and FSH.
• Nitrates for angina.
  • Nitrates cause upregulation of guanylyl cylcase in vascular endothelium (predominantly veins).
  • This results in increased cGMP –> increased protein kinase G activity –> dephosphorylation of myosine light-chain kinase –> relaxation of venous smooth muscle –> pooling of blood in veins –> decreased venous return to right atrium –> decreased preload –> decreased myocardial oxygen demand –> alleviation of cardiac pain.
  • Repeated use of nitrates results in diminished venodilatory effect.

Additive

• Combined effect of Drug A + Drug B is equal to the sum of their individual effects (“2+2 = 4”).
• HY USMLE example: aspirin + acetaminophen.
  • Degree of COX inhibition is the sum of both drugs individually.

Permissive

• Molecule A must be present so that Molecule B can do its job.
• HY USMLE example: cortisol is permissive of the effects of catecholamines (i.e., norepinephrine and epinephrine).
  • Alpha-1 agonism causes arteriolar vasoconstriction and an increase in BP.
  • Norepinephrine and epinephrine bind to alpha-1 receptors on arteriole endothelium.
  • Cortisol helps maintain blood pressure, not by binding to cortisol receptor where that directly increases BP; instead, cortisol upregulates alpha-1 receptors on peripheral arterioles.
  • Norepinephrine and epinephrine can now do their job.
  • Without cortisol present, there is decreased expression of alpha-1 receptors on vascular endothelium, so even if NE and E are floating around, there is insufficient alpha-1 receptor expression and BP cannot be maintained.
  • USMLE wants you to know the phrase: “cortisol is permissive of the effects of catecholamines,” where cortisol permits NE and E to do their job.
  • 43F + SLE + has surgery + intraoperatively her BP falls to 80/40; IV fluids are administered; what drug should be given? –> answer = hydrocortisone. Students always get this wrong. Patients with autoimmune disease (i.e., SLE, IBD, RA) managed with chronic corticosteroids (prednisone) will have suppression of the zona fasciculata and a decreased ability to mount a cortisol stress response during surgery or trauma –> corticosteroid in the blood is consumed –> NE and E can’t do their job –> BP falls –> give hydrocortisone (cortisol analogue) to restore alpha-1 receptor expression.

Synergistic

• Combined effect of Drug A + Drug B is greater than the sum of their individual effects (“2+2 > 4”).
• HY USMLE examples: inhibition of platelet function by clopidogrel + aspirin.
  • Clopidogrel inhibits ADP2Y12 receptor on platelets.
  • Aspirin inhibits COX.
• Ampicillin + gentamicin.
  • Ampicillin inhibits bacterial cell wall synthesis/cross-linking.
  • Gentamicin inhibits protein synthesis by inhibiting the 30S ribosomal subunit.
  • Ampicillin enables greater penetration of gentamicin into the cell.
• Gastric acid secretion (not pharmacologic but HY).
  • Acetylcholine binding to M3 receptors on parietal cells.
  • Histamine binding to H2 receptors on parietal cells.
  • Gastrin binding to gastrin receptors on parietal cells.
  • Combined effect of all three mechanisms is synergistic for gastric acid secretion.

Tachyphylaxis (tolerance)

• Desensitization after repeated/continual administration.
• HY USMLE examples: alpha-1 agonists causing rhinitis medicamentosa.
  • Alpha-1 agonism causes vasoconstriction.
  • Intranasal alpha-1 agonists (oxymetazoline, phenylephrine, midodrine) decrease blood flow through nasal mucosa, resulting in decreased inflammation. These agents are used as nasal decongestants.
  • Continual intranasal use for >4-5 days can result in decreased effect + rebound nasal congestion once stopped.
  • USMLE will ask: 16F + stuffy nose + using intranasal drug for 5 days continuously + stops using it + now has rebound nasal congestion; what drug did she use? –> answer = oxymetazoline.
• Leuprolide administered continuously for prostate cancer.
  • Leuprolide is a GnRH receptor agonist.
  • Initial effect is an increase in LH and FSH.
  • After a couple days, LH and FSH production decrease due to GnRH receptor desensitization (tachyphylaxis).
  • Should be noted that flutamide, an androgen receptor blocker, is administered concurrent to leuprolide during the first couple days in order to nullify the transient surge in LH and FSH.
• Nitrates for angina.
  • Nitrates cause upregulation of guanylyl cylcase in vascular endothelium (predominantly veins).
  • This results in increased cGMP –> increased protein kinase G activity –> dephosphorylation of myosine light-chain kinase –> relaxation of venous smooth muscle –> pooling of blood in veins –> decreased venous return to right atrium –> decreased preload –> decreased myocardial oxygen demand –> alleviation of cardiac pain.
  • Repeated use of nitrates results in diminished venodilatory effect.

We don’t give exogenous cortisol. If we want to replenish glucocorticoid acutely, we give hydrocortisone.

—

Permissive

• Molecule A must be present so that Molecule B can do its job.
• HY USMLE example: cortisol is permissive of the effects of catecholamines (i.e., norepinephrine and epinephrine).
  • Alpha-1 agonism causes arteriolar vasoconstriction and an increase in BP.
  • Norepinephrine and epinephrine bind to alpha-1 receptors on arteriole endothelium.
  • Cortisol helps maintain blood pressure, not by binding to cortisol receptor where that directly increases BP; instead, cortisol upregulates alpha-1 receptors on peripheral arterioles.
  • Norepinephrine and epinephrine can now do their job.
  • Without cortisol present, there is decreased expression of alpha-1 receptors on vascular endothelium, so even if NE and E are floating around, there is insufficient alpha-1 receptor expression and BP cannot be maintained.
  • USMLE wants you to know the phrase: “cortisol is permissive of the effects of catecholamines,” where cortisol permits NE and E to do their job.
  • 43F + SLE + has surgery + intraoperatively her BP falls to 80/40; IV fluids are administered; what drug should be given? –> answer = hydrocortisone. Students always get this wrong. Patients with autoimmune disease (i.e., SLE, IBD, RA) managed with chronic corticosteroids (prednisone) will have suppression of the zona fasciculata and a decreased ability to mount a cortisol stress response during surgery or trauma –> corticosteroid in the blood is consumed –> NE and E can’t do their job –> BP falls –> give hydrocortisone (cortisol analogue) to restore alpha-1 receptor expression.

a) Oxymetazoline, phenylephrine, midodrine.

b) Alpha-1 agonists.

c) Rhinitis medicamentosa as a result of tachyphylaxis.

—

Tachyphylaxis (tolerance)

• Desensitization after repeated/continual administration.
• HY USMLE examples: alpha-1 agonists causing rhinitis medicamentosa.
  • Alpha-1 agonism causes vasoconstriction.
  • Intranasal alpha-1 agonists (oxymetazoline, phenylephrine, midodrine) decrease blood flow through nasal mucosa, resulting in decreased inflammation. These agents are used as nasal decongestants.
  • Continual intranasal use for >4-5 days can result in decreased effect + rebound nasal congestion once stopped.
  • USMLE will ask: 16F + stuffy nose + using intranasal drug for 5 days continuously + stops using it + now has rebound nasal congestion; what drug did she use? –> answer = oxymetazoline.
• Leuprolide administered continuously for prostate cancer.
  • Leuprolide is a GnRH receptor agonist.
  • Initial effect is an increase in LH and FSH.
  • After a couple days, LH and FSH production decrease due to GnRH receptor desensitization (tachyphylaxis).
  • Should be noted that flutamide, an androgen receptor blocker, is administered concurrent to leuprolide during the first couple days in order to nullify the transient surge in LH and FSH.
• Nitrates for angina.
  • Nitrates cause upregulation of guanylyl cylcase in vascular endothelium (predominantly veins).
  • This results in increased cGMP –> increased protein kinase G activity –> dephosphorylation of myosine light-chain kinase –> relaxation of venous smooth muscle –> pooling of blood in veins –> decreased venous return to right atrium –> decreased preload –> decreased myocardial oxygen demand –> alleviation of cardiac pain.
  • Repeated use of nitrates results in diminished venodilatory effect.

a)

Neonate with sepsis is most likely Group B Strep. However E. coli and Listeria must also be covered.

Ampicillin + gentamicin is HY empiric combo given to neonates with sepsis.

On the 2CK obgyn NBME, ampicillin + gentamicin is an answer for this Q; vancomycin + ceftriaxone is incorrect (empiric for non-neonatal meningitis).

b)

Synergistic

• Combined effect of Drug A + Drug B is greater than the sum of their individual effects (“2+2 > 4”).
• HY USMLE examples: inhibition of platelet function by clopidogrel + aspirin.
  • Clopidogrel inhibits ADP2Y12 receptor on platelets.
  • Aspirin inhibits COX.
• Ampicillin + gentamicin.
  • Ampicillin inhibits bacterial cell wall synthesis/cross-linking.
  • Gentamicin inhibits protein synthesis by inhibiting the 30S ribosomal subunit.
  • Ampicillin enables greater penetration of gentamicin into the cell.
• Gastric acid secretion (not pharmacologic but HY).
  • Acetylcholine binding to M3 receptors on parietal cells.
  • Histamine binding to H2 receptors on parietal cells.
  • Gastrin binding to gastrin receptors on parietal cells.
  • Combined effect of all three mechanisms is synergistic for gastric acid secretion.

a)

Nitrates cause upregulation of guanylyl cylcase in vascular endothelium (predominantly veins).

This results in increased cGMP –> increased protein kinase G activity –> dephosphorylation of myosine light-chain kinase –> relaxation of venous smooth muscle –> pooling of blood in veins –> decreased venous return to right atrium –> decreased preload –> decreased myocardial oxygen demand –> alleviation of cardiac pain.

Repeated use of nitrates results in diminished venodilatory effect (tachyphylaxis).

b)

Tachyphylaxis (tolerance)

• Desensitization after repeated/continual administration.
• HY USMLE examples: alpha-1 agonists causing rhinitis medicamentosa.
  • Alpha-1 agonism causes vasoconstriction.
  • Intranasal alpha-1 agonists (oxymetazoline, phenylephrine, midodrine) decrease blood flow through nasal mucosa, resulting in decreased inflammation. These agents are used as nasal decongestants.
  • Continual intranasal use for >4-5 days can result in decreased effect + rebound nasal congestion once stopped.
  • USMLE will ask: 16F + stuffy nose + using intranasal drug for 5 days continuously + stops using it + now has rebound nasal congestion; what drug did she use? –> answer = oxymetazoline.
• Leuprolide administered continuously for prostate cancer.
  • Leuprolide is a GnRH receptor agonist.
  • Initial effect is an increase in LH and FSH.
  • After a couple days, LH and FSH production decrease due to GnRH receptor desensitization (tachyphylaxis).
  • Should be noted that flutamide, an androgen receptor blocker, is administered concurrent to leuprolide during the first couple days in order to nullify the transient surge in LH and FSH.
• Nitrates for angina.
  • Nitrates cause upregulation of guanylyl cylcase in vascular endothelium (predominantly veins).
  • This results in increased cGMP –> increased protein kinase G activity –> dephosphorylation of myosine light-chain kinase –> relaxation of venous smooth muscle –> pooling of blood in veins –> decreased venous return to right atrium –> decreased preload –> decreased myocardial oxygen demand –> alleviation of cardiac pain.
  • Repeated use of nitrates results in diminished venodilatory effect.