PCOL2605 ADR&I Report Case 5: SID: 520479799

Question 1: What might have caused Paulo’s constipation? Explain the mechanism/s
which may underlie any suspected adverse drug reaction and/or drug interaction.

The potential cause for Paulo’s constipation is his use of verapamil. Verapamil is a calcium
channel blocker indicated for angina management and is commonly associated with
constipation as an adverse effect (AMH, 2023). Verapamil inhibits the entry of calcium ions
by binding to the cell membranes of slow L-type calcium channels in vascular smooth
muscle. This decreases the intracellular calcium concentration which reduces muscle
contractility and promotes muscle relaxation (Fahie, 2023). Verapamil has a profound effect
on gut smooth muscle, reducing gut motility and slows down stool movement. The
decreased contraction of smooth vascular muscle within the gut results in constipation
(Wing, 1997).

Question 2: What might have caused Paulo’s hypotensive crisis? Explain the
mechanism/s which may underlie any suspected adverse drug reaction and/or drug
interaction.

The likely cause of Paulo’s hypotensive crisis is his concurrent use of glyceryl trinitrate and
tadalafil. Tadalafil and glyceryl trinitrate are contraindicated and the co-administration of the
two drugs causes a severe drug interaction. This interaction can cause profound
hypotension due to their synergistic vasodilatory effects (AMH, 2023).

Glyceryl trinitrate and tadalafil are classed within two groups of medications known
respectively as nitrates and phosphodiesterase 5 (PDE 5) inhibitors. The combination of
these two drug classes is known to result in severe hypotensive effects as nitrates potentiate
the vasodilatory effect of PDE5 inhibitors (MIMS Australia, 2023). Nitrates provide an
exogenous source of nitric oxide (NO) that mediates the therapeutic effect of the drug
whereas PDE5 inhibitors selectively inhibits phosphodiesterase type 5 which is normally
responsible for the breakdown of cGMP (AMH, 2023). NO diffuses into smooth muscle cells
and binds to soluble guanylate cyclase, causing a conformational change that activates the
enzyme. This enzyme catalyses the conversion of guanosine triphosphate (GTP) into cyclic
guanosine monophosphate (cGMP). cGMP then acts as a second messenger molecule and
activates protein kinase G which decreases intracellular calcium concentration and causes
protein phosphorylation (Russwurm and Koesling, 2004). These combined effects decrease
muscle contractility and lead to vasodilation in smooth muscle tissue, lowering blood
pressure. As both medications work to increase the intracellular concentration of cGMP, their
additive effects pose a high potential for profound hypotension (Stockley’s Drug Interactions,
2023). Therefore, this major interaction between glyceryl trinitrate and tadalafil is the most
likely cause of Paulo’s hypertensive crisis, especially since the adverse reaction occurred
following his administration of tadalafil.

Question 3: What advice would you give Paulo and his doctor regarding his angina
medications?

Both adverse drug events are predictable Type A (augmented), adverse drug interactions.
Constipation is a known side effect of verapamil that is caused by the mechanism of action
of the drug. Similarly, the hypotensive crisis caused by the concurrent use of tadalafil and
glyceryl trinitrate is a known adverse effect of this drug interaction (AMH, 2023).

Paulo needs to consult with his doctor or pharmacist to inform him regarding any dangerous
interactions that could occur with specific classes of medications. I would advise Paulo to
avoid taking additional medications that have been previously prescribed to him as they
could pose a risk for serious drug interactions. I would specifically advise him to stop taking
Tadalafil for his erectile dysfunction since it is classified within the PDE5 inhibitors. If Paulo
still requires another erectile dysfunction medication, I would recommend one that does not
interact with the medications he currently takes for his angina. Two examples of this would
be papaverine or alprostadil which are both indicated for use in erectile dysfunction (AMH,
2023). Neither of these two medications pose drug interactions with glyceryl trinitrate or
verapamil (MIMS Australia, 2023). However, both of these medications are intracavernosal
injections and may be too invasive for Paulo’s preference. If Paulo finds these two
medications too intrusive but he requires an erectile dysfunction medication on occasion, he
should consult his doctor about possibly changing his angina medication from a nitrate to a
different class of medications that does not interact with PDE5 inhibitors.

To reduce Paulo’s experience with constipation, I would advise his doctor to consider
lowering the dose of verapamil back to the lower starting dose of 80 mg three times a day
and maintain his verapamil use at this dosage for another two weeks. This is because the
vasodilatory adverse effects of calcium channel blockers usually subside with prolonged use
of the medication (AMH, 2023). If Paulo’s constipation symptoms subside, his doctor can
then increase his dosage back to the maintenance dose of 160 mg three times a day.
Another recommendation I would make to Paulo’s doctor is to consider changing Paulo’s
use of verapamil to another medication. Verapamil is known to have the greatest effect on
gut motility compared to other calcium channel blockers so his doctor could consider
changing his medication to another belonging to the same class. Diltiazem, amlodipine, and
felodipine are some examples of calcium channel blockers that are indicated for angina
treatment. Converse to verapamil, these calcium channel blockers do not include
constipation in their list of common adverse effects. Moreover, neither diltiazem, amlodipine,
or felodipine cause interactions with glyceryl trinitrate and can be co-administered (AMH,
2023.

As general advice to Paulo and his doctor, they should actively monitor Paulo’s condition to
ensure that his medication regimen for treating angina is effective for managing his
symptoms and does not cause any excessive adverse effects that impair his quality of life.

Question 4: Adverse Event Report Form

PCOL2605 ADR and Drug Interactions Report:

Adverse Event Report Form

Instructions:

• Follow the instructions in question 4 for completing this form.

• Replace the underscore/underline with your text and fill in the tables
• This is “Question 4”. Insert at the end of your document that contains your
answers to Questions 1-3.

Step 1: Reporter details

Your case identifier (Case #, e.g., Case 1): Case 5

Student ID: 520479799

Step 2: Patient Details

Patient (Initials): PS
Age at time of adverse event: 68

Sex: Male

Step 3: Medicine details

List all medicines the patient was taking at the time of the adverse event

Brand Generic name Product’s role in adverse event (suspected/not

name suspected)

Minitran 10 Glyceryl Suspected

Trinitrate

Isoptin Verapamil Suspected

Metamucil Psyllium Not suspected

Cialis Tadalafil Suspected

Step 4: Reaction details

Provide a short description of the adverse event or interaction.

This section should be a maximum of 40 words (no +/- 10% permitted), i.e., 1-2 sentences,
and should focus on the symptoms of the reaction and the suspected drugs involved. Further
information on the patient’s history etc can be provided in the next step.

Reaction/symptoms short description:

Constipation following the introduction of verapamil into medication regimen. Severe drug
interaction arising from the concurrent use of glyceryl trinitrate and tadalafil, likely cause of
the hypotensive crisis.

Outcome:

Place an X next to the outcome below based on the information provided in the scenario.

Recovered/resolved
 Recovering/resolving

Not recovered/not resolved/ongoing X

Recovered/resolved with sequelae

Fatal

Unknown

Step 5: Additional details

Use this section to include information not already provided on the sequence of events, any
treatment provided, or any other relevant information such as medical history, test result or
known allergies.

This section should be a maximum of 100 words (no +/- 10% permitted).

Adverse event narrative:

68-year-old male with angina, taking glyceryl trinitrate 10 mg/24 hours patches for
prophylactic treatment. The original treatment did not fully manage his angina episodes, his
doctor prescribes additional verapamil 80 mg, three times daily as an initial dose. Two weeks
later, his doctor increases the verapamil dosage to the maintenance dose of 160 mg, three
times daily, and he seeks advice for a laxative to treat his constipation. The pharmacist
recommends Metamucil and he takes this as he gets home. Patient goes into hypotensive
crisis following the use of tadalafil 10 mg. An ambulance is called. No known allergies.

Form adapted from TGA online adverse event reporting portal. Anyone can report adverse
events relating to medicines, vaccines, or medical devices to the TGA. For further
information about reporting adverse events go to: https://www.tga.gov.au/reporting-adverse-
events
References:

AMH. (2023). Alprostadil. Australian Medicines Handbook Pty Ltd. [Accessed Oct 25 2023].
Available from: https://amhonline-amh-net-
au.ezproxy.library.sydney.edu.au/chapters/genitourinary-drugs/drugs-sexual-
dysfunction/other-drugs-sexual-dysfunction/alprostadil?menu=vertical

AMH. (2023). Amlodipine. Australian Medicines Handbook Pty Ltd. [Accessed Oct 25 2023].
Available from: https://amhonline-amh-net-
au.ezproxy.library.sydney.edu.au/chapters/cardiovascular-drugs/antihypertensives/calcium-
channel-blockers/amlodipine?menu=vertical

AMH. (2023). Diltiazem. Australian Medicines Handbook Pty Ltd. [Accessed Oct 26 2023].
Available from: https://amhonline-amh-net-
au.ezproxy.library.sydney.edu.au/chapters/cardiovascular-drugs/antihypertensives/calcium-
channel-blockers/diltiazem?menu=vertical

AMH. (2023). Felodipine. Australian Medicines Handbook Pty Ltd. [Accessed Oct 26 2023].
Available from: https://amhonline-amh-net-
au.ezproxy.library.sydney.edu.au/chapters/cardiovascular-drugs/antihypertensives/calcium-
channel-blockers/felodipine?menu=vertical

AMH. (2023). Glyceryl Trinitrate. Australian Medicines Handbook Pty Ltd. [Accessed Oct 24
2023]. Available from: https://amhonline-amh-net-
au.ezproxy.library.sydney.edu.au/chapters/cardiovascular-drugs/drugs-
angina/nitrates/glyceryl-trinitrate?menu=hints

AMH. (2023). Papaverine. Australian Medicines Handbook Pty Ltd. [Accessed Oct 25 2023].
Available from: https://amhonline-amh-net-
au.ezproxy.library.sydney.edu.au/chapters/genitourinary-drugs/drugs-sexual-
dysfunction/other-drugs-sexual-dysfunction/papaverine

AMH. (2023). Phosphodiesterase 5 inhibitors + nitrates. Australian Medicines Handbook Pty

Ltd. [Accessed Oct 24 2023]. Available from: https://amhonline-amh-net-
au.ezproxy.library.sydney.edu.au/interactions?first=tadalafil&second=glyceryl+trinitrate

AMH. (2023). Tadalafil (genitourinary). Australian Medicines Handbook Pty Ltd. [Accessed
Oct 25 2023]. Available from: https://amhonline-amh-net-
au.ezproxy.library.sydney.edu.au/chapters/genitourinary-drugs/drugs-sexual-
dysfunction/phosphodiesterase-5-inhibitors-genitourinary/tadalafil-genitourinary

AMH. (2023). Verapamil. Australian Medicines Handbook Pty Ltd. [Accessed Oct 24 2023].
Available from: https://amhonline-amh-net-
au.ezproxy.library.sydney.edu.au/chapters/cardiovascular-drugs/antihypertensives/calcium-
channel-blockers/verapamil

Fahie, S. Cassagnol, M. (2023). Verapamil. National Library of Medicine. StatPearls.

StatPearls Publishing. [Accessed Oct 24 2023]. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK538495/

MIMS Australia. (2023). Glyceryl Trinitrate Drug Interactions. MIMS Online. [Accessed Oct
24 2023]. Available from: https://www-mimsonline-com-
au.ezproxy.library.sydney.edu.au/Search/DrugAlertDetails.aspx?ModuleName=Drug%20Inte
ractions&searchKeyword=glyceryl+trinitrate

MIMS Australia. (2023). Verapamil Hydrochloride Drug Interactions. MIMS Online.

[Accessed Oct 24 2023]. Available from: https://www-mimsonline-com-
au.ezproxy.library.sydney.edu.au/Search/DrugAlertSearch.aspx?ModuleName=Drug%20Int
eractions&searchKeyword=verapamil

Russwurm, M., & Koesling, D. (2004). NO activation of guanylyl cyclase. The EMBO Journal,
23(22), 4443–4450. https://doi.org/10.1038/sj.emboj.7600422

Stockley’s Drug Interactions. (2023). Glyceryl trinitrate and tadalafil drug interactions.
Medicines Complete. [Accessed Oct 24 2023]. Available from: https://www-
medicinescomplete-
com.ezproxy.library.sydney.edu.au/#/interactions/stockley?terms=glyceryl%20trinitrate,tadal
afil

Wing, L.M.H. (1997). Calcium channel antagonists. Australian Prescriber. Therapeutic

Guidelines. [Accessed Oct 24 2023]. Available from:
https://australianprescriber.tg.org.au/articles/calcium-channel-
antagonists.html#:~:text=Verapamil%27s%20intrinsic%20natriuretic%20effect%20balances,
gut%20motility%20and%20causes%20constipation
Declaration:
I declare that no AI tools or technologies were used in any part of the preparation of this
assessment.