W2 Pharmacokinetics & drug interactions of antihypertensive drugs

Question 1

ADME Pharmacokinetics: (hypertensives)
What factors affect absorption?

Answer 1

• The route of administration (significant)
• Oral administration is the most common route for antihypertensive drugs
• Factors influencing drug absorption include the drug’s solubility, presence of food, and pH of the stomach and intestines.
• Some antihypertensive drugs may also be administered intravenously or topically

Question 2

ADME Pharmacokinetics: (hypertensives)
What factors affect distribution?

Answer 2

• Antihypertensive drugs often target specific sites, such as blood vessels or the kidneys.
• Protein binding can affect drug distribution, as highly protein-bound drugs may be less available to exert their effects.

Question 3

ADME Pharmacokinetics: (hypertensives)
What factors affect metabolism ?

Answer 3

• Most drugs are metabolised in the liver by hepatic enzymes.
• The cytochrome P450 enzyme system is responsible for metabolising many antihypertensive drugs.
• Drug metabolism can result in the formation of active or inactive metabolites.
• Genetic variations in drug-metabolising enzymes can influence an individual’s response to antihypertensive drugs.

Question 4

ADME Pharmacokinetics: (hypertensives)
What factors affect excretion ?

Answer 4

• Kidneys play a crucial role in drug excretion.
• The rate of drug elimination depends on renal function, glomerular filtration rate, and other factors.
• Some drugs undergo active tubular secretion, which can also affect excretion

Question 5

Treatments for hypertension
4 classes:

Answer 5

ACEi (ramipril)
ARB (losartan)
CCB (amlodipine)
Thiazide-like diuretic (indapamide)

Also:
Not included
beta-blocker
alpha-blocker
spironolactone

Question 6

Which organ plays a crucial role in the excretion of antihypertensive drugs?

Answer 6

Kidneys

Question 7

When do drug interactions occur?

Answer 7

When the presence of one drug affects the pharmacokinetics or pharmacodynamics of another drug

Question 8

What are additive drug interactions?

Answer 8

When the combination of two drugs produces an effect equal to the sum of their individual effects.

Question 9

What are synergistic drug interactions?

Answer 9

When the combination of drugs produces an effect greater than the sum of their individual effects

Question 10

What are antagonistic drug interactions?

Answer 10

When the combination of drugs dimities or cancels out their individual effects

Question 11

What is the class of drugs that end in ‘pril’?

Answer 11

ACE Inhibitors

Question 12

Ramipril:
What are its 4 functions?
What are its side effects? (4)

Answer 12

Functions:
Prodrug= Inhibits ACE (Comp inhibitor)
Angiotensin ll dec so RAAS dec
1. Arterial and venous vasodilation
2. Decrease blood volume
3. Downregulation of sympathetic activity
4. Suppression of hypertrophy (cardiac and vascular)

Side effects:
* Hypotension
* Hyperkalaemia (potassium retention)
* Dry cough (up to 35%)
- ACE usually inhibits bradykinin
* Abnormal taste- Thiol moiety

Question 13

Ramipril:
What are its ADME properties?

Answer 13

A= Take on empty stomach to improve absorption. 40-66% bioavailable depends on the drug
Short half-life <2 hours
D= Binds to tissue and plasma protein
M= Extensively metabolised (75%) in the liver by the cytochrome p450 enzyme CYP2C8
E= Urine

Question 14

ACE inhibitors e.g. Ramipril example interactions

Answer 14

Drug-drug interactions
Concurrent use of ACE inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the effectiveness of ACE inhibitors and increase the risk of renal impairment, as NSAIDs can counteract the vasodilatory effects of ACE inhibitors.

Drug-food interactions
Consuming high-sodium meals or foods rich in potassium (such as bananas or oranges) can counteract the effects of ACE inhibitors by potentially increasing blood pressure or interfering with the balance of electrolytes.

Drug-herbal interactions
Taking St. John’s wort (Hypericum perforatum) along with ACE inhibitors may reduce the effectiveness of the medication due to St. John’s wort inducing DME that can accelerate the breakdown of ACE inhibitors.

CYPP450 inducers
Concurrent use of rifampin, an antibiotic and a potent cytochrome P450 inducer, with ACE inhibitors can accelerate the metabolism of ACE inhibitors, potentially reducing their effectiveness and requiring higher doses for adequate blood pressure control.

CYPP450 repressors
Concurrent use of fluoxetine, a selective serotonin reuptake inhibitor (SSRI) and a cytochrome P450 repressor, with ACE inhibitors can inhibit the metabolism of ACE inhibitors, potentially increasing their blood levels and leading to an increased risk of side effects.

Hypotension & hyperkalaemia
Aliskiren (↑ risk of renal impairment)
Allopurinol (↑ risk of hypersensitivity and haematological reactions)
Azathioprine (↑ risk of anaemia and/or leucopenia)
Everolimus (↑ risk of angioedema)
Lithium (↑ [lithium])

Question 15

What are the class of drugs ending in ‘sartan’?

Answer 15

Angiotensin ll receptor blockers (ARBs)

Question 16

Losartan
What is it used to treat?
What are the adverse effects?

Answer 16

An ARB used to treat hypertension, diabetic nephropathy and reduce the risk of stroke
* Hypotension
* Hyperkalaemia (due to potassium retention is mediated by the reduction of aldosterone)
* Renal impairment - GFR, creatinine levels
* Angio-oedema
* Dizziness

Question 17

ADME of Losartan:

Answer 17

*Losartan is approximately 33% orally bioavailable. Losartan has a Tmaxof 1 hour and the active metabolite has a Tmaxof 3-4 hours
*The volume of distribution of losartan is 34.4±17.9L and 10.3±1.1L for the active metabolite (E-3174)
Losartan is 98.6-98.8% protein bound and the active metabolite is 99.7% protein bound in serum
** Metabolised in the liver (CYP450 2C9) **
*Oral radiolabelled losartan is 35% recovered in urine and 60% in faeces
*Active metabolite has a half life of 6-9 hours

Adverse effects:
*Hypotension
*Hemodialysis will not remove losartan or its active metabolite due to their high rates of protein binding

*190 known drug-drug interactions
*Food delays absorption, but not extent. Avoid potassium-containing salt substitutes
*The metabolism of Losartan can be decreased when combined with Ginkgo biloba.
*The metabolism of Losartan can be increased when combined with St. John’s Wort.

Question 18

PHARMACOKINETIC drug interactions when taking losartan:

Answer 18

1. Concomitant increased risk of hyperkalaemia, hypotension, and renal impairment (angiotensin-converting enzyme (ACE) inhibitorsandaliskiren)
2. Volume depletion and a risk of hypotension (previous diuretics)
3. Lithium (reversible increases in serum lithium concentrations and toxicity)
4. Attenuation of antihypertensive effect, worsening of renal function, including possible acute kidney injury, and hyperkalaemia (nonsteroidal anti-inflammatory drugs and COX-2 inhibitors)
5. Increased risk of hyperkalaemia (amiloride, ciclosporin, eplerenone, heparins, potassium canrenoate, potassium salts, spironolactone, tacrolimus, triamterene,trimethoprim)
6. Enhanced hypotensive effect (Alpha-blockers, alprostadil, antipsychotics, anxiolytics, beta-blockers, baclofen, calcium channel blockers, clonidine, co-beneldopa, co-careldopa, diazoxide, hydralazine, hypnotics, levodopa, methyldopa, minoxidil, monoamine oxidase inhibitors, moxisylyte, moxonidine, nitrates, SGLT2 inhibitors, sodium nitroprusside, tizanidine, tricyclic antidepressants)

Adverse effects:
Hypotension
Hyperkalaemia (due to potassium retention is mediated by the reduction of aldosterone)
Renal impairment - GFR, creatinine levels
Angio-oedema
Dizziness

Question 19

What drug class of antihypertensive ends in ‘dipine’?

Answer 19

Dihydropyridine Calcium channel blockers (CCB)
e.g. Amlodipine, Felodipine

Question 20

Amlodipine

Answer 20

• Used to treat hypertension and angina
• Does not change SAN function or AV conduction BUT dec Vascular smooth muscle contractility and dec BP

Depolarisation or actions of PKA (via β-adrenoreceptor activation) cause Ca2+ influx via L-type channels.
Lead to contraction.

Ca2+ channel blockers (CCBs) bind to the α subunit of L-type channels.
Prevents Ca2+ influx via depolarisation or PKA activation
Reduced cardiomyocyte or VSMC contraction

Question 21

What are the effects of CCBs like amlodipine?
1. Cardiac
2. Vascular

Answer 21

1. Dec Myocardial contractility, force myocardial contraction and dec conduction velocity (depends on firing of SA and AV nodes)
2. Vasodilate peripheral blood vessels

Question 22

What are the TWO TYPES OF CCB?

Answer 22

1. dihydropyridine (…dipine drugs) – act on smooth muscle cells of blood vessels, decrease vascular resistance and ↓↓bp (vascular specific)
2. non-dihydropyridine – greater effect on heart, less effective for vasodilation vessels e.g. diltiazem and verapamil
   (cardiac specific)

Question 23

CCB ADME:

Answer 23

Bioavailability: Amlodipine is orally administrated with a bioavailability of 64–90%.

A: Amlodipine reach peak plasma concentration (tmax) 6–12h after administration, while steady state plasma concentrations will be reached within 7–8days of daily dosing.

D: Amlodipine has a high volume of distribution (21L/kg) and a large proportion of the dose is distributed in the tissue with ~ 90% of the circulating drug being bound to the plasma membrane.

M: Amlodipine is extensively metabolised in the liver into its inactive metabolites viaCYP3A4/5.

E: Amlodipine is slowly cleared with an elimination half-life of 40 to 60h. If discontinued, BP returned to baseline after 1week. Urine is the major route of elimination. Amlodipine is converted to inactive metabolites (60%), which are excreted into the urine while 10% of the excreted drug remains unchanged.
Amlodipine is converted from dihydropyridinebmoiety to a pyridine derivative (M9). Fecal excretion accounts for 20–25% of the dose

Question 24

What are the adverse effects of dihydropyridine CCBs?

Answer 24

• Bradycardia
• Abdominal pain, nausea, and vomiting.
• Angio-oedema.
• Dizziness.
• Drowsiness.
• Flushing.
• Gingival hyperplasia.
• Headache.
• Myalgia.
• Palpitations and tachycardia.
• Peripheral oedema.
• Syncope

Reflex tachycardia – sympathetic nervous system detect ↓BP so ↑↑HR

Question 25

Calcium channel blockers e.g. amlodipine example interactions

Answer 25

Drug-drug interactions
Simultaneous use of CCB and statin medications can increase the serum levels of statins, potentially leading to statin toxicity e.g. muscle pain and liver toxicity.

Question 26

Thiazide-like diuretic (indapamide:
What does it treat?
How does it work?

Answer 26

1. inhibits the Na+/Cl- cotransporter of DCT, leading to reduced sodium reabsorption
2. ??unrelated to diuresis…
   - ↓ responsiveness to pressor agents
   
   • ↓ peripheral resistance

↓ systolic blood pressure
↓ left ventricular mass index
↓ oxidative stress
↓ platelet aggregation
↓ microalbuminuria associated with diabetes

Question 27

Thiazide-like diuretic
Adverse effects:

Answer 27

Postural hypotension
Hyperglycaemia
Hypokalaemia
Other electrolyte imbalances — hyponatraemia, hypomagnesaemia, and hypercalcaemia have also been noted
Cardiac arrhythmias

Hypokalaemia – long QT (potentially increasing the risk of torsade de pointes) when given with Amiodarone and other …ide drugs
electrolyte imbalances

Question 28

ADME of Indipamide

Answer 28

A
The bioavailability of indapamide is virtually complete after an oral dose and is unaffected by food or antacids
Indapamide is highly lipid-soluble due to its indoline moiety
D
VD 25 - 60 L/kg
Approximately 76-79% of indapamide is protein bound.
Indapamide binds primarily to alpha 1-acid glycoprotein and less significantly to serum albumin and lipoproteins.
extensively and preferentially bound to erythrocytes
M
Extensive metabolism in the liver, the majority of indapamide excreted is metabolized, with only 7% remaining unchanged
CYP3A4 is the main enzyme involved in the corresponding hydroxylation, carboxylation, and dehydrogenation reactions
E
An estimated 60-70% of indapamide is eliminated in the urine, while 16-23% is eliminated in the faeces.

Question 29

Drug interactions: indapamide

Answer 29

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers (ARBs)— ACE inhibitors and ARBs can cause a very rapid fall in blood pressure in a person who is volume-depleted.
Alpha-blockers — enhanced hypotensive effect and increased risk of first-dose hypotension.
Amisulpride, atomoxetine, pimozide — increased risk of ventricular arrhythmias.
Aminophylline, reboxetine — increased risk of hypokalaemia.
Amiodarone, disopyramide, flecainide — hypokalaemia caused by thiazide diuretics increases the risk of cardiac toxicity of these drugs.
Aldesleukin, alprostadil, anxiolytics, baclofen, beta-blockers, calcium channel blockers, clonidine, co-beneldopa, co-careldopa, hydralazine, hypnotics, levodopa, monoamine oxidase inhibitors, methyldopa, minoxidil, moxonidine, nitrates, phenothiazines, sodium nitroprusside, tizanidine — enhanced hypotensive effect.

Question 30

Thiazide diuretics e.g. indapamide example interactions

Answer 30

Drug-drug interactions
Using thiazide diuretics in combination with NSAIDs can reduce the diuretic and antihypertensive effects of thiazides due to NSAIDs inhibiting renal blood flow and decreasing the efficacy of thiazides.

Drug-food interactions AND Drug-herbal interactions
Consuming licorice can lead to decreased potassium levels and increased blood pressure, counteracting the effects of thiazide diuretics.
This is due to licorice
- inhibiting the breakdown of cortisol, which can cause sodium and water retention
- decrease in potassium levels, as both can lead to potassium loss

CYP450 inducers
Co-administration of carbamazepine, an antiepileptic drug and cytochrome P450 inducer, with thiazide diuretics can increase the metabolism of thiazides, potentially resulting in reduced blood levels and diminished diuretic and antihypertensive effects.

CYP450 repressors
Co-administration of amiodarone, an antiarrhythmic drug with cytochrome P450 repressor activity, and thiazide diuretics can inhibit the metabolism of thiazides, resulting in increased blood levels and potentially enhancing their diuretic and antihypertensive effects.

Question 31

Effects of Grapefruit juice: (antagonistic effect)

Answer 31

Inhibits the activity of cytochrome P450 enzymes, leading to increased blood levels of certain antihypertensive drugs

Question 32

What is the effect of NSAIDs on antihypertensive drugs?

Answer 32

Antagonistic effect= Can decrease the effectiveness of antihypertensive drugs and potentially contribute to increased blood pressure