Question

Mr T is a 67 year old retired Navy veteran. He has been taking simvastatin for 2 years to treat elevated cholesterolemia. During a recent visit to a 24 hour acute care clinic in a local mall he was prescribed clarithromycin for an acute sinus infection.Two days later Mr T arrives in the emergency room complaining of generalized muscle pain, muscle weakness and dark colored urine. Tests revealed myoglobin in the urine and a serum creatinine of 186 micromol/l (usual baseline for this patient was 90 micromol/l). A diagnosis of rhabdomyolysis is made.

1. Create a pharm card for each medication listed in the case.

2. Include drug generic name, routes of administration, indication/uses, side effects, contraindications, drug interactions, food interactions, method of metabolism, method of excretion

3. Define and describe rhabdomyolysis

4. What is causing the rhabdomyolysis AND describe how /why it developed.

5. How can Mr T avoid this complication in the future? What adjustments can you make in his medications now? How can you advise him?

After six weeks Mr. T is back to normal. He has returned to taking his normal dose of simvastatin and his sinus infection is resolved. Mr. T wants to stop taking medications, exercise, lose weight and become a healthy individual. He decides to go on a grapefruit diet to lose 20 pounds. One week after starting the diet Mr T begins to suffer muscle aches and pains and a darkening of his urine. He demands to be taken off his medication because he feels it is causing these problems.

1. Why have Mr. T’s symptoms returned?

List 8 factors that can affect drug bioavailability.


Explain the term ‘first-pass effect’ and give examples of two drugs that undergo significant first-pass effect.


identify three routes of drug administration that avoid ‘first-pass’ hepatic effects.

Answer 1

Pharm card for simvastatin:

Brand name: Zocor

Routes of administration: oral (tablet form)

Uses:

Simvastatin is utilized alongside an appropriate eating routine to help bring down "terrible" cholesterol and fats, (for example, LDL, triglycerides) and raise "great" cholesterol (HDL) in the blood. It has a place with a gathering of drugsknown as "statins." It works by lessening the measure of cholesterol made by the liver. Bringing down "terrible" cholesterol and triglycerides and raising "great" cholesterol diminishes the danger of coronary illness and forestalls strokes and heart attacks.In expansion to eating a legitimate eating routine, (for example, a low-cholesterol/low-fat eating regimen), other way of life changes that may enable this solution to work better incorporate working out, getting in shape if overweight, and halting smoking

Indications:

Treatment with lipid-modifying specialists ought to be just a single segment of numerous hazard consider intercession people at altogether expanded hazard for atherosclerotic vascular ailment because of hypercholesterolemia. Medication treatment is demonstrated as an assistant to slim down when the reaction to an eating regimen limited in immersed fat and cholesterol and other nonpharmacologic measures alone has been insufficient. In patients with coronary illness (CHD) or at high danger of CHD, Simvastatin tablets can be begun at the same time with abstain from food.

Side effects:

Keep in mind that your specialist has recommended this medicine since he or she has judged that the advantage to you is more prominent than the danger of reactions. Many individuals utilizing this medicine don't have genuine side effects.A modest number of individuals taking simvastatin may have mellow memory issues or perplexity. On the off chance that these uncommon impacts happen, converse with your doctor.This medication may occasionally cause muscle issues (which can once in a while prompt intense conditions called rhabdomyolysis and immune system myopathy). Tell your specialist immediately in the event that you build up any of these manifestations amid treatment and if these side effects endure after your specialist stops this medication: muscle torment/delicacy/shortcoming (particularly with fever or strange tiredness), change in the measure of urine.This prescription may once in a while cause liver issues. In the event that you see any of the accompanying uncommon however genuine symptoms, tell your specialist quickly: yellowing eyes/skin, dim pee, extreme stomach/stomach torment, constant queasiness/vomiting.A intense unfavorably susceptible response to this medication is uncommon. Be that as it may, look for quick restorative consideration on the off chance that you see any side effects of a genuine allergicreaction, including: rash, tingling/swelling (particularly of the face/tongue/throat), serious dazedness, inconvenience relaxing.

Contraindications:

Simvastatin is contraindicated in the accompanying conditions:

• Concomitant organization of solid CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone and cobicistat-containig item).
• Concomitant organization of gemfibrozil, cyclosporine, or danazol.
• Hypersensitivity to any segment of this solution.
• Active liver malady, which may incorporate unexplained persevering heights in hepatic transaminase levels.
• Women who are pregnant or may end up noticeably pregnant. Serum cholesterol and triglycerides increment amid typical pregnancy, and cholesterol or cholesterol subsidiaries are fundamental for fetal advancement. Since HMG-CoA reductase inhibitors (statins) diminish cholesterol combination and perhaps the union of other naturally dynamic substances got from cholesterol, Simvastatin may cause fetal mischief when regulated to a pregnant lady. Atherosclerosis is a perpetual procedure and the stopping of lipid-bringing down medications amid pregnancy ought to have little effect on the result of long haul treatment of essential hypercholesterolemia. There are no sufficient and very much controlled investigations of utilization with Simvastatin amid pregnancy; be that as it may, in uncommon reports inborn peculiarities were watched following intrauterine introduction to statins. In rodent and rabbit creature proliferation examines, Simvastatin uncovered no proof of teratogenicity. Simvastatin ought to be directed to ladies of childbearing age just when such patients are exceedingly improbable to consider. On the off chance that the patient ends up noticeably pregnant while taking this medication, Simvastatin ought to be suspended promptly and the patient ought to be advised of the potential peril to the embryo.
• Nursing moms. It isn't known whether Simvastatin is discharged into human drain; be that as it may, a little measure of another medication in this class passes into bosom drain. Since statins have the potential for genuine antagonistic responses in nursing babies, ladies who require treatment with Simvastatin ought not breastfeed their newborn children

Drug interactions:

​ The danger of myopathy and rhabdomyolysis is expanded by large amounts of statin movement in plasma. Simvastatin is utilized by the cytochrome P450 isoform 3A4. Certain medications which repress this metabolic pathway can raise the plasma levels of Simvastatin and may build the danger of myopathy. These incorporate itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide anti-infection agents erythromycin and clarithromycin, and the ketolide anti-toxin telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the stimulant nefazodone, cobicistat-containing items, or grapefruit juice. Mix of these medications with Simvastatin is contraindicated. In the event that fleeting treatment with solid CYP3A4 inhibitors is unavoidable, treatment with Simvastatin must be suspended over the span of treatment.

The consolidated utilization of Simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated.

Alert ought to be utilized while recommending different fibrates with Simvastatin, as these specialists can cause myopathy when given alone and the hazard is expanded when they are coadministered.

Instances of myopathy, including rhabdomyolysis, have been accounted for with Simvastatin coadministered with colchicine, and alert ought to be practiced while recommending Simvastatin with colchicine.

The advantages of the consolidated utilization of Simvastatin with the accompanying medications ought to be precisely weighed against the potential dangers of mixes: other lipid-bringing down medications (different fibrates, ≥ 1 g/day of niacin, or, for patients with HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine.

Instances of myopathy, including rhabdomyolysis, have been seen with Simvastatin coadministered with lipid-altering measurements (≥1 g/day niacin) of niacin-containing items. In a progressing, twofold visually impaired, randomized cardiovascular results trial, a free wellbeing observing panel recognized that the frequency of myopathy is higher in Chinese contrasted and non-Chinese patients taking Simvastatin 40 mg coadministered with lipid-altering measurements of a niacin-containing item. Alert ought to be utilized while treating Chinese patients with Simvastatin in measurements surpassing 20 mg/day coadministered with lipid-adjusting dosages of niacin-containing items. Since the hazard for myopathy is measurements related, Chinese patients ought not get Simvastatin 80 mg coadministered with lipid-altering dosages of niacin-containing items. It is obscure if the hazard for myopathy with coadministration of Simvastatin with lipid-adjusting measurements of niacin-containing items saw in Chinese patients applies to other Asian patients.

Food interactions:

Assimilation of simvastatin, evaluated with respect to an intravenous reference dosage, in each of two creature species tried, arrived at the midpoint of around 85% of an oral measurement. In creature ponders, after oral dosing, simvastatin accomplished considerably higher focuses in the liver than in non-target tissues. In any case, since simvastatin experiences broad first-pass digestion, the accessibility of the medication in the foundational is low. Pinnacle plasma fixation happens 1.3 - 2.4 hours after organization.

Method of metabolism:

Hepatic, simvastatin is a substrate for CYP3A4. The real dynamic metabolites of simvastatin are β-hydroxyacid metabolite and its 6'- hydroxy, 6'- hydroxymethyl, and 6'- exomethylene subordinates.

Method of excretion:

Following an oral measurements of 14C-named simvastatin in man, 13% of the dosage was discharged in pee and 60% in dung.

Pharm card for clarithromycin:

Brand name: Biaxin

Routes of administration:

Oral measurement (suspension and tablets): For bacterial diseases: Adults and adolescents : 250 to 500 milligrams (mg) like clockwork for seven to fourteen days.Children a half year of age and more seasoned :7.5 mg for each kilogram (kg) of body weight at regular intervals for seven to ten days. For treatment of Mycobacterium avium complex (MAC):Adults and young people: 500 mg each twelve hours.Children a half year of age and more established : 7.5 mg for each kg of body weight, up to 500 mg, at regular intervals.

Uses:

To decrease the improvement of medication safe microorganisms and keep up the viability of Clarithromycin and other antibacterial medications, Clarithromycin tablets ought to be utilized just to treat or forestall diseases that are turned out to be or emphatically suspected to be caused by helpless microscopic organisms. Whenever culture and helplessness data are accessible, they ought to be considered in choosing or changing antibacterial treatment. Without such information, nearby the study of disease transmission and vulnerability examples may add to the empiric choice of treatment.

Indications:

Clarithromycin is utilized to treat bacterial contaminations in a wide range of parts of the body.It is powerful against both Gram Positive and some Gram Negative life forms, Mycoplama and Chlamydiae. It is both bactericidal and bacteriostatic . It is likewise used to treat Mycobacterium avium complex (MAC) disease.

Side effects:

The accompanying genuine antagonistic responses are depicted beneath and somewhere else in the marking:

·         Acute Hypersensitivity Reactions

·         QT Prolongation

·         Hepatotoxicity

·         Serious Adverse Reactions Due to Concomitant Use with Other Drugs

·         Clostridium difficile Associated Diarrhea

·         Exacerbation of Myasthenia Gravis

Contraindications:

Principle contraindications are extreme touchiness and use with drugs like terfenidine and astemizole.

Drug interactions:

With Carbamazepine,Digoxin, Terfenadine, Theophylline,Warfarin : Clarithromycin may expand the occurrence of antagonistic impacts of these medications. With Rifabutin, Rifampin : Rifabutin or rifampin may diminish the measure of clarithromycin in the blood.With Zidovudine : Clarithromycin may diminish the measure of zidovudine in the blood

Food interactions:

Nourishment allow quickly before dosing expanded the degree of ingestion from the 500-mg tablet definition by around 25%.Clarithromycin is consumed from small digestive system, the medication gets in part decimated by the gastric squeeze so it must be regulated in enteric covered shape. It is mostly gathered in the bile.

Method of metabolism:

Clarithromycin hinders a liver protein, CYP3A4, engaged with the digestion of numerous other generally recommended drugs. Taking clarithromycin with different pharmaceuticals that are utilized by CYP3A4 may prompt startling increments or declines in medicate levels.

Method of excretion:

Thirty to 40% of an oral measurements of clarithromycin is discharged unaltered or as a dynamic metabolite through the kidneys, and the rest of discharged by means of the bile. After a solitary 500 mg measurements, terminal half-life most likely surpasses 40h.

Define and describe rhabdomyolysis:

Rhabdomyolysis is a condition in which skeletal muscle is separated, discharging muscle proteins and electrolytes from inside the muscle cells. Dangers of rhabdomyolysis incorporate muscle breakdown and kidney disappointment on the grounds that the cell part myo-globin is dangerous to the kidneys. Rhabdomyolysis is generally extraordinary, yet it frequently happens as the aftereffect of broad muscle harm as, in smash damage or electrical stun. Medications or poisons may likewise cause this issue. Fundamental illnesses that can likewise prompt rhabdomyolysis incorporate collagen vascular ailments, for example, foundational lupus erythematosus.

What is causing the rhabdomyolysis AND describe how /why it developed.

Rhabdomyolysis is a genuine disorder due to an immediate or aberrant muscle damage. It comes about because of the demise of muscle strands and arrival of their substance into the circulation system. This can prompt genuine intricacies, for example, renal (kidney) disappointment. This implies the kidneys can't evacuate squander and thought pee. In uncommon cases, rhabdomyolysis can even reason demise. In any case, incite treatment frequently brings a decent result. This is what you have to think about rhabdomyolysis.

Rhabdomyolysis Causes

There are numerous horrendous and nontraumatic reasons for rhabdomyolysis. In the principal class, causes include:

• A smash damage, for example, from a car collision, fall, or building breakdown
• Long-enduring muscle pressure, for example, that caused by delayed immobilization after a fall or lying oblivious on a hard surface amid sickness or while affected by liquor or medicine
• Electrical stun damage, lightning strike, or severe singeing
• Venom from a snake or creepy crawly chomp

Nontraumatic reasons for rhabdomyolysis include:

• The utilization of liquor or illicit medications, for example, heroin, cocaine or amphetamines
• Extreme muscle strain, particularly in somebody who is an untrained competitor; this can occur in world class competitors, as well, and it can be more perilous if there is more bulk to separate.
• The utilization of solutions, for example, antipsychotics or statins, particularly when given in high dosages
• A high body temperature (hyperthermia) or warmth stroke
• Seizures or wooziness tremens
• A metabolic confusion, for example, diabetic ketoacidosis
• Diseases of the muscles (myopathy, for example, inherent muscle protein insufficiency or Duchenne's strong dystrophy
• Viral contaminations, for example, this season's flu virus, HIV, or herpes simplex infection
• Bacterial contaminations prompting poisons in tissues or the circulatory system (sepsis)

A past history of rhabdomyolysis additionally builds the danger of having rhabdomyolysis once more.

How can Mr T avoid this complication in the future? What adjustments can you make in his medications now? How can you advise him?

There are more opportunities to emerge intricacies incorporate the accompanying:

• Electrolyte variations from the norm
• Hypoalbuminemia
• Hyperuricemia
• Compartment disorder
• Acute kidney damage (AKI) and renal disappointment
• Disseminated intravascular coagulation (DIC, a late complexity)

Changes in accordance with forestall difficulties:

Way of life related treatment measures might be considered, as takes after:

• Dietary adjustment to help address metabolic clutters or inherent blunders of digestion
• Avoidance of strenuous exercises if such exercises cause intermittent myalgias, myopathy, or rhabdomyolysis
• Maintenance of legitimate hydration amid athletic effort
• Prompt thoughtfulness regarding pointers of warmth weariness amid hot and moist conditions
• Continuation of treatment

Why have Mr. T’s symptoms returned?

Grape fruit taking has reversed the condition.

Abstain from eating grapefruit or drinking grapefruit juice while utilizing this pharmaceutical unless specialist trains generally. Grapefruit can expand the measure of this pharmaceutical in the circulatory system. Need to counsel specialist or drug specialist for more points of interest. Take this prescription frequently to get the most advantage from it. Make sure to take it in the meantime every day. It is critical to keep taking this prescription regardless of whether he feels well. A great many people with elevated cholesterol or triglycerides don't feel wiped out. It is critical to keep on following specialist's recommendation about eating routine and exercise. It might take up to a month prior get the full advantage of this medication.

List 8 factors that can affect drug bioavailability.


In pharmacology, bioavailability is a subcategory of ingestion and is the part of a managed dosage of unaltered medication that achieves the fundamental dissemination, one of the chief pharmacokinetic properties of medications. There are numerous current advances and factors influencing Bioavailability. It incorporates Absorption, digestion and Food impact of Drugs. Physico-compound variables, first pass digestion and Energy subordinate efflux transporters are additionally talked about in BA/BE World Congress.

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Explain the term ‘first-pass effect’ and give examples of two drugs that undergo significant first-pass effect.


The First pass impact (otherwise called first-pass digestion or presystemic digestion) is a wonder of medication digestion whereby the centralization of a medication is incredibly lessened before it achieves the foundational course. It is the portion of medication lost amid the procedure of ingestion which is by and large identified with the liver and gut divider. Outstanding medications that experience a noteworthy first-pass impact are imipramine, morphine, propranolol, buprenorphine, diazepam, midazolam, pethidine, pot, cimetidine, lidocaine, and nitroglycerin.

To start with pass digestion may happen in the liver (for propranolol, lidocaine, chloromethiasole and GTN) or in the gut (for benzylpenicillin and insulin).

After a medication is gulped, it is consumed by the stomach related framework and enters the hepatic entrance framework. It is helped through the entryway vein into the liver before it achieves whatever is left of the body. The liver uses many medications, once in a while to such a degree, to the point that exclusive a little measure of dynamic medication rises up out of the liver to whatever is left of the circulatory framework. This first go through the liver accordingly significantly diminishes the bioavailabilityof the medication.

The four essential frameworks that influence the primary pass impact of a medication are the catalysts of the gastrointestinal lumen, gut divider chemicals, bacterial compounds, and hepatic proteins.

In medicate configuration, tranquilize hopefuls may have great druglikeness however bomb on first-pass digestion since it is biochemically specific.

Elective courses of organization like suppository, intravenous, intramuscular, inhalational airborne, transdermal and sublingual evade the main pass impact since they enable medications to be consumed specifically into the foundational dissemination.

Medications with high first pass impact have a significantly higher oral measurements than sublingual or parenteral dosage. There is checked individual variety in the oral measurements because of contrasts in the degree of first pass digestion. Oral bioavailability is obviously expanded in patients with serious liver sicknesses like cirrhosis. It is additionally expanded if another medication contending with it in first pass digestion is given simultaneously. E.g. propranolol and chlorpromazine.

Identify three routes of drug administration that avoid ‘first-pass’ hepatic effects.

Elective courses of organization like suppository, intravenous, intramuscular, inhalational vaporized, transdermal and sublingual keep away from the first pass effect since they enable medications to be retained specifically into the fundamental dissemination.