Citalopram: Drug absorption and Oral Bioavailability

1 Citalopram Section 1 Drug absorption Oral bioavailability Citalopram is a selective serotonin reuptake inhibitor that has been given approval by the United States Food and Drug Administration for treatment of people suffering from major depression. Citalopram works by impacting on brain chemicals whose imbalance results in depression (Aronson 2012). Oral bioavailability of citalopram is estimated at 80% following intake of a Citalopram tablet (Pato & Zohar 2001). In comparison to tablets, the relative bioavailability of citalopram solutions is approximated to be at least 25% greater (Gschwend 2005). Nevertheless, doses of solutions correspond to those of tablets. Absorption of citalopram occurs rapidly after an oral administration of the drug and according to Gschwend (2005) food intake does not affect absorption of citalopram in any way.

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Gastrointestinal absorption and first pass hepatic extraction on citalopram Citalopram is metabolized to its active and inactive metabolites in the liver (Purse 2012).

A large percentage of unchanged citalopram remain as the predominant compound in plasma after metabolism (Schatzberg & Nemeroff 2009). The fact that citalopram is a lipophilic compound contributes to it’s almost 100% absorption in the gastrointestinal tract (Hales 2009).

Even though citalopram is subject to first pass effect the rate at which this effect occurs is insignificant as compared to other elective serotonin inhibitors (Schatzberg & Nemeroff 2009).

Parenteral formulation of citalopram Citalopram is available as a parenteral formulation. Development of parenteral formulations of citalopram was not as a result of problems linked to gastrointestinal absorption or excessive first pass metabolism. Research has revealed that the first pass effect subjected to citalopram is not significant enough to warrant development of a formulation. Its high lipophilicity is believed to have contributed greatly to the development of formulations (Hales 2009).

Section 2: Drug formulation and routes of administration Besides citalopram being taken in form of tablets and solutions, the drug can also be administered intravenously as a formulation (Schatzberg & Nemeroff 2009). The drug can also be administered in the form of infusions.

The dose forms and strengths available in Australia Various dosage strengths of citalopram available in Australian market are 10mg, 20 mg, 30 mg, and 40 mg. Even though the recommended daily dose is 20mg, the dosage may be

3 increased or decreased in accordance with the severity of the disease. Some of the brand names used in Australia for citalopram are Citrol, Seropram, Talam, Celapram, Talohexal and Citopam.

Administration issues followed for safe efficacious use After administration with citalopram, health care providers closely monitor patients to detect possible cases of side effects, worsening of depression together with emergence of suicidal thoughts. It is appropriate to give citalopram medications in small quantities to minimize the risk of overdose attempt (Purse 2012). It is important to review and adjust citalopram dosages every two to three weeks. Careful considerations should however, be made before adjustment of citalopram doses.

Section 3 Drug distribution and plasma protein binding of citalopram The apparent volume of distribution of citalopram is estimated at about 12.3 liters per kilogram of body mass (Purse 2012). Citalopram and its metabolites have been shown to have extremely high plasma protein binding capacity. Research has revealed that citalopram has minimal affinity for a variety of receptors including adrenoceptors and muscarine cholinergic receptors among others (Hales 2009). A lack of affinity for these receptors provides an explanation to the reason why citalopram does not result in numerous adverse effects (Schatzberg & Nemeroff 2009). Citalopram has also been shown to have the capacity to bind to plasma proteins (Pato & Zohar 2001).

Loading dose of citalopram Citalopram can be used as a loading dose, whereby the initial dose is higher but it is gradually decreased. The loading dose for citalopram is usually 20mg, but this dose may be decreased to 10mg if it results in development of adverse negative effects in a patient. The

4 starting dose for citalopram should not be more than 20mg due to its high possibility of causing side effects such as vomiting, dizziness and migraine (Purse 2012).

Section 4 Clearance Concepts Excretion of citalopram usually takes place in the liver as well as the kidneys. 85% of the total Citalopram daily dose is excreted through the liver, whereas the remaining 15% is excreted through the kidneys. Approximately 80% of the total citalopram daily fraction excreted through the kidneys is usually unchanged (Pato & Zohar 2001). Whereas the systemic plasma clearance of citalopram is estimated at 0.33 liters per minute, the rate of oral plasma clearance is estimated at 0.41 liters per minute (Purse 2012). The other mode of clearance for this drug is hepatic otherwise referred to as residual clearance, which is estimated at 0.35 liters per minute. The fact that only half of the total dose of citalopram is excreted through urine provides solid support to the perception that fecal elimination plays a major role in excretion of citalopram (Schatzberg & Nemeroff 2009).

Research has revealed that cytochrome P450 3A4 is the hepatic enzyme solely responsible for the breakdown of citalopram (Pato & Zohar 2001). Induction of this enzyme would therefore result in increased metabolism of this drug, an aspect that would subsequently result in increased clearance. Inhibition of hepatic enzyme would decrease metabolism and eventually lead to a decrease in the rate of clearance (Spratto & Woods 2011).

5. Adjustment of citalopram dosage in the presence of cardiac impairment and/or renal dysfunction It is recommended that a dose adjustment be carried out for persons presenting with rates of renal clearance that are lower than 25 mL/min. Whereas no dose adjustment is recommended for persons with renal rate of clearance greater than 25mL/min, health care professionals advice

5 that citalopram should be used cautiously for patients whose renal rate of clearance is below 25mL/min (Schatzberg & Nemeroff 2009). Schatzberg and Nemeroff (2009) note that citalopram should never be used in individuals presenting with congenital long QT syndrome since this drug can delay repolarization of the heart even longer resulting in abnormal cardiac rhythms that are fatal.

Section 5 Half-life Research has revealed that elimination half life of citalopram is approximately one and a half days (Spratto & Woods 2011). Elderly persons are believed to have decreased clearance for citalopram in addition to longer half-lives for the drug due to a decreased rate of metabolism.

Even though Citalopram is among the few drugs that are believed to have linear pharmacokinetics, the drug takes a long time to achieve steady state plasma concentration following intake of tablets (Ayd 2000). It has however, been revealed that under steady-state circumstances there is a linear association between citalopram dosages and concentrations of this drug in plasma (RxList 2012).

Section 6 Therapeutic Drug Monitoring Response to citalopram in a hospital setting is determined through assessing the effectiveness in addition to tolerability of the drug. The drug is presumed to be effective if it does not result in development of adverse side effects. The rate of development of negative effects associated with treatment of depressive disorders using citalopram is also considered in the determination of pharmacodynamic response of a patient to citalopram. Citalopram can be used both in hospital and pre-hospital settings. The drug is not usually used in community settings. It is advisable to seek medical advice before initiating treatment with this drug due to its numerous contraindications.

6 Drug Profile activities for Module 5 Section 1: Life stages as a factor in variability Before administration of citalopram, a thorough evaluation of personal health details should be carried out. Citalopram dose differs greatly between patients of various ages. The initial daily dose of an adult suffering from depression is set at 20mg. This dosage may however, be increased by 20mg to a maximum dose of 40mg once every week. Maintenance dose of citalopram for adults is 20-40mg (Schatzberg & Nemeroff 2009). Initial daily dose of citalopram for children below the age of 11 years is 10mg. This dosage can however, be increased gradually by 5mg per day after every two weeks for children not responding to the initial doses. For persons between the age of 12 and 18 years the initial dose for this drug is set at 20mg per day.

This dose can be increased gradually by 10mg per day every two weeks in accordance with the clinical requirement of a patient (Ayd 2000).

Section 2: Impact of disease states: Dosage adjustment in individuals with hepatic disease The fact that citalopram is metabolized in the liver implies that disorders affecting the liver can have negative implications on metabolism and clearance of this drug. The rate of elimination of citalopram is usually slower in persons presenting with abnormal hepatic conditions (Schatzberg & Nemeroff 2009). It has also been revealed that steady state concentrations for citalopram at a given dose are almost twice as high in a person presenting with liver disorders as compared to a person whose liver is functioning normally. As a result, people with hepatic disorders should be prescribed with minimal dosages of citalopram in order to minimize potential cases of hepatotoxicity (Schatzberg & Nemeroff 2009). The recommended daily dose of citalopram for people suffering from hepatic conditions is 20mg. The dose may however, be increased by 20mg daily for patients who are not responding (Pato & Zohar 2001).

7 In comparison to persons with normal renal and hepatic function, the rate of elimination of citalopram and its two major metabolites has been shown to be slightly higher.

Section 3: Drug dependence, misuse and abuse Citalopram has been approved as a safe drug for management of depressive disorders, but on the other hand prolonged use of this drug can lead to development of drug dependence.

Research has revealed that approximately 68% of women and 32% of men taking citalopram hydrobromide may develop drug dependence (Schatzberg & Nemeroff 2009). Health care professionals point out that even though citalopram is a potent medication for depression and depressive disorders it should not be extensively used in patients below 18 years of age due to the high rate of suicide related behavior among patients in this age bracket (Schatzberg & Nemeroff 2009). Despite the fact that there is insufficient clinical data regarding citalopram overdose, a number of deadly incidences associated with citalopram overdose have been reported (Spratto & Woods 2011). Some of the adverse symptoms associated with overdose of citalopram include: convulsion, vomiting, bradycardia, ventricular arrhythmia, stupor, agitation and hypertension (Schatzberg & Nemeroff 2009). A specific antidote for citalopram overdose has not yet been identified. Treatment of citalopram overdose is symptomatic (Aronson 2008). Inducing of vomiting has been recognized as an effective strategy in the management of citalopram overdose. Sodium sulfate, which is an osmotically working laxative, or activated carbon should be given following inducing of vomiting (Aronson 2012). Stomach evacuation is also an effective measure in the management of citalopram overdose. It is also important to monitor vital signs together with assessing possible effects of the drugs on the heart (Spratto & Woods 2011).

8 Reference List Aronson, JK 2008, Meyler's side effects of psychiatric drugs, Mahwah, NJ: Elsevier.

Aronson, JK 2012, Side effects of drugs annual: A worldwide yearly survey of new data in adverse drug reactions, Oxford, OX: Elsevier.

Ayd, FJ 2000, Lexicon of psychiatry, neurology, and the neurosciences, Philadelphia, PA: Lippincott Williams & Wilkins Gschwend, MH 2005, ‘Bioavailability investigation of two different oral formulations of Citalopram, a so-called 'second generation' antidepressant drug’, Arzneimittelforschung, Vol. 55, no. 12, pp. 730-7 Hales, RE 2009, Study guide to psychopharmacology: A Companion to the American psychiatric, Arlington, VA: American Psychiatric Pub. Spratto, GR & Woods, AL 2011, Delmar nurse's drug handbook 2012, Clifton Park, NY: Cengage Learning.

Pato, MT & Zohar, J 2001, Current treatments of obsessive-compulsive disorder, Washington, DC: American Psychiatric Pub. Purse, M 2012, Celexa (citalopram), [online] Available at: http://bipolar.about.com/od/celexa/a/meds_celexa.htm [Accessed May 17 2012] RxList 2012, Celexa, [online] Available at: http://www.rxlist.com/celexa-drug/clinicalpharmacology.htm [Accessed May 17 2012] Schatzberg, AF & Nemeroff, CB 2009, The American psychiatric publishing, Arlington, VA: American Psychiatric Pub

9 Module 4 - Case Study Questions 1 The dose and frequency of administration you would use?

One of the factors that affect the dosage of Glyceryl trinitrate is the type of infusion made use of. Dose recommendation symbolized as glyceryl trinitrate mcg/min can only be given as a starting rate of infusion. Some of the major factors to consider before administering the drug to Leonard include assessing him for presence of circulatory disorders such as acute circulatory failure, hypotension and cardiogenic shock among others. Assessing the medical history of the patient will help determine whether Leonard has myocardial infarction, a condition under which glyceryl trinitrate should only be made use of strictly by the treating doctors. Consumption of other drugs should also be considered in determining the dosage and frequency of administering glyceryl trinitrate. Leonard is concerned which implies that the current dosage needs to be either down-regulated or increased in accordance with his therapeutic response. The frequency of administration also needs to be regulated under the guidance of current dosage of Glycerine trinitrate to minimize possible cases of overdose or underdose.

The patient’s vital signs and history you consider important?

Presence of medical history of cardiovascular disorders is important in the determination of dosage and frequency of administration of Glycerine trinitrate. The vital signs of the patient will help determine whether current medications are generating any positive results or not. Mr. Leonard is taking other drugs most of which have been shown to develop adverse side effects.

Monitoring of vital signs will therefore assist in determining the dosage of Glycerine trinitrate to start with.

10 Questions 2 1. pharmacodynamic rationale for administering this drug Based on the fact that glyceryl trinitrate is used in the management of heart disorders, it would be expected of the drug to reduce the stress and pressure exerted on cardiac muscles by a variety of factors including reduced myocardial flow of blood.

2. The mechanism of action of GTN. Glyceryl trinitrate has been shown to posses the capacity to relax smooth muscles.

Relaxation of smooth muscles results in reduction of systolic pressure. Anti-angina effects of Glyceryl trinitrate are dependent on its ability to reduce myocardial demand of oxygen. This drug results in peripheral vasodilation, an aspect which leads to decreased venous return.

Consequently, energy expenditure in the left ventricle reduces significantly thereby reducing the workload for heat muscles (Aronson 2009).

3. The pharmacokinetic rationale for the sublingual route of administration of Glyceryl trinitrate has an efficient rate of oral absorption. The drug is also readily metabolized. Absorption of the drug in the gastrointestinal tract is also high. However, bioavailability of the drug is minimal due to its high first pass effect. Bioavailability of the drug is about 1% following administration through the mouth (Aronson 2009).

4. Any specific instructions or advice you would give to Leonard regarding the use of this medication I would advice Leonard on the possibility of development of a severe headache following administration of this drug. I would also advise Leonard to take minimal doses of this drug to reduce cases of methaemoglobinaemia from occurring.

11 Question 4 1. What is your clinical reasoning for giving Leonard aspirin at this stage?

The pharmacodynamic rationale for administering aspirin in this setting Aspirin can be administered at this stage to reduce pain and associated inflammation.

Aspirin also minimizes the risk of death by inhibiting cases of blood clotting.

3. The mechanism of action of aspirin relevant to this setting Aspirin mainly works through blocking the action of cyclooxygenase. Obstruction of cyclooxygenase production minimizes production of prostaglandin, the chemical that triggers pain.

4. Anything you would consider before giving Leonard this drug and the reasons for these Considerations It is however, important to determine whether Leonard is allergic to aspirin, since development of an allergy at this stage would aggravate an already worse medical condition.

5. The advice you would give Leonard about the drug and the way in which it is administered.

Some of the advice I would give Leonard concerning this drug is that he should never take it before being prescribed by a doctor. It is also advisable to keep doses for this drug as minimal as possible to reduce cases of aspirin overdose. Lower doses also minimize the risk of internal bleeding

12 Question 5 1. What is the rational for administering clopidogrel to Leonard?

Clopidogrel is an extremely effective drug in the management of ischemic heart disease.

It prevents the formation of clots in persons who have in the recent past had a heart attack. This drug is administered to Leonard based on the fact that he has poor circulation of blood.

2. The pharmacodynamic rationale for administering clopidogrel It is expected that after administration of clopidogrel the flow of blood to heart muscles and other parts of the body will be enhanced. It is also expected that possibility of clots formation will be eliminated.

3. The mechanism of action of clopidogrel Clopidogrel functions though inhibiting certain subtypes of ADP receptor that pays a key role in the activation of platelets. Clopidogrel functions mainly through inhibition of platelet aggregation.

4. What are the implications of administering clopidogrel prior to coronary angiography?

Even though clopidogrel is a highly effective drug, its administration may result in hemorrhage in the digestive tract. The drug can also increase the risk of cerebral hemorrhage (Khan 2005).

5. In what clinical situation would it be inappropriate to administer clopidogrel to Leonard?

It would be inappropriate to administer clopidogrel in situations whereby the patient is taking other drugs such as omeprazole since concomitant administration may result in adverse effects. The drugs should also not be administered if the patient is presenting with extremely minimal levels of white blood cells.

13 Module 5 - Clinical Case Clinical features of the scenario that leads one to administer oxygen The clinical features that led to administration of oxygen are cyanosis and lack of breathing. Vincent is unconscious and does not have the strength to breath normally. Cyanosis, which is characterized by nail-beds and bluish lips, reveals lack of oxygen in circulation an aspect that may result in fatal effects (Hillman & Bishop 2004).

The physiological rationale for administering oxygen The fact that Vincent is not breathing normally is the major factor that have led to decreased oxygen level in his blood. Administration of oxygen will protect Vincent from possible cases of permanent damage of major body organs. Administration of oxygen will support Vincent’s life in preparation for specialized care.

The intended outcomes of administering oxygen The intended outcome for administration of oxygen is restoration of normal breathing. It is also expected that after administration of oxygen Vincent's consciousness will be restored. In addition to restoration of consciousness, it is also expected that Vincent's normal sight will be restored.

Basis of Vincent’s list of current medication, prior to undertaking any further intervention: Risk factors relevant to the safety of yourself and Johnny and action to take One of the major risks associated with Vincent's current condition is that he is taking a variety of medications all of which may lead to adverse side effects. Ceftriaxone for instance, may result in gastrointestinal side effects such as abdominal pain, vomiting, nausea and flatulence among others. Administration of some other drugs may result in negative drug-drug interactions. It is also hard to administer drugs to Vincent's while he is in an unconscious state. In

14 addition, the fact that Vincent is an alcoholic, there is a higher possibility that he may not respond to some drugs. Therefore, in order to minimize the risk of developing adverse negative effects it is important to stabilize Vincent’s condition.

Question 3 – Assuming that Vincent is an alcoholic but has no predisposing co-morbidities, discuss the possible reasons why Vincent is more affected than Johnny, noting: Interactions with Vincent’s current medications The potential impact of Vincent’s alcoholism Potential recent changes to Vincent’s lifestyle or drug use habits The alcoholic condition of Vincent may have contributed to being affected more by heroine as compared to Johnny. Vincent may also have taken a higher dose of heroine as compared to his friends. Another factor that may have contributed to Vincent being affected more is that his body may not have been in a position to down-regulate the effects of heroine.

Also it may have been possible that it was Vincent's first time to engage in drugs.

Question 4 – Mechanisms by which an opioid agonist (such as heroin) causes respiratory depression. In your response, consider the: Molecular mechanism of action of opioid agonists The main mechanism of action of opioid agonists, such as heroine, is through inhibiting release of neurotransmitters. Opioid agonists inhibit release of neurotransmitters through directly impacting on calcium ion channels. This reduces entry of calcium ions into intracellular space in addition to increasing outward flow of potassium ions. The period of repolarisation and the time of action potential are significantly decreased. These effects are produced by opioid receptors and are coupled through G-proteins. Opiods have also been shown to act together with other intracellular effector mechanisms such as the adenylate cyclase system (Chahl 1996).

15 Pathophysiology of opioid-induced respiratory depression The normal mechanism of breathing regulation is complex and comprises of central and peripheral mechanisms of control. Chemo-receptors have been shown to actively respond to low arterial pressure. These receptors also respond to high arterial pressure of carbon dioxide. These two responses are believed to contribute to initiation of breathing together with other responses.

Opiods are believed to negatively impact on the chemical response of receptors. Opioids induce respiratory depression through minimizing the rate of respiration as well as the tidal volume.

Therapeutic opioid doses given to patients suffering from a variety of painful conditions is believed to lead to a significant depression of the body’s response to carbon dioxide (Ouellette & Joseph 2010).

Question 5 Pharmacodynamic rationale for administering naloxone Naloxone is an opioid antagonist that is usually administered for purposes of counteracting the effects developed through overdose of opioids. This drug is usually administered to offset life-threatening effects such as respiratory and nervous system depression.

This drug is also used in the management of addiction associated with opioids (Society of Gastrointestinal Nurses and Associates 2012).

Mechanism of action of naloxone The mechanism of action of naloxone is not fully understood. It has however been proposed that this drug works through antagonizing the effects of opioids. Naloxone is believed to actively compete for binding sites together with opioids (Society of Gastrointestinal Nurses and Associates 2012). The perception that naloxone has a higher receptor binding capacity as compared to opioid implies that the effects of opioids will be counteracted.

16 Pharmacological considerations of current approaches to narcotic overdose The fact that Vincent appears to be both an alcohol and opioid addict creates the need to administer a strong opioid antagonist. Naloxone has the capacity to counteract all ht negative effects associated with opioid overdose. Naloxone does not result in adverse effects that can aggravate the clinical condition of the patient (Society of Gastrointestinal Nurses and Associates 2012). For instance, naloxone does not lead to respiratory depression, and psychological dependence. The drug can be re-administered if Vincent does not respond in the expected manner.

Question 6 Pharmacological impact of Vincent’s drug use It is expected that after administering naloxene, Vincent will experience relieve from depression in both the respiratory and nervous system. Moreover, the addictive nature of the opioids will also be addressed by naloxene will competitively binds on the opioid receptors more competitively. Nevertheless, continued use of the addictive opioids will continue to impair his respiratory and nervous systems by adding more stress to these systems. This may culminate into failure of these systems.

Potential need for further medical treatment and tests Even though Vincent has become more conscious it is important to take him to hospital because he has become a bit confused after administration of naloxone. There is a likelihood of Vincent taking more heroine since he is an addict. Vincent may also end up taking more alcohol that may make him even more confused. There is need to carry out more tests to detect possible adverse effects that may have resulted due to excessive intake of alcohol and heroine.

17 Reference List Aronson, JK 2009, Meyler's side effects of cardiovascular drugs, Mahwah, NJ: Elsevier Chahl, LA 1996, Opioids - mechanisms of action, [online] Available at http://www.australianprescriber.com/magazine/19/3/63/5, accessed May 20, 2012 Hillman, K & Bishop, G 2004, Clinical Intensive Care and Acute Medicine, New York, NY: Cambridge University Press.

Khan, MI 2005, Encyclopedia of heart diseases, Burlington, MA: Academic Press Ouellette, RG & Joseph, A 2010, Pharmacology for Nurse Anesthesiology, Mississauga, Ontario: Jones & Bartlett learning, Society of Gastrointestinal Nurses and Associates 2012, Naloxone [online] Available at http://www.sgna.org/issues/sedationfactsorg/medications/naloxone.aspx, Accessed May 20, 2012