1. Lithium mediates the mechanism of action of lithium salts. Lithium possibly influences the second messenger systems of IP₃, cAMP and DAG by decreasing various enzymes important for re-circulation and conversion of membrane phosphor-inositides. Thus in effect influencing cholinergic and monoamine neurotransmission (Brand, 2021).
2. The therapeutic index of lithium is 0.5-1.5nM, thus it is a very narrow therapeutic index, because with concentrations higher than 2nM toxicity is experienced. The clinical significance of this narrow therapeutic index, is n high risk for toxicity but also doses that is sub-therapeutic. The plasma levels should thus be monitored very carefully (Brand, 2021).
3. In the case of recurrent or resistant depression, lithium can be combined with antidepressants for better antidepressant-effects (SAMA & UCT, 2020).

When a patient does not respond to lithium or valproate as antimanic drugs individually, it can be used in combination with each other (Katzung, 2018).

If a patient does not respond to carbamazepine as mood stabilizer, lithium can be used in combination (Katzung, 2018).

Lithium is otherwise used as a single drug in treating acute manic attacks, treatment for self-mutating or aggressive behaviour and also as prophylaxis for hypomanic and manic episodes (SAMA & UCT, 2020).

4. - Lithium in combination with traditional antipsychotic drugs has an increased or worsened   

  EPS (extrapyramidal symptoms).

- In combination with phenytoin, carbamazepine, losartan, metronidazole, methyldopa and  

  calcium-ion channel blockers it causes neurotoxicity.

- Interaction  caffeine, antacids or theophylline with lithium causes decreased effectiveness    

  due to an increase in the renal excretion of lithium (Brand, 2021).

5. The major side effects of lithium is:

• Weight gain
• Sexual dysfunction
• Fatigue and muscle weakness
• Edema
• Nocturia, polyuria or polydipsia
• Sedation, aphasia, ataxia and tremors
• Acne
• Alopecia
• Nephrogenic diabetes insipidus
• Leucocytosis
• Thyroid enlargement (Brand, 2021).

6. Lithium is a category D in pregnancy (Katzung, 2018). A patient  cannot breastfeed while taking lithium due to the excretion of lithium in high concentration is breast milk (SAMA & UCT, 2020).

7. .

• Treatment of self-mutilating or aggressive behaviour.
• Prophylaxis of hypomanic and manic episodes.
• Treatment of an acute manic episode (SAMA & UCT, 2020).

8./9.) Miss B. Polar is using two drugs along with her lithium-drug causing interaction, both additional drugs is increasing the concentration of lithium in her body. Using the NSAID (Indocid®) caused weight gain, due to the toxicity resulting in combination with lithium (Brand, 2021; Drugs.com, 2020). To try and treat her weight gain she decided to use a diuretic which also causes lithium toxicity. Thus this explains her fatigue, tiredness, polydipsia, feeling shaky and nauseous (Brand, 2021).

My recommendation would be that she stops to use both the diuretic and NSAID. She can rather use another pain stiller such as paracetamol or orphenadrine if she has pain again in the future to help prevent lithium toxicity and thus weight gain (Brand, 2021). She can try to exercise (more) and eat healthy in order to loose the gained weight.

Reference list

Brand, L. 2021. Antipsychotic drugs and lithium salts. Study unit 9 [pdf]. Unpublished lecture notes on eFundi, FKLG312. Potchefstroom, NWU.

Drugs.com. 2020. Indocid (Rectal). https://www.drugs.com/cons/indocid.html Date of access: 1 May 2021.

Katzung, B.G. 2018. Basic & Clinical Pharmacology. 14th ed. International: McGraw-Hill Education.

South African Medical Association (SAMA) & University of Cape Town (UCT). 2020. 13th ed. Pretoria: South African Medical Association

2. D₂-receptors in mesolimbic dopamine pathway are particularly blocked by the typical antipsychotic drugs (Brand, 2021).
3. Atypical drugs blocks 5-HT_2A-receptors less more potently than blocking D₂-receptors, whereas typical drugs works through blocking D₂ -receptors more potently that 5-HT_2A-receptors (Katzung, 2018).
4. D₂-receptors (Brand, 2021).
5. Haloperidol, because it is a potent D₂-receptor blocker which results in a high incidence of extrapyramidal side effects (Brand, 2021).
6. The alfa receptors and muscarinic receptors (Brand, 2021; Brink, 2020).

Reference list:

Brand, L. 2021. Antipsychotic drugs and lithium salts. Study unit 9 [pdf]. Unpublished lecture notes on eFundi, FKLG312. Potchefstroom, NWU.

Brink, C.B. 2018. Inleidende Farmako-Fisiologie van die Perifere Senuweestelsel. Study unit 3a [PowerPoint presentation]. Unpublished lecture notes on eFundi, FKLG212. Potchefstroom, NWU.

Katzung, B.G. 2018. Basic & Clinical Pharmacology. 14th ed. International: McGraw-Hill Education.

1. Phenytoin, topiramate, phenobarbitone, oxcarbazepine, carbamazepine and topiramate. All these anticonvulsants has an effect on the metabolism of oral contraceptives (the Pill) (Brand, 2021).

The anticonvulsants mentioned above are strong-inducers of the enzymes, cytochrome P450 enzyme and glucuronyl transferase enzymes and cause a reduction in oral contraceptive levels, which has a failure in birth-control as result (Katzung, 2018).

There are however anticonvulsants that does not affect the metabolism of oral contraceptives. These drugs are: levetiracetam, gabapentin, valproate, vigabatrin, lamotrigine (Brand, 2021; Katzung, 2018)).

2. Yes, these drugs can decrease the valproate and lamotrigine serum levels (Brand, 2021).
3. These drugs are mostly metabolized by 1st order metabolism in the liver. Neonates has slower metabolism than children, babies and adults, thus anticonvulsants will take longer to metabolize and lower doses should be given, to prevent toxicity. Adult’s have a slower  metabolism than children and babies, thus children and babies should receive higher doses than adults, to ensure therapeutic effectivity. Geriatric patients should be given lower doses anticonvulsants, because they have decreased liver- and kidney function and would not be able to metabolize the drugs as well as adults would, which could lead to toxicity if their doses are equal to adult’s doses (Brand, 2021).
4. It is important to do plasma blood level monitoring with the following cases, as a guide for dosing efficacy. These cases are: during pregnancy, when the patient experiences breakthrough seizures, with a change in drug formulation to help with dose adjustments, to assess adherence, to determine the individual’s therapeutic concentration range when in remission, when medication that interacts is removed or added to the regimen and to determine whether drug levels are related to adverse effects (Katzung, 2018).

Reference list

Brand, L. 2021. Anti-epileptic drugs. Study unit 4 [pdf]. Unpublished lecture notes on eFundi, FKLG312. Potchefstroom: NWU.

Katzung, B.G. 2018. Basic & Clinical Pharmacology. 14th ed. International: Mc Graw Hill Education.

1. Chronic alcohol intake causes a tolerance to alcohol. The occurrence of tolerance due to chronic alcohol intake can be due to induction of the MEOS (Microsomal Ethanol-Oxidizing System) and thus the up-regulation of this pathway (Katzung, 2018; Brand, 2021).
2. Chronic alcohol use causes alcoholic fatty liver-condition. This condition is luckily reversible, however it can progress to alcoholic hepatitis, cirrhosis and eventually liver failure. All these conditions listed above decreases functioning of the liver. For this conditions to take place the following liver-metabolism problems can occur: the oxidation and synthesis of fatty acid is not correctly regulated, metabolic repercussions of the oxidation of ethanol in the liver (Katzung, 2018). Liver microsomal enzyme’s activity is increased due to the liver-conditions (Brand, 2021).
3. Wernicke-Korsakoff syndrome is a syndrome caused by a thiamine deficiency, usually due to alcoholism, with ataxia, paralysis of the external eye muscles and a confused state that can develop to a coma, is the common characteristics of this syndrome. This syndrome is treated with thiamine-therapy (Katzung, 2018).
4. Fetal alcohol syndrome is a syndrome with which a baby is born, due to chronic alcohol abuse of a mother during pregnancy (especially the first trimester) (Brand, 2021; Katzung, 2018). This causes teratogenic effects. This syndrome has behavioral and cognitive abnormalities for the fetus and later human and also a wide range of abnormalities with development of the fetus and child (Brand, 2021). Characteristic abnormalities include: the underdevelopment of the midfacial area, microcephaly, minor joint abnormalities, the retardation of intra-uterine growth and poor coordination. When the case is more severe the baby can also have mental retardation and congenital heart defects. The mechanism of action of alcohol causing teratogenic effects is however unknown. What is known, is that the liver at fetal-stage has no or just minor alcohol dehydrogenase activity, thus causing the fetus to be dependent on the placental- and maternal enzymes to eliminate the alcohol (Katzung, 2018).
5. With acute alcohol intake the liver blood flow decrease and/or the enzyme activities of the liver decrease this can thus inhibit the metabolism of drugs take that are dependent on the enzymes, for example. With the chronic intake of alcohol can cause higher than normal levels (even toxic levels) of drugs in the body which is dependent on cytochrome P450 for conversion to active metabolites. Due to the increased activity of cytochrome P450 this can lead to hepatotoxicity (Katzung, 2018).
6. Tricyclic antidepressants, sedative-hypnotic drugs,  phenothiazines and acetaminophen (Katzung, 2018).

Reference list

Brand, L. 2021. Alcohols. Study unit 3 [pdf]. Unpublished lecture notes on eFundi, FKLG 312. Potchefstroom: NWU.

Katzung, B.G. 2018. Basic & Clinical Pharmacology. 14th ed. International: Mc Graw Hill Education.

1. Alcohol undergo zero-order kinetics in the body. This is due to the limited amount of NAD (nicotinamide adenine dinucleotide), the co-enzyme influencing the conversion of alcohol (ethanol) to acetaldehyde, by alcohol dehydrogenase. When there are not enough NAD left to help with the metabolism of alcohol (usually due to a high alcohol intake), the rest of the alcohol will also be metabolized by the Microsomal Ethanol-Oxidizing System (MEOS). When high alcohol consumption occurs regularly the MEOS system will be used regularly leading to the induction of this system. This system consists primarily of cytochrome P450 enzymes and the metabolism and clearance of other drugs, not only alcohol, that are metabolized by cytochrome P450-enzymes. Toxic byproducts of this cytochrome P450 reactions also increase, due to the induction of this enzymes. The induction of this enzymes also plays a part in the development of tolerance for alcohol (Brand, 2021; Katzung, 2018).
2. There are 2 metabolic pathways (enzyme-systems) for  the metabolism of ethanol.
   1. Alcohol Dehydrogenase pathway

This is the primary pathway for the metabolism of moderate to low amounts of ethanol, which takes place in the liver, primarily. Ethanol (alcohol) is converted to acetaldehyde by the enzyme alcohol dehydrogenase which catalyse this conversion. With this conversion, nicotinamide adenine dinucleotide also known as NAD⁺ (an co-enzyme), is also converted to NADH. This pathway is dependent on this co-enzyme and thus follows zero-order kinetics (Brand, 2021; Katzung, 2018).

Note: Small amounts of alcohol dehydrogenase is found in the stomach and brain (Katzung, 2018).

1. 2. Microsomal Ethanol-Oxidizing System (MEOS) a.k.a. Mixed function oxidase system

Ethanol is converted to acetaldehyde with MEOS. With this conversion, NADPH (co-factor) and oxygen is also converted to NADP⁺ and water (Katzung, 2018)

Both these pathways forms acetaldehyde which are then further converted to acetate with the enzyme aldehyde dehydrogenase and the co-enzyme NAD⁺, which is in turn converted to NADH (Katzung, 2018).

3. The drugs that can influence the metabolism of ethanol is as follow:

• Fomepizole can inhibit the enzyme, alcohol dehydrogenase, at the Alcohol Dehydrogenase pathway (Katzung, 2018).

The effect of this inhibiting will cause the accumulation of ethanol in the body due to the fact that it cannot be converted acetaldehyde.

• Aldehyde dehydrogenase can be inhibited by the drugs: cephalosporins, disulfiram, hypoglycemic drugs and metronidazole.

The effect of the inhibition of aldehyde dehydrogenase: Acetaldehyde cannot be converted to acetic acid and accumulates in the body (Brand, 2021). Acetaldehyde is toxic to the body’s cells and liver. The result of ethanol use together with these drugs, causes the patient to have symptoms of: nausea, hypotension, throbbing, confusion, flushing, headache, sweating and vomiting (Katzung, 2018).  

Reference list

Katzung, B.G. 2018. Basic & Clinical Pharmacology. 14th ed. International: Mc Graw Hill Education.

Brand, L. 2021. Alcohols. SU 3 [pdf]. Unpublished lecture notes on eFundi, FKLG 312. Potchefstroom: NWU.

There are many alternative medicines to treat insomnia and anxiety. Examples of botanical substances in this regard, for example, is: Kava-Kava, Melatonin, Ginkgo Biloba and Ginseng.

1. Kava-Kava (Piper methysticum) (Richards, 2020):

Kava-Kava potentiates the actions of the GABA as neurotransmitter on the GABA_A receptor    and thus act like benzodiazepines. Kava-Kava also enhance the release of serotonin and dopamine. Thus Kava-Kava can be used as an sedative-hypnotic and anxiolytic (Earle). 

2. Melatonin is responsible to regulate the sleep-wake cycles. Melatonin improves sleep quality, duration, onset and rapid eye movement via the sedative-hypnotic effects. According to clinical studies, sleep architecture may be altered by oral melatonin-supplements. Insomnia due to β-blockers, can be treated with melatonin. Melatonin can also be used as a pre- and/or post-operative substance to reduce anxiety (Katzung, 2018).

3. Ginkgo Biloba

This extract can be used for cerebral insufficiencies, such as anxiety and depression, thus acts as an anxiolytic. Ginkgo biloba causes an enhancement in the synaptosomal reuptake of dopamine and serotonin (Katzung, 2018).

4. Ginseng

Ginseng increases the levels of dopamine and serotonin in the cerebral cortex. Ginseng an anxiolytic activity also due to stimulation of the pituitary adrenocortical system and being an agonist at glucocorticoid receptors (Katzung, 2018).

Other natural substances not mentioned in the Katzung textbook:

Valerian (Valeriana officinalis) which has a relaxing and sedating effect. This substance has an sedative-hypnotic effect and will thus also help with insomnia by inducing sleep. The mechanism of action for Valerian is the inhibition of GABA catabolism and thus the increase in GABA in the Central Nervous System (Cloete, 2020). A patient’s heart rate will also be lowered (Exploring your mind, 2018). Do not take Valerian with other sedatives or alcohol (Richards, 2020).

Linden Blossom (Linden), also has a anxiolytic and sedative-hypnotic effect (Exploring your mind, 2018).

Tryptophan an element that can be found in, for example: bananas, oily fish, pineapples, chicken, egg yolks, etc. This element has anxiolytic effects. Tryptophan increase serotonin production and release which help to balance your mood (Exploring your mind, 2018).

Omega-3, found in for example fish, reduce your levels of cortisol, also known as the stress hormone (Exploring your mind, 2018). Thus having anxiolytic effects.

Hops also has sedative and sedativr-hypnotic effects (Exploring your mind, 2018).         

Ashwagandha (Withania somnifera)

This is a type of herb called an adaptogen. A clinical trial showed less cortisol (stress hormone) in patients taking this herb. Thus this has an anxiolytic effect on a patient (Richards, 2020).

Lavender

Lavender can be used as a short term anxiolytic due to the fact that it contains linalool acetate and linalyl acetate (Richards, 2020).

Galphimia glauca

This plant reduces General Anxiety Disorder-symptoms and thus act as an anxiolytic (Richards, 2020).

Passionflower (Passiflora)

The species, P. incarnata, have shown to alleviate anxiety, restlessness and nervousness, thus it acts as an anxiolytic (Richards, 2020).

It is important for a patient to consult with a pharmacist or doctor on possible drug-interactions, before using these natural substances (Exploring your mind, 2018).

Reference list

Richards, L. 2020. 9 herbs for anxiety. https://www.medicalnewstoday.com/articles/herbs-for-anxiety Date of access: 4 March 2021.

Earle, C. How To Take Kava For Anxiety. https://redstormscientific.com/take-kava-for-anxiety/ Date of access: 4 March 2021.

Exploring your mind. 2018. 5 Natural Anxiolytics. https://exploringyourmind.com/5-natural-anxiolytics/ Date of access: 4 March 2021.

Katzung, B.G. 2018. Basic & Clinical Pharmacology. 14th ed. International: Mc Graw Hill Education.

Cloete, T. 2020. Chemiese verbindings in plante. Study unit 2.2[pdf]. Unpublished lecture notes on eFundi, FCHG222. Potchefstroom: NWU.

1. The lipophilicity of the drug affect the oral absorption and distribution. The more lipophilic the drug the easier and thus faster it enters the Central Nervous System, through crossing the blood-brain-barrier. Also the conversion of a prodrug, for example Clorazepate, via acid hydrolysis in the stomach, to an active form. In the case of Clorazepate the active form is desmethyldiazepam which can be absorbed into the blood. Thus this determines the time of onset of effects of this drugs (Katzung, 2018).
2. Redistribution is the fast distribution of highly lipid soluble drugs to the kidneys, brain and heart but are excreted quickly forming a depot in fat and muscles. This drugs can now be released at a slow pace from this depot. The drugs that are redistributed are eliminated slowly and will not be eliminated within 24 hours (Brand, 2021).
3. Benzodiasepine-metabolism consists of 3 steps which cause biotransformation of the drugs through hepatic microsomal enzymes:

Step 1: Dealkylation

This dealkylation of the benzodiazepines forms active metabolites of the drug.

Step 2: Oxidation via cytochrome P450 enzymes

The P450 enzymes, especially the CYP3A4, catalyze alphilic hydroxylation of the benzodiazepines to form active metabolites.

Step 3: Conjugation

Glucuronic acid forms water soluble glucoronides, of the active metabolites, which is excreted in the urine. This glucoronides are inactive metabolites (Brand, 2021).

4. Prazepam, Diazpam and Chlirdiazepoxide and Chlorazepate. Active metabolites formed, form the last mentioned benzodiazepines, has an extended duration of action. Cumulative effects could be caused by multiple doses (Brand, 2021; Katzung, 2018).
5. Temazepam, lormetazepam, lorazepam and oxazepam. This drugs can be useful to give to patient with a decreased cytochrome P450 activity, eg. an elderly patient, patients with liver cirrhosis, if a patient is using P450-enzymes and also neonates of mothers who used benzodiazepines before the neonate’s birth (Brand, 2021).
6. Enzyme induction is the induced expression of an enzyme due to the repeated administration of a specific drug. This induced expression happens by a reduction in the rate of degradation or  increasing the rate of synthesis. The result of induction is an acceleration of substrate metabolism. This usually cause a decrease in the pharmacologic action. Certain old sedative-hypnotic drugs, used long-term, may increase hepatic microsomal drug metabolizing enzyme activity. Examples of this drugs is meprobamate and barbiturates, especially phenobarbital. This drugs then cause induction by increasing hepatic metabolism (Katzung, 2018).

Reference list

Brand, L. 2021. Sedative-hypnotic drugs. Study unit 2 [pdf]. Unpublished lecture notes on eFundi, FKLG312. Potchefstroom: NWU.

Katzung, B.G. 2018. Basic & Clinical Pharmacology. 14th ed. International: Mc Graw Hill Education.

1. Anterograde amnesia is the inability of a patient to remember occurings that took place during the duration of drug-action in the body. This effect is caused by benzodiazepines in a dose-dependent manner (Brand, 2021).
2. With the long-term use of benzodiazepines, a patient’s time needed to fall asleep will be shortened.    An increase in the total sleep-time will be experienced, if the patient sleeps less than 6 hours as a normal pre-medication range. REM sleep is also affected by benzodiazepines according to the dosage. The higher the dosage the more the patient’s REM sleep is depressed. Phase 2 NREM sleep duration is increased, while phase 4 NREM sleep is decreased (Brand, 2021). The group of newer hypnotics decrease the time to persistant sleep (Katzung, 2018).

Thus these newer hypnotics and benzodiazepines is useful to treat insomnia to improve a pastient's sleep patters, where ever the problem my be.

3. Benzodiazepines: Lorazepam, midazolam, diazepam. These medication can have a supplementary therapy-use. This is that this drugs cause anterograde amnesia and anxiolysis. Thus this drugs is used as premedication (Katzung, 2018).  This can be effective to reduce anxiety pertaining medical procedures, especially with anterograde amnesia that influences the patient’s memory of the occurring.
4.  Metharbital and phenobarbital are the barbiturates that can be used for it’s anticonvulsant effects for generalized tonic-clonic seizures treatment. Various benzodiazepines have anticonvulsant effects to be used in the management of seizures. These benzodiazepines include: lorazepam, diazepam, clonazepam, nitrazepam. With the use of sedative-hypnotics in the treatment of convulsions an impairment in psycho-motor function may be caused (Katzung, 2018).
5. Benzodiazepines and carbamates can exert an effect on muscle-relaxation. The following mechanism is applicable: These drugs inhibit the polysynaptic reflexes and internucial transmission. A depression in transmission, at the neuromuscular junction, may take place with the use of high doses (Katzung, 2018).
6. Sedative-hypnotic drugs has an influence on the respiratory and cardiovascular systems in the body (Katzung, 2018).

Respiratory system:

The respiratory system is depressed, dose related, with the use of sedative-hypnotics. In a healthy patient the effect is similar to the respiratory changes when a person sleep. Patients who suffer from pulmonary disease may experience excessive respiratory depression, even at therapeutic doses.

Death can be caused with an overdose of this drugs, through depression of the medullary respiratory center (Katzung, 2018).

Cardiovascular system:

In healthy patients sedative-hypnotic drugs, does not have a significant effect on the cardiovascular system with the use of this drugs as hypnotics with normal doses.

Patient who already have disease(s) that impair their cardiovascular function, for example heart failure or hypovolemic states, can experience a depression in cardiovascular function already at the use of normal doses. This is most likely caused by actions on medullary vasomotor centers. Circulatory collapse can be caused by the depression of vascular tone and also myocardial contractility with toxic doses of sedative-hypnotics. This depression happens due to peripheral and central effects due to adenosine action that is facilitated (Katzung, 2018).

Reference list

Katzung, B.G. 2018. Basic & Clinical Pharmacology. 14th ed. International: McGraw-Hill Education.

Brand, L. 2021. Sedative-Hypnotic drugs. Study unit 2 [pdf]. Unpublished study notes on eFundi, FKLG312. Potchefstroom: NWU.

1. Ligand-gated channels and Voltage-gated channels (Brand 2021).

2. Voltage-gated channels respond to membrane potential-changes of cells to open the channel(s). But a ligand-gated channel opens directly by the binding of the neurotransmitter to the ionotropic receptor (Katzung, 2018:369). An all-or-nothing fast action potential is initiated for the voltage-gated channel to elicit an effect (Katzung, 2018:369). But the binding of a neurotransmitter gives an effect at a ligand-gated channel and does not need to have a certain number of receptors activated to elicit an effect. Some voltage-sensitive potassium and calcium channels act slower, thus altering the discharge-rate of the neuron. Although the ligand-gated synaptic transmission happens fast (Katzung, 2018:369-370).

5. EPSP (Excitatory postsynaptic potential): The product of an excitatory pathway, which is also a small depolarization. This results from the binding of an excitatory transmitter to an ionotropic receptor, which then increase the permeability of the channel to cations (Katzung, 2018:371). For example: Acetyl choline binding to a Nicotinic receptor causes depolarization and hence increases the permeability of the channel to sodium (Brand, 2021).

Versus:

IPSP (Inhibitory postsynaptic potential): A selective opening of chloride-channels due to hyperpolarization in response to a stimulation in the inhibitory pathway (Katzung, 2018:371). For example:  Binding of y-amino butyric acid to the GABA_A receptor opens a chloride channel due to hyperpolarization (Brand, 2021).

6. Calcium release is due to the propagation of an action potential down the axon of a presynaptic neuron which then activates voltage sensitive calcium channels in the synaptic terminal. Calcium thus flows into the synaptic terminal which are now responsible for the fusion of synaptic vesicles with the post-synaptic membrane due to an increase in intra-terminal calcium concentration. Ultimately this results in the release of the neurotransmitter out of the vesicle and into the synaptic cleft. Channels on the post-synaptic membrane can now be opened by the binding of neurotransmitters to post-synaptic receptors.  The opening of the post-synaptic ion channels causes a brief membrane permeability change to the ions. Thus a synaptic potential is formed. This means that calcium is responsible for the fusion of vesicles with the pre-synaptic membrane and thus the release of neurotransmitters in the synaptic cleft (Katzung, 2018:371).

Reference list

Brand, L. 2021. Introduction. Study unit 1 [pdf]. Unpublished lecture notes on eFundi, FKLG 312. Potchefstroom: NWU.

Katzung, B.G. 2018. Basic & Clinical Pharmacology. 14th ed. International: McGraw-Hill Education. p. 369-371.