Appendix № 9 contains 7 medicines that acts on cardiovascular system and blood coagulation. Five of them are from the group of cardiac glycosides while the other are coumarin anticoagulant drugs.

Cardiac glycosides are natural compounds isolated from various plants such as Digitalis lanata, Digitalis purpurea, Strophantus spp., Nerium oleander, etc. They are composed of a sugar moiety, a steroid and a lactone ring. Cardiac glycosides have a complex mechanism of action and exert a positive inotropic and bathmotropic effects as well as a negative chrono- and dromotropic effects. The positive inotropic effect is associated with inhibition of Na⁺/K⁺-ATPase in cardiomyocytes (Botelho et al. 2019). Cardiac glycosides are characterized by a low therapeutic index and a long plasma half-life (digoxin has a half-life of 36–48 hours) resulting in an increased risk of cumulation and digitalis intoxication. Patients with renal disease are more susceptible to toxic effects because cardiac glycosides are excreted in urine mainly unchanged. In addition, many drugs as well as electrolyte disorders may increase their toxicity. Digitalis intoxication is manifested by nausea, vomiting, weakness, impaired color vision, atrioventricular (AV) block, ventricular arrhythmias which can be life-threatening (Pita-Fernández et al. 2011; Rehman and Hao 2023).

Oral anticoagulants (acenocoumarol and ethyl biscoumacetate) are derivatives of coumarin which has a natural origin. Coumarin anticoagulants are vitamin K antagonists. They block the enzyme vitamin K epoxide reductase (VKOR) which inhibits the synthesis of vitamin K-dependent coagulation factors [II, VII, IX, X] and disrupts the coagulation process (Liu et al. 2021). The most serious problem that can occur with coumarin anticoagulant treatment is bleeding which may be potentially fatal in some cases. Regular laboratory tests (monitoring and maintenance of the INR value in the optimal therapeutic range) are required in order to ensure adequate coagulation and prevent bleeding (Holbrook et al. 2012).

Table 2 shows the pharmacotherapeutic group, therapeutic indications and serious adverse reactions for each drug as well as the defined daily dose (DDD) according to the World Health Organization (WHO). The DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults (WHO 2023h). Table 3 summarizes the information for the prescribing and dispensing of the medicines in this group, availability of marketing authorization in Bulgaria and the trade name of the authorized products.

From the performed review of the available regulatory documentation, it is clear that only 3 of the listed INNs (metildigoxin, digoxin and acenocoumarol) are authorized in Bulgaria. In addition, other antithrombotic agents (new oral antithrombotic agents) are widely prescribed in recent years but are not included in Appendix № 9. It remains unclear whether this is due to the better safety profile of these drugs or because the list has not been updated recently (Sikka and Bindra 2010).

Drugs acting on peripheral and central nervous system that are included in Appendix № 9 belong to different pharmacotherapeutic groups (peripherally acting muscle relaxants, parasympathomimetics, parasympatholytics, etc.) and have various indications for use. Peripherally acting muscle relaxants are used during surgical procedures to provide muscle relaxation, which is achieved by blocking the transmission of nerve impulses at neuromuscular synapses. Most clinically used neuromuscular blocking drugs are quaternary ammonium compounds (tubocurarine, atracurium, pancuronium, etc.) and belong to the non-depolarizing neuromuscular blocking agents. They are competitive antagonists of N₂-cholinergic receptors in skeletal muscle cells and prevent the interaction of acetylcholine with N₂-cholinergic receptors, resulting in muscle relaxation (D’Souza et al. 2023). Suxamethonium has a different mechanism of action and is classified as depolarizing neuromuscular blocking agent. It acts as an agonist of N₂-cholinergic receptors, but causes prolonged depolarization in contrast to acetylcholine, which also leads to blockade of neuromuscular transmission and skeletal muscle relaxation (Hovgaard and Juhl-Olsen 2021). Both groups of neuromuscular blocking agents have specific adverse reactions that are listed in Table 4. Some of them may be potentially fatal, such as idiosyncratic reactions (malignant hyperthermia) after suxamethonium application. Furthermore, the use of suxamethonium in patients with genetically determined pseudocholinesterase deficiency that is responsible for its metabolism can lead to markedly prolonged paralysis. Neuromuscular blockers are administered intravenously to achieve general anesthesia, usually in combination with general anesthetics, M-cholinoblockers, etc., so there is a significant risk of drug interactions (Lee 2009). Information for the use of neuromuscular blockers in Bulgaria is given in Table 5. In this group DDDs have not been established because the doses used vary substantially.

In general, in Appendix № 9 are included 7 non-depolarizing neuromuscular blocking agents but only 3 of them are with granted marketing authorization in Bulgaria.

Parasympathomimetics mimic the effects of acetylcholine as a result of activation of the parasympathetic nervous system. They can be divided into 3 subgroups - cholinomimetics acting on muscarinic and nicotinic receptors (directly and indirectly acting), muscarinic agonists and nicotinic agonists. Most cholinomimetics are agonists of cholinergic receptors, in contrast to indirectly-acting cholinomimetic, also known as anticholinesterase drugs. They act by inhibiting acetylcholine esterase activity, the main enzyme that is responsible for the breakdown of acetylcholine. The result is accumulation of endogenous acetylcholine in the synapses and activation of the parasympathetic nervous system (Forrester et al. 2016). In Appendix № 9 are included acetylcholinesterase inhibitors (galantamine, neostigmine, pyridostigmine, ambenonium) and muscarinic agonists (pilocarpine). Main pharmacological effects of cholinomimetics are stimulating of gastrointestinal and bladder motility, miosis, excessive salivation, sweating, urinary urgency, bronchoconstriction and increased bronchial secretion, improvement of nerve impulse transmission in skeletal muscle cells, while some improve acetylcholine neurotransmission mostly in the central nervous system. Adverse reactions of parasympathomimetics are related to the mechanism of action and are due to overactivation of the parasympathetic nervous system (Singh and Sadiq 2023). The therapeutic indications and adverse drug reactions of cholinomimetics included in Appendix № 9 are presented in Table 6.

Anticholinergic drugs are competitive antagonists of M-cholinergic receptors that suppress the effects of acetylcholine and reduce the activity of the parasympathetic nervous system. Pharmacological effects of parasympatholytic agents are spasmolytic and broncholytic effects, mydriasis, increased heart rate, urinary retention, etc. Anticholinergic drugs included in Appendix № 9 are 4 and belong to different pharmacotherapeutic groups (Table 6). Intoxication with anticholinergics causes the so-called atropine-like effects - xerostomia, mydriasis, tachycardia, dizziness, fatigue, constipation, urinary retention, dry skin due to suppression of sweating, fever, etc. It’s often used the memory aid “red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare, full as a flask’ to remember the common symptoms of anticholinergic toxicity (Ghossein et al. 2023). In Table 7 is summarized the information on the use of parasympathomimetics and anticholinergic drugs included in Appendix № 9 in Bulgaria.

In conclusion, two of the listed parasympathomimetic drugs that are cholinesterase inhibitors and one anticholinergic agent are not authorized in Bulgaria. However, there is cholinesterase inhibitors that have marketing authorization in Bulgaria but are not included in the Appendix.

The other drugs acting on the Nervous system are ergotamine, nalorphine, naloxone and tetracaine. They have different mechanism of action and indications. Ergotamine is an ergot alkaloid. It selectively binds and activates serotonin (5-HT)_1B and (5-HT)_1D receptors located on intracranial blood vessels, resulting in vasoconstriction and reduction in cerebral blood flow that may relieve some types of headaches (Silberstein and McCrory 2003). Nalorphine and naloxone are competitive antagonist of opioid receptors. Unlike naloxone, nalorphine has agonistic effect at the kappa opioid receptors (KOP) (Theriot et al. 2023). Tetracaine is a local anesthetic from the amino-esters class. It’s a membrane-stabilizing drug which reversibly blocks the voltage-gated sodium channels in the neuronal cell membrane (Adeleve 2020). Indications and side effects of these drugs are shown in Table 8. In Bulgaria tetracaine is used only in combination with other drugs (Table 9).

Ergotamine and nalorphine are not authorized in Bulgaria although they are listed in Appendix № 9. Surprisingly, another opioid antagonist – naltrexone has marketing authorization in Bulgaria but is not listed in Appendix № 9. In addition, other local anesthetic from the class of amino-esters (procaine) is available in Bulgaria but is not included in the Appendix. Furthermore, local anesthetics from the amino-amides class (lidocaine, mepivacaine, bupivacaine, etc.) that are authorized in Bulgaria are not listed in Appendix № 9 too.

Appendix № 9 includes 3 medicinal products related to anabolic steroids (Ministry of Health 2010). They are synthetic derivatives of testosterone that have anabolic and androgenic effects due to activation of intracellular androgen receptors and influencing the expression of glucocorticoid receptors. Anabolic effects are the stimulation of protein synthesis in skeletal muscle cells, stimulation of red blood cells production, improvement of athletic performance, etc., while androgenic effects are associated with a number of hormonal changes that in most cases are undesirable. Anabolic and androgenic effects cannot be completely separated and are common to all anabolic steroids, although some of the synthetic steroids (nandrolone, oxymetholone, metandienone) show predominant anabolic effects. Myotrophic–androgenic index is used for evaluation of anabolic and androgenic effects of the anabolic steroids (Kicman 2008). Therapeutic indications and adverse reactions for the anabolic steroids, included in Appendix № 9 are shown in Table 10. Anabolic steroids are prescription-only medicines although they are sometimes used to increase muscle mass and physical endurance without medical consultation. Long-term use of anabolic steroids is associated with serious adverse effects and should be avoided (Farzam 2021). None of the anabolic steroids included in Appendix № 9 is authorized for use in Bulgaria (BDA 2017).

In the present study we analyzed and summarized the available information about the medicinal products included in Appendix № 9 to Art. 17, para. 1 of Ordinance № 28/9.12.2008, issued by the Minister of Health. The list includes 70 drugs and all of them, except butylscopolamine (INN is in the OTC list) for oral administration are available only by prescription. Most medicines listed in Appendix № 9 may be potentially dangerous even when taken in therapeutic doses. These drugs belong to different pharmacotherapeutic groups and have a variety of indications for use. For а better presentation of the information, the medicines were divided into four groups – Medicines acting on peripheral and central nervous system, Medicines acting on cardiovascular system and blood coagulation, Antineoplastic and immunomodulating agents and Anabolic steroids.

In the first part of this article, we reviewed the available information about the medications acting on cardiovascular system, nervous system and anabolic steroids. A total of 31 drugs are included in these groups but we established that half of them (16 drugs) are not registered for use by the Bulgarian Drug Agency (BDA) to date and are not used in clinical practice in Bulgaria. On the other hand, in Bulgaria there are some medicinal products that have a marketing authorization granted by the BDA or are authorized for use under a centralized procedure under Regulation (EC) №726 / 2004 of the European Parliament and of the Council of 31 March 2004 but are not included in the Appendix although they belong to the same pharmacologic and pharmacotherapeutic group with medicines listed in Appendix № 9. The information is summarized in Table 11. These medicines have identical mechanism of action and similar therapeutic indications but have not been added to the list with medications that must be stored in a locked cabinet. The presented information about drugs authorization in Bulgaria is up-to-date as of June 2023 (BDA 2017).

The question remains whether these drugs, shown in Table 11 have better safety profile or there is a different reason they are not included in the Appendix. Furthermore, it remains unclear when the list of medicines in Appendix 9 was last updated, as well as the criteria for inclusion of drugs in it. It would be useful to present detailed and up-to-date information on the medicinal products listed in Appendix № 9 during the professional trainings organized by the Bulgarian Pharmaceutical Union.