Pharmacology

1. PHL- 210 Pharmacology By Prof. Sabry Attia Pharmacology and Toxicology Dep.

2. Nervous System

3. Types of Nervous System

4. Some anatomic and neurotransmitter features of peripheral nervous system

5. Efferent nerves of the peripheral nervous system

6. The major components of the central and peripheral nervous systems and their functional relationships. Stimuli from the environment convey information to processing circuits within the brain and spinal cord, which in turn interpret their significance and send signals to peripheral effectors that move the body and adjust the workings of its internal organs.

7. Drugs Affecting Motor Function Mechanisms for influencing skeletal muscle tone. Inhibition of neuromuscular transmission and electromechanical coupling

8. A. Drugs Acting on Motor Systems: Muscle Relaxants 1. Non-depolarizing muscle relaxants (competitive antagonist) d-tubocurarine • Semi-synthetic compound. • Only I.V. • Competitive antagonist towards Ach on nicotinic receptors. • Onset: about 4 min. • Duration: about 30 min. • Antidote: acetylcholinesterase inhibitor. • Adverse effects: bronchospasm, urticaria and hypotension. Pancuronium • Synthetic compound. • 5-fold more potent than d-tubocurarine, with somewhat longer duration of action. • Not likely to cause bronchospasm, urticaria and hypotension. • Adverse effects: increased heart rate and blood pressure Newer compounds are vecuronium, pipecuronium, alcuronium, gallamine, mivacurium, and atracurium.

9. 2. Depolarizing muscle relaxants (agonists) Succinylcholine (suxamethonium) • Double ACh molecule. • Only I.V. • Synthetic compound. • Agonist at endplate nicotinic cholinoceptors, but it produces muscle relaxation due to the persistent depolarization of the endplate and adjoining membrane regions. • Duration: about 10 min. • Adverse effects: hyperkalemia (risk of cardiac arrhythmias). Prolonged muscle relaxation and apnea in patients with a genetic deficiency in pseudocholinesterase. • Used at the start of anesthesia to facilitate intubation of the patient. • Antidote: no specific antidote but the transient bradycardia can be treated by atropine. Moreover, artificial respiration, and oxygen must be readily available .

10. B. Drugs Acting on the Parasympathetic Nervous System Responses to activation of the parasympathetic: • Activation of ocular parasympathetic fibers (miosis and accommodation of near vision). • ↑ Secretion of saliva and intestinal fluids (promotes digestion of foodstuffs; transport of intestinal contents). • Allowing a decreased tidal volume (↑ bronchomotor tone) and ↓ cardiac activity. • Wall tension is ↑ by detrusor activation with a concurrent relaxation of sphincter tonus (micturition).

11. B. Drugs Acting on the Parasympathetic Nervous System Acetyl-choline (ACh) as a transmitter: (release, effects, and degradation ) • During activation of the nerve membrane, Ca2+ is thought to enter the axoplasm and to activate protein kinases. As a result, vesicles discharge their contents into the synaptic gap. • At the postsynaptic effector cell membrane, ACh reacts with M1 receptors on nerve cells, e.g., in ganglia. M2 receptors mediate Ach effects on the heart. M3 receptors mediate Ach effects on gut and bronchi and glandular epithelia. • Released ACh is rapidly hydrolyzed and inactivated by a specific Ach-esterase, present on pre- and post-junctional membranes, or by a less specific serum cholinesterase, a soluble enzyme present in serum and interstitial fluid.

12. B. Drugs Acting on the Parasympathetic Nervous System 1. Parasympathomimetics ACh is too rapidly hydrolyzed and inactivated by AChE to be of any therapeutic use; however, its action can be mimicked by other substances, namely Pilocarpine • Direct Parasympathomimetics as Carbachol, methacholine, bethanechol, Pilocarpine and Arecoline (refreshing & mild stim. betel chewing). • Indirect Parasympathomimetics asEsters of carbamic acid (carbamates such as physostigmine and neostigmine) and Phosphoric acid (organophosphates such as paraoxon, echothiophate and parathion. The rate-limiting step in ACh hydrolysis is deacetylation of the enzyme, which takes only milliseconds, thus allowing a high turnover rate and activity of AChE. De-carbaminoyl-ation following hydrolysis of carbamates takes hours to days, the enzyme remaining inhibited as long as it is carbaminoylated. Cleavage of the phosphate residue, i.e. de-phosphoryl-ation, is practically impossible; enzyme inhibition is irreversible.

13. B. Drugs Acting on the Parasympathetic Nervous System 1. Parasympatho-mimetics Uses of parasympathomimetics • In postoperative atonia of the bowel or bladder (neostigmine). • In myasthenia gravis to overcome the relative ACh-deficiency at the motor endplate • In de-curarization before discontinuation of anesthesia to reverse the neuromuscular blockade caused by non-depolarizing muscle relaxants. • As antidote in poisoning with parasympatholytic drugs because it has access to AChE in the brain (physostigmine). • In the treatment of glaucoma (neostigmine, pyridostigmine, physostigmine pilocarpine paraoxon and ecothiopate): however, their long-term use leads to cataract formation. • Insecticides (parathion). Although they possess high acute toxicity in humans, they are more rapidly degraded than is the insecticide DDT following their emission into the environment. • Tacrine (Cognex) is not an ester and interferes only with the choline-binding site of AChE. It is effective in alleviating symptoms of dementia in some subtypes of Alzheimer’s disease. Donepezil (Aricept), galantamine, and rivastigmine (Exelon) are newer, more selective.

14. B. Drugs Acting on the Parasympathetic Nervous System 2. Parasympatho-lytics Effects of parasympathetic stimulation (blue arrow) and blockade (red) Parasympathomimetics are substances acting agonistically at the M cholinoceptor (blue arrows). Parasympatholytics are substances acting antagonistically at the M cholinoceptor (shown in red in the panels).

15. B. Drugs Acting on the Parasympathetic Nervous System 2. Parasympatholytics ((Atropine-like drugs)) Uses of parasympatholytics: Atropine; is used to prevent cardiac arrest and as a preanesthetic medication to prevents a possible hypersecretion of bronchial mucus, which cannot be expectorated by coughing during anesthesia. Homatropine; is used as mydriatics (for diagnostic use). Benzatropine; is used in treatment of Parkinson’s disease. Pirenzepine; is used in treatment of gastric and duodenal ulcers. Ipratropium; is used in treatment of bronchial asthma, bradycardia and heart block. N-butylscopolamine; is used in treatment of biliary & renal colic. Scopolamine; is used in treatment of motion sickness. Contraindications for parasympatholytics:Glaucoma and Prostatic hypertrophy with impaired micturition. Atropine poisoning: Peripheral (tachycardia; dry mouth; hyperthermia, flashing and constipation) and Central ( restlessness, agitation, psychic disturbances and hallucinations) effects. Treatment of Atropine poisoning, general measures (gastric lavage, cooling with ice water) or therapy with indirect parasympathomimetic as physostigmine.

17. C. Drugs Acting on the Sympathetic Nervous System Responses to sympathetic activation • CNS • Eye • Saliva • Bronchi • Sweat glands • Heart • Liver • Intestinal tract • Bladder • Skeletal muscle

18. C. Drugs Acting on the Sympathetic Nervous System Sympathetic Transmitter nor-epinephrine (NE also called nor-adrenaline) Synthesis of nor-epinephrine Releases of nor-epinephrine Fate of nor-epinephrine • Neuronal re-uptake • Inactivated by MAO • Inactivated by COMT

19. C. Drugs Acting on the Sympathetic Nervous System 1. Sympathomimetics Adrenoceptors (adrenergic receptors) Sympathomimetics (i.e., adrenoceptor agonists)

20. C. Drugs Acting on the Sympathetic Nervous System 1. Sympathomimetics Clinical uses of adrenoceptor agonists 1.Cardiovascular system • cardiac arrest as adrenaline • cardiogenic shock as dobutamine • heart block as isoprenaline, which can be used temporarily while electrical pacing is being arranged. 2. Anaphylactic shock (acute hypersensitivity): adrenaline is the first-line treatment 3. Respiratory system (asthma): selective β2-receptor agonists (salbutamol, formoterol) 4. Nasal decongestion: drops containing phenylephrine, oxymetazoline or ephedrine reduces mucosal blood flow and, hence, capillary pressure. Fluid exuded into the interstitial space is drained through the veins, thus shrinking the nasal mucosa. Due to the reduced supply of fluid, secretion of nasal mucus decreases. 5. Miscellaneous indications • Adrenaline can be used to prolong local anaesthetic action by delaying the removal of local anesthetic. • Inhibition of premature labour (salbutamol) • α2-agonists as clonidine used in hypertension, menopausal flushing, lowering intraocular pressure and migraine prophylaxis.

21. C. Drugs Acting on the Sympathetic Nervous System 2. Sympatholytics Sympatholytics (Sympathatic blockers) 1. α-Sympatholytics (α-blockers) • non-selective (blocks both post-synaptic and pre-synaptic α-adrenoceptors) as phentolamine. • selective α1-blockers as prazosin and terazosin. • α-blockers are used in treatment of hypertension and in benign hyperplasia of the prostate. • side effects of α-blockers are postural hypotension. 2. β-Sympatholytics (β-Blockers) • non-selective as propranolol. • selective β1-receptors as metoprolol, acebutolol, bisoprolol. • β-blockersare used in treatment of angina pectoris, tachycardia, hypertension, glaucoma. • side effects of β-blockers are congestive heart failure, bradycardia, bronchial asthma, hypoglycemia in diabetes mellitus and sedation. 3. α and β blockers as • Carvendilol; used in congestive heart failure with other drugs. The most common side effects include dizziness, fatigue, hypotension, diarrhea, asthenia, bradycardia, and weight gain. • Labetalol; It has a particular indication in the treatment of pregnancy-induced hypertension. It is also used to treat chronic hypertension and hypertensive crisis. 4. Centrally acting anti-adrenergics drugs They are capable of lowering transmitter output from sympathetic neurons. Their action is hypotensive however, being poorly tolerated, they enjoy only limited therapeutic use. Examples are Clonidine, Methyldopa, Reserpine and Guanethidine.

22. C. Drugs Acting on the Sympathetic Nervous System 2. Sympatholytics • Clonidine.Clonidine is an α2-agonist whose high lipophilicity permits rapid penetration through the blood-brain barrier. In addition, activation of pre-synaptic α2-receptors in the periphery leads to a decreased release of both nor-epinephrine (NE) and acetylcholine. Side effects. Dry mouth; rebound hypertension after abrupt cessation of clonidine therapy. • Methyldopa. It converts in the brain to α-methyl-dopamine, and then to α-methyl-NE thus competes for a portion of the available enzymatic activity (inhibition of Dopa-decarb-oxylase), so that the rate of conversion of L-dopa to NE (via dopamine) is decreased. The false transmitter α-methyl-NE can be stored; however, unlike the endogenous mediator, it has a higher affinity for α2- than for α1-receptors and therefore produces effects similar to those of clonidine. The same events take place in peripheral adrenergic neurons. Adverse effects. Fatigue, orthostatic hypotension, extrapyramidal Parkinson-like symptoms, hepatic damage, immune-hemolytic anemia.

23. C. Drugs Acting on the Sympathetic Nervous System 2. Sympatholytics • Reserpine. It abolishes the vesicular storage of biogenic amines (NE, dopamine, serotonin = 5-HT). To a lesser degree, release of epinephrine from the adrenal medulla is also impaired. Adverse effects. Disorders of extrapyramidal motor function with development of pseudo-Parkinsonism, sedation, depression, stuffy nose, impaired libido, and impotence; increased appetite. These adverse effects have rendered the drug practically obsolete.

24. C. Drugs Acting on the Sympathetic Nervous System 2. Sympatholytics • Guanethidine. It has high affinity for the axolemmal and vesicular amine transporters. It is stored instead of NE, but is unable to mimic the functions of the latter. In addition, it stabilizes the axonal membrane, thereby impeding the propagation of impulses into the sympathetic nerve terminals. Storage and release of epinephrine from the adrenal medulla are not affected, owing to the absence of a re-uptake process. The drug does not cross the blood-brain barrier. Adverse effects. Cardiovascular crises are a possible risk: emotional stress of the patient may cause sympatho-adrenal activation with epinephrine release. The resulting rise in blood pressure can be all the more marked because persistent depression of sympathetic nerve activity induces supersensitivity of effector organs to circulating catecholamines.

25. Peripheral Nervous System at Glance Somatic (motor) nerve (causes skeletal muscle contraction) • The neurotransmitter is acetyl-choline (ACh). • ACh is hydrolyzed by acetyl-cholin-esterase. • Receptor is Nicotinic (N). • Convulsant as tetanus toxin, strychnine. • Centrally acting muscle relaxants as benzo-diazepines, baclofen, clonidine. • Non-depolarizing muscle relaxants as curare, d-tubo-curarine, pan-curonium. • Depolarizing muscle relaxants as succinyl-choline. Parasympathetic nervous system (like when you eat) • The neurotransmitter is acetyl-choline (ACh). • Receptors are Muscarinic (M) and Nicotinic (N) receptors. • ACh is hydrolyzed by acetyl-cholin-esterase. • Parasympatho-mimetics may be direct as carbachol, pilocarpine, arecoline or indirect as physostigmine, neostigmine, paraoxon, parathion. • Parasympatho-lytics as atropine, hom-atropine, benz-atropine, pirenzepine, ipr-atropium, N-butyl-scopolamine, scopolamine. Sympathetic nervous system (like when you play football) • The neurotransmitter is nor-epinephrine (NE). • Receptors are α and β receptors. • NE is decreased at the receptors by neuronal re-uptake, MAO or COMT. • Sympatho-mimetics may be direct as epinephrine (adrenaline) nor-epinephrine (nor-adrenaline), iso-proterenol, phenyl-ephrine, dobutamine, salbutamol or indirect as cocaine, ephedrine, amphetamine. • Sympatho-lytics as phentol-amine (post-synaptic and pre-synaptic α receptors blocker), prazosin (α1), propranolol (β1 and β2), metoprolol, acebutolol, bisoprolol (β1 > β2), carvendilol and labetalol (α and β), clonidine (pre-synaptic α2-agonist), methyldopa (act as a false transmitter α-methyl-NE), reserpine (abolishes the vesicular storage of NE), guanethidine (stored instead of NE and stabilizes the axonal membrane).

26. Analgesics Drugs Pain sensation can be influenced or modified as follows: • elimination of the cause of pain. • suppression of transmission of nociceptive impulses in the spinal medulla (opioids). • inhibition of pain perception (opioids, general anesthetics). • altering emotional responses to pain, i.e., pain behavior (antidepressants as “co-analgesics”). • lowering of the sensitivity of nociceptors (antipyretic analgesics, local anesthetics). • interrupting nociceptive conduction in sensory nerves (local anesthetics).

27. Opioid Analgesics • Endogenous opioids enkephalins, β-endorphin, dynorphins. • Exogenous opioids morphone, heroin, pentazocine, pethidine, meperidine, methadone, fentanyl > 80 times of morphine, noscapine, codeine, tramadol. • Opioid receptors are; μ (Mu), delta (δ), Kappa (Ƙ). • Mode of action of opioids 1. hyperpolarization (↑ K+). 2. ↓ release of excitatory transmitters and ↓ synaptic activity (↓ Ca2+). Action of endogenous and exogenous opioids at opioid receptors

28. Effects of opioids • Analgesic effectby inhibition of nociceptive impulse transmission and attenuation of impulse spread and inhibition of pain perception → floating sensation and euphoria → dependence • Antitussive effectby inhibition of the cough reflex. • Emetic effectby stimulation of chemoreceptors but this effect disappears with repeated use. • Miosis effectby stimulating the parasympathetic portion of the oculomotor nucleus → PPP • Antidiarrheic effectthrough ↑ segmentation, ↓ propulsive peristalsis, ↑ tone of sphincters

29. Opioid Tolerance • Rout of administrations: orally, parenterally, epidurally or intrathecally or transdermal. • With repeated administration of opioids, their CNS effects can lose intensity (increased Tolerance). In the course of therapy, progressively larger doses are needed to achieve the same degree of pain relief. • Development of tolerance does not involve the peripheral effects as locomotor stimulation and constipation, so that persistent constipation during prolonged use may force a discontinuation of analgesic therapy. • Physiological tolerance involves changes in the binding of a drug to receptors or changes in receptor transductional processes related to the drug of action. • Person who is tolerant to morphine will also be cross-tolerant to the analgesic effect of fentanyl, heroin, and other opioids. Note that a subject may be physically dependent on heroin can also be administered another opioid such as methadone to prevent withdrawal reactions. • Methadone has advantages of being more orally effective and of lasting longer than heroin. • Methadone maintenance programs allow heroin users the opportunity to maintain a certain level of functioning without the withdrawal reactions. • Toxic effects of opioids are primarily from their respiratory depressant action and this effect shows tolerance with repeated opioid use. • Opioids might be considered “safer” in that a heroin addicts drug dosage would be fatal in a first-time heroin user.

30. Opioid Dependence • Physiological dependenceoccurs when the drug is necessary for normal physiological functioning, this is demonstrated by the withdrawal reactions. • Withdrawal reactions are usually the opposite of the physiological effects produced by the drug. • Acute withdrawal can be easily precipitated in drug dependent individuals by injecting an opioid antagonist such as naloxone.

31. Morphine antagonists and partial agonists • Pure Agonist: has affinity for binding plus efficacy. • Pure Antagonist: has affinity for binding but no efficacy. • Mixed Agonist-Antagonist: produces an agonist effect at one receptor and an antagonist effect at another such as Buprenorphine. • Partial Agonist: has affinity for binding but low efficacy. • The effects of opioids can be abolished by the antagonists naloxone or naltrexone. Given by itself, neither has any effect in normal subjects; however, in opioid-dependent subjects, both precipitate acute withdrawal signs. • Naloxone is effective as antidote in the treatment of opioid-induced respiratory paralysis. • Naltrexone may be used as an adjunct in withdrawal therapy. • Buprenorphine behaves like a partial agonist at μ and antagonist Ƙ-receptors. Pentazocine is an antagonist at μ-receptors and an agonist at Ƙ-receptors. Both are classified as “low-ceiling” opioids, because neither is capable of eliciting the maximal analgesic effect obtained with morphine or meperidine.

32. Drugs for Treating Bacterial Infections • Bacterial infection. • Immune response. • Infectious disease develops with inflammatory signs. • Antibacterial drugs (antibiotics).

33. Classification of antibiotics by mechanism of action Inhibition of cell-wall synthesis such as penicillins and cephalosporins. Inhibition of folate synthesis such as sulfonamides and trimethoprim. Inhibition of nucleic acid synthesis such as rifampin, quinolones and metronidazole. Inhibition of protein synthesis such as tetracyclines, aminoglycosides, chloramphenicol, erythromycin and clindamycin. NB. Polymyxins and tyrothricin antibiotics enhance cell membrane permeability. Due to their poor tolerability, they are prescribed only for topical use.

34. Antibacterial drugs (antibiotics) • Bactericidal effect. • Bacteriostatic effect. • Bacterial resistance: natural resistance or acquired resistance (mutation).

35. Cell wall • Peptideglycan (aminosugars N-acetyl-glucosamine and N-acetyl-muramyl acid). • Animal and human cells lack a cell wall.

36. 1. Inhibitors of Cell Wall Synthesis; the β-lactam penicillins 6-amino-penicillanic acid (6-APA) • Disrupt cell wall synthesis by inhibiting transpeptidase. • Well tolerated (0.6 - 60 g ). • Hypersensitivity. • Convulsions. • t1/2 ~ 0.5 h. • High doses. • With probenecid. • Depot forms. • Inact. by gastric a. • Penicillinase sens. • Narrow margin.

37. 1. Inhibitors of Cell Wall Synthesis, the β-lactam penicillins • Advantages; • Acid resistance. • Penicillinase resistance. • Spectrum; combination with inhibitors of penicillinase (clavulanic acid, sulbactam, tazobactam).

38. 1. Inhibitors of Cell Wall Synthesis; the β-lactam cephalosporins 7-aminocephalosporanic acid • Transpeptidase inhibitors.. • Acid stable. • Resistant to Penicillinase and β-lactamase but Cephalosporinase sensitive. • Broad-spectrum antibacterials and well tolerated by patients. • All can cause allergic reactions, some also renal injury, and bleeding.

39. Inhibitors of Cell Membran Synthesis; • Bacitracin and vancomycin • Disrupt cell wall synthesis by inhibiting transpeptidase. • Active only against gram-positive bacteria. • Markedly nephrotoxic. • Transpeptidase inhibitor. • Used in bowel inflammations occurring as a complication of antibiotic therapy. • It is not absorbed orally.

40. 2. Inhibition of folate synthesis; sulfonamides & trimethoprim • DHF is made from folic acid, a vitamin that cannot be synthesized in the body, but must be taken up from exogenous sources. • THF is a co-enzyme in the synthesis of purine bases and thymidine. • Most bacteria are capable of synthesizing DHF, from p-aminobenzoic acid. • Selective interference with bacterial biosynthesis of THF can be achieved with the bacteriostatics sulfonamides and trimethoprim. • Sulfonamides act as false substrates. • Trimethoprim inhibits bacterial DHF reductase, the human enzyme being significantly less sensitive than the bacterial one. • Co-trimoxazole is a combination of trimethoprim and sulfamethoxazole. • Sulfasalazine is used to treat ulcerative colitis and terminal ileitis or Crohn’s disease.

41. 3. Inhibition of nucleic acid synthesis; rifampin, quinolones and metronidazole Substances that inhibit reading of genetic information at the DNA template damage the regulatory center of cell metabolism. • The gyrase catalyzes DNA opening, underwinding, and closing the DNA double strand underwinding. • Quinolones are inhibitors of bacterial gyrases. • Quinolones are used for infections of internal organs and urinary tract infections. • The bactericidal metronidazole, damage DNA by complex formation or strand breakage. • Under anaerobic conditions, metronidazole will converted to reactive metabolites that attack DNA takes place (hydroxylamine). • Rifampin inhibits the bacterial enzyme that catalyzes DNA template-directed RNA transcription (RNA polymerase). • Rifampin acts bactericidally against mycobacteria (tuberculosis and leprosy), as well as many gram-positive and -negative bacteria.

42. 4. Inhibition of protein synthesis; tetracyclines, aminoglycosides, chloramphenicol, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,. • Protein synthesis means translation into a peptide chain of a genetic message first copied (transcribed) m-RNA. • Tetracyclines inhibit the binding of t-RNA-AA complexes. Their action is bacteriostatic and affects a broad spectrum of pathogens. Disadvantage: Inactivation by chelation of Ca2+, Mg2+, Al3+, Fe2+/3+ etc. • Aminoglycosides induce the binding of “wrong” t-RNA-AA complexes, resulting in synthesis of false proteins. Aminoglycosides are bactericidal. Their activity spectrum encompasses mainly gram-negative organisms. Disadvantage: Nephrotoxicity and Vestibular ototoxicity. • Chloramphenicol inhibits peptide synthetase. It has bacteriostatic activity against a broad spectrum of pathogens. Disadvantage: bone marrow toxicity.

43. 4. Inhibition of protein synthesis; erythromycin and clindamycin. • Erythromycin suppresses advancement of the ribosome. Its action is predominantly bacteriostatic and directed against gram-positve organisms. Erythromycin is well tolerated. It is a suitable substitute in penicillin allergy or resistance. • Azithromycin, clarithromycin, and roxithromycin are derivatives with greater acid stability and better bioavailability. The compounds mentioned are the most important members of the macrolide antibiotic group, which includes josamycin and spiramycin. An unrelated action of erythromycin is its mimicry of the gastrointestinal hormone motiline (↑ interprandial bowel motility). • Clindamycin has antibacterial activity similar to that of erythromycin. It exerts a bacteriostatic effect mainly on gram-positive aerobic, as well as on anaerobic pathogens. Clindamycin is a semisynthetic chloro analogue of lincomycin, which derives from a Streptomyces species. Taken orally, clindamycin is better absorbed than lincomycin, has greater antibacterial efficacy and is thus preferred. Both penetrate well into bone tissue.

44. 4. Inhibition of protein synthesis; tetracyclines, aminoglycosides, chloramphenicol, erythromycin and clindamycin.

46. Drugs for Treating Fungal infections Denture-induced stomatitis Oral Candidosis (Thrush) Angular Stomatitis • Fungi are plant-like non-photosynthetic Eukaryotes that may exist in colonies of single cells (yeast) or filamentous multicellular aggregates (molds or hyphae). • Human fungal infections have increased dramatically in incidence and severity due mainly to: • Denture wearing • Cancer treatment and the HIV epidemic. • Critical care accompanied by increases in the use of broad-spectrum antimicrobials. • Fungal infections can be divided into: • Superficial infections (affecting skin, nails, scalp or mucous membranes). • Systemic infections (affecting deeper tissues and organs) • Superficial infections caused by candida species may be treated with topical applications of clotrimazole, miconazole, ketoconazole, nystatin, or amphotericin B. • Chronic generalized mucocutaneous candidiasis is responsive to long-term therapy with oral fluconazole, terbinafine, ketoconazole. • Many antifungal agents are quite toxic, and when systemic therapy is required these agents must often be used under strict medical supervision.

47. Drugs for Treating Fungal infections • Imidazole derivatives; inhibit ergosterol synthesis. Fluconazole, itraconazole and ketoconazole are available for oral administration. May induceliver damage and inhibit steroidogenesis. • Polyene antibiotics; amphotericin B and nystatin bind with ergosterol, forming a transmembrane channel that leads to monovalent ion (K+, Na+, H+, Cl-) leakage. Amphotericin B is poorly tolerated (chills, fever, CNS disturbances, impaired renal function, phlebitis at the infusion site). • Flucytosine; disrupts DNA and RNA synthesis. It is well tolerated. • Griseofulvin; acts as a spindle poison to inhibit fungal mitosis. The need for prolonged administration, the incidence of side effects, and the availability of effective and safe alternatives have rendered griseofulvin therapeutically obsolete.

48. Disinfectants and Antiseptics • Disinfection = killing of pathogens. • Sterilization = killing of all germs. • Antisepsis = reduction of germ numbers on skin and mucosal surfaces. • These can be achieved by chemical or physical means [ionizing irradiation, dry or moist heat, or superheated steam (autoclave, 120 °C) to kill microorganisms]. • The basic mechanisms of action involve denaturation of proteins, inhibition of enzymes, or a dehydration. • Agents for chemical disinfection ideally should cause rapid, complete, and persistent inactivation of all germs, but at the same time exhibit low toxicity (systemic toxicity, tissue irritancy, antigenicity) and be non-deleterious to inanimate materials. • Disinfection of floors or excrement • Disinfection of instruments • Skin disinfection • Disinfection of mucous membranes • Wound disinfection

49. Dentifrices • Dentifrices are agents used along with a toothbrush to clean and polish natural teeth. • They are supplied in paste, powder, gel or liquid form. • Toothpaste essential components are an abrasive, binder, surfactant and humectant. • Abrasives are insoluble particles help remove plaque and calculus from the teeth. • The additional fluoride in toothpaste has beneficial effects on the formation of dental enamel and bones.