GROUP 14 PHARMACOLOGY PRESENTATION SLIDES.pptx

MAKERERE UNIVERSITY

1. Pharmacotherapy of BPH, Cancer of the prostate and Erectile Dysfunction NAMES OF STUDENTS REGISTRATION NUMBER YIKI ISAAC 22/U/20823/HTP AWOR MOLLY 22/U/20687/HTG NAKIMPI HARRIET 22/U/20817/HTP 11/15/2024 6:52:56 PM 1

2. BENIGN PROSTATIC HYPERPLASIA Learning objectives What is benign prostatic hyperplasia? What are the causes/risk factors for BPH? Pathophysiology of BPH. Clinical manifestations of BPH. Classes of drugs used in the management of BPH. Examples of drugs commonly used in the management of BPH. Pharmacodynamics of the common drugs used. Pharmacokinetics of the common drugs used . 11/15/2024 6:52:57 PM 2

3. BENIGN PROSTATIC HYPERPLASIA BASICS Acronym : BPH. Synonym : Benign Prostatic Hypertrophy. Definition : It is a condition in which there is proliferation of both the smooth muscle and epithelial cell lines of the prostate. This results in increased volume of the prostate and may cause compression of the urethra and obstructive symptoms (see Figure 1 in slide 4 page 4) Clinically presents with storage and/or voiding symptoms collectively referred to as lower urinary tract symptoms (LUTS). These include difficulty initiating stream, frequency, or dysuria. 11/15/2024 6:52:57 PM 3

4. COMPARING A NORMAL AND ABNORMAL PROSTATE GLAND DUE TO BPH Normal BPH Hypertrophied detrusor muscle Obstructed urinary flow PROSTATE BLADDER URETHRA Roehrborn CG, McConnell JD. In: Walsh PC et al, eds. Campbell’s Urology. 8th ed. Philadelphia, Pa: Saunders; 2002:1297-1336. 11/15/2024 6:52:57 PM 4

5. Pathophysiology and aetiology ……..1……. BPH is common and involves a complex pathophysiology with several endocrine and local factors and a remodeled microenvironment. Its relationship to aging is well documented. At birth the prostate is pea sized, and growth of the gland is gradual until puberty. A period of rapid development continues until the third decade of life, when the prostate reaches adult size. Around 40 to 45 years of age, benign hyperplasia begins and continues slowly until death. Although dihydrotestosterone (DHT) is necessary for normal prostatic development, its role in BPH remains unclear. 11/15/2024 6:52:57 PM 5

6. 11/15/2024 6:52:57 PM 6 Pathophysiology and aetiology ……..2……. Develops in prostatic periurethral or transition zone (see Figure 2 in slide 7) Hyperplastic nodules of stromal and epithelial components increase glandular components. On contraction causes obstructive voiding symptoms- dynamic component of BPH. Increased prostatic mass mechanically blocks the urethra – static component of BPH. Exact aetiology is unknown.

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8. 11/15/2024 6:52:57 PM 8 RISK FACTORS Most significant risk factor is age. Increased risk with higher free prostate-specific antigen (PSA) levels, heart disease, and use of β -blockers. Low androgen levels from cirrhosis/chronic alcoholism can reduce the risk of BPH. Obesity and lack of exercise can cause LUTS to be more significant. No evidence of increased or decreased risk with smoking, alcohol, or any dietary factors

9. BPH HAS TWO COMPONENTS A static component that is related to the enlargement of the prostate (obstructing urethra); and. A dynamic component that represents the tone or the degree of contraction of the smooth muscle within the prostate. It is mediated by α1 adrenergic receptors (and is increased in BPH due to increase in muscle mass). This resists urine outflow. 11/15/2024 6:52:57 PM 9

10. Clinical manifestations Obstructive Symptoms Hesitancy Weak urine stream Straining to pass urine Prolonged micturition Feeling of incomplete bladder emptying Urinary retention. Leaking Urine Filling/storage Symptoms Increased Urgency Increased Frequency. Nocturia Urge incontinence COMPLICATIONS Acute urinary retention. Frequent infections w/c may worsen symptoms. Sexual dysfunction, including erectile dysfunction and ejaculatory disorders’ Haematuria . 11/15/2024 6:52:57 PM 10

11. Criteria of general management of BPH Comprehensive History taking. General physical examinations Laboratory Examinations Radiology/imaging . AVAILABLE OPTIONS DURING TREATMENT: Pharmacological treatment. Surgical treatment. Regular Follow up in patients with mild symptoms 11/15/2024 6:52:57 PM 11

12. Ultrasound results and Laboratory results indicative of BPH 11/15/2024 6:52:57 PM 12

13. Classes of drugs used in managing BPH Non selective alpha 1 antagonists a) Short acting: Prazosin, Alfuzosin b) Long acting: Terazosin, Doxazosin Selective alpha 1 A antagonists Tamsulosin , Silodosin Antiandrogens: 5- alpha reductase inhibitors Finasteride , Dutasteride Miscellaneous PDE 5 inhibitors – Sildenafil, Tadalafil GnRH agonists – Naferelin acetate, Leuprolide AND add Antibiotics if infections are present 11/15/2024 6:52:57 PM 13

14. Distribution of Alpha Receptors in the Prostate and Bladder Pelvic Floor External Sphincter Internal Sphincter Trigone Detrusor Prostate Gland 11/15/2024 6:52:57 PM 14

15. Distribution of alpha receptors on the prostate and the urinary bladder………2……... 11/15/2024 6:52:57 PM 15

16. Alpha 1 adrenergic receptor blockers. Suffix…… osin . More effective. Less toxic. Their action is immediate. They act on the dynamic component and relax smooth muscles in prostatic capsules, bladder neck (trigone) and urethra . Thus, they reduce the bladder neck resistance to the urine outflow. They also have additional antihypertensive effect. Drugs are- Prazosin Terazosin Doxazosin Alfuzosin Tamsulosin Silodosin 11/15/2024 6:52:57 PM 16

17. 11/15/2024 6:52:57 PM 17 PRAZOSIN A quinazoline derivative that acts selectively by blocking postsynaptic α1 receptors Brand name: Minipress IUPAC name: [ 4-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-1-piperazinyl](2-furyl) methanone . Formulation: A capsule MECHANISM OF ACTION Action on α 1 > α 2 Potent inhibitor of cyclic nucleotide phosphodiesterases . Thus, it: Dilates the arteries (lowering blood pressure) and the veins (reducing the venous return and cardiac output); Reduces the tone of the internal sphincter of the bladder thus decreasing the resistance to urinary outflow in patients with benign prostatic hyperplasia .

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19. PK Well absorbed orally Bioavailability 50 – 70 % Tightly bound to plasma proteins Metabolized in liver Short Duration of action 7 to 10 hrs Initial dose 1mg at bed time Off label use in BPH, 1-5mg, twice daily Excreted in the urine 11/15/2024 6:52:57 PM 19 It does not cause tachycardia as it does not block presynaptic α2 receptors

20. Terazosin Structural analog of prazosin More soluble in water than prazosin More effective than finasteride in treatment of BPH Bioavailability is 90%, highly protein bound t 1/2 is 12 hrs, duration of action more than 18 hrs, once daily dosing Metabolized in by demethylation , dealkylation in liver 40% excreted in urine 11/15/2024 6:52:57 PM 20

21. 11/15/2024 6:52:57 PM 21 Contraindications : In patients with known sensitivity to quinazolines Side effects – First dose hypotension, dizziness, fatigue Used with caution in patients taking diuretics, other antihypertensive agents, phosphodiesterase 5 inhibitors Dosage : initially 1 mg daily at bed time, 10 mg/day for maximal effect in BPH

22. Doxazosin Structural analog of prazosin Bioavailability 65%, highly protein bound t 1/2 is 20 hrs, duration of action around 36hr Metabolized in by demethylation , dealkylation in liver Most of the metabolites are excreted in feces Contraindications In patients with known with sensitivity to quinazolines 11/15/2024 6:52:57 PM 22

23. 11/15/2024 6:52:57 PM 23 DRUG INTERACTIONS OF DOXAZOSIN Used with caution in patients taking diuretics, other antihypertensive agents, phosphodiesterase 5 inhibitors, in hepatic dysfunction Side effects – first dose hypotension, dizziness, fatigue, headache Dosage : intially 1 mg, maintainace dose is 1 – 8mgdaily Extended release formulations are also available

24. Alfuzosin Used extensively for treatment of BPH, not approved for treatment of HTN Bioavailability 64% t 1/2 is 3-5 hrs Substrate for CYP3A4 Contraindicated in patients with moderate to severe hepatic impairment, known hypersensitivity, in patients taking other CYP3A4 inhibitors Avoided in patients with prolonged QT syndrome Dosage: 10 mg extended release tablet daily 11/15/2024 6:52:57 PM 24

25. SELECTIVE ALPHA 1A AND ALPHA 1D ADRENERGIC RECEPTOR ANTAGONISTS Tamsulosin and Silodosin are usually preferred. In the doses used, they rarely cause hypotension and syncope, which may occur following less selective α1 antagonists due to their action on vascular smooth muscle. Tamsulosin may however, cause diminished or retrograde ejaculation. Intraoperative Floppy Iris syndrome (IFIS) has been reported during cataract surgery in patients taking alpha blockers. History of intake of tamsulosin or other α1 blockers should be elicited prior to cataract surgery. The other ocular adverse effects include blurred vision and amblyopia(Lazy eye) 11/15/2024 6:52:57 PM 25

26. Tamsulosin Brand names: Faramsil MR, Flomaxtra XL, Pamsvax XL , Tabphyn MR etc. Formulations Tablets A Benzene sulfonamide More effective in treatment of BPH, little effect on BP Well absorbed t 1/2 is 5 – 10 hrs Extensively metabolized by CYPs As α1-adrenergic blockers cause relaxation of the ureteric muscle and may allow the passage of a small stone , tamsulosin has been used to treat patients with ureteral stones measuring less than 1 cm , especially those in the distal ureter. 11/15/2024 6:52:57 PM 26

27. 11/15/2024 6:52:57 PM 27 Contraindications In patients with sulfa allergy. In patients taking CYP inhibitors Side effect R etrograde ejaculation. Intra operative floppy syndrome Dosage : 0.4mg starting dose, maintain with 0.4-0.8mg SILODOSIN A Selective for α 1A receptors t 1/2 is 13-14 hrs Metabolized by glucuronidation Dosage: 8 mg daily Side effects: retrograde ejaculation Contraindicated in patients with renal impairment, severe hepatic impairment

28. 5 alpha reductase inhibitors. Suffix …. steride . In prostate, testosterone converted to dihydroxy testosterone ( DHT ) by 5 alpha reductase enzyme. DHT increases the growth in prostate Drugs : Finasteride Dutasteride 11/15/2024 6:52:57 PM 28

29. Two 5 -Reductase (5AR) Isoenzymes Convert Testosterone to DHT Testosterone Type II 5AR Type I 5AR Prostate enlargement DHT 11/15/2024 6:52:57 PM 29

30. Near Complete DHT Suppression Requires Inhibiting Both 5 AR Isoenzymes Dutasteride Dutasteride Finasteride Prostate volume reduced Bartsch G et al. Eur Urol . 2000;37:367 380. DHT Testosterone Type II 5AR Type I 5AR 11/15/2024 6:52:57 PM 30

31. 11/15/2024 6:52:57 PM 31 FINASTERIDE Brand names : Proscar and propecia Chemical name: 17β-(N-tert- butylcarbamoyl )-4-aza-5α-androst-1-en-3-one . PK Bioavailability 63% t 1/2 is 6-8 hrs Dosage 5 mg daily Excreted in urine, semen Effective only in patients with palpably enlarged prostate in comparison to the alpha 1 adrenergic receptor antagonists that are effective in patients with or without enlargement.

32. 11/15/2024 6:52:57 PM 32 PD MODE OF ACTION A 5-alpha reductase inhibitor. Mechanism of action Inhibits type 2 isoform of 5 alpha reductase hence blocks the conversion of testosterone to dihyidrotesterone especially in the male external urethra. This enzyme changes testosterone to another dihyidrotesterone hormone that causes the prostate to grow. It will increase testosterone levels in the body, which decreases prostate size. The effect of finasteride will only last as long as the medicine is taken.

33. 11/15/2024 6:52:57 PM 33 Therapeutic uses • Benign prostatic hyperplasia : Given orally in the dose of 5 mg daily, it causes 40-50% improvement in about 50% of the patients after several months of use. Hence it is combined with α1 blocker. • Androgenetic alopecia in men: 1 mg/day. Adverse reactions: It can cause occasional decreased libido, diminution in semen volume and impotence. Women of child bearing age should avoid handling crushed or broken tablets as the drug, after absorption through the skin, can cause abnormalities of the external genitals of a male fetus, should the woman be pregnant. As finasteride is excreted in the semen, the use of a condom is recommended if the sexual partner is pregnant or is likely to become pregnant. Contraindications Contraindicated in patients with obstructive uropathy or prostate cancer

34. Dutasteride An analog of finasteride with similar properties excep ; Inhibits both isoforms of 5 alpha reductase Bioavailability 60% Half life is 5 wks Metabolized by cytochrome p 450 Dosage: 0.5mg daily Side effects: decreased libido, ejaculatory dysfunction, impotence, gynaecomastia 11/15/2024 6:52:57 PM 34

35. 5 alpha reductase inhibitors and alpha blocker combination 0.5mg Dutasteride & 0.4 mg Tamsulosin combination Used in treatment of symptomatic BPH in men with enlarged prostate 11/15/2024 6:52:57 PM 35

36. PDE 5 INHIBITORS. Suffix ……. afil . Mechanism of Action of Phosphodiesterase 5 inhibitors : Selective inhibitor of cGMP specific PDE5 Decreases cGMP conc. in corpus cavernosa & pulmonary arteries, in smooth muscles of prostrate, bladder & blood vessels. 11/15/2024 6:52:58 PM 36 This Photo by Unknown Author is licensed under CC BY

37. TADALAFIL PDE-5 inhibitor 5 mg OD has been reported to relieve some urinary symptoms of BPH but does not significantly improve the urinary flow rate. It is much less effective than α1 blockers. Half life – 17 hrs. Metabolized by CYP 450 Also used in pulmonary hypertension, erectile dysfunction If erection lasting for more than 4 hrs- requires emergency treatment. Contraindications : Patients using nitrates. Not combined with alpha blockers due to risk of bp lowering Stop- if sudden loss of vision in one or both eyes, if sudden decrease or loss of hearing Drug Interactions: CYP inhibitors increase Tadalafil exposure, and CYP inducers decrease exposure 11/15/2024 6:52:58 PM 37

38. SURGICAL TREATMENT INVASIVE MINIMALLY INVASIVE - Open prostatectomy Transurethral resection of prostate( TURP) Transurethral incision of prostate (TUIP) - Transurethral electro vaporizations ( TUEV) - Transurethral microwave thermotherapy (TUMT) - Transurethral needle ablation - Laser ablation - High intensity focused ultrasound - Transurethral ethanol ablation - Water induced thermotherapy 11/15/2024 6:52:58 PM 38

39. CANCER OF THE PROSTATE Learning objectives What is a prostate cancer? What are the causes/risk factors for cancer of the prostate? Pathophysiology of cancer of the prostate. Clinical manifestations of cancer of the prostate. Classes of drugs used in the management of cancer of the prostate. Examples of drugs commonly used in the management of cancer of the prostate. Pharmacodynamics of the common drugs used. Pharmacokinetics of the common drugs used . 11/15/2024 6:52:58 PM 39

40. Prostate Cancer 11/15/2024 6:52:58 PM 40 BASICS The prostate is a male reproductive organ that contributes seminal fluid to the ejaculate. The prostate gland is about the size of a walnut , averaging 20 to 25 g in volume in an adult male; tends to enlarge after age 50 years. Three distinct zones delineate the functional anatomy of the prostate: P eripheral zone (largest, neighbors rectal wall, palpable on DRE, most common location for prostate cancer), C entral zone (contains the ejaculatory ducts), A nd transition zone (located centrally, adjacent to the urethra). Prostatic epithelial cells produce prostate-specific antigen (PSA), which is used as a tumor marker and in screening.

41. Prostate Cancer Prostate cancer is the carcinoma of prostate gland that may spread to other parts of the body particularly bones and lymph nodes. Incidence According to the National Cancer Institute SEER data, an estimated 161,360 men in the United States will be newly diagnosed with carcinoma of the prostate ( CaP ) in 2017 ). Prevalence About 3 million men are living with CaP in the United States. An estimated 26,730 men in the United States died of CaP in 2017 Mean age at diagnosis is 66 years. Prostate cancer is the most commonly diagnosed nonskin cancer in men in the United States (~11.6% lifetime risk) and second leading cause of cancer death in men (only ~3% of all CaP results in CaP -related death) . 11/15/2024 6:52:58 PM 41

42. Pathogenesis of cancer of the prostate In prostate cancer, the cells of these prostate glands  mutate  into cancer cells. Mutation is majorly in p53 gene, BCL2 and ERK5 or alteration in Akt kinase signaling contribute toward the development of prostate cancer. The prostate glands require hormones, known as androgens that are involved in cell survival and apoptosis. Androgens: testosterone, dehydroepiandrosterone and dihydrotestosterone.   Initially, small clumps of cancer cells remain confined to prostate glands, a condition known as  carcinoma in situ or prostatic intraepithelial neoplasia (PIN). 11/15/2024 6:52:58 PM 42

43. Over time, these cancer cells begin to multiply and spread to the surrounding prostate tissue forming a tumor. Eventually, the tumor may grow large enough to invade nearby organs such as the nearby lymph nodes or the rectum, or metastasize to bone, lymphatic system and bladder. RISK FACTORS A complete understanding of the causes of prostate cancer remains UNCLEAR. Obesity Age Family History Lower levels of Vit. D Prostatitis Elevated Blood levels of Testosterone 11/15/2024 6:52:58 PM 43

44. Clinical manifestations Weak or interrupted urine flow Blood in urine Nocturia Dysuria Pain in Pelvis, spine and ribs Lymphedema Renal insufficiency GENERAL CRITERIA OF MANAGEMENT Comprehensive history taking. General Physical Examinations. Laboratory and radiological/imaging. Treatment. Follow up 11/15/2024 6:52:58 PM 44

45. Diagnostic Parameters Prostate-Specific Antigen Blood Test: Prostate-specific antigen (PSA) is a protein produced by the prostate gland. All men have a small amount of PSA in their blood, and it increases with age. Prostate cancer can increase the production of PSA, and so a PSA test looks for raised levels of PSA in the blood that may be a sign of the condition in its early stages. NORMAL PSA level should usually be below 2.5. Mostly PSA levels upto   4.0  ng/mL is considered as normal. ABNORMAL LEVEL OF PSA: I f a man has a PSA level above  4.0  ng/mL, doctors would often recommend a prostate biopsy to determine whether prostate cancer is present. If PSA level is very high, cancer has probably spread beyond the prostate. 11/15/2024 6:52:58 PM 45

46. 11/15/2024 6:52:58 PM 46 A SERUM PSA TEST RESULT OF A 65 YEAR OLD MALE TEST VALUE : 43.5ng/ml NORMAL REFERENCE VALUE 0 TO 4 ng/dl

47. 2. Digital Rectal Examination: DRE is useful in ruling out prostate enlargement caused by benign prostatic hyperplasia. 3. Biopsy: This aid in the diagnosis and help to determine the Gleason score. Gleason score: The samples of tissue from the biopsy are studied in a laboratory. If cancerous cells are found, they can be studied further to see how quickly the cancer will spread. This measure is known as the Gleason score. 11/15/2024 6:52:58 PM 47

48. The lower the score, the less likely the cancer will spread: A Gleason score of six or less means the cancer is unlikely to spread. A Gleason score of seven means there is a moderate chance of the cancer spreading. A Gleason score of eight or above means there is a significant chance the cancer will spread. 4. MRI and CT Scan: To access the extension into the bladder and lymph nodes for staging the cancer and to evaluate bone metastasis. 11/15/2024 6:52:58 PM 48

49. Treatment: Prostatectomy : Removal of Prostate gland. 2. Radiotherapy: External Beam Radiotherapy: Radiation directed towards the whole pelvis externally. Brachytherapy (radioactive seeds): Tiny radioactive seeds are placed in the body close to tumor. 3. Hormone Therapy: The goal is to reduce levels of hormones, called androgens, in the body, or to prevent them from reaching prostate cancer cells. There are different types of drugs that lower testosterone levels. 11/15/2024 6:52:58 PM 49

50. HORMONAL ANTAGONISTS ACTING ON THE HYPOTHALAMIC GONADOTROPIC AXIS 11/15/2024 6:52:58 PM 50 This Photo by Unknown Author is licensed under CC BY

51. Luteinising Hormone (LH) Blockers:   Luteinising hormone blockers stop the pituitary gland making the hormone. So the testicles don't receive the message telling them to make testosterone. Examples of LH blockers include: Leuprorelin Goserelin Acetate Buserelin Triptorelin Histrelin LH blockers are given as injections or as implants under the skin. THESE DRUGS ARE NOT COMMONLY USED 11/15/2024 6:52:58 PM 51

52. Anti Androgens: Anti-androgens stop androgens from working by binding to the receptors and stop testosterone to bind with receptors so that cancer can’t be able to grow. Examples of anti androgens include: Bicalutamide Flutamide Enzalutamide Anti-androgen treatment may be combined with LH blocker as first-line hormone therapy. This is called combined androgen blockade (CAB). 11/15/2024 6:52:58 PM 52

53. 4. Chemotherapy: Chemotherapy is sometimes used if prostate cancer has spread outside the prostate gland and hormone therapy isn't working.  For prostate cancer, chemotherapy drugs are typically used one at a time. Some of the chemo drugs used to treat prostate cancer include: Docetaxel Cabazitaxel 11/15/2024 6:52:58 PM 53

54. Doxorubicin Etoposide Vinblastine Paclitaxel Carboplatin In most cases, the first chemo drug given is docetaxel, combined with the steroid drug prednisone. If this drug does not work (or stops working), a newer drug called cabazitaxel is given specially in cases when cancer has stopped responding to hormone therapy and chemotherapy. 11/15/2024 6:52:58 PM 54

55. 11/15/2024 6:52:58 PM 55 DOCETAXEL Brand name: Taxotere Formulation: A solution for infusion:10mg/ml MECHANISM OF ACTION It exerts cytotoxic action by a novel mechanism. It binds to tubulin and enhances its polymerization to form excess of microtubules: a mechanism opposite to that of vinca alkaloids. The microtubules are stabilized and their depolymerization is prevented. This stability disrupts the normal dynamic reorganization of the microtubule network that is essential for interphase and mitotic functions. Abnormal arrays or 'bundles’ of microtubules are produced throughout the cell cycle. Cytotoxic action of paclitaxel emphasizes the importance of tubulin microtubule dynamic equilibrium

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57. PK OF DOCETAXEL PK is consistent with a three-compartment model . The initial rapid decline represents the distribution to the peripheral compartments, and the late (terminal) phase is partly due to a relatively slow efflux of docetaxel from the peripheral compartment. W idely distributed in tissues with a mean volume of distribution of 74 L/m2 after 100 mg/m2, every 3 weeks. Metabolism: Pimarily by the CYP3A4 isoenzyme . Excretion: The mean terminal elimination half-life is 116 hours (92 to 135 hours). Approximately 6% of docetaxel is excreted through urine, while about 75% is excreted through feces. 11/15/2024 6:52:58 PM 57

58. USES Other cancers managed with docetaxel Advanced or metastatic breast cancer Non-small cell lung cancer (after failure on other cytotoxic agents) Hormone-resistant prostate cancer (in combination with prednisolone) Gastric adenocarcinoma Head and neck cancer Operable node-positive and node-negative breast cancer 11/15/2024 6:52:58 PM 58

59. DOSE AND DURATION Administer as a one-hour infusion every 3 weeks Dose and duration depend on the patient, the type of cancer being treatment, neutrophil count and concurrent cytotoxic therapy. Pre-treat with oral dexamethasone as below Breast, non-small cell lung, gastric, head and neck cancers 16 mg per day (e.g. 8 mg twice daily for 3 days, starting on the day just before docetaxel administration Prostate cancer 8 mg given at 12 hours, 3 hours and 1 hour before docetaxel infusion 11/15/2024 6:52:58 PM 59

60. 11/15/2024 6:52:58 PM 60 Contra-indications Hypersensitivity to docetaxel. Patients with neutrophil count < 1,500 cells/mm3 Severe liver impairment Side effects Neutropenia, thrombocytopenia, anaemia Hypersensitivity reactions Localised skin erythema of hands and feet Infections Dyspnoea Alopecia, nail disorders Nausea, vomiting, diarrhoea , stomatitis, constipation Weakness, lethargy, pain

61. 11/15/2024 6:52:58 PM 61 Interactions CYP450 enzyme inhibitors e.g. ketoconazole, itraconazole, clarithromycin (increased risk of adverse reactions) Pregnancy Do not use Breast-feeding Discontinue breastfeeding Storage After reconstitution, store at 2−8°C Caution  Pre-treatment with oral dexamethasone or prednisolone is recommended for reducing fluid retention and hypersensitivity reactions  Men and women have to use effective contraception during and after treatment with docetaxel  Anticancer medicines should only be handled by HWs

62. ERECTILE DYSFUNCTION Learning objectives What is an erectile dysfunction? What are the causes/risk factors for erectile dysfunction? Pathophysiology of erectile dysfunction. Clinical manifestations of erectile dysfunction. Classes of drugs used in the management of erectile dysfunction. Examples of drugs commonly used in the management of erectile dysfunction. Pharmacodynamics of the common drugs used. Pharmacokinetics of the common drugs used . 11/15/2024 6:52:57 PM 62

63. ERECTILE DYSFUNCTION Honey: What is the problem today ,you are weak today. Boo: It’s not you . . ……………………… It’s me. Journal of Sexual Medicine 2007 Jan:4(1):57:65 Epub 2006 Nov 1 11/15/2024 6:52:58 PM 63

64. 11/15/2024 6:52:58 PM 64 BASICS Erectile dysfunction (ED) is the consistent or recurrent inability to acquire or sustain an erection of sufficient rigidity and duration for sexual intercourse. In the past, ED was assumed to be a symptom of the aging process in men, but it is more often the result of concurrent medical conditions of the patient or from medications that patients may be taking to treat those conditions. Sexual problems are frequent among older men and have a detrimental effect on their quality of life but are infrequently discussed with their physicians. Synonym(s): impotence

65. 11/15/2024 6:52:58 PM 65 Incidence by Race Not Significantly Different (40+) Whites – 22% Blacks – 24% Hispanics – 20% Increased Incidence Age Diabetes Mellitus Hypertension Moderate/Severe LUTS Decreased Incidence Exercise and college education – vs – less than HS

66. PHYSIOLOGY OF ERECTION Complex event involving integration of: Psychologic Neurologic Endocrine/Hormonal Vascular & Local anatomic systems Release of NO from NANC nerves and endothelial cells Stimulates guanylate cyclase enzyme system in penile smooth muscle ↑ levels of cGMP & ↓ Ca 2+ Smooth muscle relaxation Enhancement of arterial inflow / veno -occlusion → adequate firmness Return to flaccid state: cGMP is hydrolyzed to GMP by phosphodiesterase type 5 11/15/2024 6:52:58 PM 66

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68. 11/15/2024 6:52:58 PM 68 Psychogenic  Performance Anxiety, Depression  Loss of libido, Impaired NO release Neurogenic  Stroke , Spinal Cord Injury, DR  Lack of nerve impulse/transmission Hormonal  Hypogonadism , Hyperprolactinoma  Inadequate NO release Vasculogenic  Atherosclerosis , Hypertension  Impaired arterial or venous flow Medication-Induced  Antihypertensives , Antidepressants, etc.  Central suppression, Vascular Insuff

69. Antipsychotics, Antidepressants Disruption of serotonergic, noradrenergic, and dopamine neurotransmitter pathways involved in sexual function Amitriptyline, Buspirone, Fluoxetine, Sertraline Antihypertensives β-adrenergic Blockers – Potentiation of α-1 adrenergic activity in the penis Atenolol, Metoprolol, Propranolol, etc. Thiazide Diuretics – Unknown, but thought to be due to increased uric acid levels Ca 2+ -channel blockers, ACE-I, A 2 RBs 11/15/2024 6:52:58 PM 69 DRUG INDUCED IMPOTENCE

70. Drug induced impotence Proton Pump Inhibitors Inhibits DDAH; leads to increase of ADMA (inhibitor of NO)  decreases NO synthase. Induction of hepatic CYP-dependent testosterone metabolism in vitro. Conversion to β- hydroxytestosterone . Esomeprazole, Lansoprazole H 2 -receptor Antagonists ↓ libido; ↑ E ↑ prolactin (gynecomastia; galactorrhea) Erectile failure via an antiandrogenic effect Erection promoting action of histamine likely due to H 2 receptor activation Cimetidine 11/15/2024 6:52:58 PM 70

71. General management of erectile dysfunction involves; Comprehensive History taking. General physical examinations Laboratory Examinations Radiology/imaging . 11/15/2024 6:52:58 PM 71

72. CLASSES OF DRUGS USED Phosphodiesterase type 5 (PDE5) Inhibitors Sildenafil Citrate – 1998 25/50/100mg – max dose: 100mg* Vardenafil HCl – 2003;2010 2.5/5/10/20mg – max dose: 20mg* Tadalafil – 2003; (qd use, 2008) 2.5/5/10/20mg – max dose: 20mg*/5mg daily Avanafil – 2012 50/100/200mg – max dose: 200mg* 11/15/2024 6:52:58 PM 72

73. 11/15/2024 6:52:58 PM 73 Prostaglandin E 1 Alprostadil Physicians who prescribe intracavernous injection therapy should: (1) inform patients of the potential occurrence of prolonged erections. (2) have a plan for the urgent treatment of prolonged erections and (3) inform the patient of the plan. Alternative Options Papaverine, Pumps, Prosthesis/Implants Arginine, Yohimbine, Maca, Ginko biloba, Panax Ginseng Trazodone, Apomorphine, VIP, Testosterone, DHEA

74. 11/15/2024 6:52:58 PM 74 SILDENAFIL This methylpiperazine compound inhibits the enzyme PDE-5 in the corpora cavernosa of the penis, thereby prolonging the life of cGMP at that site. This causes relaxation of the smooth muscle of the corpora cavernosa permitting inflow of blood into the sinuses resulting in better erection. The presence of NO is essential for this action. It does not improve sex desire (libido), orgasm or ejaculation. By itself, it does not bring about erection but it improves the quality and duration of erection in response to sexual stimulation. It is not of much value in subject with loss of erection due to spinal or other damage to innervation, and in those who lack libido.

75. 11/15/2024 6:52:58 PM 75 GENERIC NAME: BRAND NAMES: IUPAC/CHEMICAL NAME : Pyrazol [4,3-d]pyrimidin-7-one. STRUCTURE: Absorption, fate and excretion: After a single oral dose, peak plasma level is reached in 30-120 minutes with bioavailability of 40%. High fat meal delays its absorption. The plasma t½ is 2-4 hours and its clinical effectiveness lasts for 4 hours. It is metabolised in the liver by CYP3A4. It is used in the dose of 25-100 mg on empty stomach, an hour before the intended coitus.

76. 11/15/2024 6:52:58 PM 76 Adverse reactions: Sildenafil causes headache, dyspepsia, nasal congestion and priapism. The drug potentiates the hypotensive effects of nitrates, and hence its administration to persons who are using nitrates in any form is dangerous. Further, there is some cardiac risk of angina or MI associated with sexual activity, especially in the elderly. As many users of drugs for impotence are likely to be elderly, although such therapy may increase the patients’ ‘ vigour ’ and make them feel ‘younger’ it can also increase the risk of morbidity and mortality during sexual activity.

77. 11/15/2024 6:52:58 PM 77 It occasionally imparts bluish tinge to vision due to its effect on the PDE-6 in the retina. It is contraindicated in persons with retinal degenerative disorders. The drug has been reported to cause Non- Arteritic -Ischemic Optic Neuritis (NAION), leading to acute loss of vision. The plasma levels of sildenafil and its ADR increase in subjects over age 65, those with renal/hepatic impairment and in those who are being concurrently treated with CYP3A4 inhibitors such as erythromycin.

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79. Summary ED is becoming increasingly prevalent and reported cases are expected to rise (+600k/year) Highly related to other disease states and may be preventable via non-pharmacologic interventions and lifestyle changes Drug Utilization Review should be considered when diagnosing/treating ED as many drugs can contribute to ED Commercial options are currently limited, but quickly growing Partnering with a compounding lab can provide several alternatives and has ability to customize therapy while improving and/or maximizing patient outcomes 11/15/2024 6:52:58 PM 79

80. REFERENCES GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS - 12th Ed. Pharmacology and Pharmacotherapeutics SATOSKAR , 23 rd edition - KATZUNG BASIC AND CLINICAL PHARMACOLOGY 12 th edition Essentials of medical pharmacology KD TRIPATI ,7 th edition Principles of Pharmacology HL SHARMA , KK SHARMA, 2 nd edition RANG AND DALE PHARMACOLOGY – 7 th edition 11/15/2024 6:52:58 PM 80

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