Drugs, Sex & Pharmacology PDF Fall 2023

Drugs, Sex & Pharmacology PCOL825A, Fall 2023 DrugsSexRnR 1 1 Phases of The Human Sexual Response ! The human sexual response is generally broken down into four major neurobiological phases • sexual desire or sexual want or urge (libido)* • arousal or excitement phase in which the body prepa...

Drugs, Sex & Pharmacology PCOL825A, Fall 2023 DrugsSexRnR 1 1 Phases of The Human Sexual Response ! The human sexual response is generally broken down into four major neurobiological phases • sexual desire or sexual want or urge (libido)* • arousal or excitement phase in which the body prepares for intercourse: erectile tissues swell, heart rate and respiration generally increase, there is enhanced tactile sensitivity, possible flushing of the skin • sexual intercourse leading to possible orgasm, involving involuntary muscle contractions, emission/ejaculation (in males) and a general feeling of euphoria • resolution in which the body returns to its pre-excited state *Note: as formulated by Masters & Johnson (1966) in their ground-breaking model of the human sexual response cycle, they identified four phases. However, in contrast to the above, “sexual desire” was not included as a specific phase and the “sexual intercourse/orgasm” phase shown above was split into separate phases: “plateau” and “orgasm”. 2 2 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 1 Drugs, Sex & Pharmacology PCOL825A, Fall 2023 The “Active” Phases of The Human Sexual Response Differ in Their Neurobiological Underpinnings ! Sexual desire or libido is largely a function of the cerebral cortex and is heavily influenced by cultural and/or social factors • testosterone appears to be “permissive” in both men and women, but there is no direct correlation between circulating levels and the extent of desire • activation of dopaminergic signaling pathways influences sexual desire Venus of Urbino, Titian, 1538 Barberini Faun, Greek, 2nd century BC 3 3 The “Active” Phases of The Human Sexual Response Differ in Their Neurobiological Underpinnings ! Sexual arousal involves an interplay between the autonomic nervous system and peripheral sensory nerves as well as the cerebral cortex to influence smooth muscle contraction/relaxation in erectile tissues ! Orgasm involves the autonomic nervous system and activation of a sacral-spinal reflex leading to stimulation of somatic motor nerves resulting in contraction of skeletal muscles in the genital-anal region Le Baiser, Auguste Rodin, 1882 4 4 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 2 Drugs, Sex & Pharmacology PCOL825A, Fall 2023 Neurobiology of Erectile Tissue/Non-Aroused State Sympathetic NS tonic activity-inhibitory Som atic release of NE, activation of a1-AR vascular SM contraction decreased blood flow flaccid 5 5 Neurobiology of Erectile Tissue/Sexual Arousal Sympathetic NS tonic activity OFF ON 3-Types of Arousal • psychogenic • reflexogenic • nocturnal (REM) Parasympathetic NS activation-facilitatory Som atic release of nitric oxide (NO) vascular smooth muscle relaxation swelling of the erectile tissue 6 6 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 3 Drugs, Sex & Pharmacology PCOL825A, Fall 2023 Swelling Occurs When Relaxation of the Vascular Smooth Muscle (SM) Allows Blood to Flow into the Sinusoidal Spaces ! The helicine arteries and trabecular SM surround the sinusoidal spaces and contraction of the SM prevents swelling (flaccid) I ie ! Nitric oxide (NO) stimulates the formation of cGMP causing relaxation of the SM ! Relaxation the SM allows blood to flow into the sinusoidal spaces and swelling occurs (erect) ump.si ! Type-5 phosphodiesterase (PDE-5) breaks down cGMP to reverse the process ! Inhibitors of PDE-5 prevent the break down of cGMP; thus, promoting relaxation and swelling m Erect sinusoidal spaces Flaccid Smooth Muscle Cell helicine arteries trabecular smooth muscle 7 7 Ejaculation and Orgasm Involves the Activation of Genital Sensory Afferent Nerves and a Sacral-Spinal Reflex (5HT2A receptor activation inhibits) in males results in activation of efferent sympathetic nerves and the movement of sperm, prostate and seminal fluid into the bulbar urethra (emission) due to SM contraction (NE a1-AR) followed by ejaculation (males) and orgasm (males and females) due to activation of efferent somatic motor nerves Som atic and contraction of skeletal muscles in the genital/anal region; due to activation of nicotinic receptors by acetylcholine vas deferens prostate seminal vesicles tactile activation of sensory afferents 8 8 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 4 Drugs, Sex & Pharmacology PCOL825A, Fall 2023 Skeletal Muscles Stimulated During Orgasm Bulbar Urethra--where sperm, prostate and seminal fluid collect prior to ejaculation 9 9 Drugs can Both Interfere and Facilitate Sexual Function ! Interference can be very distressing and can lead to poor compliance ! Facilitation can improve quality of life ! Treating sexual dysfunction issues should involve a multidisciplinary approach and, where appropriate, involve the potential sexual partners ! Before relying on a pharmacological approach, consideration should be given to interpersonal issues and modifying behaviors that may contribute to sexual dysfunction issues 10 10 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 5 Drugs, Sex & Pharmacology PCOL825A, Fall 2023 Drugs May Act at Several Levels of Sexual Function: Sometimes with Opposing Effects ! Ethanol is a good example: • as noted by Shakespeare in Macbeth, “it provokes the desire, but it takes away the performance” ! Phentolamine is another example: • it can facilitate erection/arousal by blocking the tonic activity of the sympathetic NS; but can interfere with emission/ejaculation, which also depends upon sympathetic NS activation ! A rule of thumb: if a problem develops after the initiation of drug therapy, there is a good chance it is drug-related ! But, if the onset of problems is slow, or if sexual activity is infrequent, the association of sexual dysfunction with drug use may be missed ! The good news, most drug-induced sexual problems are reversible 11 11 Antidepressants and Sexual Function ! Stimulation of 5HT2A receptors in the sacral spinal cord by serotonin (5HT) can interrupt the genital-sacral-spinal reflex required for ejaculation and orgasm resulting in sexual dysfunction ! Increased 5HT in the CNS also appears to decrease sexual desire ! Use of antidepressants that inhibit 5HT reuptake (SSRIs, TCAs, SNRIs, etc.) are frequently associated with sexual dysfunction, most commonly anorgasmia and decreased desire ! Bupropion and nefazodone have fewer issues related to sexual dysfunction; followed by mirtazepine and trazodone ! In rare cases the use of some antidepressants is associated with priapism (probably a1-AR antagonism) and spontaneous orgasm, often associated with yawning (dopamine related???) 12 12 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 6 Drugs, Sex & Pharmacology PCOL825A, Fall 2023 Antipsychotics and Sexual Function ! A proper functioning dopaminergic (DA) signaling pathway appears to be important for the maintenance of sexual desire ! This is supported by the evidence that the blockade of DA receptors by antipsychotics is frequently associated with decreased libido ! Ejaculation and orgasm may also be adversely affected by antipsychotics due to “off target” a1-AR antagonism ! Hyperprolactinemia caused by many antipsychotics can also decrease sexual desire and arousal in both men and women by inhibiting the secretion of gonadotropin-releasing hormone (Gn-RH), resulting in decreased levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone and estrogen 13 13 Antihypertensives and Sexual Function ! Antihypertensives that block a1-AR’s (eg, prazosin, phentolamine, etc) can interfere with ejaculation and orgasm ! Centrally acting sympatholytics (methyl dopa) and peripherally acting agents (guanethidine and reserpine) may also cause sexual dysfunction ! Spironolactone has significant anti-androgenic activity, which can decrease sexual desire and interfere with arousal and orgasm ! Thiazide diuretics and beta-blockers may also interfere with sexual function; but the evidence is not strong and the mechanism unknown ! ACE inhibitors have NOT been associated with sexual dysfunction ! Nitrates have been used to facilitate erection/arousal and are contraindicated with the use of PDE-5 inhibitors 14 14 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 7 Drugs, Sex & Pharmacology PCOL825A, Fall 2023 Drugs Used to Treat Erectile Dysfunction (ED) ! Prior to the development of the PDE-5 inhibitors, a number of approaches had been used (and still are used occasionally) • some foods and animal parts: usually the nastier, or more rare, the better • the first successful pharmacological approach involved an intra-penile injection of papaverine (smooth muscle relaxant) and phentolamine (a1-AR antagonist) • later Caverject® (alprostadil), also given by intra-penile injection, was developed which employed prostaglandin-E1 (smooth muscle relaxant) oysters ginseng 15 15 The Development of Viagra® (sildenafil) Revolutionized the Treatment of Erectile Dysfunction 16 16 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 8 Drugs, Sex & Pharmacology PCOL825A, Fall 2023 TYPE-5 PDE INHIBITORS RELATIVE SELECTIVITY FOR PDE ISOFORMS type PDE-1 sildenafil vardenafil tadalafil 375 1012 10500 avanafil 10192 PDE-2 heart PDE-4 PDE-5 1* 1 1 PDE-6 16 21 550 PDE-8 PDE-9 less selective between PDE-5 and PDE-6 4875 5952 1096 inflam 1 erectile 121 retina more selective for PDE-5 over PDE-6 PDE10 PDE11 vascular olfactory PDE-3 PDE-7 tissue 25 T-cell T-cell ?? 1192 brain 19231 ?? *Actual IC50's: sildenafil, 1 = 1.6 nM; vardenafil, 1 = 0.084 nM; tadalafil, 1 = 4.0 nM; avanafil, 1 = 5.2 nM From Kotera et al., J Urology 188:668-674, 2012 17 17 Major Side Effects of PDE-5 Inhibitors ! Headache (10-16%) ! Flushing (5-12%) ! Dyspepsia (4-12%) ! Nasal congestion (~4%) ! Orthostatic hypotension (2-3%, much higher risk with nitrates) ! Impaired color vision (~3%, less with avanafil and tadalafil) ! Priapism (rare) ! Hearing loss (rare) ! Sudden death (rare) 18 18 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 9 Drugs, Sex & Pharmacology PCOL825A, Fall 2023 PDE-5 Inhibitors: Other Indications ! Pulmonary arterial hypertension • sildenafil • tadalafil ! Benign prostatic hyperplasia • tadalafil ! Other off-label or experimental indications • vasospasm, Raynaud’s phenomenon • anti-depressant induced sexual dysfunction • premature ejaculation • high altitude pulmonary edema • female sexual dysfunction 19 19 Female Sexual Dysfunction (FSD) ! The symptoms of FSD fall into four broad categories • low sexual desire • normal sexual desire, but impaired arousal; or an absence or lack of desire that causes marked distress and/or interpersonal difficulties (HSDD, DMS-5) • difficulty with orgasm • pain during sexual activity, including intercourse ! There are wide variety of potential causes, which may be interrelated • physical: this could include medical conditions (eg, neuropsychiatric disorders, heart disease, diabetes, etc) and the drugs used to treat these conditions • hormonal, especially related to aging and menopause Agnolo Bronzino The Triumph of Venus (c. 1545) 20 20 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 10 Drugs, Sex & Pharmacology PCOL825A, Fall 2023 Female Sexual Dysfunction (FSD) ! Psychological and social • untreated anxiety and depression, life-stress, history of sexual abuse • unresolved conflicts with a partner about sex and/or other issues Agnolo Bronzino The Triumph of Venus (c. 1545) 21 21 Potential Treatments for Female Sexual Dysfunction ! Estrogen replacement in post-menopausal women (also post-ovariectomy) • must be balanced by increased risk of cardiovascular disease ! Testosterone replacement • testosterone patch (Intrinsa®)-approved in Europe, but not U.S. • testosterone gel (LibiGel®)-phase-3 trials ! Sildenafil?? Tested, but failed: a possible reason • the role of turning “off” the inhibitory sympathetic pathway • versus turning “on” the facilitatory parasympathetic pathway • the “off” pathway may be more dominant in women because of the evolutionary “cost” of pregnancy ! OTC lubricants, mechanical devices, other.. Vella®, Scream Cream®?? ! In 2015 the FDA approved flibanserin (Addyi®).. but??? ! In 2019 the FDA approved bremelanotide (Vyleesi®).. but??? 22 22 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 11 Drugs, Sex & Pharmacology PCOL825A, Fall 2023 There are Serious Issues Concerning the Efficacy and Safety of Flibanserin ! Results from 5 published and 3 unpublished studies* involving 5,914 women showed the following results: • the number of satisfying sexual events increased from 2.8 to 4.5 times/month; but the placebo group showed an increase from 2.7 to 3.7 times/month • ~1 in 8 patients discontinued due to Adverse Events • the incidence of dizziness = 11.4% • the incidence of sleepiness and fatigue ~10% • the incidence of nausea = 10.4% • it took 4 weeks of treatment to see an effect • the women’s overall feeling of improvement was small to none • should not be taken with alcohol • the initial cost was ~$800.00/month an increase of 0.7 “satisfying sexual events” per month!! *Jaspers et al. JAMA Intern Med. Published online February 29, 2016. doi:10.1001/jamainternmed.2015.8565 23 23 Flibanserin was Originally Developed as an Antidepressant ! Pharmacologically flibanserin is a serotonin 5-HT1A receptor agonist; 5-HT2A antagonist; and a dopamine D4 receptor partial agonist ! Flibanserin appears to affect sexual desire and perhaps arousal by actions within the CNS ! Flibanserin does not act peripherally on the sexual organs to directly affect sexual arousal (genital engorgement/lubrication) ! Flibanserin must be taken chronically, once a day, for at least four weeks to show an effect 24 24 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 12 Drugs, Sex & Pharmacology PCOL825A, Fall 2023 Flibanserin Should Never Have Been Approved for the Treatment of Female Sexual Dysfunction ! In the conclusions of the FDA’s own Clinical Medicine Reviewers: “flibanserin’s effects on low sexual desire, though statistically significantly greater than placebo, are of marginal clinical benefit and do not outweigh the clinically significant and potentially life-threatening risks associated with this chronically administered product” ! In fact it was not approved when it was reviewed in 2010 and 2013 ! However in 2015 it was approved after pressure was put on Congress and the FDA by a “women’s advocacy group” called Even the Score ! The Even the Score campaign was managed by Blue Engine Message & Media, a public relations firm hired by Sprout Pharmaceuticals, the company which owned the rights to flibanserin ! Two days after the FDA approved flibanserin, Sprout was acquired by Valeant Pharmaceuticals for ~$1 billion in cash 25 25 Flibanserin Should Never Have Been Approved for the Treatment of Female Sexual Dysfunction Addyi approved Aug 15, 2015 26 26 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 13 Drugs, Sex & Pharmacology PCOL825A, Fall 2023 Bremelanotide Isn’t Really Much Better ! Nonselective melanocortin receptor agonist originally developed as a potential sunless tanning agent (melanotan) ! Injected under the skin ~45 minutes before anticipated coitis ! 25% of patients receiving Vyleesi had an increase of 1.2 in their “sexual desire score” (out of 6); compared to 17% of the controls ! 35% of patients receiving Vyleesi had a decrease of 1 or more in their “sexual distress score” (out of 4); compared to 31% of the controls ! There were no differences in the number of “satisfying sexual events” ! 40% of patients experienced nausea; 20% flushing; 11% headache ! 1% reported darkening of the gums and parts of the skin including the face and breasts, which did NOT go away in half the patients ! increases in systolic (6 mm) and diastolic (3 mm) were observed that generally resolved within 12 hrs 27 27 Is it possible that some of the issues related to the diagnosis and treatment of FSD are a selfserving medicalization of women’s sexuality by the pharmaceutical industry to create an unrealistic “solution” for a “problem” that might be more about making money than solving a problem?? 28 28 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 14