Infections and sex - Lecture notes 6 PDF

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PHA2022 Semester 2, 2020 Lecture notes with diagrams...

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Infections and sex PHA2022

DS Lesson

Learning outcomes  Discuss the concept of selective toxicity and its relevance to the treatment of infectious diseases  Describe, using specific examples, the potential targets of anti-infective agents  Explain the differences in development / effectiveness of antibacterial and antiviral drugs  Discuss problems associated with the use of drugs for the treatment of infectious diseases  Discuss the requirements for an effective contraceptive  Compare and contrast the various types of hormonal contraceptives with regards to mechanisms of action, risks and benefits  Compare and contrast drugs used for the treatment of erectile dysfunction with regards to mechanism of action, risks and benefits

Suggested readings Rang & Dale chapter 35 Female contraceptives 433434 Male contraceptives 436438

Infectious Diseases Infectious/invading organisms Viruses Prokaryotes

Bacteria Mycobacteria Eukaryotes Fungi Protozoa Helminths (worms) Prions Malignant/cancerous cells

Treating infectious diseases Our ability to control infectious diseases is a recent development We have developed many antiinfective drugs Antibiotics: Amoxicillin(amoxycillin) Cefalexin(cephalexin) Ciprofloxacin

Anti-virals:

Clarithromycin

Aciclovir

Doxycycline

Oseltamivir

Erythromycin

Ritonavir

Gentamicin

Tenofovir/emtricitabine

Isoniazid

Anti-protozoans:

Metronidazole

Atovaquone/proguanil

Rifampicin

Doxycycline

Vancomycin

Metronidazole

Anti-fungals: AmphotericinB

Quinine Anti-helminths:

Caspofungin

Albendazole

Fluconazole

Ivermectin

Old diseases - old problems Measles Tetanus Poliomyelitis Ebola Old diseases - new problems Malaria TB New diseases - new problems HIV Hendra virus Zika virus COVID19

Nosocomial infections Hospital acquired infections Examples: Ventilator-associated pneumonia Staphylococcus aureus Methicillin resistant Staphylococcus aureus Candida albicans Clostridium difficile Tuberculosis

Urinary tract infection Hospital-acquired pneumonia Gastroenteritis

Zoonotic infections Passed from animals to humans

Factors impacting our control of infectious diseases Rapid population growth → urbanisation War and political change Increased movement of people Changing pattern of human health Lack of effective and affordable weapons against infections

When are drugs needed? Our immune system is usually able to deal with things on its own, but in some people drugs are required Newborn babies do not yet have a strong immune system

People with existing diseases Immunocompromised people The elderly People on transplant medication Chemo patients

Selective toxicity Anti-infective drugs need to be toxic to the pathogen, but not to our own body To achieve selective toxicity: Identify the infecting organism Identify a target (pathway or structure) that is present in the pathogen but not the host Exploit differences in enzymes or structures between pathogen and host

Antibiotics

Targeting the cell wall Transpeptidases are enzymes unique to bacteria Targeting these enzymes causes weakening of the cell wall, leading to lysis and cell death Amoxycillin (a penicillin) targets transpeptidase Cephalexin (a cephalosporin) also targets transpeptidase - used in penicillin sensitive patients Targeting transglycosidases interferes with the synthesis of the cell wall Vancomycin (a glycopeptide) targets transglycosidase, and is reserved for the treatment of severe infections that are resistant to other drugs

Targeting the bacterial ribosome Mammalian = 80S 60S and 40S subunits) Bacterial = 70S 50 S and 30S subunits) Erythromycin is a broad spectrum antibiotic that targets the 50S subunit of the to prevent movement of the ribosome along the mRNA Cloramphenicol binds to the 50S subunit to inhibit formation of peptide bonds Tetracycline interferes with the attachment of tRNA to mRNA Streptomycin changes the shape of the 30S subunit, causing the mRNA to be read incorrectly

Antivirals Because virusus replicate intracellularly using host cell

machinery, there are limited targets for antiviral drugs At some stages in viral action there are virus-specific proteins, which can be a target However, these proteins are specific to the virus e.g. a drug that targets herpes virus proteins will not work against COVID19 Broad spectrum activity is therefore extremely difficult to achieve for antivirals

Problems with the use of antimicrobial drugs Our aim in all drug therapy is to produce drugs with a high selectivity for the pathogen i.e. a high therapeutic index

Adverse effects All antimicrobials cause some adverse effects We have to weigh up the benefits and side-effects to determine if a drug is useful in a particular case

Amoxycillin

Erythromycin

Targets cell wall → less adverse effects

Targets ribosomes → more adverse effects

More commonly prescribed

Prescribed when amoxycillin is not appropriate (penicillin hypersensitivity)

Effects on commensal microflora Not all microbes in the human body are pathogenic Human microbiome is really important for our health Taking antibiotics can upset the balance of microflora in the GIT e.g. e. coli is in our gut, and is only harmful in large numbers → possible after other populations in the gut have been wiped out This results in a superinfection

Antibiotic resistance “The greatest possibility of evil in self-medication is the use of too small doses so that instead of clearing up infection the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out which can be passed to other individuals and from them to others until they reach someone who gets a septicaemia or pneumonia which penicillin cannot save.” - Alexander Fleming, 1945 Microbes can fail to respond to a particular drug for various reasons: Naturally resistant strains are present Spontaneous mutations can cause resistance Transmission of genes from other organisms can introduce resistance

into a population Increased resistance → decreased effectiveness of drugs Multi-resistant bacteria → superbugs Consequences of antimicrobial resistance: Mortality Resistant infections are often more fatal Morbidity Prolonged illness → greater chance for resistant organisms to spread in the population Cost Increased cost of care Newer drugs are more expensive People are sicker for longer → in hospital for longer → treatment is more expensive Limited solutions Fewer new drugs being developed Factors contributing to the spread of resistance: Natural selection favours the survival of resistant strains (selection pressure) Indiscriminate use (medical and veterinary) Is an antibiotic actually needed? Is the right antibiotic being used? Is the dose and duration of the treatment appropriate? Counterfeit antibiotics In countries without rigorous drug approval processes

Infections and Sex Hormonal contraception (pre-class reading) We currently only have contraceptives for females, due to difficulties of working with the male reproductive system 1 egg per month vs 1 million sperm per day) Female ovulation: Mid cycle surge of FSH and LH triggers ovulation Oestrogen and progesterone render endometrium suitable for implantation and make cervical mucous more viscous, allowing sperm to enter more easily All female contraceptives contain a progesterone component, and some also contain an oestrogen component We can't give oestrogen alone, has negative effects Forms of hormonal contraception: Oral contraceptives (combined or progestin alone) Implant and injective (progesterone only) Vaginal ring (combination) Patch (combination) Contraceptive hormones: Inhibit gonadotrophin LH and FSH release, inhibiting ovulation Impede implantation Impede cervical mucous Components of hormonal contraceptives: Oestrogen component:

Ethinyl oestradiol EE Mestranon 3-methylether of EE Progestin component Derivatives of progesterone (e.g. medroxyprogesterone) Derivatives of testosterone 2nd generation (e.g. levonorgestrel and norethynodrel) - side effects include acne and unwanted hair growth 3rd generation (e.g. gestodene and desogestrel) cardiovascular effects have led to restrictions on their use Minor adverse effects: Weight gain Mild nausea Flushing Dizziness Depression Irratability Skin changes Serious adverse effects include cardiovascular complications such as DVT and PE (pulmonary emobolism) The risk of serious adverse effects is increased if they have other risk factors: Diabetes Family history Smokers Oestrogen containing formulations are associated with: Increased growth of breast cancer cells Migraines Decreased lactation (contraindicated for breast feeding women)

What makes a good contraceptive? Choice of contraceptives are based on:

Types of contraception and their effectiveness:

Effectiveness Side-effects Ease of use Stage of reproductive life Affordability Male birth control is really difficult to achieve In females we target the release of 1 egg per month, whereas in males we have to target around 100 million sperm per day Male contraceptive adverse effects: Acne Mood disorders Raised libido Female contraceptive adverse effects: Anxiety Weight gain Nausea Headaches Reduced libido Blood clots Cardiovascular issues A lot more things

Least effective have the least adverse effects, most effective have the most adverse effects

Combined oral contraceptives (COCs) The combined oral contraceptives are the most common contraceptives Contains both oestrogen and progesterone COCs have many non-contraceptive benefits: Lighter periods Regular cycles Reduces dysmenorrhoea (pain/cramps) Reduced premenstrual tension No ovulation pain Reduced blood loss Suppression of ovarian cysts and endometriosis Most COCs are available as 28 day regimens 21 active tablets and 7 sugar pills The hormone free interval HFI may reduce incidence of hormone withdrawal symptoms and can increase contraceptive effectiveness There are also extended cycle regimes (monophasic) Active tablets for more than 28 days e.g. Yaz Flex → 120 active pills and then a break

Types of COCs Classic COCs

Phasic COCs

Fixed dose of hormones

23 different doses

Further classified by dose of oestrogen

Mimics natural variation in the menstrual cycle

High → 50μg Standard → 30μg Low → 20μg

Long term effects of COCs

No adverse effects on overall mortality Beneficial effects: Protection against endometrial and ovarian cancers No adverse effects on cardiovascular outcomes

Progesterone only pill (POP) These use second generation levonorgestrel Also called the mini-pill Don't have the same multi-faceted action as the COC → only targets ovulation, not the endometrium and mucous Avoids the adverse effects associated with oestrogen content Can be used in breastfeeding women Can be taken by smokers Can be taken by people with a family history of thromboembolism No adverse effect of blood clotting (e.g. DVT Disadvantages: Headaches, bloating and weight gain are common Erratic bleeding Must be taken within 3 hours of regular time to be effective

Long lasting contraception Injection (depo) Progesterone only Medroxyprogesterone acetate 150mg every 12 weeks) Same mechanism of action as COCs Disadvantages: Can't withdraw dose (if adverse reaction)

Menstrual chaos (erratic bleeding) Delayed return of fertility Wight gain Bone density effects

Implant (implanon) Progesterone only Etonogestrel 68mg every 3 years) Same mechanism of action as COCs Advantages: Long action Steady blood levels Removable Disadvantages Menstrual chaos (erratic bleeding) Delayed return of fertility Wight gain Bone density effects

Emergency contraception (morning after pill) Prevents pregnancy after unprotected intercourse or possible failure of other contraceptive method Progesterone only Levonorgestrel 1.5mg) 84% efficacy if taken within 72hrs of intercourse Contraceptive effect up to 120hrs after intercourse Well tolerated, no contraindications Can cause vomiting in 15% of people

The emergency contraception pill has different mechanisms of action depending on the stage in the cycle Prior to ovulation → prevents or delays ovulation, alters uterine secretions and mucous After ovulation → alter uterine secretions and mucous, impair luteal function Does not provide ongoing contraception

Erectile dysfunction (ED) ED is the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance Prevalence is age related → 10% in early adulthood, up to 80% in old age

Organic causes of ED

Psychogenic causes of ED

Vascular disease

Depression

Medications

GAD

Smoking

Performance anxiety

Alcohol

Physiology of erection  Sexual arousal  Parasympathetic nerve stimulation  Nitric oxide release  GTP → cGMP  cGMP → 5'GMP (catalysed by PDE5  Vasodilation in corpus carvenosum

 Increased blood flow  Erection

Vasodilators Vasodilators were first trialled, but we don't want vasodilation everywhere Had to be injected into the penis which is a bit of a turn off, exacerbating the problem Includes papaverine and alprostadil Adverse effect → causes persistent erection without stimulus (painful, 4hrs) because it bypasses the sexual arousal part of erection

Viagra Sildenafil (viagra) inhibits PDE5, preventing the breakdown of cGMP, causing prolonged erection only when normal sexual stimulation is present Oral preparation (no injection needed) Peak concentration in 30120 mins Drug interactions → grapefruit juice, CYP inhibitors Side effects → vasodilation occurring elsewhere Hypotension Visual disturbances Ventricular tachycardia (can be serious) Contraindicated if taking nitrates Many elderly males (main demographic taking Viagra) are taking nitrates for cardiovascular problems

Other PDE-5 inhibitors Tadalafil Cialis) and Vardenafil Levitra) Similar efficacy and tolerability Differences in pharmacokinetics Sildenafil → 60 min onset, 34hr duration Tadalafil → 30 min onset, 36hr duration

Now used to treat hypertension, under a different name so that Viagra connotations aren't present...