F23-Week13-Slides PDF Pharmacology Lecture Notes

GALACTOGOGUES OXYTOCICS AND TOCOLYTICS OXYTOCICS FOR PPH Readings: Ch 28 & 29 in Pharmacology Revealed © Dr. E. Cates, Fall2023 1 AGENDA • • • • • • Final Exam Information Galactagogues Oxytocics and tocolytics for labour Oxytocics for PPH Tranexamic Acid Student presentations (start at 10:30)...

GALACTOGOGUES OXYTOCICS AND TOCOLYTICS OXYTOCICS FOR PPH Readings: Ch 28 & 29 in Pharmacology Revealed © Dr. E. Cates, Fall2023 1 AGENDA • • • • • • Final Exam Information Galactagogues Oxytocics and tocolytics for labour Oxytocics for PPH Tranexamic Acid Student presentations (start at 10:30) © Dr. E. Cates, Fall2023 2 FINAL EXAM INFORMATION Good luck on the final next week! Congratulations on a term well-done! • Monday December 11th from 0900-1200 • MDCL 2232 and 3019 • Check your writing location on TEAMS. If you go to the wrong room, moving to the correct location comes out of your writing time. • Approximately 135 points. • Cumulative • However, approximately 50% of final exam content will come from material covered since Test #2 • Drug names should be the generic, not the TRADE name, and be spelled correctly for full points • Remember your assigned readings, cases, and any additional CPGs assigned in class • MCQ, T/F, Short answer in the style you’ve seen before. © Dr. E. Cates, Fall2023 3 LAST TIME, ON PHARMACOTHERAPY… • Anti-Emetics • Pain and Analgesics • Local Anesthetics • General Anesthetics © Dr. E. Cates, Fall2023 4 Domperidone (MOTILIUM) • Dopamine receptor antagonist • Designed to improve gastric motility and decrease nausea • It’s effects on lactation are side-effects • Domperidone as a galactagogue is an off-label use • Concerns about the effect of domperidone on heart arrhythmias particularly QT interval prolongation which could lead to ventricular tachyarrhythmia • Led to a “black box warning” against domperidone • Evidence-based response in support of domperidone written by a group of MDs and IBCLCs © Dr. E. Cates, Fall2023 6 Domperidone - MECHANISM • Dopamine receptor antagonist • Blocks the effect of dopamine (prolactin-inhibiting hormone) on the prolactin-producing cells in the anterior pituitary • This disinhibition increases prolactin secretion • Increase in prolactin secretion enhances milk production https://www.youtube.com/watch?v=o6dx4uZCxBI © Dr. E. Cates, Fall2023 7 Image Sourced From: www.austincc.edu Domperidone - EFFECTS • • • • Increase in milk production is normally seen in 3-5 days but can take 2-3 weeks to see maximal effect Prescription is normally for at least 3 weeks (3-8 wks is standard) To stop, dose must be slowly decreased (decrease by 1 tablet every 2-5 days) If there is no effect on milk production, decrease by another tablet every 2-5 days BUT if milk production is decreased from reduction, return to effect dose and once milk supply is reestablished try decreasing dose again in 2 wks Domperidone – International BreastFeeding Centre (ibconline.ca) © Dr. E. Cates, Fall2023 8 METABOLISM & EXCRETION • The drug is rapidly absorbed orally and metabolized in the liver • Extensive first-pass metabolism • Oral bioavailability is only 13% to 17% • Because of extensive liver metabolism of the drug, it should not be given to clients with significant hepatic impairment © Dr. E. Cates, Fall2023 9 ADVERSE EFFECTS • Very few side-effects of domperidone (except ventricular tachyarrhythmia) • Many organizations consider domperidone compatible with breastfeeding • Infant exposure from breast milk is minimal • ~1% of maternal dose • Domperidone is given to infants in NICU for reflux (GERD) so safe even at higher doses • Dystonia possible side effect in infants © Dr. E. Cates, Fall2023 10 DRUG INTERACTIONS • Domperidone is metabolized by CYP3A4 • Strong inhibitors of CYP3A4, such as erythromycin and azole-antimycotics affect metabolism of domperidone • Ketoconazole is a potent CYP3A4 inhibitor which increases the half-life of the domperidone and increases the likelihood of overdose; about a 3x increase in circulating levels of domperidone are seen with co-administration of oral/IV ketoconazole • Topically applied ketoconazole is reported as not appearing in the blood in measurable quantities after use or <3% absorption of drug into the bloodstream after use © Dr. E. Cates, Fall2023 11 SMOOTH MUSCLE CONTRACTION • At term, the myometrium is one, large smooth muscle • Smooth muscle contracts when myosin light-chain kinase (MLCK) phosphorylates the myosin head • Allows the myosin head to attach to the actin filament • Myosin pulls past the actin – “power stroke” • MLCK is activated when it binds with a calciumcalmodulin complex © Dr. E. Cates, Fall2023 13 Image Sourced From: www.bio.Miami.edu Image Sourced From: www.rtmsd.org SMOOTH MUSCLE CONTRACTION • Due to the need for Ca+2 to activate MLCK the force of smooth muscle contraction is regulated by the amount of Ca+2 in the cytoplasm • Increases in intracellular [Ca+2] are due to release from either the sarcoplasmic reticulum or extracellular sources • Can inhibit smooth muscle contraction by either having low intracellular [Ca+2], or by stimulating phosphokinase A (PKA) • PKA modifies MLCK so that it can’t bind to the calciumcalmodulin complex © Dr. E. Cates, Fall2023 14 INCREASING CELLULAR Ca+2 • An increase in the second messengers inositol trisphosphate (IP3) and diacylglycerol (DAG) • IP3 binds to the sarcoplasmic reticulum, allowing the release of Ca+2 • DAG opens Ca+2 channels on the cell membrane • IP3 can also activate voltage-gated Ca+2 channels on the cell surface • Letting more extracellular Ca+2 into the cell © Dr. E. Cates, Fall2023 15 OXYTOCIN FOR INDUCTION/AUGMENTATION • Agents that cause uterine contractions are called oxytocics (from the Greek – oxy = swift, tokos = childbirth) • Include both prostaglandins and oxytocin Oxytocin • Nonapeptide produced by the posterior pituitary • Synthetic oxytocin sold as a clear aqueous solution for IM injection or IV infusion (PITOCIN) • Receptors for oxytocin exist in the myometrium, myoepithelial cells of breast ducts, glandular cells of breast alveoli, brain • Oxytocin receptors in the myometrium increase greatly in number in the 3rd trimester (partially b/c of effects of estrogen) © Dr. E. Cates, Fall2023 16 OXYTOCIN FOR INDUCTION/AUGMENTATION • Contractions of the uterus are largely the result of prostaglandins and oxytocin produced during a positive feedback loop • Doses of oxytocin are sometimes given to induce or augment labour • Stimulates the positive feedback loop • Associated with the cervical stretch induced by the initial uterine contractions • Oxytocin also has an affinity for the antidiuretic hormone receptor • Effect of this? • Uterus may also be hypersensitive to oxytocin, leading to uterine tachysystole • Problem with this? © Dr. E. Cates, Fall2023 17 Oxytocin Ca2+ Ca2+ Ca2+ 2+ Ca 2+ Ca channel Gq 2+ Ca Ca2+ Ca2+ 2+ 2+ Ca Ca Ca2+ Ca2+ Ca2+ PIP2 IP3 +DAG Ca2+ Ca2+ Second messengers © B Wainman, McMaster © Dr. E. Cates, Fall2023 Ca2+ THIS TIME 4 YEARS AGO… © Dr. E. Cates, Fall2023 19 PROSTAGLANDINS • PGE1, PGE2, PGF2α and their analogues (e.g. misoprostol) may stimulate uterine contractions • Main receptors in the uterus for the PGE family are EP1 and EP3; misoprostol is synthetic PGE1, dinoprostone is PGE2 • FP receptors for PGF2α, e.g., carboprost (HEMABATE) • Used for cervical ripening, given per vagina: • Dinoprostone (PGE2) supplied at Prostin E2 Vaginal Gel, 1mg or 2mg placed in posterior vaginal fornix and may be repeated 6 hrs later • PREPIDIL (0.5mg dinoprostone) used for intracervical use • Any problems with gel? What if the uterus is hyperstimulated? • CERVIDIL (control-released dinoprostone vaginal insert): polymer base with 10mg dinoprostone attached to retrieval string; releases 0.3mg PGE2 per hours in vagina for 12 hr © Dr. E. Cates, Fall2023 20 MISOPROSTOL • Used for treatments for ulcers since it reduces gastric acid secretion (binds to prostaglandin receptors on surface of gastric cells; trade name CYTOTEC) • Misoprostol PO or PR for labour induction is not standard in Canada because of risks associated with uterine rupture and hypertonus (can lead to fetal distress) • Becoming more common in some centres • Prostanoids are not used for cervical ripening in people with previous cesarean delivery, uterine surgery or ruptured membranes • Common off-label uses include medical abortion, cervical ripening before surgical abortion, induction after intrauterine fetal death (its use for PPH will be discussed later in this lecture) © Dr. E. Cates, Fall2023 21 HERBAL OXYTOCICS – CASTOR BEAN • Castor oil is made from cold pressing the seeds (beans) of the ripe fruit of Ricinus communis • Oil consists of: • • • • 87% ricinoleic acid 7% oleic acid 3% linoleic acid 2% palmitic acid Image Sourced From: www.myseeds.co Image Sourced From: www.plantsguru.com • Active oxytocic component appears to be ricinoleic acid • Taken PO, ricinoleic acid acts as a uterine stimulant, but the mechanism is unclear • Shown to bind to the EP3 receptor in uterus and bowel • Effects, in part thought to be due to the increased stimulation of the bowel therefore the uterus is stimulated via an irritant effect • Adverse effects: nausea, vomiting, and subsequent dehydration © Dr. E. Cates, Fall2023 22 TOCOLYTICS FOR LABOUR • Tocolysis – from the Greek • Tokos = childbirth • Lysis = loosening • Attempted to prevent preterm labour or relieve uterine tachysystole (sometimes used for ECV) • None of the clinically used tocolytic agents will be able to suppress myometrial contractions in the presence of strong stimulation of the myometrium © Dr. E. Cates, Fall2023 23 Nifedipine (ADALAT) • A Ca+2 channel blocker • Works by blocking entry of extracellular Ca+2 into myometrial cells • Slow/stop uterine contractions • Sometimes used in hypertensive disorders of pregnancy as well as it dilates blood vessels • Few undesirable side-effects • Commonly reported = headache and hypotension (10-20% of cases) © Dr. E. Cates, Fall2023 24 NITROGLYCERIN • Glyceryl trinitrate, NITROL • Primarily a heart medication for the treatment of angina • Used off-label for tocolysis in cases of uterine tachysystole • Either as a skin patch or a sublingual spray • Mechanism = production of nitric oxide from nitroglycerin • NO travels to smooth muscle cells, activates guanylyl cyclase • GC converts GTP to cGMP • cGMP causes sequestration of Ca+2 • Smooth muscle cells relax • Relaxes smooth muscle (both in blood vessels and the myometrium) © Dr. E. Cates, Fall2023 Image Sourced From: www.biomed.brown.edu 25 Salbutamol (VENTOLIN) • Uncommonly used for tocolysis in cases of uterine tachysystole • A β2-adrenergic agonist that relaxes the myometrium to some degree • Mechanism: • • • • • • • Stimulation of the β2-adrenergic receptor Activates the Gs protein Stimulates adenylate cyclase Stimulates PKA PKA phosphorylates MLCK MLCK cannot bind to the Ca+2-calmodulin complex Muscle cannot contract © Dr. E. Cates, Fall2023 26 Salbutamol Gs Ca2+ Ca2 Ca2+ + 2+ Ca Ca2+ Ca2+ PKA 2+Ca2+ Ca Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ ATP cAMP+ PPi Second messenger © B Wainman, McMaster © Dr. E. Cates, Fall2023 POSTPARTUM HEMORRHAGE (PPH) • Defined as blood loss of more than 500mL following a vaginal delivery or more than 1000mL after a Caesarean delivery • Clinically, any amount of blood loss that results in S&Sx of hypovolemic shock or hemodynamic instability should be considered a PPH • Primary PPH occurs in 2-6% of births worldwide, secondary or delayed PPH in 1-3% © Dr. E. Cates, Fall2023 29 THE “4 Ts” UNDERLYING PPH AOM CPG #17 - PPH © Dr. E. Cates, Fall2023 30 UTERINE CONTRACTION • Usually, normal uterine contractions after delivery prevent PPH • Special helical arrangement of myosin and actin in the uterus allow for contraction of the entire organ • Uterine contraction compresses the spiral arteries enough to slow blood flow and allow clot formation • Active management of the 3rd stage is thought to reduce the likelihood of PPH 31 © Dr. E. Cates, Fall2023 OXYTOCICS FOR THE TREATMENT OF PPH First Line Treatment • Oxytocin Second or Third Line Treatment • Ergonovine maleate • Carboprost tromethamine • Misoprostol Third Line • Carbetocin © Dr. E. Cates, Fall2023 32 OXYTOCIN AOM CPG #17 - PPH © Dr. E. Cates, Fall2023 33 Oxytocin Ca2+ Ca2+ Ca2+ 2+ Ca 2+ Ca channel Gq 2+ Ca Ca2+ Ca2+ 2+ 2+ Ca Ca Ca2+ Ca2+ Ca2+ PIP2 IP3 +DAG Ca2+ Ca2+ Second messengers © B Wainman, McMaster © Dr. E. Cates, Fall2023 Ca2+ OXYTOCIN – SIDE EFFECTS • Very common (>10%): • Vascular effects: feeling of warmth, flushing, hypotension • Gastrointestinal: nausea, abdominal pain • Skin effects: pruritus • Common (1-10%): • Nervous system disorders: headache, dizziness, tremor • GI: vomiting, metallic taste • Rare (less than 1%): • Cardiac disorders: tachycardia • Structurally related to ADH, theoretical potential for water retention and water intoxication (hyponatremia) • Oxytocin and carbetocin can get into milk but it’s a tiny amount and will be degraded by peptidases in infant GI tract • May cause milk let-down • Allergic reactions are highly unlikely © Dr. E. Cates, Fall2023 35 ERGONOVINE MALEATE AOM CPG #17 - PPH © Dr. E. Cates, Fall2023 36 Ergonovine Ca2+ Ca2+Ca2+ Gq 2+ Ca Ca2+ 2+ Ca 2+ 2+ Ca Ca Ca2+ Ca2+ Ca2+ Ca2+ channel Ca2+ PIP2 IP3 +DAG Ca2+ Ca2+ Second messengers © B Wainman, McMaster © Dr. E. Cates, Fall2023 Ca2+ ERGONOVINE – SIDE EFFECTS • Side effects: • Nausea and vomiting (oral) • Stimulates α1-adrenoreceptors found in blood vessels which leads to an increase in blood pressure • Headache • Contraindications • Pregnancy • Hypertension © Dr. E. Cates, Fall2023 38 Misoprostol (CYTOTEC) AOM CPG #17 - PPH © Dr. E. Cates, Fall2023 • Synthetic prostaglandin (E1 analog) • Binds to the Binds to EP1 or EP3 receptor • Generally used if oxytocin or ergonovine have failed • GI effects (vomiting and diarrhea), but those are less when given PR • Advantages: low cost, stable, shelf life of several years 39 Misoprostol Ca2+ Ca2+ Ca2+ 2+ Ca 2+ Ca channel Gq 2+ Ca Ca2+ Ca2+ 2+ 2+ Ca Ca Ca2+ Ca2+ Ca2+ PIP2 IP3 +DAG Ca2+ Ca2+ Second messengers © B Wainman, McMaster © Dr. E. Cates, Fall2023 Ca2+ Misoprostol Ca2+ Ca2+ G Ca2+ i Ca2+ 2+ Ca Ca2+Ca2+ 2+ 2+ Ca Ca Ca2+ Ca2+ Ca2+ Ca2+ Ca2 Ca2+ + Ca2+ ATP Ca2+ Ca2+ Ca2+ Ca2+ © B Wainman, McMaster © Dr. E. Cates, Fall2023 Ca2+ Ca2+ MISOPROSTOL – ADVERSE EFFECTS • Adverse effects: – Shivering (13% within an hour, 3 % between 2-6 hr) – Fever (pyrexia) (4% within an hour and 12% between 2-6hr) – Diarrhea after 1 hr (5%) that typically subsides <12 hr – Uterine hypertonus – Asthma exacerbation is commonly seen as a possibility particularly if there is a known sensitivity to one of the other E family of prostaglandins but the EP1 receptor is not on bronchioles… • Drug interactions: – Misoprostol will interact with other uterotonic agents but that is the idea… © Dr. E. Cates, Fall2023 42 Carboprost tromethamine (HEMABATE) • Synthetic prostaglandin (F2α analog) • Binds to the Prostaglandin E2 receptor EP1 subtype • Can be given q15min up to 8 times (pneumonic: HEMABATE has 8 letters) – 88% need just one dose • Expensive, and heat and light sensitive © Dr. E. Cates, Fall2023 AOM CPG #17 - PPH 43 Carbetocin AOM CPG #17 - PPH © Dr. E. Cates, Fall2023 44 Carbetocin Ca2+ Ca2+ Ca2+ 2+ Ca 2+ Ca channel Gq 2+ Ca Ca2+ Ca2+ 2+ 2+ Ca Ca Ca2+ Ca2+ Ca2+ PIP2 IP3 +DAG Ca2+ Ca2+ Second messengers © B Wainman, McMaster © Dr. E. Cates, Fall2023 Ca2+ Tranexamic acid (CYKLOKAPRON) • An inhibitor of fibrinolysis used to treat bleeding • An adjunct treatment for PPH • Even if the PPH is thought to be due to tone • This is because some of the bleeding may also be due to trauma AND because the increase in clotting may buy time to manage hemorrhage due to tone while minimizing blood loss • Becoming increasingly common to add to the management algorithm (even fairly upstream in the process) • Side-effects include nausea/vomiting and visual disturbances or dizziness (non-severe) © Dr. E. Cates, Fall2023 47 HEMOSTASIS - COAGULATION Review of clotting cascade: 1. Injury 2. Vascular Spasm 3. Platelet Plug Formation • Activated platelets become spiked and stick to each other and the wound site • Release mediators to activate and attract other platelets 4. Coagulation • Fibrinogen is converted to fibrin which forms a mesh to produce/stabilize the clot © Dr. E. Cates, Fall2023 48 Tranexamic acid (CYKLOKAPRON) © Dr. E. Cates, Fall2023 49 Tranexamic acid (CYKLOKAPRON) • Shown to reduce maternal death but not hysterectomy • Reduces the need for laparotomy to control bleeding • Dose is 1g IV (rate of 1mL/min given over 10min) • Can be repeated if: • Bleeding persists after 30min • Bleeding re-starts within 24hours © Dr. E. Cates, Fall2023 50