Medical Translation: Welcome to our webinar

Transcription

1 r Welcome to our webinar Medical Translation: The Pharmacodynamics and Physiological Effects of Drug Classes Commonly Studied during Clinical Trials with Carmen Cross 13 February

2 How to interact with us

3 Bedford Gazette, Friday, October 19, 1917, p. 2

4 Agenda Introduction: key terms, overview of drug classes, standard medical uses Diuretics Proton pump inhibitors Sulfonylureas Selective serotonin reuptake inhibitors (SSRIs) Angiotensin converting enzyme (ACE) inhibitors Supposed mechanism(s) of action Q&A

5 Key Terms Pharmacodynamics: the study of the action of a drug on the body Pharmacokinetics: the effect of the body on the drug (Absorption, Distribution, Metabolism, Excretion) Mechanism(s) of action: biochemical interaction(s) through which a drug is thought to produce its pharmacological effect Drug target: the site where a drug binds to either increase or decrease activity (enzymes, structural proteins, nuclear hormone receptors)

6 Drug Classes Drug Class Typical Treatment Uses Types/Examples Diuretic Proton-pump inhibitor (PPI) Sulfonylurea Selective serotonin reuptake inhibitor (SSRI) Angiotensin-converting enzyme (ACE) inhibitor Heart failure, hypertension, cirrhosis of the liver, generalized edema, certain kidney diseases Dyspepsia (indigestion), gastroesophageal reflux disease (GERD), gastrinomas Management of diabetes mellitus (type 2 diabetes) Depression, anxiety disorders, obsessive compulsive disorder (OCD) Hypertension, congestive heart failure, diabetic nephropathy Loop diuretic (Torsemide), potassium-sparing diuretic, calcium-sparing diuretic, thiazide Omeprazole (Prilosec) Esomeprazole (Nexium) Glimepiride Glyclopyramide Sertraline (Zoloft) Fluoxetine (Prozac) Benzapril (Lotensin) Lisinopril (Listil)

7 Measuring Pharmacodynamics Not limited to parent drug molecule Pharmacological effects may include transport process inhibition and enzyme activity alteration Concerned with measuring drug efficacy and identifying potential safety issues General relationship between drug concentration and pharmacological effect (dose-response curve)

8 Dose-response curve

9 Loop Diuretics An Overview Primarily block the reabsorption of Cl, Na and H 2 Oin the nephrons and increase the excretion of sodium and H 2 O Results in increased urine output Increased H 2 O and electrolyte reduces blood volume and blood pressure Loop diuretics work in the thick ascending Loop of Henle.

10 Diuretics Mechanism of Action Thick ascending loop potassium, chloride and sodium reabsorbed by Na-K-2Cl symporter (carrier protein) by secondary active transport Diuretics inhibit the Na-K-2Cl carrier protein. Chloride and sodium not reabsorbed and excreted

11 Loop Diuretics Clinical Considerations Maximum dose may need to be increased for: Loop diuretic resistance renal insufficiency (decreases blood flow to kidneys and GFR) Congestive heart failure Common adverse drug reactions (usually dose-related): syncope, hyponatremia, hypomagnesemia, hypokalemia, Hyperuricemia, chondrocalcinosis, electrolyte imbalances (less common: hypocalcemia, increased serum creatinine concentration). May lead to renal failure in patients taking concomitant NSAID and ACE inhibitor.

12 Loop Diuretics Clinical Considerations Very potent with a rapid onset of action Very useful when rapid diuresis is needed Effect lasts about 2 hours Effective as a single daily dose treatment

13 Proton-Pump Inhibitors Mechanism of Action Main function: increase gastric ph (and thus decrease stomach s acidity) Work in second phase of chemical digestion (gastric phase) Inhibitory action not reversible on single copy of enzyme Binds to the H + /K + ATPase ( proton pump ) Found on the surface of parietal cells in the gastric mucosa. Regulates gastric acid secretion Gastric acid is composed of HCl, KCl and NaCl.

14 Proton-Pump Inhibitors Mechanism of Action Binding prevents H ions going into the stomach Blocks gastric acid secretion PPIs suppress acid-mediated breakdown of proteins Can lead to an increased risk of food allergies

15 Proton-Pump Inhibitors Clinical Considerations Most potent acid secretion inhibitors available. Block all gastric acid secretion patients may become achlorhydric Generally well-tolerated. Long-term use may lead to increased bone fractures and decreased B 12 absorption and B 12 deficiency. Common adverse drug reactions: Nausea, diarrhea, abdominal pain (less common: community-acquired pneumonia). 8 February 2012: The Food and Drug Administration (US): PPIs may increase the risk of Clostridium difficile infection

16 SSRIs Used mainly to treat depression and anxiety disorders. 1 st class of psychotropic drugs discovered using rational drug design. SSRIs are designed to inhibit the reuptake of serotonin. Variously selective for other monoamine transporters Have a weak affinity for the noradrenaline and dopamine transporter

17 SSRIs Mechanism of Action Presynaptic cell releases neurotransmitters (incl. serotonin) Receptors on postsynaptic cell recognizes neurotransmitter and relay signal About 10% is lost; 90% is taken up again into the presynaptic cell

18 SSRIs Mechanism of Action Serotonin remains in synaptic cleft and can keep stimulating receptors on the postsynaptic cell What is the role of astrocytes? High serotonin levels flood autoreceptors marked decrease of serotonin production

19 SSRIs Clinical Considerations 6-8 weeks to reach maximum efficiency. Adverse effects usually occur within the 1 st month. Nausea, sexual dysfunction, akathisia, suicidal ideation, hypomania (especially for bipolar patients), drowsiness, mydriasis, withdrawal syndrome (but SSRIs are considered to be non-addictive). NSAIDs may reduce SSRI efficiency and increase risk of bleeding.

20 Sulfonylureas An Overview Increase insulin release from beta cells in the pancreas 65-80% of cells in the islets of Langerhans Beta cells store and release insulin. Improve insulin secretion and insulin sensitivity in tissues May also increase insulin availability with reduced hepatic clearance Insulin is responsible for lowering blood glucose concentration.

21 Sulfonylureas Mechanism of Action Block ATP-dependent K + channels releases insulin

22 Sulfonylureas Mechanism of Action Bind to an ATP-dependent K + channel on the cell membranes of beta cells Stimulates a slow efflux of potassium (hyperpolarizing) Causes the electric potential to become more positive over the membrane voltage-gated Ca 2+ channels open Ca 2+ stimulates the fusion of secretory vesicles containing insulin, and insulin is secreted

23 Sulfonylureas Clinical Considerations Ineffective when there is no insulin production (e.g. type 1 diabetes) Adverse effects: hypoglycemia, impaired kidney function, thrombocytopenia, photosensitivity, hypoglycemia, agranulocytosis and photosensitivity May limit glucose production in the liver and decrease lipolysis

24 ACE Inhibitors An Overview Primarily act on the renin-angiotensin-aldosterone system (RAAS) to inhibit the angiotensin-converting (ACE) enzyme. Decrease tension on blood vessels and blood volume Lowers blood pressure The RAAS regulates fluid and blood pressure balance. Mainly involve the kidney, liver, lungs, heart and adrenal cortex. The kidneys release renin (mediates extracellular volume and arterial vasoconstriction) from the juxtaglomerular apparatus.

25 ACE Inhibitors Mechanism of Action Renin starts to hydrolyze angiotensinogen into angiotensin I (a weak vasoconstrictor). ACE converts angiotensin I to angiotensin II (a potent vasoconstrictor). Constriction of systemic and renal blood vessels

26 ACE Inhibitors Mechanism of Action Systemic vasoconstriction increases peripheral vascular resistance Blood pressure increases Renal vasoconstriction decreases glomerular filtration. Water and sodium retained Blood volume and blood pressure increase.

27 ACE Inhibitors Mechanism of Action Angiotensin II stimulates release of aldosterone by the adrenal cortex. Increases reabsorption of water and ions into bloodstream increased fluid volume and blood pressure

28 ACE Inhibitors Mechanism of Action ACE inhibitors block the action of the angiotensin-converting enzyme. Angiotensin I is not converted into angiotensin II No resulting renal and systemic vasoconstriction and release of aldosterone

29 ACE Inhibitors Clinical Considerations An abnormally active RAAS = hypertension ACE inhibitors lower blood pressure by blocking action of ACE. May cause renal impairment cause? May cause hyperkalemia due to suppression of angiotensin II Known to cause congenital birth defects, stillbirths and neonatal deaths. Beneficial for treating heart failure and left ventricular hypertrophy after MI

30 ACE Inhibitors Contraindications ACE inhibitors are contraindicated for people with: Renal and/or aortic valve stenosis Hypovolemia Hypersensitivity to ACE inhibitors Previous angioedema with ACE inhibitor treatment Women who are pregnant and/or breastfeeding

31 Q & A Thank you! carmensuecross@yahoo.com