Y11. Pharmacopeia: Endocrine Pharmacology

PAST QUESTIONS – U02. Endocrine Pharmacology (Click to Open)

SYLLABUS (Fourth Edition, 2023)

LEVEL 1	LEVEL 2	LEVEL 3
Hypoglycaemic drugs
Insulin – Rapid and Short acting	Insulin – Long Acting	Biguanides
		SGLT2 Inhibitors
		Sulphonyl ureas
	Glucocorticoids	Mineralocorticoids
	Vasopressin analogues	Glucagon
	Desmopressin	Thyroxine
	Terlipressin

N.B. The Syllabus tables used in out Pharmacopeia seem incomplete, but that is intentional because we have only included groups/classes/drugs which are mentioned directly in the syllabus or have been asked before in the exams.

TRAINEE EXPECTATIONS

Trainees are expected to understand a drug’s pharmacology in the context of normal physiology, extremes of age (i.e., neonates, paediatrics, and the elderly), obesity, pregnancy (including foetal implications) and critical illness. An understanding of potential toxicity and relevant antidotes is also expected. Agents may be listed in more than one section when they are used for different indications.
This is not an exhaustive list of all drugs relevant to or important in ICU practice. Each drug or classes of drugs have been assigned a details of understanding level outlined below. This is a guide to the minimum level of knowledge expected for that drug.
For classes of drugs where examples are not specified, it is suggested a prototypical drug from the class be studied, as well as the relevant variations within the class exploring the major differences that exist between the agents in that class.

LEVELS OF UNDERSTANDING

Level 1	Level 2	Level 3
For these drugs, a detailed knowledge and comprehension of:	For these drugs a detailed knowledge of:	For these drugs a detailed knowledge of:
Class, Indications, and dose
Mechanism of Action
Pharmacodynamics and Adverse effects
Pharmacokinetics	Important pharmacokinetic differences or considerations when using in ICU
Pharmaceutics

CICMWrecks Tables (Click to Open)

MASTER TABLES	Hypoglycaemic Drugs
	Corticosteroids
	Other Hormones
INDIVIDUAL TABLES	Hydrocort vs Methylpred vs Dexamethasone
	Hydrocortisone
	Short Acting Insulin (Actrapid)

MASTER TABLES

HYPOGLYCAEMIC AGENTS

Pharmacopeia - Hypoglycaemic agents

	Insulin Aspart (Novorapid)	Insulin Neutral (Actrapid)	Insulin Glargine (Lantus)	Insulin Isophane (Protophane)	METFORMIN	SGLT2 Inhibitors	SULFONYLUREAS
GROUP	Insulin – Rapid	Insulin - Short	Insulin - Long	Insulin - Intermediate	Biguanides	SGLT2 Inhibitors	Sulfonylurea
CICM Level of Understanding	Level 1	Level 1	Level 2	Level 2	Level 3	Level 3	Level 3

INTRODUCTION							1. first-generation: tolbutamide 2. second-generation: gliclazide, glibenclamide 3. third-generation: glimepiride.
USES	1. type I diabetes mellitus 2. diabetic emergencies 3. the perioperative control of blood sugar concentration 4. hyperkalaemia and 5. to improve glucose utilization during TPN and 6. in provocation tests for growth hormone.	1. type I diabetes mellitus 2. diabetic emergencies 3. the perioperative control of blood sugar concentration 4. hyperkalaemia and 5. to improve glucose utilization during TPN and 6. in provocation tests for growth hormone.	1. type I diabetes mellitus 2. diabetic emergencies 3. the perioperative control of blood sugar concentration 4. hyperkalaemia and 5. to improve glucose utilization during TPN and 6. in provocation tests for growth hormone.	1. type I diabetes mellitus 2. diabetic emergencies 3. the perioperative control of blood sugar concentration 4. hyperkalaemia and 5. to improve glucose utilization during TPN and 6. in provocation tests for growth hormone.	treatment of non-insulin-dependent (type II) diabetes mellitus		treatment of non-insulin-dependent (type II) diabetes mellitus


PHARMACEUTICS (PC)
PC: Chemical	Human insulin analogue with small number of amino acid substitutions allowing faster SC	Human insulin analogue Hexomer complexed with zinc that dissociates rapidly to monomers	Human insulin analogue	Human insulin analogue Addition of a protamine molecule leads to delayed absorption			An s-phenylsulfonylurea structure with substitutions on the phenyl ring and urea terminus
PC: Presentation	Clear solution 100IU/ml	Clear solution 100IU/ml	Clear solution 100IU/ml	Clear solution 100IU/ml	As 500/850 mg tablets of metformin hydrochloride MR also available.		tablet form MR also available.


PHARMACODYNAMICS (PD)
PD: Main Action	stimulation of carbohydrate metabolism, protein synthesis, and lipogenesis	stimulation of carbohydrate metabolism, protein synthesis, and lipogenesis	stimulation of carbohydrate metabolism, protein synthesis, and lipogenesis	stimulation of carbohydrate metabolism, protein synthesis, and lipogenesis	Hypoglycaemia		Hypoglycaemia
PD: Mode of Action	1. Insulin binds the alpha-subunit of insulin receptors → complex is internalized → up regulates tyrosine kinase activity via Beta subunit → insertion of GLUT 4 channels in cell membrane 2. Activates Na/K/ATPase → intracellular K+ shift 3. Direct action on lipoprotein lipase	1. Insulin binds the alpha-subunit of insulin receptors → complex is internalized → up regulates tyrosine kinase activity via Beta subunit → insertion of GLUT 4 channels in cell membrane 2. Activates Na/K/ATPase → intracellular K+ shift 3. Direct action on lipoprotein lipase	1. Insulin binds the alpha-subunit of insulin receptors → complex is internalized → up regulates tyrosine kinase activity via Beta subunit → insertion of GLUT 4 channels in cell membrane 2. Activates Na/K/ATPase → intracellular K+ shift 3. Direct action on lipoprotein lipase	1. Insulin binds the alpha-subunit of insulin receptors → complex is internalized → up regulates tyrosine kinase activity via Beta subunit → insertion of GLUT 4 channels in cell membrane 2. Activates Na/K/ATPase → intracellular K+ shift 3. Direct action on lipoprotein lipase	- Enhance peripheral action of insulin - ↑ rate of anaerobic glycolysis and ↓ rate of gluconeogenesis - Inhibit intestinal absorption and ↓ peripheral utilization of glucose		- Liberates insulin from pancreatic beta-cells (prolong depolarization in membrane → ↓ permeability to K+ → open Ca++ channel → Ca++ influx → Insulin release)
PD: Route & Doses	SC, IV	SC, IV	SC	SC	PO 1-3gm daily in divided doses		PO
PD: Metrics (Onset/ Peak/ Duration)	<10min 15-60min 3-4 hours	5-15min 1-3 hours 3-4 hours	Onset 4 hours Duration 18-36 hours Flat profile	Onset 90-120min Duration 8-10 hours
PD: Effects	Metabolic: - Increases rate of diffusion into cells, especially hepatic (GLUT 4) and increases activity of glucokinase - Inhibits glycogenolysis and gluconeogenesis - Stimulate glycogenesis - Inhibits lipolysis and increases lipogenesis - Increases active transport of amino acids into cells, stimulates mRNA translation and inhibits catabolism - Increases K+/Mg uptake into cells	Metabolic: - Increases rate of diffusion into cells, especially hepatic (GLUT 4) and increases activity of glucokinase - Inhibits glycogenolysis and gluconeogenesis - Stimulate glycogenesis - Inhibits lipolysis and increases lipogenesis - Increases active transport of amino acids into cells, stimulates mRNA translation and inhibits catabolism - Increases K+/Mg uptake into cells	Metabolic: - Increases rate of diffusion into cells, especially hepatic (GLUT 4) and increases activity of glucokinase - Inhibits glycogenolysis and gluconeogenesis - Stimulate glycogenesis - Inhibits lipolysis and increases lipogenesis - Increases active transport of amino acids into cells, stimulates mRNA translation and inhibits catabolism - Increases K+/Mg uptake into cells	Metabolic: - Increases rate of diffusion into cells, especially hepatic (GLUT 4) and increases activity of glucokinase - Inhibits glycogenolysis and gluconeogenesis - Stimulate glycogenesis - Inhibits lipolysis and increases lipogenesis - Increases active transport of amino acids into cells, stimulates mRNA translation and inhibits catabolism - Increases K+/Mg uptake into cells	CVS: - ↓ intestinal absorption of glucose, folate, vit B12 - no effect on gastric motility - ↑ utilization of glucose and cause weight loss Metabolic/Other: - ↑ sensitivity to peripheral actions of insulin by ↑ no of low affinity binding sites (RBC, Adipocytes, hepatocytes, sk. Muscle) - inhibits metabolism of lactate and ↓ plasma TG, cholesterol, pre-beta lipoprotein		Metabolic/Other: - ↓ plasma TG, cholesterol, FFA Gliclazide ↓ microthrombosis: - partially inhibit platelet aggregation and adhesion - fibrinolytic - ↑ tPA activity Glimepiride extra-pancreatic: - ↑ active glucose transport molecules - lipogenesis and glycogenesis in fat and muscle - inhibits hepatic gluconeogenesis (by ↑ Fructose-2,6-bisphosphate)
PD: Side Effects / Toxicity	1. Hypoglycaemia 2. Allergic reactions- local more common. Protaphane may lead to protamine antibodies that only become relevant when large dose protamine administered IV 3. Lipodystrophy 4. Drug interactions- tetracyclines prolong effects of insulin	1. Hypoglycaemia 2. Allergic reactions- local more common. Protaphane may lead to protamine antibodies that only become relevant when large dose protamine administered IV 3. Lipodystrophy 4. Drug interactions- tetracyclines prolong effects of insulin	1. Hypoglycaemia 2. Allergic reactions- local more common. Protaphane may lead to protamine antibodies that only become relevant when large dose protamine administered IV 3. Lipodystrophy 4. Drug interactions- tetracyclines prolong effects of insulin	1. Hypoglycaemia 2. Allergic reactions- local more common. Protaphane may lead to protamine antibodies that only become relevant when large dose protamine administered IV 3. Lipodystrophy 4. Drug interactions- tetracyclines prolong effects of insulin	- Does not cause hypoglycaemia when used on its own - GI disturbances - Lactic acidosis (rare)		- Hypoglycaemia - GI disturbances - Cholestatic jaundice - LFT derangement - Leucopenia, thrombocytopenia - some Potentially teratogenic


PHARMACOKINETICS (PK)
PK: Absorption	- Inactive when administered orally Factors affecting exogenous insulin absorption: - Site of injection (abdominal wall least variable) - Regional blood flow; Ambient temperature; Exercise - Depth of injection	- Inactive when administered orally Factors affecting exogenous insulin absorption: - Site of injection (abdominal wall least variable) - Regional blood flow; Ambient temperature; Exercise - Depth of injection	- Inactive when administered orally Factors affecting exogenous insulin absorption: - Site of injection (abdominal wall least variable) - Regional blood flow; Ambient temperature; Exercise - Depth of injection	- Inactive when administered orally Factors affecting exogenous insulin absorption: - Site of injection (abdominal wall least variable) - Regional blood flow; Ambient temperature; Exercise - Depth of injection	Slowly absorbed from small intestine PO BA: 50-60%		Well absorbed PO BA: 100%

PK: Distribution
Protein binding (PK: Distribution)	Minimal PB (<10%)	Minimal PB (<10%)	Minimal PB (<10%)	Minimal PB (<10%)	Not protein bound		95-99% Albumin bound
Volume of distribution (PK: Distribution)	Vd 0.02L/kg (slightly larger in the diabetic patient).	Vd 0.02L/kg (slightly larger in the diabetic patient).	Vd 0.02L/kg (slightly larger in the diabetic patient).	Vd 0.02L/kg (slightly larger in the diabetic patient).			gliclazide 0.42 l/kg glibenclamide 0.15 l/kg glimepiride 0.12 l/kg

PK: Metabolism	Rapidly metabolized in liver, kidney and muscle by glutathione insulin transhydrogenase	Rapidly metabolized in liver, kidney and muscle by glutathione insulin transhydrogenase	Rapidly metabolized in liver, kidney and muscle by glutathione insulin transhydrogenase	Rapidly metabolized in liver, kidney and muscle by glutathione insulin transhydrogenase	No metabolites		extensive hepatic metabolism via CYP2C9 to inactive metabolites

PK: Excretion	Metabolites excreted in urine. Plasma half life of minutes	Metabolites excreted in urine.	Metabolites excreted in urine.	Metabolites excreted in urine.	Unchanged in urine		30-50% excreted in urine Remainder in feces
- Clearance (PK: Excretion)	1.2 L/h/kg				> GFR (Active tubular secretion)		Gliclazide 12-20 hrs Gliblencamide 1-2hrs Glimepiride 5-8hrs
- Half Life (PK: Excretion)	T-half beta (80 mins)				Elimination half life 1.7-4.5 hrs		Elimination impaired in severe renal impairment


SPECIAL POINTS					Not recommended in renal impairment		Hypoglycaemia with NsAIDs, salicylates, sulfonamides, oral anticoagulants, MAoIs, and beta-adrenergic antagonists Long acting sulfonylureas should be stopped prior to major surgery

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CORTICOSTEROIDS

Pharmacopeia - Corticosteroids

	HYDROCORTISONE	METHYLPREDNISOLONE	DEXAMETHASONE	FLUDROCORTISONE
GROUP	Glucocorticoid	Glucocorticoid	Glucocorticoid	Mineralocorticoid
CICM Level of Understanding	Level 2	Level 2	Level 2	Level 3

INTRODUCTION	Natural Dose Equivalence 25	Synthetic Dose Equivalence 4	Synthetic Dose Equivalence 0.75	Synthetic
USES	1. as replacement therapy in adrenocortical deficiency states and in the treatment of 2. allergy and anaphylaxis 3. asthma 4. panoply of autoimmune disorders 5. eczema and contact sensitivity syndromes and 6. in leukaemia chemotherapy regimes and 7. for immunosuppression after organ transplantation	1. as replacement therapy in adrenocortical deficiency states and in the treatment of 2. allergy and anaphylaxis 3. hypercalcaemia 4. asthma 5. panoply of autoimmune disorders 6. some forms of red eye and 7. in leukaemia chemotherapy regimes and 8. for immunosuppression after organ transplantation.	1. as replacement therapy in congenital adrenocortical deficiency states and in the treatment of 2. allergic disorders 3. asthma 4. many autoimmune and rheumatologic disorders 5. eczema and contact sensitivity syndromes and 6. leukaemia and lymphoma chemotherapy regimes and 7. immunosuppression after organ transplantation 8. palliative treatment of tumours 9. prevention of post-operative and chemotherapy-induced nausea and vomiting 10. ophthalmic inflammatory diseases 11. acute exacerbations of inflammatory bowel disease 12. acute severe skin diseases 13. cerebral oedema 14. bacterial meningitis—prevents hearing loss 15. tests for Cushing’s syndrome 16. hypercalcaemia of malignancy, sarcoidosis, and vitamin D toxicity 17. antenatal use in preterm labour 18. myasthenia gravis 19. autoimmune renal disease and 20. has been used for epidural injection.	used to treat adrenocortical insufficiency and salt-losing adrenogenital syndrome.


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	10/20mg tablets White lyophilized power to be mixed in water Other topical preparations	White powder – mixed with water	0.5/2mg tablets Oral solution Vials – white powder	100mcg tablets


PHARMACODYNAMICS (PD)
PD: Main Action	Anti-inflammatory	Anti-inflammatory	Anti-inflammatory	To replace endogenous aldosterone
PD: Mode of Action	lipid solubile → crosses cell membranes → bind to steroid receptors via “zinc finger” binding site → signal trascribed via second messenger → alters gene transcription and the production of proteins	lipid solubile → crosses cell membranes → bind to steroid receptors via “zinc finger” binding site → signal trascribed via second messenger → alters gene transcription and the production of proteins	lipid solubile → crosses cell membranes → bind to steroid receptors via “zinc finger” binding site → signal trascribed via second messenger → alters gene transcription and the production of proteins	Bind to mineralocorticoid receptors → Renal: ↑ Na resorption, K excretion lipid solubile → crosses cell membranes → bind to steroid receptors via “zinc finger” binding site → signal trascribed via second messenger → alters gene transcription and the production of proteins
PD: Route & Doses	PO,TOP, IV, IM, IA	PO,TOP, IV, IM, IA, epi	PO,TOP, IV, IM, IA	PO
PD: Metrics (Onset/ Peak/ Duration)	Dur: 8-36h	Dur: 12-36h	Dur: 36-54h	Dur: 3-5 days
PD: Effects	1. Metabolic effects ▪ ↑’s gluconeogensis ▪ ↑ protein catabolism and lipolysis → muscle wasting and thin skin and fat redistribution (cushingoid) ▪ ↑ bone catabolism → osteoporosis ▪ ↑ glucose release but ↓ absorption from the GIT 2. Anti inflammatory effects ▪ ↓’d phospholipase A2 → ↓ arachidonic acid → ↓ prostaglandins 3. Immunosupression ▪ ↓’d inflammatory mediators ▪ ↓ IL 1-2 → ↓’d lymphocyte prod ▪ altered neutrophil and macrophage function	1. Metabolic effects ▪ ↑’s gluconeogensis ▪ ↑ protein catabolism and lipolysis → muscle wasting and thin skin and fat redistribution (cushingoid) ▪ ↑ bone catabolism → osteoporosis ▪ ↑ glucose release but ↓ absorption from the GIT 2. Anti inflammatory effects ▪ ↓’d phospholipase A2 → ↓ arachidonic acid → ↓ prostaglandins 3. Immunosupression ▪ ↓’d inflammatory mediators ▪ ↓ IL 1-2 → ↓’d lymphocyte prod ▪ altered neutrophil and macrophage function	1. Metabolic effects ▪ ↑’s gluconeogensis ▪ ↑ protein catabolism and lipolysis → muscle wasting and thin skin and fat redistribution (cushingoid) ▪ ↑ bone catabolism → osteoporosis ▪ ↑ glucose release but ↓ absorption from the GIT 2. Anti inflammatory effects ▪ ↓’d phospholipase A2 → ↓ arachidonic acid → ↓ prostaglandins 3. Immunosupression ▪ ↓’d inflammatory mediators ▪ ↓ IL 1-2 → ↓’d lymphocyte prod ▪ altered neutrophil and macrophage function	- sodium and water retention (aldosterone like) - inc Na reabsorption on distal tubles, K+ and H+ excretion Glucocorticoid action: Metabolic, Anti-inflammatory effects, Immunosuppresion
PD: Side Effects / Toxicity	▪ Adrenal supression via negative feedback on the HPA ▪ Fluid retention - via weak mineralcorticoid activity ▪ Vascular reactivity - plays a permissive role in the actions of catecholamines on vessels Inhaled: oral candidiasis (poor technique), dysphonia, minor adrenal suppresion	▪ Adrenal supression via negative feedback on the HPA ▪ Fluid retention - via weak mineralcorticoid activity ▪ Vascular reactivity - plays a permissive role in the actions of catecholamines on vessels	▪ Adrenal supression via negative feedback on the HPA ▪ Fluid retention - via weak mineralcorticoid activity ▪ Vascular reactivity - plays a permissive role in the actions of catecholamines on vessels	GI disturbances Weight gain Allergy


PHARMACOKINETICS (PK)
PK: Absorption	IV Rapidly given PO or PR PO BA: 50%	IV	IV PO BA 80-90%	Rapid and complete

PK: Distribution
Protein binding (PK: Distribution)	CBG 70%, Alb 20%	80%	70%	70-80% (Albumin, Corticosteroid binding Globulin)
Volume of distribution (PK: Distribution)	0.5 L/kg	Low	Low	80-85 L

PK: Metabolism	Liver – Tetrahydrocortisone	Liver	Liver – CYP3A4	Liver – CYP3A - 2 main metabolites

PK: Excretion	Urine	Urine	Urine	80% urine 20% feces
- Clearance (PK: Excretion)	167-283 ml/min			40 L/h
- Half Life (PK: Excretion)	0.5-1.5h	2-4h	3.5-5h	18-36hrs


SPECIAL POINTS Glucocorticoid Action Mineralocorticoid Action Duration	100 1 Short	20 Min Intermediate	4 Min Long	15 150 Long

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OTHER HORMONES

Pharmacopeia - Other Hormones

	THYROXINE	GLUCAGON	ARGIPRESSIN (VASOPRESSIN)	DESMOPRESSIN (dDAVP)	TERLIPRESSIN
GROUP	Thyroid hormone	Pancreatic Hormone	Vasopressin Hormone	Vasopressin Analogue	Vasopressin Analogue
CICM Level of Understanding	Level 3	Level 3	Level 1	Level 2	Level 2

INTRODUCTION			Is a naturally occurring nonapeptide-9AA	Synthetic analogue of 8-arginine vasopressin (ADH) Antidiuretic peptide drug displays enhanced antidiuretic potency, fewer pressor effects due to V2-selective actions, and a prolonged half-life and duration of action compared to endogenous ADH	analogue of vasopressin – Prodrug Peiptidases  Lysine vasopressin used as a vasoactive drug in the management of hypotension. It has been found to be effective when norepinephrine does not help Longer duration of action than Vasopressin
USES	1. hypothyroidism 2. myxoedema coma, and 3. goitre	1. in the treatment of hypoglycaemia and 2. to facilitate radiological investigation of the gastrointestinal tract and has been used in the management of 3. cardiogenic shock 4. renal colic 5. acute diverticulitis, and 6. propranolol overdose.	Catecholamine sparing drug in shock Diabetes insipidus Bleeding in vWF def / mild haemophilia	Central DI – ADH replacement (Intranasal/parenteral) Nocturnal polyuria (intranasal). Haemostasis in Haemophilia with fVIII def or Type 1 Von Willebrand disease during surgical procedures and postoperatively to maintain hemostasis (parenteral).	Commonly used to stop bleeding of varices in the food pipe (oesophagus). Hepatorenal syndrome


PHARMACEUTICS (PC)
PC: Chemical	iodine-containing amino acid derivatives of thyronine.	polypeptide hormone extracted from the alpha cells of the pancreatic islets of Langerhans	Prod hypothal. released by the posterior pituitary similar to oxytocin complex molecule wt	Deamino Arginine Vasopressin	Prodrug of lysine Vasopressin
PC: Presentation	Levothyroxine tablets - 25/50/100 micrograms of levothyroxine sodium Triiodothyronine: 20mcg tablets or while lyophilized powder for reconstitution in water	- Prefilled syringes 1mg - Vials 1/10mg lypophilized glucagon HCl with lactose – reconstituted with glycerol and water	measured in international units 20 IU/ml vial requiring dilution for eff¬ective delivery. It cannot be given orally as it is inactivated by trypsin	sublingual tablet, intra nasal spray, IV/IM	IV


PHARMACODYNAMICS (PD)
PD: Main Action	Modulation of growth and metabolism	Elevation of blood sugar concentration, positive inotropism and chronotropism, and relaxation of smooth muscle	Acts at the GPCR Vasopressin receptors	Acts at the GPCR Vasopressin receptors	Acts at the GPCR Vasopressin receptors
PD: Mode of Action	combine with a ‘receptor protein’ within the cell nucleus - thereby activate the DNA transcription process - leading to an increase in the rate of RNA synthesis and a generalized increase in protein synthesis	acts via cell membrane receptors which stimulate adenylate cyclase activity, leading to an increase in the intracellular concentrations of cAMP. The final effects of the hormone are mediated via a cascade of protein kinases	Acts at the GPCR Vasopressin receptors V1 on vascular smooth muscle Inc intracellular Ca conc, vasoconstrictive V1 on platelets increase platelet aggregation V2 on the nephron Aquaporin-2 trafficking from intracellular vesicle membrane – allowing water reabsorption V2 on endothelial cells – allow vWF release that prevents breakdown of factor VIII V3 (prev V1b) on pituitary Contribute to ACTH release	Acts at the GPCR Vasopressin receptors V1 on vascular smooth muscle – vasoconstrictive – markedly less than ADH (1500x less than ADH) V1 on platelets - increase platelet aggregation – more potent than ADH V2 on the nephron - expressed in the renal collecting duct (CD) - antidiuretic actions (10x ADH)	Acts at the GPCR Vasopressin receptors V1 on vascular smooth muscle - vasoconstrictive V1 on platelets - increase platelet aggregation V2 on the nephron - antidiuretic actions
PD: Route & Doses	PO Levothyroxine: 25-300mcg daily in divided doses – titrated to response and TFTs Triiodothyronine: PO 10-60mcg/day IV 5-20mcg 4-12hrly	IV, IM, SC - 1-5mg IV infusion in 5% glucose: 1-20mg/hr	IV infusion 0.01–0.04 units/min	sublingual tablet, intra nasal spray, IV/IM 0.1 to 1.2 mg divided into 2 or 3 doses	IV 1-2mg terlipressin acetate (0.85-1.7mg Terlipressin) Q6 hourly
PD: Metrics (Onset/ Peak/ Duration)	Levothyroxine: 24hr latency, peak 6-7 days Triiodothyronine: acts in 6hrs, peak 24hrs	Onset: IV- within 1 min IM/SC – 8-10min Dur: 10-30min	Rapid onset
PD: Effects	CVS: - Positively inotropic, chronotropic (Beta) - inc SBP, dec DBP - Vasodilation from peripheral O2 consumption RS: Inc rate and depth of respiration from inc BMR CNS: Stimulatory: tremor, hyperreflexia GI: Inc Appetite, Secretory activity and motility GU: Control of sexual function and menstruation Metabolic: promote gluconeogenesis and inc mobilization of glycogen stores Lipolysis, inc FFA Inc Protein synthesis	CVS: marked positive inotropic and somewhat less marked positive chronotropic effects (synergistic with beta-agonist) GIT: red GI tone and secretions GU: decreases the ureteric tone and has a small effect in improving the renal blood flow and urine output. Metabolic/other: - increases gluconeogenesis, glycogenolysis, lipolysis, proteolysis, and ketogenesis → ↑ blood sugar - stimulates release of endogenous catecholamines and may cause hypokalaemia secondary to an increase in the rate of insulin secretion.	Vasoconstriction – increased MAP Pulmonary vasodilation Increased vWF, factor VIII Antidiuretic: reduced urine output, resolution of polydypsia	Vasoconstriction (less) Increased platelet aggregation Antidiuretic (more)	Vasoconstriction Increased platelet aggregation Antidiuretic
PD: Side Effects / Toxicity	Thyrotoxicosis	Nausea/vomiting Hypo/hyperglycaemia Diarrhoea allergy	Hyponatraemia with H2O retention May cause severe vasoconstriction -CVC only Arrhythmias at higher doses GIT smooth muscle constriction cramping, nausea, diarrhoea	OD – Hyponatremia (Seizure, altered mental state, arrythmias, edema)	Hyponatraemia with H2O retention May cause severe vasoconstriction -CVC only Arrhythmias at higher doses GIT smooth muscle constriction cramping, nausea, diarrhoea


PHARMACOKINETICS (PK)
PK: Absorption	PO BA 100%	Inactive orally	IV only	BA SL: 0.25% PO: 0.08-0.16% Intranasal: 10%	IV only

PK: Distribution			limited data
Protein binding (PK: Distribution)	Thyroid-binding globulin Levo: 99.97% Tri: 99.5%		No PB	20%	30%
Volume of distribution (PK: Distribution)	Levo 0.2 L/kg Tri: 0.5 L/kg		0.14 L/kg	0.2-0.32 L/kg	0.5 L/kg Biphasic plasma curve

PK: Metabolism	35% of Levothyroxine → Triiodothyronine (liver, kidney), inactive T3 Conjugate to glucuronide and sulfate → bile Some Enterohepatic recirc	Proteolysis – splanchnic, hepatic, renal	Metabolised by peptidases (Vasopressinases) to amino acids	Minimal hepatic metabolism	minimal

PK: Excretion	20-40% faeces unchanged		65% unchanged in urine	65% unchanged in urine	urine
- Clearance (PK: Excretion)	Levo: 1.7 ml/min Tri: 17 ml/min	8-12 ml/min/kg Halved in renal failure
- Half Life (PK: Excretion)	Levo: 6-7 days Tri: 2 days	3-6min	10-35 mins	2-3hrs	50-70min


SPECIAL POINTS	- Increase warfarin effect - Beta agonists – inhibit conversion of levothyroxine to triiodothronine	- potentiates warfarin effect

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INDIVIDUAL TABLES

Hydrocort vs. Methylpred vs. Dexamethasone

Pharmacopeia - Corticosteroids

	HYDROCORTISONE	METHYLPREDNISOLONE	DEXAMETHASONE
GROUP	Glucocorticoid	Glucocorticoid	Glucocorticoid
CICM Level of Understanding	Level 2	Level 2	Level 2

INTRODUCTION	Natural Dose Equivalence 25	Synthetic Dose Equivalence 4	Synthetic Dose Equivalence 0.75
USES	1. as replacement therapy in adrenocortical deficiency states and in the treatment of 2. allergy and anaphylaxis 3. asthma 4. panoply of autoimmune disorders 5. eczema and contact sensitivity syndromes and 6. in leukaemia chemotherapy regimes and 7. for immunosuppression after organ transplantation	1. as replacement therapy in adrenocortical deficiency states and in the treatment of 2. allergy and anaphylaxis 3. hypercalcaemia 4. asthma 5. panoply of autoimmune disorders 6. some forms of red eye and 7. in leukaemia chemotherapy regimes and 8. for immunosuppression after organ transplantation.	1. as replacement therapy in congenital adrenocortical deficiency states and in the treatment of 2. allergic disorders 3. asthma 4. many autoimmune and rheumatologic disorders 5. eczema and contact sensitivity syndromes and 6. leukaemia and lymphoma chemotherapy regimes and 7. immunosuppression after organ transplantation 8. palliative treatment of tumours 9. prevention of post-operative and chemotherapy-induced nausea and vomiting 10. ophthalmic inflammatory diseases 11. acute exacerbations of inflammatory bowel disease 12. acute severe skin diseases 13. cerebral oedema 14. bacterial meningitis—prevents hearing loss 15. tests for Cushing’s syndrome 16. hypercalcaemia of malignancy, sarcoidosis, and vitamin D toxicity 17. antenatal use in preterm labour 18. myasthenia gravis 19. autoimmune renal disease and 20. has been used for epidural injection.


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	10/20mg tablets White lyophilized power to be mixed in water Other topical preparations	White powder – mixed with water	0.5/2mg tablets Oral solution Vials – white powder


PHARMACODYNAMICS (PD)
PD: Main Action	Anti-inflammatory	Anti-inflammatory	Anti-inflammatory
PD: Mode of Action	lipid solubile → crosses cell membranes → bind to steroid receptors via “zinc finger” binding site → signal trascribed via second messenger → alters gene transcription and the production of proteins	lipid solubile → crosses cell membranes → bind to steroid receptors via “zinc finger” binding site → signal trascribed via second messenger → alters gene transcription and the production of proteins	lipid solubile → crosses cell membranes → bind to steroid receptors via “zinc finger” binding site → signal trascribed via second messenger → alters gene transcription and the production of proteins
PD: Route & Doses	PO,TOP, IV, IM, IA	PO,TOP, IV, IM, IA, epi	PO,TOP, IV, IM, IA
PD: Metrics (Onset/ Peak/ Duration)	Dur: 8-36h	Dur: 12-36h	Dur: 36-54h
PD: Effects	1. Metabolic effects ▪ ↑’s gluconeogensis ▪ ↑ protein catabolism and lipolysis → muscle wasting and thin skin and fat redistribution (cushingoid) ▪ ↑ bone catabolism → osteoporosis ▪ ↑ glucose release but ↓ absorption from the GIT 2. Anti inflammatory effects ▪ ↓’d phospholipase A2 → ↓ arachidonic acid → ↓ prostaglandins 3. Immunosupression ▪ ↓’d inflammatory mediators ▪ ↓ IL 1-2 → ↓’d lymphocyte prod ▪ altered neutrophil and macrophage function	1. Metabolic effects ▪ ↑’s gluconeogensis ▪ ↑ protein catabolism and lipolysis → muscle wasting and thin skin and fat redistribution (cushingoid) ▪ ↑ bone catabolism → osteoporosis ▪ ↑ glucose release but ↓ absorption from the GIT 2. Anti inflammatory effects ▪ ↓’d phospholipase A2 → ↓ arachidonic acid → ↓ prostaglandins 3. Immunosupression ▪ ↓’d inflammatory mediators ▪ ↓ IL 1-2 → ↓’d lymphocyte prod ▪ altered neutrophil and macrophage function	1. Metabolic effects ▪ ↑’s gluconeogensis ▪ ↑ protein catabolism and lipolysis → muscle wasting and thin skin and fat redistribution (cushingoid) ▪ ↑ bone catabolism → osteoporosis ▪ ↑ glucose release but ↓ absorption from the GIT 2. Anti inflammatory effects ▪ ↓’d phospholipase A2 → ↓ arachidonic acid → ↓ prostaglandins 3. Immunosupression ▪ ↓’d inflammatory mediators ▪ ↓ IL 1-2 → ↓’d lymphocyte prod ▪ altered neutrophil and macrophage function
PD: Side Effects / Toxicity	▪ Adrenal supression via negative feedback on the HPA ▪ Fluid retention - via weak mineralcorticoid activity ▪ Vascular reactivity - plays a permissive role in the actions of catecholamines on vessels Inhaled: oral candidiasis (poor technique), dysphonia, minor adrenal suppresion	▪ Adrenal supression via negative feedback on the HPA ▪ Fluid retention - via weak mineralcorticoid activity ▪ Vascular reactivity - plays a permissive role in the actions of catecholamines on vessels	▪ Adrenal supression via negative feedback on the HPA ▪ Fluid retention - via weak mineralcorticoid activity ▪ Vascular reactivity - plays a permissive role in the actions of catecholamines on vessels


PHARMACOKINETICS (PK)
PK: Absorption	IV Rapidly given PO or PR PO BA: 50%	IV	IV PO BA 80-90%

PK: Distribution
Protein binding (PK: Distribution)	CBG 70%, Alb 20%	80%	70%
Volume of distribution (PK: Distribution)	0.5 L/kg	Low	Low

PK: Metabolism	Liver – Tetrahydrocortisone	Liver	Liver – CYP3A4

PK: Excretion	Urine	Urine	Urine
- Clearance (PK: Excretion)	167-283 ml/min
- Half Life (PK: Excretion)	0.5-1.5h	2-4h	3.5-5h


SPECIAL POINTS Glucocorticoid Action Mineralocorticoid Action Duration	100 1 Short	20 Min Intermediate	4 Min Long

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Hydrocortisone

Pharmacopeia - Corticosteroids

	HYDROCORTISONE
GROUP	Glucocorticoid
CICM Level of Understanding	Level 2

INTRODUCTION	Natural Dose Equivalence 25
USES	1. as replacement therapy in adrenocortical deficiency states and in the treatment of 2. allergy and anaphylaxis 3. asthma 4. panoply of autoimmune disorders 5. eczema and contact sensitivity syndromes and 6. in leukaemia chemotherapy regimes and 7. for immunosuppression after organ transplantation


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	10/20mg tablets White lyophilized power to be mixed in water Other topical preparations


PHARMACODYNAMICS (PD)
PD: Main Action	Anti-inflammatory
PD: Mode of Action	lipid solubile → crosses cell membranes → bind to steroid receptors via “zinc finger” binding site → signal trascribed via second messenger → alters gene transcription and the production of proteins
PD: Route & Doses	PO,TOP, IV, IM, IA
PD: Metrics (Onset/ Peak/ Duration)	Dur: 8-36h
PD: Effects	1. Metabolic effects ▪ ↑’s gluconeogensis ▪ ↑ protein catabolism and lipolysis → muscle wasting and thin skin and fat redistribution (cushingoid) ▪ ↑ bone catabolism → osteoporosis ▪ ↑ glucose release but ↓ absorption from the GIT 2. Anti inflammatory effects ▪ ↓’d phospholipase A2 → ↓ arachidonic acid → ↓ prostaglandins 3. Immunosupression ▪ ↓’d inflammatory mediators ▪ ↓ IL 1-2 → ↓’d lymphocyte prod ▪ altered neutrophil and macrophage function
PD: Side Effects / Toxicity	▪ Adrenal supression via negative feedback on the HPA ▪ Fluid retention - via weak mineralcorticoid activity ▪ Vascular reactivity - plays a permissive role in the actions of catecholamines on vessels Inhaled: oral candidiasis (poor technique), dysphonia, minor adrenal suppresion


PHARMACOKINETICS (PK)
PK: Absorption	IV Rapidly given PO or PR PO BA: 50%

PK: Distribution
Protein binding (PK: Distribution)	CBG 70%, Alb 20%
Volume of distribution (PK: Distribution)	0.5 L/kg

PK: Metabolism	Liver – Tetrahydrocortisone

PK: Excretion	Urine
- Clearance (PK: Excretion)	167-283 ml/min
- Half Life (PK: Excretion)	0.5-1.5h


SPECIAL POINTS Glucocorticoid Action Mineralocorticoid Action Duration	100 1 Short

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Short Acting Insulin (Actrapid)

Pharmacopeia - Hypoglycaemic agents

	Insulin Neutral (Actrapid)	SGLT2 Inhibitors
GROUP	Insulin - Short	SGLT2 Inhibitors
CICM Level of Understanding	Level 1	Level 3

INTRODUCTION
USES	1. type I diabetes mellitus 2. diabetic emergencies 3. the perioperative control of blood sugar concentration 4. hyperkalaemia and 5. to improve glucose utilization during TPN and 6. in provocation tests for growth hormone.


PHARMACEUTICS (PC)
PC: Chemical	Human insulin analogue Hexomer complexed with zinc that dissociates rapidly to monomers
PC: Presentation	Clear solution 100IU/ml


PHARMACODYNAMICS (PD)
PD: Main Action	stimulation of carbohydrate metabolism, protein synthesis, and lipogenesis
PD: Mode of Action	1. Insulin binds the alpha-subunit of insulin receptors → complex is internalized → up regulates tyrosine kinase activity via Beta subunit → insertion of GLUT 4 channels in cell membrane 2. Activates Na/K/ATPase → intracellular K+ shift 3. Direct action on lipoprotein lipase
PD: Route & Doses	SC, IV
PD: Metrics (Onset/ Peak/ Duration)	5-15min 1-3 hours 3-4 hours
PD: Effects	Metabolic: - Increases rate of diffusion into cells, especially hepatic (GLUT 4) and increases activity of glucokinase - Inhibits glycogenolysis and gluconeogenesis - Stimulate glycogenesis - Inhibits lipolysis and increases lipogenesis - Increases active transport of amino acids into cells, stimulates mRNA translation and inhibits catabolism - Increases K+/Mg uptake into cells
PD: Side Effects / Toxicity	1. Hypoglycaemia 2. Allergic reactions- local more common. Protaphane may lead to protamine antibodies that only become relevant when large dose protamine administered IV 3. Lipodystrophy 4. Drug interactions- tetracyclines prolong effects of insulin


PHARMACOKINETICS (PK)
PK: Absorption	- Inactive when administered orally Factors affecting exogenous insulin absorption: - Site of injection (abdominal wall least variable) - Regional blood flow; Ambient temperature; Exercise - Depth of injection

PK: Distribution
Protein binding (PK: Distribution)	Minimal PB (<10%)
Volume of distribution (PK: Distribution)	Vd 0.02L/kg (slightly larger in the diabetic patient).

PK: Metabolism	Rapidly metabolized in liver, kidney and muscle by glutathione insulin transhydrogenase

PK: Excretion	Metabolites excreted in urine.
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)


SPECIAL POINTS

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Y11. Pharmacopeia: Endocrine Pharmacology

CICMWrecks Tables (Click to Open)

MASTER TABLES

HYPOGLYCAEMIC AGENTS

Pharmacopeia - Hypoglycaemic agents

CORTICOSTEROIDS

Pharmacopeia - Corticosteroids

OTHER HORMONES

Pharmacopeia - Other Hormones

INDIVIDUAL TABLES

Hydrocort vs. Methylpred vs. Dexamethasone

Pharmacopeia - Corticosteroids

Hydrocortisone

Pharmacopeia - Corticosteroids

Short Acting Insulin (Actrapid)

Pharmacopeia - Hypoglycaemic agents

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