ADRI KOK

NETCARE UNION AND CLINTON

HOSPITALS

ALBERTON

31st MAY 2015

THE TOP 10 MEDICATION ERRORS

DISCLOSURES

ADVISORY BOARDS: AstraZeneca, Abbott , BMS, Pfizer,

Novartis, Janssen Pharmaceuticals, Boehringer-Ingelheim,

NovoNordisk, Sanofi, Merck, MSD, Lilly.

SPEAKER PANEL: Astrazeneca, Abbott, Boehringer-

Ingelheim, BMS, Janssen Pharmaceuticals, Lilly, Novartis,

NovoNordisk, Merck, MSD, Sanofi, Aspen-GSK,

Pharmaplan , Pfizer.

OPINION PAPERS: NovoNordisk, MSD, Astrazeneca.

RESEARCH INVOLVEMENT: Sanofi, NovoNordisk,

Novartis, MSD, Astrazeneca, Pfizer, Amgen. 2

POSSIBLE CAUSES

• ELDERLY

• RENAL + HEPATIC IMPAIRMENT

• CO-MORBIDITIES : 133 interactions T2DM

89 Depression

111 Heart failure

( BMJ 2015: 350. p 949 )

DRUG INTERACTIONS

INAPPROPRIATE PRESCRIBING, DOSAGES

PHARMACY, NURSING, CLARITY

Slide No. 4 • •

CLARITHROMYCIN

• REDUCES ACTIVITY of P450 SYSTEM

• POTENTIATING EFFECT : SIMVASTATIN

GEMFIBROZIL

RISK of RHABDOMYOLYSIS

• POTENTIATING EFFECT : AMLODIPINE

RISK of HYPOTENSION

STATIN TOXICITY

• FIBRATES Gemfibrozil 15x Fenofibrate

• AZOLE antifungals eg. Voriconazole, Fluc, etc

• AMIODARONE

• Erythromycin, Clarithromycin, NOT Azithromycin

• PROTEASE inhibitors eg. Ritonavir

• VERAPIMIL, DILTIAZEM

• Least with PRAVASTATIN

• Most with SIMVASTATIN, LEVOSTATIN

• Non-concurrent dosing can help

STATINS

• NOT ALL MUSCLE PAINS ARE DUE TO STATINS

• CHECK CK, TSH, Vit D

• CHECK drug interactions

• Stop statin for a week, restart Rosuvastatin 2x/ week

or Atorvastatin alternate days

• Add Ezetimide , allows lower statin dosage

( IMPROVE-IT trial )

Rhabdomyolysis 0,01 %, Hepatic toxicity 0,0001%

Myalgia with pravastatin

• Linked to low vit D level

• If < 35 give Vit D weekly

( Int J of Cardiol 2015: ( 178) 111-116 )

LEVOFLOXACIN / QUINOLONES

• Quinolone related HYPERAESTHESIA

Neuropathy may develop within one week

• 81% prevalence hyperaesthesia

• May be permanent

• TENDONOPATHY

• Esp. Achilles

• Older patients

• Assoc. corticosteroids

• May affect shoulder, hand, Achilles = rupture

QUINOLONES contd.

• ARRHYTHMIA

• Esp. risk with Moxy, less with Cipro

• INSOMNIA

• RETINAL DETACHMENTS

• PERIPHERAL NEUROPATHY

TRAMADOL

• u opiod receptor binding, dependent on Cyt P 450

enzyme for activation ….. Active metabolite

• Large fluctuations possible/ individual pt

• Inhibits neuronal uptake of serotonin, epinephrine so

may precipitate SEROTONIN SYNDROME

• Esp with co-prescribed antidepressants

• Risk of HYPOGLYCEMIA even low doses, esp. elderly,

increased risk in pts DM

• FOUNIER et al JAMA 8 DEC 2014

TRAMADOL ( TRAMACET, TRAMZAC Co, ULTRACET)

• HYPOGLYCAEMIA• (JAMA Dec 2014)

• SEIZURES

• SEROTONIN SYNDROME

• Esp. SSRI’S, higher dose

• Possibility of dependence

WARFARIN ( COUMADIN )

• Most frequent admission : overwarfaranised

• Laboratory adjustment excessive

• Obese patients 84% increased risk major bleed

• Stepwise 3 levels of obesity : BMI > 30

• Require increased dose, longer to achieve Rx level

• ? WEIGHT RELATIONSHIP :Not proven with NOAC’s• ( Ogunsha Arteriosclerosis, Thrombosis, Vascular biology 2015 Scientific sessions)

WARFARIN cont.

• MOST SEVERE INTERACTION:

• TMP/ Sulfa

• Erythromycin

• Amiodarone: prolonged half life

• Propafenone

• Ketoconazole, Fluconazole

• Itraconazole

• metronidazole

WARFARIN cont.

• MOST SEVERE

• TMP/ Sulfa

• Erythromycin

• Amiodarone : prolonged half-

life

• Propafenone

• Keto, Flu, Itraconazole

• Metronidazole

• POSSIBLE

• Quinolones

• Omeprazole

• Clarithromycin

• Azithromycin

LINEZOLID ( ZYVOXID )

• MAO inhibitors within 2 weeks of such a product eg. phenelzine,

meclobemide

• Potential increased BP

• Avoid in uncontrolled HT eg. phaeo, thyrotoxicosis, vasopressors ,

dopaminergic agents

• Serotonin syndrome : avoid in carcinoid, SSRI’s, TCA’s

• Serotonon 5 HT1 R agonists, buspirone, meperidine (Pethidine)

• Reversible myelosuppression

• Lactic acidosis

• Peripheral + optic neuropathy > 28 days

• Risk of seizures

• C.diff, mild diarrhoea to fatal colitis

SEROTONIN SYNDROME

• COGNITIVE DYSFUNCTION

• HYPERPYREXIA

• HYPEREFLEXIA

• INCOORDINATION

LACTIC ACIDOSIS

• Recurrent nausea

• Vomiting

• Unexplained acidosis

• Low bicarb. level

OEDEMA

• CCB’s : less with non-dihydropyridines Verapamil,

Diltiazem

• Pramipexole ( Pexola )

• Pioglitazones ( TZD’s )

• NSAID’s

• 7-8% gabapentin, pregabilin

• Omeprazole

• Estrogen

• Testosterone

HYPERKALAEMIA

• TMP/SULFA:

• TRIMETHOPRIM acts like Amiloride

• K+ sparing with decreased excretion by 40%

• At risk: elderly

chronic renal failure

high dose steroids

ACE inhibitors/ ARB

sulphonylureas inhibit CYP2C9( J Geront Biol Sci 2015 ( 70 ) 247-54)

Odds ratio sudden death 1.38!

PRAMIPEXOLE ( PEXOLA )

• Dose related

• Compulsive behaviour

• Also assoc dopaminergic drugs ( Levodopa, Sinemet )

• Gambling

• Aberrant sexual behaviour

• Binge eating

• Compulsive buying

HYPONATREMIA

• Paroxetine and other SSRI’s

• esp. elderly

females

low BMI

concomitant diuretics esp. HCTZ

• HCTZ, Indapamide

• SNRI’s

• Carbamazepine ( Tegretol )

• Ecstasy

CRITICAL ILLNESS

• SEVERE INFECTION SIRS VASODILATATION

INCREASED CO

• TRAUMA, BURNS FLUID EXTRAVASATION

MAJOR SURGERY FLUIDS, VASOACTIVE AGENTS

• Increased Vd HYDROPHILIC

• ORGAN FAILURE HEPATIC: Decrease clearance

LIPOPHILIC

AKI: decrease clearance/

HYDROPHILIC, NB. INCREASED RENAL CLEARANCE

HYPOALBUMINEMIA, PROTEIN BINDING

KIDNEY AND HEPATIC FAILURE

ANTIBIOTIC USE AND

ADJUSTMENTS

PLASMA PROTEIN BINDING

• HIGHLY PROTEIN BOUND > 80%

CLINDAMYCIN, TEICOPLANIN, CEFTRIAXONE

40-60%: AZTREONAM, VANCO,MOXIFLOXACIN,

LINEZOLID, CEFOTAXIME, LEVOFLOX, CIPROFLOX

< 20%: IMIPENEM, AMOXICLAV,CEFIPIME,

CEFTAZIDIME, METRONIDAZOLE, MEROPENEM

AB PROPERTIES

HYDROPHILIC

BETA-LACTAMS:

PENICILLINS

CEPHALOSPORINS

CARBAPENEMS

MONOBACTAMS

GLYCOPEPTIDES

AMINOGLYCOSIDES

LOW VOLUME OF DISTRIBUTION

INABILITY TO DIFFUSE THRU

MEMBRANES

INACTIVE VS INTRACELLULAR

ORGANISMS

RENAL ELIMINATION UNCHANGED

LIPOPHILIC

MACROLIDES

FLUOROQUINOLONES

TETRACYCLINES

CHLORAMPHENICOL

RIFAMPICIN

LINEZOLID

HIGH VOLUME OF DISTRIBUTION

ABILITY TO DIFFUSE THRU

MEMBRANES

ACTIVE VS INTRACELLULAR

ORGANISMS

ELIMINATED AFTER LIVER

METABOLIZATIONPEA + VIALA,CLIN INF DIS 2006, (42) : 1764-1771

SIEVING COEFFICIENT DURING CVVHD

Sc = Cuf/ Cp

• HIGHEST:CEFOTAXIME > 1

• 0,8 -1: AMIKACIN, TOBRAMYCIN, IMIPENEM,

CEFTAZIDIME, METRONIDAZOLE

• 0,6-0,8: PIPERACILLIN, GENTA, VANCO,AMPI,

PENICILLIN,CIPROFLOX

• < 0,4: CLINDA, CEFTRIAXONE,TEICOPLANIN,

OXACILLIN

PK/PD RELATIONSHIPS

• BETA-LACTAMS,

GLYCOPEPTIDES,OXAZOLIDINONES

• TIME-DEPENDENT ANTI-BACTERIAL ACTIVITY

• TIME ABOVE MIC : Cmin > MIC

PK/PD RELATIONSHIPS

• AMINOGLYCOSIDES

CONCENTRATION DEPENDENT ANTIBACTERIAL

ACTIVITY

OPTIMAL EXPOSURE: Cmax/ mic > 10

AUC / MIC > 40-50 vs G +ve

AUC / MIC > 125 vs G -ve

DOSING ANTIFUNGALS + AB / CVVHD

• AMIKACIN

• MEROPENEM

• PIP/TAZ

• VANCO

• TEICOPLANIN

• LINEZOLID

• CIPROFLOXACIN

• TIGECYCLINE

• COLISTIN

• VORICONAZOLE

• FLUCONAZOLE

• CEFEPIME

• GENTAMYCIN

• BACTRIM

• CLINDAMYCIN

• 25mg/kg TDM

• 2g over 3hrs TDS

• 16g/2g by CI

• 35mg/kg over 4 hr, 14mg/kg

• TDM= 25-30mg/l

• 10mg/kg bd, 8mg/kg bd

• 600mg bd

• 800mg, 400mg tds

• 150mg, 100mg bd

• 9 MIU, 4,5 MIU tds

• 8mg/kg bd, 6mg/kg bd

• 600mg bd

• 2g tds

• 7mg/kg daily

• 1 200mg/240mg ( 3 amps), 2 amps

tds

• 900 mg qid

THE CASE FOR AMIKACIN

• CONC- DEPENDENT ( PEAK ) BACTERICIDAL

ACTIVITY

• 1g AMIKACIN in AKI with CRRT?

• NEED AT LEAST 25mg/kg loading dose

• THEN DOSE / TDM

• REMOVAL of AMIKACIN during CRRT

• PEAK is linked to BACTERIAL KILLING

• TOXICITY more related to exposure time rather than

peak intensity

THE CASE FOR BETALACTAMS

• PIP/TAZ not good tissue penetration esp alveolar space,

VAP

• TIME DEPENDENT

• REMOVAL during CRRT very effective

• LOADING DOSE most often neglected ( 4g)

• MAINTENANCE 16 – 20g / 24 hrs

• SEVERAL STUDIES ( including substudy from IVOIRE

trial) confirm underdosing of BETALACTAMS 80% of

patients when administered in bolus

BOSELLI et al, CRIT CARE MED 2008; 36: 1500-1506

BOYAN, HONORE et al, ICM 2013; 39: 1535-1546

THE CASE FOR VANCOMYCIN

• POOR TISSUE PENETRATION esp ALVEOLAR

• NEW LOADING DOSE 35mg/kg in 4hrs

• MAINTENANCE DOSE 14mg/kg/ 24hrs

• EFFECTIVE ELIMINATION by CRRT

• ? USE in VAP on CRRT

Need higher trough 25-30mg/ l , MIC of 1-1,5 mg/l

Higher loading dose of 25mg/kg over 2 hrs for

intermittent HD

BEUMIER, J ANTIMICR THER 2013: 68: 2859-2865

KALIL et al BMJ 2013 OCT 14th

SPAPEN, HONORE et al ANN INT CARE 2011 : 1-21

CLIN INF DIS 2011 ; 53: 124-129

WHAT ABOUT COLISTIN

• EASILY ELIMINATED by CRRT, 80% by adsorption

• LOADING DOSE of 9 MIU

• MAINTENANCE DOSE of 4,5 MIU 3x / day on CRRT

• NO toxicity found

• Change filter every 3 days

• Regimen has been infused for 15 days without toxicity

• No greater incidence of CKD

HONORE al Int J Nephr Renovasc dis 2013;6:107-111

HONORE et al BLOOD Purif 2014; 37: 291-295

HONORE et al INDIAN J Crit Care 2014; 7: 415-417

CONCLUSIONS and PERSPECTIVES

• DOSE derived from IHD cannot be simply used / CRRT

• 80% b- LACTAMS underdose in CRRT

• Amikacin at least 25mg/kg loading / CRRT

• Vanco 35mg/kg over 4 hrs loading , 14 mg/kg over

remaing 24hrs on CRRT

• Aim in particular MRSA VAP MIC of 1-1,5 mg/l, trough

value of 25- 30 mg/ l

• Colistin mainly adsorbed during CRRT , loading dose

9miu, then 4,5 miu tds , change filters every 3 days

• Adsorption of Antibiotics onto membrane NOT negligible

PROPOFOL

• If used for induction : decreased CO

• 1mg/kg ASA II –III

• > 55 years

• Maintenance ICU sedation: 0,3mg/kg body wt/hour

• max 4mg/kg

• not > 7 days, monitor lipids

• esp. TG every 2 days

• Infuse saline or 5% D/W

PROPOFOL

• CONTRA-INDICATIONS:

hypersens to Propofol

allergies to soya, peanuts

not < 16 yrs of age

PROPOFOL INFUSION SYNDROME

Metabolic acidosis

Hyperlipidemia

ARF, rhabdomyolysis

acute CCF

PROPOFOL

• DRUG INTERACTIONS: ANAESTHETIC DRUGS

• Synergism, increased sedation

• Prolonged anaesth benzo, inhalational anaesth.

• OPIOIDS

• FENTANYL increased blood levels of Prop, apnoea

• Suxamethonium/ Neostigmine brady, cardiac arrest

• INCOMPATIBLE: aminoglycosides, diazepam, digitalis,

theophylline, phenytoin, pentobarbital, sodabic,

chlordiazepoxide

• LIMITED COMPATIBILITY : dopamine, dobutamine,

epinephrine, norepinephrine, Na nitroprusside

PERFALGAN

• Not extensively protein bound

• Present in CSF within 20 min of 1g infusion.

• 2 hepatic pathways: glucoronic acid conjugation

• sulphuric acid conjugation

• < 4% via Cyt P 450 normally

• With paracetamol poisoning glutathione pathway

swamped = toxic metabolites produced

• 90% excreted urine within 24 hrs

• < 5 % unchanged

PERFALGAN

• RENAL INSUFFICIENCY:

Creat cl < 30 ml/min delayed elimination

Allow 6 hrs between doses

HEPATIC INSUFFICIENCY:

Use with caution mild to moderate liver impairment

Contra-indicated active disease, alcoholic hepatitis

due to CYP 2E1 induction

ELDERLY:

no dosage adjustments needed

PreceDEX

• Alpha-2 adrenergic receptor agonist, 6-8x affinity vs

Clonidine

• Sedative and analgesic after cardiac surgery

• 94% protein bound, liver metabolism

• 95% elimination via kidneys

• C/I : sepsis, unstable trauma, hypovolaemia, heart block,

uncontrolled cardiac failure

• CAUTION: LV dysfunction, hepatic impairment

• ELDERLY: consider dose reduction, may cause

hypotension, bradycardia

PreceDEX ( Dexmedetomidine)

• DRUG INTERACTIONS:

anaesthetics

sedatives, hypnotics

opioids

SA package insert: not to exceed infusion > 24 hrs

ULTIVA (REMIFENTANIL)

• Potent ultra short-acting opiod analgesic

• Rapid metabolism tissue and red blood cell esterases

• 70% protein bound

• Supplemental to GA / induction, maintenance

• With OD = muscle rigidity, apnoea, bradycardia

• Not a substrate for plasma cholinesterase

ULTIVA ( REMIFENTANIL)

• RENAL IMPAIRMENT:

no change up to 3 days infusion

clearance of carboxylic acid metabolite reduced

NO clinically relevant u-opiod effects

not extracted during IHD / CRRT but carboxylic acid

metabolite will be by 30% HD

HEPATIC IMPAIRMENT:

No need to reduce in hepatic impairment

severe liver failure may cause resp. depression,

titrate

ELDERLY:

reduce initial dose by 50% as more intense response

The diabetes epidemic: global projections, 2011–2030

IDF. Diabetes Atlas 5th Ed. 2011

World 2011 = 366 million2030 = 552 millionIncrease = 51%

Leads to

Diabetes

Epidemic

Visceral Fat Distribution:Normal vs Type 2 Diabetes

Normal Type 2 Diabetes

2-11

DIABESITY

• Obesity

• Type 2 Diabetes

• Hypertension

• Dyslipidemia

The Deadly Quartet

THE OMINOUS OCTET

Islet b-cell

Impaired

Insulin Secretion

Neurotransmitter

Dysfunction

Decreased Glucose

Uptake

Islet a-cell

Increased

Glucagon Secretion

IncreasedLipolysis

Increased Glucose

Reabsorption

Increased

HGP

DecreasedIncretin Effect

Blood Glucose Lowering Therapies

Glucose dependent

GLP-1 RA

a-Glucosidase

InhibitorsDPP-4 Inhibitors

Glucose independent

Exogenous Insulin

Glinides

Sulfonylurea

Metformin

TZDs

Inhibition of Glucose

Absorption

Insulin Resistance Insulin Secretion

SGLT2

inhibitors

Insulin independent

Metformin is eliminated unchanged by kidney

Accumulates in chronic kidney disease

Concern about the increased risk of lactic acidosis

Risk increased in the elderly and in the presence of other co-morbidities

Metformin in CKD

Recommendations for the use of metformin in different stages of chronic kidney disease

Avogaro A & Schernthaner G (2012)

ESRD Haemodialysis

505560 40 35 30 2545

<30>60eGFR

mL/min 1.73 m²

SmPC/

NICE

Australian

Canadian

Lipska et al.

Use with caution

Review and reduce dosage use with caution

Review use

Use with caution

SmPC: Summary of product characteristics

No problem with eGFR > 45

Reduce dose with eGFR 30-45

Do not use with eGFR <30

“Second generation”

Glibenclamide

Gliclazide – “standard” and modified release

Glimeperide

Glipizide

Sulfonylureas

Indicator Comment

Glycaemia +++

Outcomes-Microvascular-Macrovascular

Reduction (UKPDS; ADVANCE)Reduction (UKPDS long term); ADVANCE no effect

Hypoglycaemia Increased

Weight change Increase

Side effects / precautions Renal impairment (some agents)

Patient Acceptability High

Cost Low

Other

Therapeutic Options - SU

Sulfonylureas: hypoglycemia risk

*<50 mg/dL.

Tayek J. Diabetes Obes Metab. 2008; 10: 1128–1130.

0

5

10

15

20

25

30

Gliclazide

0.85

Glipizide

8.70

Glimepiride

0.86

Tolbutamide

3.50

Chlorpropamide

16.00Glyburide

16.00

Severe hypoglycemia*

n/1000 person years

Rela

tive R

isk (

%)

Inhibition of DPP-4 Increases Active GLP-1

GLP-1inactive

(>80% of pool)

ActiveGLP-1

Meal

DPP-4

IntestinalGLP-1 release

GLP-1 t½=1–2 min

Adapted from Rothenberg P, et al. Diabetes 2000; 49 (suppl 1): A39. Abstract 160-OR.

Adapted from Deacon CF, et al. Diabetes 1995; 44: 1126-1131.

PLEIOTROPIC ACTIONS of GLP-I

Insulin Secretion

β-Cell Neogenesis

β-Cell Apoptosis

Glucagon Secretion

Glucose

Production

Heart

GI TractLiver

MuscleDrucker DJ. Cell Metab. 2006;3:153-165.

Brain

Appetite

Cardioprotection

Cardiac OutputGLP-1

Stomach

Gastric

Emptying

Neuroprotection

Glucose

Uptake

_

+

Pleiotropic Actions of GLP-1

1. DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-29522. Drucker DJ and Nauck MA. Lancet. 2006;368:1696-1705

Properties/Effect

GLP-1 Receptor

Agonists1,2

DPP-4

Inhibitors1,2

Insulin production +++ ++

First-phase insulin

response +++ ++

Glucagon;

glucose output+++ +

Gastric emptying Delayed No effect

Food intake No effect

Body Weight No effect

Hypoglycemia No No

Side effects Nausea, vomiting Minimal

Incretin Therapies: Major Differences

Hypoglycaemia results in ECG abnormalities

• Abnormalities in:

• atrioventricular conduction

• ventricular depolarisation

• ventricular repolarisation

• R-wave amplification associated with norepinephrine counter-regulatory response

• T-wave flattening associated with epinephrine counter-regulatory response

Laitinen et al. Ann Noninvasive Electrocardiol 2008;13:97–105

ECG, electrocardiogram

Amplification of R-wave

Flattening of T-wave

Decrease in ST segment

P

R

S

T

Q

Prolongation of QT interval

ECG

(m

V)

Time (seconds)

Baseline

Euglycaemic hyperinsulinaemia

Hypoglycaemic hyperinsulinaemia

Cardiac ischaemia associated with hypoglycaemia episodes

• Increased episodes of chest pain and ECG abnormalities

• CGMS and Holter monitoring abnormalities

Study included patients (n=19, mean age, 58±16 years) with type 2 diabetes, a history of frequent hypoglycaemia, an HbA1c of <8% and coronary

artery disease (defined as a history of myocardial infarction, coronary bypass surgery or angioplasty)

*p<0.01 vs. episodes during hyperglycaemia and normoglycaemia

Desouza et al. Diabetes Care 2003;26:1485–9

Total episodes

Episodes with

chest pain/angina

Episodes with ECG

abnormalities

Hypoglycaemia 54 10* 6*

Symptomatic 26 10* 4*

Asymptomatic 28 – 2

Normoglycaemia without rapid changes N/A 0 0

Hyperglycaemia 59 1 0

Rapid changes in glucose (>100 mg/dL-1/h-1) 50 9* 2

Link between hypoglycaemia and acute cardiovascular events in type 2 diabetes

• Retrospective, observational study (n=860,845) assessing association between hypoglycaemic events and acute cardiovascular events

• 3.1% patients had a hypoglycaemic event during the evaluation period (1 year)

• Patients with hypoglycaemic events had 79% higher odds of acute cardiovascular events than patients without hypoglycaemic events

Johnston et al. Diabetes Care 2011;34:1164–70

SGLT2 Inhibition

A Novel Treatment Strategy for

Type 2 Diabetes

Renal Glucose Reabsorption

in Type 2 Diabetes

• Sodium-glucose cotransporter 2 (SGLT2) plays a role in

renal glucose reabsorption in proximal tubule

• Renal glucose reabsorption is increased in type 2

diabetes

• Selective inhibition of SGLT2 increases urinary glucose

excretion, reducing blood glucose

Wright EM, et al. J Intern Med. 2007;261:32-43.

SGLT1

(180 L/day) (900 mg/L)=162 g/day

10%

Glucose

No Glucose

S1

S3

Renal Handling of Glucose

SGLT2

90%

Gerich JE. Diabet Med. 2010;27:136–142.

Renal glucose re-absorption in patients with hyperglycaemia

SGLT1

SGLT2

~10%

~90%

When blood

glucose

increases above

the renal

threshold

(~10 mmol/L or

180 mg/dL), the

capacity of the

transporters is

exceeded,

resulting in

urinary glucose

excretion

Filtered glucose

load 180 g/day

69

Rationale for SGLT2 Inhibitors

• Inhibit glucose reabsorption in the renal proximal tubule

• Resultant glucosuria leads to a decline in plasma

glucose and reversal of glucotoxicity

• This therapy is simple and nonspecific

• Even patients with refractory type 2 diabetes are likely to

respond

In a challenging obese population of uncontrolled Type 2 DM

on MDI and high Insulin Requirements, add-on Empagliflozin

resulted in:

Significant improvements in HbA1c level closer to 7%

Lower Insulin requirements

Weight loss

No increased Hypoglycemia Risk

Increased Genitourinary infections

Trends of BP reductions

Conclusions

Empagliflozin as Add-On to MDI Insulin Study

THYROID DISEASE IN THE ELDERLY

HYPOTHYROIDISM

THYROID DISEASE IN THE ELDERLY

HYPOTHYROIDISM

Case Presentation

• During her routine visit to doctor, Ayesha, an apparently healthy 70-year-old woman complained of mild fatigue, dry skin, and difficulty in losing weight since last 2 years.

• The past medical and surgical history were uneventful.

• There was no reported family history of DM/HTN/IHD.

• Physical examination results were normal including a non- palpable thyroid gland.

• ECG was normal. Fasting and postprandial blood sugar and CBC were within normal limits.

• Serum TSH and FT4 tests were repeated 2 weeks after the first visit and were found to be 8.1 mIU/L and 1.4 ng/dL, respectively.

• Diagnosis: Subclinical hypothyroidism (Hashimoto’s thyroiditis)

Serum TSH 8.0 mlU/L

Serum free T4 1.3 ng/dL

Serum total cholesterol 220 mg/dL

Serum HDL cholesterol 46 mg/dL

Serum LDL cholesterol 150 mg/dl

Serum triglycerides 80 mg/dL

Thyroperoxidase antibodies Positive

Clinical Manifestations: Symptoms

• Symptoms1,2

• Tiredness/ weakness

• Dry skin

• Cold sensation

• Hair loss

• Poor concentration/memory loss

• Constipation

• Weight gain with poor appetite

• Dyspnea

• Hoarseness of voice

• Menorrhagia

• Paresthesia

• Hearing impairment

1. Ladenson P and Kim M. Cecil Medicine. 2008:1698-1713.

2. Jameson JL, et al. Harrison's Principles of Internal Medicine. 2008: 2224-2247.

Clinical Manifestations: Signs

• Signs1,2

• Cold peripheral extremities

• Dry, coarse and yellow skin

• Puffiness of face, hands and feet

• Hair loss and brittle nails

• Bradycardia/ diastolic hypertension

• Delayed tendon reflex relaxation

• Peripheral edema

• Serous cavity effusions

• Normal/enlarged/atrophied thyroid gland

• Hypothyroidism in children

• Delayed linear growth in children

• Delayed or precocious puberty

• Pseudohypertrophy of muscles1. Ladenson P and Kim M. Cecil Medicine. 2008:1698-1713.

2. Jameson JL et al. Harrison's Principles of Internal Medicine. 2008: 2224-2247.

Levothyroxine: Important Facts

• Levothyroxine sodium has a narrow therapeutic range

• Regardless of indication of use, careful dose titration is necessary to avoid consequences of over- or under-treatment

• Even small changes in the dose of LT4 can shift a patient from a euthyroid to a hyperthyroid or hypothyroid state.

• The AACE recommends the use of a high-quality brand preparation of levothyroxine

• Same brand of LT4 should be received throughout treatment

AACE medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006:1-13

http://www.aace.com/pub/pdf/guidelines/hypo_hyper.pdf.

Mild Thyroid Failure and

Aortic Atherosclerosis in Women

0

50

100

Pa

tie

nts

, %

Condition Present

Condition Absent

Presence of Aortic Atherosclerosis

Hak AE, et al. Ann Intern Med. 2000;132:270-278.

Women With

Mild Thyroid

Failure

Euthyroid

Women

Women

With Mild

Thyroid

Failure and

Antibodies

to Thyroid

Peroxidase

Euthyroid

Women

Without

Antibodies to

Thyroid

Peroxidase

Learning Objectives

Define and classify hypothyroidism

Explain the etiology of hypothyroidism

List the clinical manifestations of hypothyroidism

Explain the defining criteria and associated risks of

subclinical hypothyroidism

Discuss the treatment of overt and subclinical

hypothyroidism with levothyroxine

Describe the special conditions associated with

hypothyroidism and their management

Algorithm for Diagnosis of Thyroid Dysfunction

TSH

High Normal Low

Free T4

Low Normal

HypothyroidismSubclinical

Hypothyroidism

Normal

Free T4

High

Subclinical

HyperthyroidismHyperthyroidism

Joshi S. Journal of The Association of Physicians of India; 2011:14-20.

Cardiovascular Effects of Hypothyroidism

• Haemodynamic changes

– Increase in vascular resistance

• Decreased vasodilator action of T3 and NO

– Impaired ventricular performance

• Changes in the expression of myocyte-specific regulatory

proteins

• Increased cardiovascular risk

– Increased risk for functional cardiovascular

abnormalities

– Increased risk for atherosclerosis

Klein I.L. The Thyroid, 9 ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:774780

Biondi B, et alI. Endocrine 2004;24:1–13

Changes in Renal Function

in Hypothyroidism

Adapted from Kaptein EM. The Thyroid, 9 ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:789–795

Hypothyroidism

Changes in renal function

Renal blood flow

Glomerular filtration

Sodium conservation during sodium restriction

Potassium excretion

Free water and osmolar clearance

Oedema

Total body sodium and water

Capillary permeability

Endocrine-metabolic changes

Plasma catecholamines

Plasma renin activity

Serum aldosterone

Serum atrial natriuretic peptide

Hypertension

Plasma catecholamines

α-adrenergic response

Salt sensitivity

Hyponatraemia

Glomerular filtration

Free water delivery to distal tubule

Hyperuricaemia/gout

Cardiovascular changes

Cardiac output

Peripheral vascular resistance

Changes in Renal Function

in Hypothyroidism

Adapted from Kaptein EM. The Thyroid, 9 ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:789–795

Hypothyroidism

Changes in renal function

Renal blood flow

Glomerular filtration

Sodium conservation during sodium restriction

Potassium excretion

Free water and osmolar clearance

Oedema

Total body sodium and water

Capillary permeability

Endocrine-metabolic changes

Plasma catecholamines

Plasma renin activity

Serum aldosterone

Serum atrial natriuretic peptide

Hypertension

Plasma catecholamines

α-adrenergic response

Salt sensitivity

Hyponatraemia

Glomerular filtration

Free water delivery to distal tubule

Hyperuricaemia/gout

Cardiovascular changes

Cardiac output

Peripheral vascular resistance

Effects of Hypothyroidism on the Skeletal

System

• Decreased recruitment, maturation and activity

of bone cells

• Decreased bone turnover (bone resorption

and bone formation)

• Increased fracture risk in elderly patients– Decreased trabecular bone turnover

– Reduced renewal of bone

– Accumulation of stress fractures

– Increased risk for falling (poor muscular function)

Gittoes NJL, et al. The Thyroid, 9 ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:830–835

Hypothyroid Patient – Case

Study• 75-year-old lady with cold intolerance

– Chronic use of electric blanket with burning of the skin

• Weakness, fatigue, weight gain

• Global heart failure, bradycardia

Chronic use of electric blanket75-year-old lady with hypothyroidism

Hypothyroid Patient Case Study – Treatment

• Treatment with levothyroxine 50 µg/d for 2 weeks,

increasing the dosage to 100 µg/day for another 2 weeks

• Clinical signs of hypothyroidism already improved

Before T4 4 weeks after T4

Before T4

4 wks after T4

Achilles tendon reflex relaxation time

• Maintenance dose: 125 µg/day (1.2 µg/kg BW)

Hypothyroid Patient Case Study – Treatment

• Treatment with levothyroxine 50 µg/d for 2 weeks,

increasing the dosage to 100 µg/day for another 2 weeks

• Clinical signs of hypothyroidism already improved

Before T4 4 weeks after T4

Before T4

4 wks after T4

Achilles tendon reflex relaxation time

• Maintenance dose: 125 µg/day (1.2 µg/kg BW)

NOT ALL PEOPLE ARE THE SAME!

Always look your patient in the eyes and LISTEN to them! THEN ACT!

THE ELDERLY PATIENT with

ENDOCRINE DISEASE

WCIM 2014

ADRI KOK

SPECIALIST PHYSICIAN

NETCARE UNION HOSPITAL

SOUTH AFRICA

27TH OCTOBER 2014

SEOUL, SOUTH KOREA

91

ELDERLY?

• DIFFICULT TO DEFINE “ELDERLY” / “OLDER

PEOPLE”

• > 65 YRS?

• 2026 anticipated that > 20% > 65 yrs of age

• MANY COUNTRIES > 85 INCREASING

• WOMEN LIVE ON AVERAGE 5 YEARS LONGER

CLINICAL CLUES TO ENDOCRINE DISEASE

• ANXIETY, TREMOR

• LOSS OF TASTE

• VOICE CHANGES

• CONSTIPATION

• POLYURIA

• FALLS, BRADYCARDIA

• HYPERTHYROIDISM

• ADRENAL INSUFFICIENCY

• HYPOTHYROIDISM

• HYPOTHYROIDISM,

HYPERCALCEMIA, PTH

• DIABETES MELLITUS,

DIABETES INSIPIDUS ( ADH

action decreased)

• HYPOTHYROIDISM

ENDOCRINE CHANGES WITH AGEING

PHYSIOLOGICAL CHANGE

• MENOPAUSE: decreased

oestrogen, progesterone

• TESTOSTERONE decreased

• GROWTH HORMONE

secretion decreased

• VITAMIN D : decreased

absorption, activation

• THYROID: increased risk, esp

• Hypothyroidism

• DIABETES: increased risk,

increased insulin resistance,

decreased insulin sens.

• ADH: increased secretion

response to osmolar stimuli

CLINICAL MANIFESTATIONS

• Decreased bone mass,

• Decreased muscle mass

• Fracture risk increased

• Vaginal dryness

• Skin changes, dry, easy

bruising

• Tendency towards water

intoxication