NCD DRUGS &

IMMUNIZATION

ANITHA D.NPHARMACIST

PHC KADAMANITTA

• It is a disease which is not infectious. Such

diseases may result from genetic or lifestyle

factors.

• A non-communicable disease is an illness that is

caused by something other than a pathogen.

• The non-communicable diseases are spread by:

heredity, surroundings and behavior.

NON COMMUNICABLE DISEASE (NCD)

• Hereditary Factors

• Improper diet

• Smoking

• Other Factors

CAUSES

Hypertension

Diabetes

Cardio Vascular Disease

Cancer

Asthma

Atherosclerosis

EXAMPLES

HypertensionThe Silent killer

Force exerted by circulating blood on the arterial walls

Maximum (systolic) pressure – pressure in the artery when

the left ventricle is contracting to force the blood into

aorta and other arteries. It is 120mm Hg

Minimum (diastolic) pressure – The left ventricle & arterial

BP decreases as blood returns to the right atria & ventricle

of the heart from the venous system. It is 80mm Hg.

The normal blood pressure is 120/80.

BLOOD PRESSURE

Hypertension is high blood pressure. Blood

pressure is the force of blood pushing

against the walls of arteries as it flows

through them.

HYPERTENSION -DEFINITION

Essential (Primary) Hypertension

Secondary Hypertension

Pseudo Hypertension

White coat Hypertension

HYPERTENSION-TYPES

No medical cause

Risk factors :

Sedentary lifestyle

Obesity ( body mass index greater than

25)

Salt ( sodium) sensitivity

Alcohol, smoking

Family history

ESSENTIAL OR PRIMARY HYPERTENSION

Chronic Kidney Diseases.

Chronic Steroid Therapy & Cushing’s Syndrome.

Drug-Induced or drug related

Pheochromocytoma

Thyroid or parathyroid Disease.

Sleep Apnea.

SECONDARY HYPERTENSION

When BP measured by cuff is falsely

elevated compared to reference standard

because of hardened calcific arterial walls.

PSEUDO HYPERTENSION

BP recording in office or clinic is high while at

home is normotensive

"white coat" hypertension appear to have no greater

risk than people with normal blood pressure

WHITECOAT HYPERTENSION

1. LIFE STYLE MODIFICATION

a) Weight reduction

b) Dietary Approach

c) Dietary Sodium restriction.

d) Moderate Alcohol consumption

e) Physical activity

MANAGEMENT

MANAGEMENT

DASHdiet

Regular exercise

Loose weight , if obese

Reduce salt and high fat diets

Avoid alcohol consumption

A. FIRST LINE AGENTS

Angiotensin converting Enzyme

Inhibitors(ACEIs)

Angiotensin Receptor Blockers(ARBs)

Calcium channel Blockers(CCBs)

Thiazide Diuretics

B. SECOND LINE AGENTS

B-Blockers

Aldosterone Antagonists

PHARMACO THERAPY

ACE stands for angiotensin converting enzyme

Used to treat high BP

40% of the dose is excreted in urine

Onset of action- 1 hour

Peak- 4-6 hours

Duration of action-atleast 24 hours

Dosage-

Initial dose- 2.5mg to 5mg/day

ACE INHIBITORSENALAPRIL MALEATE

Maintenance dose- 10mg to 40mg/day in single or

divided doses

Maximum dose- 40mg/day

Administration- with or without meals. Administer

with food if GI upset occurs.

Storage- at room temperature, away from moisture

and heat.

Pregnancy- do not use

ENALAPRIL (CONTD)

POINTS TO REMEMBER

Regular BP check up

Kidney & liver function test may be needed

Very low BP with this medication may be

associated with vomiting, diarrhea or sweating

more than usual

If surgery is required stop the medicine for a short

time

Contraindicated in angioedema

ENALAPRIL (CONTD)

Avoid drinking alcohol

Do not use potassium suplements

Avoid getting up quicky from a sitting or lying

position. Get up slowly & steadily to prevent fall.

DRUG FOOD INTERACTION

Enalapril + Alcohol – increases hypotensive effect

thereby lowers BP

ENALAPRIL (CONTD)

DRUG DRUG INTERACTIONS

Enalapril + Indomethacin- decreases hypotensive

effect of enalapril. Avoid the combination.

Enalapril+ losartan/telmisartan/olmesartan-

Increases risk of hypotension, renal impairment &

hyperkalaemia

Enalapril + Aspirin- The anti hypertensive efficacy

of enalapril may be reduced by high dose of aspirin.

ENALAPRIL (CONTD)

Enalapril + Trimethoprim- serious hyperkalemia in

association with renal impairment.

Enalapril + NSAIDs- increase BP, increase risk of renal

impairment & hyperkalemia

Enalapril + rifampicin- increase in BP.

DRUG DISEASE INTERACTIONS-

Enalapril—Renal diseaseEnalapril – Liver diseaseEnalapril – strokeEnalapril – congestive heart failure

ENALAPRIL (CONTD)

It belongs to a group of drugs called angiotensin II receptor antagonists.

DOSAGE FORM

Initial Dose : 50 mg orally once a day.

Maintenance Dose: 25mg to 100mg orally in 1 to 2 divided doses

Max dose:-100mg/day

ROUTE OF ADMINISTARTION: Oral

USES

Losartan is used to treat high blood pressure.

It is used to lower the risk of stroke in certain people with heart disease.

It is used to slow long-term kidney damage in people with type 2 diabetes who

also have high BP.

ANGIOTENSIN II RECEPTOR ANTAGONISTS

LOSARTAN

USES

Losartan is used to treat high blood pressure.

It is used to lower the risk of stroke in certain

people with heart disease.

It is used to slow long-term kidney damage

in people with type 2 diabetes who also have

high BP.

LOSARTAN(CONTD)

SPECIAL DIRECTIONS & PRECAUTIONS

Can be taken with or without food.

Monitor BP regularly

Avoid alcohol : Drinking alcohol lowers BP & increases

side effects of Losartan.

Do not use potassium supplements or salt substitutes.

Avoiding getting up too fast from sitting or lying position.

Do not use in pregnancy & Lactation.

LOSARTAN CONTD…

DRUGS-DISEASE INTERACTION

LOSARTAN DEHYDRATION,HYPONATRENIA,HEMODIALYSIS

It should be used cautiously in patients on diuretics

therapy, those on dietary salt restriction, renal dialysis.

Risk for excessive hypotension.

Losartan-Congestive Heart Failure

Can cause renal impairment 0liguria Myocardia ischemia Death

LOSARTAN CONTD…

Losartan + Diltiazem : Causes low BP, Kidney function

impairment & hyperkalemia (High blood Potassium)

Losartan + Enalapril: Low BP, Kidney function impairment

& hyperkalemia .

Losartan+ChlorpheniramineMaleate/Codeine/

Phenylephrine /Potasium Iodide

Combining these medication may significantly increase potassium levels in the blood. High levels of potassium can develop into condition known as hyperkalemia. This lead to kidney failure, muscle paralysis, irregular heart rhythm & cardiac arrest.

LOSARTAN CONTD…

Limit consumption of potassium –rich foods such as

tomatoes, potatoes, bananas, plantains , Papayas,

Pears, mangoes & potassium containing salt

substitutes.

Symptoms of Hyperkalemia

1. Nausea, Vomiting

2. Tingling of hands & feet.

3. Feeling of heaviness in the legs.

4. Weak pulse

5. irregular heart beat.

LOSARTAN CONTD…

Losartan + Codaine

Additive effect in lowering Blood Pressure

Side Effects

Headache

Dizziness

Light headedness

Fainting

changes in pulse or heart rate.

Avoid driving or operating hazardous machinery.

LOSARTAN CONTD…

Losartan + Amlodipine - May increase potassium

levels in the blood. Hyper kalemia.

Losatan + NSAID (Ibuprofen) – Increase the risk of

renal impairement & hyperkalemia.

Losatan + Indomethacin –May attenuate anti

hypertensive effect of Losartan.

Losatan +Fluconazole –Reduces the conversion of

losartan to it’s active metabolite.

LOSARTAN CONTD…

Losartan + Rifampicin- Increases the metabolism of

losartan and its active metabolite which may result in

reduced anti-HT effects.

Losartan + Levodopa –Enhanced Hypertensive effect.

Losartan + Aspirin –Aspirin in doses over 300mg daily

increases risk of renal impairment.

DRUG-FOOD INTERACTION Losartan +Alcohol – Increases Hypotensive effect.

So, there is chance for low BP.Losartan + Pottasium Salts- Increased risk of

Hyperkalaemia

LOSARTAN CONTD…

ACTION- amlodipine relaxes (widens) blood

vessels & improve blood flow.

Uses- Hypertension, chest pain (angina), other

conditions caused by coronary artery disease.

Dosage-

Initial dose – 2.5mg – 5mg orally once a day

Maintenance dose- 5mg – 10mg orally once a day

CALCIUM CHANNEL BLOCKERSAMLODIPINE

Pregnancy- not recommended.Breast feeding- not recommended.Storage- at room temperature, away from moisture,

heat & light.Administration- with or without food

POINTS TO REMEMBER

Do not stop beta blockers too quickly because serious

heart problems may be caused that cannot be

prevented by amlodipine.

AMLODIPINE (CONTD)

Use with caution in heart valve problem, CHF, Liver

diseases Get up slowly & steadily.

DRUG FOOD INTERACTION

Amlodipine + Alcohol- may lower BP & may increase

side effects of amlodipine.DRUG DISEASE INTERACTION

Amlodipine-Cardiogenic Shock/Hypotension- should not be used in patients with hypotension (Systolic Pressure less than 90mm Hg).It further depresses cardiac output & BP.

AMLODIPINE (CONTD)

DRUG DRUG INTERACTIONS

Amlodipine + Aspirin –May increase BP .If already taking

the combination & if aspirin is stopped BP may decrease.

Amlodipine +Calcium Carbonate- Decreases the effect

of Amlodipine.

Amlodipine+ Metoprolol- Additive effect in lowering BP &

Heart rate.

Amlodipine+ Ibuprofen- May increase BP.

Amlodipine+Chlorpheniramine/Codeine-Additive

effect,Lowers BP.

AMLODIPINE (CONTD)

Amlodipine+MVT with minerals-can decrease effects of

Amlodipine.

Amlodipine+ Diclofenac –may increase BP.

Amlodipine + Pheno- Pheno reduce blood levels and effect of

amlodipine.

Amlodipine+ Rifampicin/INH – lowers effect of amlodipine.

Amlodipine +Clarithromycin – may increase blood levels of

amlodipine. Serious side effects like irregular heart beat,

swelling fluid retention & heart failure.

AMLODIPINE (CONTD)

It is a class of drug called beta blockers.

ACTION : Relaxing blood vessels & slowing heart rate to

improve blood flow & decrease blood pressure.

USES : To Treat high Blood Pressure, Migraine headache ,

Heart failure & prevent heart attack.

DIETARY INSTRUCTIONS : Take low salt or low sodium

diet.

STORAGE: Store at room temperature away from excess

heat & moisture

ATENOLOL

ADMINISTRATION:

Take with a full glass of water.

Take atenolol at the same time every day.

DOSAGE :Initial dose: 50 mg orally once a day. The full effect

of this dose will usually be seen within 1 to 2 weeks. If an

optimal response is not achieved, the dosage should be

increased to 100 mg orally once a day.

Max dose- 100mg/day

DRUG FOOD INTERACTION :

Atenolol+ Alcohol = Decreases the anti-Hypertension

effect.

ATENOLOL

√ Atenolol + Orange Juice = The bio availability of atenolol is moderately

reduced by orange juice.

DRUG DRUG INTERACTION

Atenolol + Diclofenac = Diclofenac reduce the effects of atenolol

in lowering BP especially if diclofenac is used regularly to treat

arthritis.

Atenolol + Antacids/Anti diarrheal = Reduce the

absorption of atenolol.

Atenolol +NSAIDS= Increase blood pressure.

Atenolol + Indomethacin= Indomethacin reduces the anti-

Hypertension effect of atenolol.

Atenolol + Nifedipine = severe hypotension & heart

failure.

ATENOLOL

IMMUNISATION

DIABETES MELLITUS

Insulin is like a key which opens the

body cell doors to allow glucose to enter.

In the absence of enough insulin, glucose

cannot enter the cells and remains in the blood

stream in high amounts (hyperglycemia)

High blood sugar due to defective or deficient

insulin action and the resulting associated

problem is called diabetes.

Cells in the body needs glucose (sugar) for

making energy required for daily life.

The food we eat turns into glucose after

digestion .

What is Diabetes?

Diabetes mellitus is a condition in which glucose

level in the blood are much higher than normal and

hence this condition is also commonly referred to as

sugar disease.

The defect in this condition is that either the

pancreas does not produce enough insulin or it

produces sufficient insulin, but the cells of the body

are unable to use the insulin properly.

DIABETES MELLITUS

Who are prone ...?

Thirst

Polyuria

Blurring of vision

Weight loss.

DIABETES MELLITUS-SYMPTOMS

The long–term effects of diabetes mellitus include

progressive development of the specific complications of

retinopathy with potential blindness, nephropathy that

may lead to renal failure, and/or neuropathy with risk of

foot ulcers, amputation, Charcot joints, and features of

autonomic dysfunction, including sexual dysfunction.

People with diabetes are at increased risk of

cardiovascular, peripheral vascular and cerebrovascular

disease.

Diabetes Long-term Effects

Type 1 diabetes

Type 2 diabetes

Gestational diabetes

Other types of Diabetes

LADA (latent autoimmune diabetes)

MODY (maturity-onset diabetes of youth)

Secondary Diabetes Mellitus

Classification of Diabetes

Was previously called insulin-dependent diabetes

mellitus (IDDM) or juvenile-onset diabetes.

Risk factors for type 1 diabetes may include

autoimmune, genetic and environmental factors.

TYPE I DIABETES

Was previously called non-insulin-dependent diabetes

mellitus (NIDDM) or adult-onset diabetes.

It usually begins as insulin resistance, a disorder in

which the cells do not use insulin properly. As the need

for insulin rises, the pancreas gradually loses its ability

to produce insulin.

Type 2 diabetes is associated with older age, obesity,

family history of diabetes, history of gestational

diabetes, impaired glucose metabolism, physical

inactivity, and race/ethnicity.

TYPE II DIABETES

A form of glucose intolerance that is diagnosed in

some women during pregnancy.

During pregnancy, gestational diabetes requires

treatment to normalize maternal blood glucose

levels to avoid complications in the infant.

GESTATIONAL DIABETES

Patients usually aged >25 years

Initial control achieved with diet alone a diet &

oral hypoglycemic agents.

Insulin dependency occurs within months but can

take 10 yrs or more.

LADA

Mutations in any one of several transcription factors

or in the enzyme glucokinase lead to insufficient

insulin release from pancreatic ß-cells, causing

MODY.

FEATURES

Young onset of diabetes

Strong family history diabetes.

Sulfonylurea sensitivity

MODY

Within MODY, the different subtypes can essentially be

divided into 2 distinct groups: glucokinase MODY and

transcription factor MODY

Glucokinase MODY requires no treatment, while

transcription factor MODY requires low-dose

sulfonylurea therapy

MODY ( CONTD)

causes of Diabetes mellitus include:

Acromegaly,

Cushing syndrome,

Thyrotoxicosis,

Pheochromocytoma

Chronic pancreatitis,

Cancer

SECONDARY DIABETES MELLITUS

o DIET

o EXERCISE

o YOGA

o MEDICATION

o INSULIN

o ORAL ANTIDIABETICS

DIABETES MELLITUS - MANAGEMENT

Patients should be educated to practice self-care. This allows the

patient to assume responsibility and control of his / her own

diabetes management. Self-care should include:

Blood glucose monitoring

Body weight monitoring

Foot-care

Personal hygiene

Healthy lifestyle/diet or physical activity

Identify targets for control

Stop smoking

SELF CARE

Dosage Form : Tablet Dose :

Initial dose: 2.5 mg to 5mg tablet once daily.

Usual Single dose: 2.5mg to 10mg.

MAXIMUM DOSE: 20 MG/DAY

A single dose of 10mg tablet must not be exceeded. Larger daily

doses must be divided into at least two separate single doses.

Usual daily dose : 5mg to 10mg

Exceeding a total daily dose of 15mg (3tablets) is not

recommended, because high doses of up to 4 tablets are more

effective in exceptional cases.

GLIBENCLAMIDE

Route of administration : Oral

Duration of action : Usually long-term therapy.Uses : Type 2 Diabetes

Indications : Non insulin dependent Type 2 diabetes

mellitus .Whenever blood glucose levels cannot be controlled

adequately by diet, Physical exercise & weight reduction alone.

It can be given together with insulin & can be combined with

other oral antidiabics.

Uses: Action: Glibenclamide lowers the blood glucose by

stimulating the release of insulin from the pancreas, an effect

dependent upon functioning beta cells.

GLIBENCLAMIDE (CONTD)

Other mechanism include reduction of basal hepate glucose production and enhancement of peripheral insulin action at post-receptor sites.

Glibenclamide has a mild diuretic action & increase free water clearence.

Glibenclamide is nearly completely absorbed after oral administration & it is extensively bound 99%to serum proteins.

Peak concentration is reached in 2-6 hrs. Glibenclamide is completely metabolized in the liver. It is excreted as metabolites in bile & urine.

Special direction & Precautions: Daonil is to be taken before food. Do not skip

meals after the tablets have been taken. Correction of dosage must be considered

GLIBENCLAMIDE (CONTD)

Contradictions

Patients with Type I IDDM

Treatment of Diabetic Ketoacidosis.

Serious renal dysfunction.

Serious hepatic dysfunction.

Pregnant women.

Breast feeding woman.

Patients hypersensitive to Glibenclamide.

GLIBENCLAMIDE (CONTD)

Precautions Patients should be made aware of hypoglycemic &

Hyperglycemic symptoms.

Hyperglycemic Symptoms Increased urinary frequencyIntensive thirstDryness of mouth & dry skin

Hypoglycemic Symptoms Intensehunger,Nausea,Vomiting,Sweating,Tremor,Restles

sness,Speech disorder, Headaches, Loss of self –control, Loss of consciousness up to & including coma, shallow respiration & bradycardia.

GLIBENCLAMIDE (CONTD)

Regular monitoring of glucose levels in blood & urine.

Hypoglycemia can be corrected by immediate intake of carbohydrates. Eg: Glucose, Sugar, Tea, Fruit, Juice.

Patient must carry minimum 20gms of glucose with them all times.

Contradictions1) Hemolytic anemia: Treatment of patients with

Glucose-6-Phosphate dehydrogenize (G6PD) deficiency with sulphonyl urea can lead to hemolytic anemia.

2) Pregnancy : must not be taken3) Lactation : Must not be taken

GLIBENCLAMIDE (cont)

DRUG INTERACTIONS-

DRUG DRUG INTERACTIONS-

Glibenclamide+Ciprofloxacin-increases the hypoglycemic

effect of glibenclamide

Glibenclamide+NSAIDs- increases the hypoglycemic effect

Glibenclamide + fluconazole- increases serum levels of

glibenclamide

Glibenclamide + thyroid agents- decrease hypoglycemic

effect

GLIBENCLAMIDE (cont) DAONIL

Glibenclamide+ Phenytoin- decrease hypoglycemic

effect of glibenclamide

Glibenclamide + INH/ Rifampicin- Decrease

hypoglycemic effect

Glibenclamide + salicylates- increases the

hypoglycemic effect

Glibenclamide + oestrogens-decrease hypoglycemic

effect

Glibenclamide + bosentan- may increase

hepatotoxic effect of bosentan

GLIBENCLAMIDE (C ONTD)

DRUG FOOD INTERACTION

Glibenclamide + Alcohol- May cause disulfuram

like reactions

DRUG DISEASE INTERACTION

Glibenclamide- renal dysfunction

Glibenclamide- hepatic dysfunction

GLIBENCLAMIDE(CONTD)

It was discovered in Japan in 1981. It is an alpha-

glucosidase inhibitor.

Action- Voglibose delays the absorption as well as

digestion of dietary polysacharides by reversibly

inhibiting carbohydrate digestive enzyme like sucrose,

maltose etc.

It has additive effect with sulphonylurea

It diminishes weight increasing effects of

sulphonylurea

VOGLIBOSE

USES- In NIDDM patients as immunotherapy In combination with other OHAs In addition to insulin in DM patients

DOSAGE-

Maximum dosage- 0.6mg/day

Initial dosage- 0.2-0.3mg bd

ADMINISTRATION- before meals

VOGLIBOSE(CONTD)

CONTRAINDICATIONS-

Hypersensitivity to the drug

Diabetic ketoacidosis

Inflammatory bowel disease, chronic ulceration,

intestinal obstructions

Disorders of digestion or absorption

PREGNANCY/LACTATION- not to be used

STORAGE- store below 30 c

VOGLIBOSE(CONTD)

ACTION-Metformin works by suppressing glucose

production in the liver.

DOSAGE-

Initial dose- 500mg orally twice a day

Extended release- 500-2000mg/day

Maximum dose- 2500mg/day

USES-Type II diabetes, polycystic ovary syndrome

PREGNANCY/LACTATION- not to be used

METFORMIN

POINTS TO REMEMBER-

Should not be given to children younger than 10 yrs old

Extended release metformin should not be given to

children younger than 17 yrs old

In case of x-ray or CT scan using a dye, temporarily

stop metformin

ADMINISTRATION- with food

METFORMIN( CONTD)

It is an oral antidiabetic drug in the biguanide class

It works by suppressing the glucose production by liver

Drug of choice in the treatment of type 2 diabetes

Only antidiabetic drug shown to prevent cardiovascular

complictions of diabetes

Helps to reduce LDL cholesterol & triglyceride level

French physician Jean Sterne published first clinical trial of

metformin as a treatment for diabetes in 1957. He coined

the word “Glucophage”

METFORMIN

Chemical name: N,N-Dimethyl

imidodicarbonimidic diamide

As of 2010, metformin is one of the only

two oral antidiabetics in the WHO’s list of

essential medicines, the other one is

glibenclamide

METFORMIN

Metformin + metoprolol: cause hypoglycemia

Metformin + Lasix: increase the effect of metformin

which may lead to a condition called lactic acidosis

Metformin + levothyroxine: levothyroxine may interfere

with blood glucose control & reduce the effect of metformin

Metformin + cimetidine: increases plasma concentration

of metformin, thereby reducing clearance of metformin by

kidneys.

METFORMIN DRUG DRUG INTERACTION

Alcohol + metformin: may cause a

condition called lactic acidosis (serious

metabolic complication associated with

metformin accumulation in plasma usually at

levels exceeding 5mcg/ml)

symptoms-increasing sleep, weakness, slow

heart rate, stomach pain, shortness of breath

METFORMIN -ALCOHOL/FOOD INTERACTION

1. LACTIC ACIDOSIS: metformin is contraindicated

in patients with renal dysfunction. metformin

should not be administered to patients with

acute or chronic metabolic acidosis.

2. Metformin—B12 deficiency: Metformin may

interfere with vitamin B12 absorption

METFORMIN –DISEASE INTERACTION

It is a long acting sulfonylurea antidiabetic drug

Used to treat type 2 diabetes mellites

Mode of action: increase insulin production by pancreas

( It is not used in type 1 diabetes because in type 1

diabetes the pancreas is not able to produce insulin)

GLIMEPIRIDE

MAJOR INTERACTION

GLIMEPIRIDE + GATIFLOXACIN: Gatifloxacin can

affect blood glucose levels. Both hyper &

Hypoglycemia have been reported. Severe cases of

hypoglycemia during treatment with gatifloxacin has

resulted in coma & even death

GLIMEPIRIDE DRUG-DRUG INTERACTION

MODERATE INTERACTION

Glimepiride + hydrocortisone/methyl

prednisolone/ dexamethasone/ ethinyl

estradiol/ hydrochlorthiazide/

amitryptyllin/phenobarbital/ theophylline /INH/

levothyroxine: may interfere with blood glucose

level control & reduce effectiveness of glimepiride Glimepiride + aspirin/ ibuprofen/ amoxicillin/

clarithromycin: increase effects of glimepiride & cause blood sugar levels to get too low

GLIMEPIRIDE (CONTD)

Glimepiride + aluminium hydroxide/magnesium carbonate: increase the effects of glimepiride. Should be administered at least two hrs. before or after magnesium carbonate

Glimepiride + ethanol: avoid alcohol. Both hyper & hypoglycemia may occur

Glimepiride + ampicillin/atenolol/diclofenac/ranitidine/escitalopram/ fluconazole/metoprolol: increase effects of glimepiride & may cause hypoglycemia

DISEASE INTERACTION

RENAL/LIVER DISEASE

GLIMEPIRIDE

VISION WITHOUT ACTION IS A

DREAM. ACTION WITHOUT

VISION IS SIMPLY PASSING

THE TIME. ACTION WITH

VISION IS MAKING A

POSITIVE DIFFERENCE.