PROKINETICS , ANTIEMETICS, ANOREXIANTS - PowerPoint Presentation

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PROKINETICS , ANTIEMETICS, ANOREXIANTS

NWAIWUSlide2

PROKINETIC AGENTS

Medications that enhance coordinated GI motility and transit in the GI tract.

Pharmacologically and chemically diverse.Slide3

NEURAL REGULATION OF GASTRIC MOTILITY

Stimulation by cholinergic neurons.

Inhibition by adrenergic neurons.

Modulatory influence of the enteric nervous system where dopamine and serotonin play a role. Thus D2 and 5-HT

3

receptor antagonists as well as 5-HT

4

agonists stimulate gastric motility.Slide4

Prokinetics

1

. Medication used to

a. ↑coordinated motility of the GIT

b. ↑transit time of foods in GIT

2. Therapeutic uses

a. GERD

b.

Gastroperesis

(delayed gastric emptying)

c.

Pseudoobstruction

i

. False obstruction (no intrinsic obstruction if bowel is dissected)

ii. Maybe due to

1. Muscle abnormalities

2. Nervous defect

d. Constipation Slide5

Categories of

Prokinetics

1. Cholinergic agents

a. Cholinergic derivatives

i

.

Bethanechol

Acetylcholinesterase

inhibitor

i

.

Neostigmine

2. Dopamine receptor antagonist

a.

Benzimidazole

derivatives

i

.

Domperidone

3. 5HT (Serotonin) receptor modulators

a.

Cisapride

b.

Metaclopromide

(

maxolon

®)

4.

Motilin

– like agent

.

Macrolide

i

. Erythromycin Slide6
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METOCLOPRAMIDE

CNS effects characteristic of dopaminergic blockade.

Antagonism of emesis induced by apomorphine and ergotamine

Hyperprolactinemia

Significant extrapyramidal symptoms

Anxiety,depression

Drowsiness, dizziness and anxietySlide10

THERAPEUTIC USES

Diabetic

gastroparesis

.

Esophageal reflux.

Prevention of nausea and vomiting from a variety of causes including pregnancy.

Mechanism of action;

Dopaminergic

antagonist, blocks G.I. Effects caused by local or systemic administration of

dopaminergic

agonists.

May promote release of ACH from

myenteric

neurons.

ADVERSE EFFECTS

Extrapyramidal

effectsSlide11

CISAPRIDE

Effects on motility of the stomach and small bowel closely resemble those of metoclopramide.

Increases colonic motility and can cause diarrhea.

Devoid of dopamine antagonist activity. Thus it does not influence concentration of prolactin in plasma or cause extrapyramidal symptoms.Slide12

THERAPEUTIC USES

Disorders of gastric

hypomotility

. Efficacy equals that of

metoclopramide

and

domperidone

without the side effects that result from dopamine receptor

blocakde

.

Gastroesophageal

reflux disease.

Gastroparetic

conditions.

Chronic idiopathic constipation and colonic

hypomotility

.

ADVERSE

EFFECTS

Transient

abdominal cramping and diarrhea. May increase absorption of diazepam and alcohol.Slide13
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Antiemetic and Antinausea AgentsSlide15

Definitions

Nausea

Unpleasant feeling that often precedes vomiting

Emesis (vomiting)

Forcible emptying of gastric, and occasionally, intestinal contents

Antiemetic agents

Used to relieve nausea and vomitingSlide16

VC and CTZ

Vomiting center (VC)

Chemoreceptor trigger zone (CTZ)

Both located in the brain

Once stimulated, cause the vomiting reflexSlide17

Mechanism of Action

Many different mechanisms of action

Most work by blocking one of the vomiting pathways, thus blocking the stimulus that induces vomitingSlide18

NEURAL PATHWAYS LEADING TO EMESIS

Coordinated by the vomiting center.

This center receives input from CTZ.

From vestibular apparatus via the cerebellum.

From higher brainstem and cortical structures.

From visceral afferents in the periphery.

From emetic substances in the circulation.Slide19

EMETIC RESPONSE

Following stimulation of the vomiting center, emesis is mediated by various efferent pathways.Slide20

NAUSEA AND VOMITING

Thought to be protective reflexes.

Nausea occurs initially followed by reduced gastric tone, reduced peristalsis and increased tone in the duodenum and

upper jejunum. Gastric reflux then occurs.

Accompanied by multiple autonomic phenomena (salivation, shivering, vasomotor changes).Slide21

Blood born

emetics

Local

Irritants

Emetic Center

Higher Centers

Sensory

Input

Memory, fear, dread,

and anticipation

Stomach

and small int

Pharynx

(gagging)

Inner

ear

cerebellum

CNS

Periphery

BLOOD BRAIN BARRIER

5-HT

3

CTZ

5-HT

3

D2

M1

Solitary tract

nucleus

5-HT

3

D2

M H1

Vagal and

sympathetic

afferents

Glossoph.,

trigeminal affs.Slide22

NEUROTRANSMITTER PATHWAYS OF EMESIS

Serotonin acting at 5-HT

3

receptors

is an important emetic signal and transmitter in the afferent pathways from the stomach and small intestine, in the CTZ and in the solitary tract nucleus.

Dopamine acting at D

2

receptors

is implicated in emetic signaling thru the trigger zone and the solitary tract nucleus.

Substance P/

neurokinin

1 receptor-

substance P induces vomiting and binds to NK-1 receptors in the abdominal

vagus

, STN and the area

postrema

.

Slide23

NEUROTRANSMITTER PATHWAYS OF EMESIS

Histamine and H

1

receptors are concentrated in the solitary tract nucleus as well.

Cholinergic and

histaminergic

synapses seem to be involved in transmission from the vestibular apparatus to the emetic center.

Basis for use of H

1

receptor antihistamines and

muscarinic

cholinergic antagonists in motion sickness.

Sensory stimuli such as pain and sight can contribute to vomiting as can the anticipation of an unpleasant experience.Slide24

ANTIEMETIC AGENTS

5-HT

3

antagonists

D

2

antagonists

NK1 receptor antagonists

Corticosteroids

Cannabinoids

Antihistamines

Muscarinic antagonists

BenzodiazepinesSlide25
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An anorectic

or

anorexic

(from the

Greek

an

- = "without" and

orexis

= "appetite"), also known as

anorexigenic

,

anorexiant

, or

appetite suppressant

, is a

dietary supplement

and/or

drug

which reduces

appetite

, resulting in lower food consumption, leading to

weight loss

.

By contrast, an appetite stimulant is referred to as

orexigenic

.

APPETITE Slide32

APPETITE

The

hypothalamus

is the controller stimulated by:

OREXIGENIC PEPTIDES

(appetite inducers)

e.g. agouti-protein and neuropeptide Y

ANOREXIGENIC PEPTIDES

(appetite suppressants)

e.g. melano-cortin which, with effects on specific receptors (MC1R), decreases food intake and increases energy expenditureSlide33

Central Controls are Influenced by Circulating HORMONES:

INSULIN: provides signals related to blood glucose levels

LEPTIN: signaling consistency of body fat stores

and, in addition

The GUT HORMONESSlide34

The GUT HORMONES

GRELIN: secreted by the stomach

fundus

(when empty) increases appetite and hence food intake

NO: nitric oxide (not a hormone but dilates the empty stomach hence very

orexigenic

)

CHOLECYSTOKININE and PEPTIDE YY3-36: secreted by endocrine lining cells of the distal gut and colon when food present hence appetite suppressants (

anorexigenic

)Slide35

• Obesity is a chronic medical condition associated with significant morbidity. Obesity increases the risk of developing type-2 diabetes mellitus, hypertension, coronary heart disease, gall bladder disease, sleep

apnea

, and osteoarthritis. Obesity is also associated with some cancers, including endometrial, breast and colon cancer.

• Obesity is defined as body weight 30% over the ideal body weight. Drug therapies are initiated for patients with a body mass index (BMI) of ≥ 30 with no concomitant risk factors or diseases and for patients with a body mass index of ≥ 27 with concomitant risk factors or diseases. Some risk factors or diseases that may warrant

antiobesity

drug therapy are hypertension,

hyperlipidemia

, coronary heart disease, type-2 diabetes, and sleep

apnea

.

• ObesitySlide36

Anorexia Nervosa:

A Classic Eating Disorder

A disease of the mid-adolescent period characterized by:

INTENSE FEAR OF GAINING WEIGHT

DENIAL OF THE SERIOUSNESS of the CURRENT LOW WEIGHT

PRESENCE of AMENORRHEA in post-

menarchal

females for at least 3 consecutive periods

periods occurring following estrogen administration DO NOT

COUNT

Definite

neuro

-psychiatric disorder

More frequently encountered in young post-pubertal females of college ageSlide37

Bulimia Nervosa

Characterized episodes of binge eating alternating with purging

Female to male ratio 10:1

Some genetic factors may be involved, but and above all

cultural attitudes

toward standards of physical attractiveness

3 modalities are the most frequent:

Self induced vomiting via “fingers” or ipecac

Abuse laxatives (e.g. bisacodyl, cascara or senna)

Misuse diuretics

In addition to diuretics also diet pills (containing ephedrine)Slide38

Obesity Treatments

Caloric restrictions: with necessity to restrict fats to less than 30% of the total caloric intake

Modification of lifestyle and exercise:

A walk of 1 mile (1.5 m) burns 100 Kcal

Walk 2 - 3- or even 4 miles, 4 or 5x weekly, and add some resistance exercise 2 or 3 times weekly (all under some supervision).

The dietary variations: The Atkins Diet or the high protein low carbohydrate (only 20 grams of CHO/day)Slide39

Used to treat obesity

Anorexiants

benzphetamine (Didrex)

methamphetamine (Desoxyn)

phentermine (Ionamin)

orlistat (Xenical)

Lipase inhibitor, not a CNS stimulant

Also used to treat obesity

May cause fecal incontinence

Anorexiants

39

Copyright © 2014 by Mosby, an imprint of Elsevier Inc.Slide40

Suppress appetite control centers in the brain

Increase the body’s basal metabolic rate

Mobilization of adipose tissue stores

Enhanced cellular glucose uptake

Reduce dietary fat absorption

Mechanism of Action

40

Copyright © 2014 by Mosby, an imprint of Elsevier Inc.Slide41

Orlistat

(

Xenical

)

Basic Function:

Prevents the absorption of fats, reducing caloric intake

Saturated version of

Lipstatin

Inhibits pancreatic lipases which break down fat molecules

Side Effects:

Oily discharge/fatty stools

Lower absorption of fat soluble vitamins

Prescription Drug PharmacodynamicsSlide42

Sibutramine (Meridia)

Phentermine

Basic Function:

Inhibits NT reuptake in brain

Serotonin

Norepinephrine

Dopamine

Enhances feeling of satiety

Increased risk of heart attack and strokes

Pulled from US market in October 2010

Still present in many counterfeit products

Basic Function:

Causes release of norepinephrine in hypothalamus

Reduces feeling of hunger

Similar structure to amphetamines

Part of Fen-Phen combination drug

Prescription Drug PharmacodynamicsSlide43

Metformin

(

Glucophage

)

Diabetes drug

For people overweight

and suffering from diabetes

to aid in weight loss

Basic function:

Lowers glucose levels

Increase insulin sensitivity

Appetite suppressant

Prescription Drug PharmacodynamicsSlide44

Common Side Effects for Prescription Drugs

Side Effects:

Nausea (minor or severe)

Constipation/Diarrhea

Dry mouth

Headaches

Insomnia

Increased blood pressure and heart rate (minor or severe)

Nervousness, confusion, and irritabilitySlide45
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Mechanisms of Action

Dronabinol

: The exact mechanism of action of

dronabinol

is unknown; although, the antiemetic activity is thought to be due to its effect on

cannabinoid

receptors within the central

nervoussystem

.

Dronabinol

may also inhibit activity in the "vomiting

center

" in the brainstem and suppress the synthesis and activity of prostaglandins.

Megestrol

: The stimulation of appetite by

megestrol

may occur as a result of an antagonizing effect on catabolic cytokines.

Megestrol

is a synthetic progestin with

antiestrogenic

properties.

Overall,

megestrol

disrupts the normal

estrogen

cycle and results in a lower luteinizing hormone (LH)

titer

.

Megestrol

also has

antineoplastic

properties via

antileutenizing

effects which are mediated through the pituitary gland.

Oxandrolone

:

Oxandrolone

is a synthetic testosterone derivative with similar androgenic and anabolic actions. Anabolic steroids, like testosterone and

oxandrolone

, promote protein anabolism and reverse catabolic processes resulting in appetite stimulation by stimulating the release of testosterone in a way that closely mimics normal physiologic testosterone levelsSlide49

Adverse Drug Reactions

Dronabinol

. The most common adverse events reported with

dronabinol

use are related to central nervous system effects, including anxiety, dizziness, drowsiness, confusion, hallucinations and feelings of depression. Limited clinical data suggest

dronabinol

decreases nausea and increases appetite but only an insignificant weight gain or, in some cases, a weight loss may occur.

Megestrol

. The most common adverse effects reported with

megestrol

use include gastrointestinal upset (

diarrhea

, gas), trouble sleeping, mood changes and testicular failure. Use in males is not highly recommended. More serious adverse events reported with

megestrol

use include inducing/exacerbating diabetes mellitus,

edema

,

thromboembolic

events and Cushing’s syndrome or adrenal insufficiency if discontinued abruptly.

The clinical data suggest

megestrol

is effective in increasing body weight but the weight gain appears to be mostly in the form of fat, which can contribute to the adverse effects of the agent.Slide50

Adverse Drug Reactions

Oxandrolone

. The most common adverse effects reported with

oxandrolone

use are related to testosterone-like effects and include acne, changes in sexual desire, deepening of the voice, unusual hair growth, menstrual irregularities, mental or mood changes and gastrointestinal upset (nausea , vomiting).

Use in females is not highly recommended. More serious adverse effects associated with

oxandrolone

use include liver damage and an increase in serum lipids. The clinical data suggest

oxandrolone

is effective in increasing body weight and lean body mass; although, some evidence suggests the weight gain may be in the form of fat.