November 19, 2010

Clinical Pharmacology
By Richard Benedict S. Roxas, R.N, MD

Adrenergic System: Sympathetic Nervous System

- Neurotransmitter: AGONIST of ALL ADRENERGIC
a. Epinephrine  Adrenal Medulla (Stress Stimulated)
- Endogenous (A. medulla)
- Drugs
- Blood route stream (Blood Vessel)
b. Norepinephrine  Released in Presynaptic Cleft (Sympathetic Nerve)
- Neurotransmitter (Nerve-Nerve/Nerve to Target Organ) (Encased in a vesicle)
- Can be also present in the blood if Dopamine (Drug) is infused in the body
- Dopamine will be converted to circulating Norepinephrine
c. Dopamine  Released Presynaptic cleft (Sympathetic nerves, CNS  Brain)
- Produced in the Brain (Mesocortical/Mesolimbic/Substancia Nigra/Hippocampal Area)

AGONIST  Stimulatory to a certain receptor or Mimic the receptor (ADRENOMIMETIC Agents)

ANTAGONIST/BLOCKER  Opposite to the receptor action or lyses (ADRENOLYTIC)

Adrenergic Receptors:

A. Alpha Receptor

Alpha 1:

- Blood Vessels  VASOCONSTRICTION (AGONIST  Stimulatory to receptor)

LEVEL OF THINKING IF VASOCONSTRICTED IPASOK SA UTAK sa M4 receptor!

a. Increase Blood Pressure

- Increase Resistance Flow  Increase Viscosity  Damage Blood Vessel Obstruction (Severe) 
Ischemia  Necrosis

Resistance = Viscosity  By friction it can damage (Endothelium)  TXA2

TXA2: EFFECTS
1. Platelet Aggregation
2. Vasoconstriction
What are the factors that Enhances Hypertension?:
- Activity
- Stress
- LOVE and Happiness (Balita ko ikaw ang nanalo ng 600 BILLION sa lotto!)
- Cold Environment  Peripheral Vasoconstriction  Sympathetic Action  Alpha 1 stimulation
NOREPINEPHRINE)
- Events that mimic Hypertension (Increase Blood Volume) (WATER or BLOOD)
a. Blood Transfusion
b. IV infusion
c. Intake water/Na intake  (ALDOSTERONE via Macula Densa(DCT)  JG-CELL  RENIN RELEASE)
ANGIOTENSIN 2  AT1 receptor:
- Adrenal Cortex  ALDOSTERONE  Concentrate urine / reduce urine output  RETAINING
WATER  increasing Blood Volume  HYPERTENSION
- Cardiac Remodelling  Hypertrophy  HF
- POTENT VASOCONSTRION
b. Reduce Blood Flow in the distal part where blood vessel is located
- Cyanosis/Cold Clammy Skin/Reduced Pulses/Acidosis due accumulation CO2, Lactic Acid/Ischemia
 Necrosis(if prolonged)

ANTAGONIST to the Alpha 1 is used? Is Blocked

Blood Vessels  VASODILATION (ANTAGONIST/Blocker  Inhibitory)

a. Decrease Blood Pressure  Orthostatic Hypotension (Dizziness, Loss of LOC, Confusion)

- Heat Environment  can induce Hypotension (STEAM, SAUNA)  HEAT can stimulate alpha2
receptor  VASODILATION
Nursing-Nursingan:
a. Safety: Falls/Injury

NB: WAG WALIS WALIS ang UTAK!  Changes in the body , compensate avoid this KATULONG!

Circumstances that may cause further hypotensive effects SHOCK with drugs that has alpha 1 blocking
action:
- Drugs that induce Vasodilation (NO, calcium channel blockers, ARB)  Further over-expressing
hypotensive Effects
- Drugs that induce blood volume loss  Diuretics (BLOOD VOLUME LOSS  DECREASE BP)
- Events that induce blood volume loss  Blood Loss (trauma,donation,postpartum,vampirism),
Dehydration (Nagtatae, Strike-hunger, Vomiting, Sun bathing, Burns)
- Anaphylactic Shock  Histamine Release from Mast cell H1  VASODILATION  hypotension
- Erectile Dysfunction  Sildenafil (Viagra)  It has NO release  VASODILATION
- React with Alcohol  Respiratory Depression, Shock
- Reflex Tachycardia (Baroreceptor  Receptor Activation)
Location: HYPOTENSION is key factor for stimulating the BARORECEPTOR Arch of the aorta 
VAGUS NERVE  Medulla Oblongata Sympathetic efferents stimuate B1 of the R
side of the heart  TACHYCARDIA
 a. Increasing Work Load of the Heart  Requires energy/BF Increase Cardiac Output  Increase
BP
- Ischemic Heart Disease  CHEST PAIN
- Acute Coronary Syndrome  MI
b. Cardiac Remodeling  Hypertrophy of Heart (Myocardium & Chamber size decreasing) 
Decrease CO, it can also decrease the contraction of the heart via frank starling mechanism is
reduced (reduced stretching  less force of blood)  Heart Failure
b. Headache  Cerebral Arterial Vasodilation  Can compress nerves  Substance P, Bradykinin
PAIN in the thalamal area
c. VASODILATION can Pulls the blood to the periphery due gravity  Reduced Cerebral Blood flow
- Reduction of O2, Glucose  Lactic Acidosis  Increase Permeability (if prolonged)  COMA,
Dizziness
d. Hypotension for RAAS activation  JG cell  RENNIN  RENAL FAILURE (VASOCONSTRICTION)

Alpha 2: AGONIST  VASODILATION

Coronary Arteries, and Also Blood Vessel

Beta Receptor

Beta Agonist  STIMULATORY

- Salbutamol/Albuterol/Terbutaline/EPI/DOPA/NOR
Beta 1:
a. Heart  Right Side/Base of the Heart  TACHYCARDIA

b. Islets of Langerhans (Pancreas)  Inhibition of Beta cell to release Insulin, Alpha cell secretion 
GLUCAGON HYPERGLYCEMIA, rise FFA

c. Uterus  Uterine Relaxation

- BUNTIS:
1. Increase blood flow in the maternal side from uterus to the Placenta (Fetal Side)  it enhances
UTEROPLACENTAL BLOOD FLOW
2. Prevents abruption (separating the placenta from the uterus)
3. Acceptable FETAL WELL BEING
4. NOT GOOD DURING LABOR & POSTPARTUM (Postpartal Bleeding, Uterine Prolapse, Atony 
POST PARTUM, Delay in the engagement  during active labor within 3 cm dilatation)

d. JG Cell  Release Rennin  Product later ANGIOTENSIN 2 

- Cardiac Remodeling
- Aldosterone Release  Na & Water Retention and increase blood volume Hypertension
- Reduced Urine Output due to concentration of the urine, aldosterone effect, vasoconstriction renal
Artery  REDUCED GFR  ACUTE RENAL FAILURE
Beta 2:

a. Bronchi  Bronchodilation (relaxation smooth muscle of the bronchi)  Increase Patency

Beta Antagonist/BLOCKER  Inhibitory

- Propanolol/Metoprolol/Esmolol

Beta 1: BLOCK

a. Heart  Right Side/Base of the Heart BLOCK  BRADYCARDIA

- severe  Heart Failure  Loss perfusion blood/CO  Hypotension
- Decrease Work Load heart, Reduced Cardiac Remodeling

b. Islets of Langerhans  Stimulation of Beta cell to release Insulin, Alpha cell secretion Blocker 
GLUCAGON BLOCK
HYPOGLYCEMIA (DANGER  DEADLY loss of ATP in the neurons)

c. Uterus  Uterine Contraction

1. It decreases UTEROPLACENTAL BLOOD FLOW due to the contraction the smooth muscle of the
uterus that compresses the blood vessels that supports the uterus and reduce flow in the
placenta.  FETAL HYPOXIA
2. It can cause fetal head compression  VAGAL stimulation  BRADYCARDIA  imminent fetal
Distress
3. Fetal cord Compression
4. Early Abruption
5. Prevents bleeding, prolapsed, atony, enhances delivery of FETUS, PLACENTA, or fetal fecundities

d. JG Cell  Release Rennin Inhibitory  no production ANGIOTENSIN 2

Beta 2:

a. Bronchi  Broncho-constriction  Increase Obstruction airway-patency

1. DOB (Chemoreceptor Reflex  Accumulate Hydrogen ions due PaCO2 accumulation (pH reduced)
- Tachypnea (Increase in the ventilation rate  Muscles will contraction and exhaustion)
2. Atelectasis (Lung Collapse)  Resorptive/Obstructive Type, Affected side there can be organ
Deviation(tracheal deviation, esophageal, heart)  Can compress great vessels
3. Can induce Bronchial Asthma  Wheeze
4. Pulse oximeter: PaO2  Reduced, PaCO2  Increased (Respiratory Acidosis) due accumulation H+
 pH
Delta Receptor (D Receptor)

a. D1
b. D2
c. D3
d. D4
e. D5

The only muscarinic receptor that can be stimulated by EPI/NOR/DOPA or Adrenergic AGONIST is the
muscarinic receptor of the sweat glands of the skin  PAWIS

Cholinergic Receptors: Parasympathetic Effect/Muscarinic

NEUROTRANSMITTER: Acetylcholine Primary and (Nicotine/Caffeine)
Primary Nerve: VAGUS NERVE

AGONIST  Parasympathomimitics

ANTAGONIST  Parasympatholytic

VAGUS nerve stimulate (+ AcH) Muscarinic Receptor  AGONIST

M1  CNS N/V

M2  Inhibitory (Left side of the heart/Apex BRADYCARDIA)

M3 

a. Goblet cells/Mucus Cells (Salivary Gland(Parotid/Maxillary Gland) 

Hypersalivation/Hypersecretion
- Aspiration Risk
b. Lower Esophageal Sphincter  Relaxation

- Bolus entry in the to stomach

- GERD (Reflux)

c. Parietal Cell of the Stomach

- Hypersecretion HCl (Epigastric Pain, GI Bleeding?, Ulcer)
- This means digestion
d. Intestine
- Hyperperistalsis of the smooth muscle of the intestine  Loose Bowel Movement
e. Skeletal Muscle
- Muscle Spasm/Muscle Contraction or Movement/Muscle Rigidity
f. Bronchi
- Broncho-constriction
g. Sphincteric Tone of the ureters
- Voiding / Incontinence
h. Pupil: Pupillary constriction (Miosis)  Decrease IOP, Accomodation (Contraction of the cillary
muscle)

Parasympatholytic  Lyse Vagus action

Parasympatomimetic  promoting the action AGONIST

M4  CNS  Memory Retention (Temporal Lobe)

ANTAGONISTIC ACTION: Atropine Sulfate BLOCKS the Muscarinic Receptor

M1 : No N/V
M2: Tachycardia
M3:
a. Salivary/Mucus/Goblet  Hyposecretion, Dry Mouth
b. LES  Constriction increase pressure  NO GERD, Risk Obstruction/Achalasia/Dysphagia
c. Parietal Cell  Hyposecretion (Maldigestion)
d. Intestine  CONSTIPATION/ILEUS/Hypoperistalsis, Accumulation Gas, Abdominal Distention
e. SK  Relaxation
f. Bronchi  Bronchodilation
g. Sphincter  Urinary Retention
h. Pupils  Pupillary Dilation/Mydriasis  Blurring Vision, Increase IOP (Cycloplegic Action of the Cillary
Muscle)

Histamine  from the Mast cell/Basophil: Histamine Receptor

H1
a. Bronchi  Broncho-constriction
b. Blood Vessel Vasodilation
c. Increase Cell membrane Permeability  cellular swelling or edema Glucocorticoids
(Prednisone/Hydrocortisone, anti-histamine)
1. KATE SKIN Steroids, Anti-histamine
2. NASAL CONGESTION Apha1 agonist, Prednisone

Tachypnea  DOB due to exhausted muscle (H+)  Chemoreceptor reflex

 Hypotension  Vasodilating effect

Epinephrine  Sympathomimetic

H2  Parietal Cell  Hyperacidity (H2 Blocker: Ranitidine,Cimetidine)

H3 CNS VERIGO  Anti-histamine
Effects Blocking Histamine

1. SEDATION
2. Increase Appetite  WEIGHT GAIN

DRUGS that affects the ANXIETY

a. Panic Disorders
b. Generalized Anxiety Disorders
c. OC
d. PTSD
e. Phobia

Others:
1. Insomnia
2. Preoperative-medication
3. Interventional Measures for Aggressive Jasonian Action (JASON TINIDOR)  MINOR Tranquilizers

I. ANTI-ANXIETY AGENTS (ANXIOLYTICS)

1. Benzodiazepines  Targets  Brain Stem & Limbic System

a. GABA mimetic effect – Inhibitory neurotransmitter release
- Diazepam (Valium)  Seizure, Muscle Relaxant, Anxiety, Alcohol Withdrawal
- Lorazepam (Ativan)  Acute forms of Anxiety, Preoperative Sedation & Amnesia, Chemotherapy
induced N/V, Alcohol Withdrawal
- Alprazolam (Xanax)  Common Anxiety
- Clonazepam (Klozapin)
- Chlordiazepoxide (Librium)  Alcohol Withdrawal Preoperative Sedation, Anxiety  IM only
- Midazolam (Versed)  ONLY INJECTABLE, Moderate Sedation for Anesthesia, Anxiety in ICU (SC
Fracture, Mechanical Vent etc)

NB: Targets the blockage of Apha 1, Histamine 1 receptor, Muscarinic blocking action.

b. Uses:
- To promote Muscle relaxation (Muscarinic blocking), GABA
- Alcohol withdrawal
- Anxiety
- Depression (Adjunct)
- Preoperative Sedation to promote AMNESIA
- Anti-Seizure

c. Contra-Indication:
- Allergy, Pregnancy, Narrow-Angled Glaucoma
d. Side Effects:
- CNS Depression,
- Hypotension (Apha 1 antagonist)
- Blood Dyscrasias (immune-suppression, anemia)
- N/V? does the M1 receptor is not affected?
- Constipation(M3 antagonist)
- Dry Mouth(M3 Antagonist)
- Skin Rashes? (Due histamine?)
- PARADOXICAL (Hyperactivity & Aggressive Behavior)
- Take note that alpha 1 blocking effect and muscarinic blocking action

BE ALERT for THIS PATIENTS:

1. Highly suicidal
2. Highly JASONIAN
3. Highly Aggressive Behaviors

e. Antidote : TOXIC Symptoms: (Somnolence, Confusion, Coma, Respiratory Depression)

- Cholinergic Agent (Physostigmine)  Acetylcholinesterase Inhibitor increases the AcH  Enhances
Muscarinic Agonists/Stimulation.
- Flumazenil (Romaxicon)  Benzodiazepine Blocker
- Decontamination GI  IPECAC  CONTRAINDICATED  ASPIRATION GI CONTENTS
- Decontamination GI  Gastric Lavage (Charcoal) is ok
- Hemodialysis (Very Severe)

PREVENT TOXICITY: NURSING NURSINGAN

1. Compliance Medication
2. Check for Hording/Cheeking Medication
3. Renal & Liver Function Test  URINE OUTPUT (0.5cc/kg/hr) adult, infants (1cc/kg/hr)
- BUN, CREATININE
- ALT, AST
4. Check the blood serum levels of the drug (drugs that has narrow therapeutic index)

HOW TO PROMOTE SAFETY

1. For comparison results  MONITOR V/S, Level of Anxiety initially
2. VITAL SIGNS:
a. BP: Hypotension: Alpha 1 blocking affect causes vasodilation
- Be careful hazardous activity (Side Rails, Driving, Swimming, Occupational Hazard)
b. Cardiac Rate: Reflex Tachycardia (Barorecptor)
- chest pain?
c. Urine output (polyuria  decrease drug, oliguria  toxicity)
d. Temperature  Slightly elevated? Vasodilated
e. RR Respiratory Depression? 16 and above?
4. Check if the patient has history of unprotected sexual intercourse POSSIBLE (+) HCG
5. Verify if the mother chooses breastfeeding against bottle feeding
6. Check the fetal well being c/o Pediatrician due Benzodiazepine Parturient patient

f. Drug Interactions:
- Alcohol (Respiratory Depression)
- Liver/Renal Impairment (elderly) TOXICITY
- Nicotine, Disulfiram, MAO-Inhibitors, Cimetidine  Decrease Metabolism  Toxicity

2. Anti-Histamines H1 (Sedative Effect)

a. Hydroxyzine (Atarax Hydroxyzine HCl) (Hydroxyzine Pamoate Vistaril)
b. Comorbid effects of Insomia & Anxiety
3. Miscellaneous Agents
a. Buspirone (Buspar)  NO SEDATIVE ACTION, PEDIA USE ONLY