Janell Mayer Pharmacology WSU

Absorption

Movement of drug from its site of administration into the systemic circulation.

Bioavailability

*Fraction % of drug available in bloodstream after administration as compared to the IV route.

*IV route is 100% bioavailable.

Distribution

Movement of drug into the various body fluids and tissues.

Volume of Distribution

Mathematical concept describing the amount of drug in the body in relation to the concentration of drug in the plasma.

Lipid Solubility

A drug must be lipid soluble for adequate GI absorbtion.

Blood-Brain Barrier

Only lipid soluable drugs can cross the BBB and reach the CNS.

Protein Binding

Some drugs are bound to plasma proteins, mostly albumin. Drugs bound to these proteins are pharmacologically inactive while bound.

Metabolism

*Chemical alteration of the parent compound usually resulting in enhance excretion, inactivation, or sometimes active metabolites.

First Pass Metabolism

Drugs absorbed in the small intestine are first exposed to the liver and may be extensively metabolized before reaching systemic circulation.

Excretion

Process by which the drug is eliminated from the body. Some drugs are excreted after metabolism. Some drugs are extreted "unchanged".

Half-Life (t1/2)

*Time required for the drug's plasma concentration to be reduced by one-half.

*T1/2 does not depend on dose!

Variables that Affect Clearance (Metabolism/Excretion)

1. Neonates underdeveloped metabolic pathways.

2. Infants and children have high liver metabolism and excretion rates.

3. Natural decline in some liver enzyme activity and in renal excretion with age.

4. Hepatitis or alcohol abuse may reduce liver metabolism.

5. Genetics can play an important role in metabolism. (warfarin, codeine)

6. Renal disease may reduce excretion of renally cleared medications.

7. Congestive heart failure may reduce blood flow to the liver, kidney, and other organs that may cause a reduction in clearance.

Therapeutic Window

1. Minimal Effective Concentration: Levels lower than the minimum effective concentration will not be effective.

2. Toxic Concentration: levels near this dose may cause dramatic, unusual adverse effects, even death.

3. Therapeutic Index: is a measure of the drug's safety. The relationship between beneficial and adverse effects of a medication.

Onset of Action

The amount of time it takes to reach the minimum effective concentration.

Duration of Action

Length of time a drug can be expected to exhibit its pharmacological effects.

Half-Life

Specifically refers to plasma concentrations only, while duration of effect refers to the pharmocological action.

Efficacy

The ability of a drug to produce a desired therapeutic effect.

Potency

Measure of the amount of drug (dose,mg) required to produce a given of effect.

Potency Vs. Efficacy

Potency is rarely of clinical importance.

Receptor Theory

A drug produces an effect by combining with some specific molecular constituent (receptor). The function of the receptor or cell is modified to produce a measurable effect.

Agonist

A drug that mimics some natural compound by binding with the receptor and stimulating some cellular response.

Antagonist

A drug that binds with a receptor, blocks the receptor from stimulation, and prevents it from being triggered normally.

Affinity

Measure of the strength of attraction between a drug and its receptor. Describes the tightness of bond. A drug with a high affinity to a certain receptor is very likely to elicit that response. A drug with a low affinity, is less likely to elicit that response, or may only do so in some patients or when used in very high doses.

Affinity

Measure of the strength of attraction between a drug and its receptor. Describes the tightness of the bond. A drug with a high affinity to a certain receptor is very likely to elicit that response. A drug with a low affinity, is less likely to elicit that response, or may only do so in some patients or when used in very high doses.

Selectivity

Refers to the degree to which a drug acts upon one site relative to all possible sites. Usually, the more selective a drug is, the fewer adverse effects it will cause.

Adverse Drug Reactions

Any undesired, unintended response to a drug.

Exaggerated Drug Response

Blood pressure medication that unexpectedly bottoms out the patient's blood pressure.

Adverse Effect

Undesired pharmacological effects of a drug; usually dose related.

Toxicity

Harmful or destructive effects of a drug often seen when therapeutic doses are exceeded, the drug is used for a longer period of time than is recommended, or the drug is not properly monitored. Many use the terms toxicity and adverse effect interchangeably.

Drug Interaction

Causes increased adverse effects or decreased efficacy.

Intolerance

Adverse effect of a drug that limits its usefulness or acceptance in a patient.

Drug Allergy

Immune system mediated response, non-dose, related, unpredictable

-rash, hives, itching

-anaphylactic reaction: bronchoconstriction, swelling of lips, face, throat, tongue, sever hypotension.

High Risk Drugs

Those with a narrow therapeutic index, high incidence of adverse effects, or high incidence of allergic reactions.

High Risk Patients

Those that would be least likely to tolerate adverse effects or loss of efficacy.

I.e. the very young, the elderly, brittle diabetics, patients predisposed to arrhythmias, or epilepsy.

Drug-Drug Interaction

The four mechanisms of drug interactions are:

1. direct chemical interaction

2. pharmacokinetic interactions

3. pharmacodynamic interactions

4. Combined toxicity

Direct Chemical Interaction

Precipitation, inactivation

Pharmacokinetic Interactions

a. Altered GI Absorbtion

-Altered pH

*non-ionized form of drug is more lipid soluble and easily absorbed

-Chelation: chemical bonding that prevents absorbtion

b. Altered Distribution Protein Displacement

-Drugs bound to plasma proteins are inactive and exist in equilibrium

-Usually only clinically significant for highly bound drugs (>90%)

c. Altered Metabolism

-administration of two drugs metabolized by the same liver enzyme that can cause inc or dec in blood levels of one or both agents. Most involve the cytochrome p450 system

-Enzyme Induction

*inc metabolism=lower drug levels=loss of efficacy

*caused by one drug speeding up the shared metabolic pathway

-Enzyme Inhibition (Most common drug interaction)

*competition for the same metabolic pathway

d. Altered renal excretion: decreased cardiac output- decreased renal blood flow- decreased drug filtration- decreased drug excretion

Pharmacodynamic Interactions (Synergistic/Antagonist Drug Interactions)

a. Synergistic Effects: occurs when the effects of two drugs are greater than would have been predicted from each of their effects alon. *1+1=3

b. Antagonistic Effects: Occurs when the effects of two drugs are less than predicted from their effects when given alone. *1+1=0

Medication Errors

*Causes: wrong patient, wrong drug, wrong route, wrong dose.

*ways to reduce errors include computerized physician order entry, including pharmacist on rounds, bar code technology

*serious medication errors should be reported.

Inotropic

Relating to strength of heart muscle contraction

Lacrimation

Production of tears in the eyes, watering eyes

Mydriasis

Pupil dilation

Negative Inotrope

a drug that decreases the FORCE of heart contractions

Positive Inotrope

a drug that increases the FORCE of heart contractions

Negative chronotrope

A drug that decreases the RATE of heart contractions

Positive Chronotrope

a drug that increases the RATE of heart contractions

Venous

referring to or associated with blood veins (veins are vessels carrying blood back towards the heart. except for the pulmonary veings, all veins carry UNOXYGENATED blood)

FDA Pregnancy Categories

A&B generally safe.

C is a gray area

D: some kind of problem with the drug exists

X: contraindicated

Half-life

length of time to reduce blood levels by one half

Autonomic Nervous System

Involuntary functions

Regulation of heart rate, secretory glands, and smooth muscles

Sympathetic Nervous System (Fight or Flight Response)

*Epinephrine and norepinephrine

*Adrenergic

*B1, B2, a1, and a2

*Mobilizes energy stores for use by muscles and brain

*Regulation of the cardiovascular system and body temperature

*Redistribution of blood flow during exercise

Parasympathetic Nervous System (Rest and Digest

*Acetylcholine

*Cholinergic

*Muscarinic receptors

*Conserves energy. Usually the dominant system at rest.

*Digestion of food

*Enchances excretion of waste.

Sympathetic B1 (Heart)

1 because we only have 1 heart.

Inc. heart rate, inc. AV conduction velocity, and inc. force of contraction (ventricular)

B2 LLUV

Lungs- bronchodilation

Liver- inc liver sugar production; inc glucagon

Uterus: relaxation of uterine muscles

Vasodilation in vessels of skeletal muscle, lungs, and heart

A1 BEV

Bladder: urinary retention

Eyes: pupil dilation (mydriasis), better far vision

Vasoconstriction in vessels of skin, mucous membrans and most organs

A2

Presynaptic Neurons: stimulation decreases further norepinephrine release

Baroceptor Feedback

*Reduction in BP-> triggering of barorecptor reflex-> increased heart rate (tachycardia)

*Inc. in BP by vasoconstriction-> triggering of the barorecptor reflex-> decreased heart rate (bradycardia)

Muscarinic Agonists (SLUD)

*Exocrine glands: salivation, lacrimation, sweating, etc.

*Heart: decreased heart rate

*Smooth Muscles: relaxation of vascular smooth muscles can cause vasodilation and hypotension. Constriction of bronchial smooth muscle

*Eye: Miosis (pupillary constriction) and contaction of the ciliary muscle

Bethanechol Mechanism of Action

Bind directly to muscarinic repectors and mimic ACh. Preferentially stimulates muscarinic recptors of the GI and urinary tract.

Bethanechol Therapeutic Uses

*Treats urinary retention in postpartum and postoperative patients

*Rarely used to treat GERD to increase GI motility

Muscarinic Agonists- Cholinesterase Inhibitors Mechanism of Action

*Acetylcholinesterase is the body's natural enzyme that normally inactivates acetylcholine by cleaving it into actate and choline. AChE turns off ACh activity.

*Inhibits activity of AChE so ACh is able to be turned on and ACh levels increase.

Donepezil*, Galantamine, Rivastigmine Mechanism of Action

Inhibts the enzyme AChE, but are more specific for the AChE found in the CNS (brain).

Donepezil Therapeutic Use

Treat symptoms of Alzheimer's disease by increasing levels of ACh.

Muscarinic Antagonists

(Anti-slud)

*Exocrine: decreased salivation, acid production and bronchial secreations

*Heart: tachycardia

*Smooth Muscle: relaxation of bronchi, decreased tone of the urinary bladder, decreased tone and motility of the GI tract

*Eye: mydriasis (pupil dilation) and cycloplegia (inability to focus for near vision)

Muscarinic Antagonists Mechanism of Action

*Competes with ACh for muscarinic receptors

*Bind and block receptors

*Sympathetic NS impulses are left unopposed

Anticholinergic Adverse Effects (Anti-Slud)

Can't pee, can't see, can't spit, can't shit.

*dry mouth

*blurred vision

*constipation

*urinary retention

*tachycardia

*CNS: memory loss, confusion, restlessness, agitation, hallucination, and delirium

Atropine Therapeutic Use

*Antisecretory: blocks upper and lower respiratory tract secretions prior to surgery

*Bradycardia: treats severe bradycardia

*Antispasmodic and antidiarrheal: relaxes GI tract and bladder

*Ophthalmic-mydriatic-useful for ophthalmic exams and eye surgery

Scopolamine Therapeutic Uses

*very similar to atropine

*very effective anti-motion sickness drug-produces CNS sedation instead of excitation

*Antisecretory agent- decreases secretions as well as induces short term memory loss

Oxybutynin (Muscarinic Antagonists for Overactive Bladder)

Commond disorder affecting up to one third of Americans. Can happen at any age but is most prevalent in the elderly. Symptoms include the sudden urge to urinate with loss of moderate amounts of urine.

Epinephrine Vascular Effects

**Adrenergic Agonists

*A1 vasodilation/ vasoconstriction in skin and mucous membranes

*B2 vasodilation/ vasoconstriction in vasculature of liver, heart, skeletal muscles

*Inc./ dec. BP overall

Epinephrine Cardiac Effects

*B1 inc. heart RATE (positive chronotrope)

*B1 inc. FORCE of heart contraction (positive inotrope)

Epinephrine Pulmonary Effects

*B2 Broncho dilation/constriction

Epinephrine Miscellaneous Info

*B2 hyperglycemia, usually only a problem in diabetics

*Quick onset and short duration of action

Epinephrine Therapeutic Uses

*Stops small bleeding (inj)

*Injected with local anesthetics (like lidocaine) to prolong their effectiveness

*Treats anaphylactic shock

*Cardiac arrest, code blue

*Treats asthma (inhaled)

Norepinephrine (Adrenergic Agonist) Psychological Effects

*A1 intense vasoconstriction in skin

*Dramatic inc. in BP (vasoconstriction is unopposed due to lack of B2 effects)

*May cause reflex taxhycardia/bradycardia (due to vasoconstriction and limited B1 stimulation)

*Intense vasoconstriction can drastically reduce blood flow to kidney and extremities

Norepinephrine Therapeutic Uses

Severe septic shock

Dopamine

Receptors: Dopamine and B1> A1

*Vascular Effects

- low doses: vasoconstriction (except in the kidney and brain)

-higher doses: vasoconstriction in all areas

*Cardiac Effects

-B1 increased force of contraction; B1 increased systolic blood pressure

-Increased cardia output

*Therapeutic Uses

-drug of choice to treat cardiovascular shock

-treats acute heart failure

Factors Influencing Blood Pressure

BP=Cardiac output* Total peripheral resistance

*Increased Cardiac Output:

-inc fluid volume; excess sodium intake and sodium renal retention

-excess stimulation of the renin-angiotensin-aldosterone system

-over-activity of the sympathetic nervous system

*Increased Peripheral Resistance

-excess stimulation of the RAAS

-over-activity of the sympathetic nervous system

Normal BP

S: <120

D: <80

Prehypertension

SBP: 120-139

DBP: 80-89

Stage 1 hypertension

SBP: 140-159

DBP: 90-99

Stage 2 hypertension

SBP: > or equal 160

DBP: > or equal 100

Clonidine (A2 Adrenergic Agonists) Mechanism of Action

*Preferentially stimultes the a2-receptors of the brain stem associated with autonomic regulation of the cardiovascular system. Activation of the a2 receptor will cause neurons to quit releasing norepinephrine. Thus, a2 receptors are inhibitory in nature, this will result in decreased sympathetic output, dec BP, and dec HR

*Comes in patches and replaced weekly.

Clonidine Therapeutic Uses

*Main use is treatment of chronic hypertension.

*Can be chewed and swallowed for HTN urgencies.

*Also used for withdrawal symptoms.

Drug used for hypertension in pregnant women?

Methyldopa

Adverse Effects of Clonidine

*drowsiness (35%)

*dry mouth (40%)

*constipation

*headache

*impaired ejaculation

Clonidine Warning

Avoid abrupt withdrawal- will cause severe rebound HTN

A1 Blockers (Antagonists)

-sin drugs

A1 Blockers (-sin)

Mechanism of Action

*competitive blocking of the a1-receptors

*HTN: lowers blood pressure by causing vasodilation. Relaxes both arterial and venous smooth muscle surrounding some blood vessels

*BPH: drugs also relax the smooth muscle of the bladder neck and prostate, which improves urine flow in BPH

A1 Blockers (-sin)

Therapeutic Uses

*HTN

*urinary retention associated with benign prostatic hyperplasia

*Raynaud's disease (vasoconstriction disease)

A1 Blockers (-sin)

Adverse Effects

*Orthostatic hypotension

(FIRST DOSE EFFECT)

*Dizziness, lack of energy, drowsiness, nasal congestion, headache, decreased libido, inhibition of ejaculation

Non-Selective B Blockers

(LOL) Mechanism of Action

*Competitive blocking of the B1 and B2 receptors

*Cardiovascular effects (B1 mediated): decreased heart rate (negative chronotrope); decreased force of contraction (negative inotrope); decreased cardiac workload and oxygen demand.

Non Selective B Blockers (LOL) Therapeutic Uses

*Cardiac: hypertension, angina, post MI, heart failure, atrial fibrillation, and tachycardia

*Some used as eye drops to treat glaucoma

*Hyperthyroidism, migraine prophylaxis, essential tremor, stage fright

Non Selective B Blockers (LOL) Adverse Effects

*DO NOT STOP ABRUPTLY, MAY CAUSE DEATH

*hypotension, sexual impairment, nightmares, some dec HDL and inc TG

*Heart failure, reduced cardiac output (fatigue) arrhythmias, and bradycardia (B1 mediated)

*Bronchoconstriction (B2 mediated)

*May mask signs and symptoms of hypoglycemia in diabetes

2nd Gen: Cardioselective B1-Blockers (LOL)

Mechanism of Action

*selectively blocks B1 receptors

*these agents have a higher affinity for the B1 receptors than the B2. Can lose selectivity at higher doses

2nd Gen: Cardioselective B1 Blockers (LOL) Therapeutic Uses

*Cardiac: hypertension, angina, post MI, heart failure, atrial fibrillation, and tachycardia

2nd Gen: Cardioselective B1 Blockers (LOL)

Adverse Effects

*same hypotensive, cardiac, and sexual side effects as non selective B blockers

*less likely to cause peripheral vasoconstriction, bronchoconstriction, or hypoglycemia, but can still mask hypoglycemia

*DO NOT STOP ABRUPTLY

*Use caution in patients with severe congestive heart failure or diabets. Safer than non-selective agents for patients with diabetes, asthma and COPD

CarvediLOL (3RD gen) Beta Blockers with Vasodilating Actions

(a1,B1, B2)

*Therapeutic Uses: HTN and heart failure

*similar side effects to the a1 blockers (except will not cause reflex tachycardia) and the same side effects as the non-selective B blockers

LabetaLOL (a1, B1, B2)

Beta Blockers with Vasodilating Actions

*not used for HF. Not commonly used for hypertensive emergencies. Similar to Carvedilol

NebivoLOL (B1) B Blockers with Vasodilating Actions

*used to treat hypertension

*promotes synthesis and release of nitric oxide causing vasodilation